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Oral Maxillofacial Surg Clin N Am 15 (2003) xi – xii

Preface
Current concepts in the management of
maxillofacial infections

Daniel M. Laskin, DDS, MS Robert A. Strauss, DDS, MD


Guest Editors

There have been many advances in the manage- the public news media and professional journals
ment of head and neck infections since we last edited a almost daily. In some cases we even have created
Clinics of North America issue on this subject more new sources of infection ourselves by developing
than 10 years ago. New classes of antimicrobial environments conducive to bacterial growth, such as
agents, noninvasive imaging techniques, improved around implants.
culturing methods, and a clearer understanding of In this issue of the Oral and Maxillofacial Surgery
the normal and pathologic functioning of the immune Clinics of North America, we have attempted to
system are just some of the changes that have address some of the important and topical areas of
occurred. These and other technologic advances have knowledge in the diagnosis and management of
enhanced dramatically our ability to diagnose and infectious diseases that practicing oral and maxillofa-
treat these infections rapidly and accurately. As a cial surgeons face. Some articles examine new areas
result, the incidence of serious morbidity and mortal- of interest, such as peri-implantitis and infections
ity from odontogenic infections has fallen signifi- associated with facial skin resurfacing, whereas others
cantly over the years. provide timely updates of our understanding of con-
It should be noted, however, that vigilance regard- tinually evolving topics, such as HIV/AIDS, chronic
ing research and technologic change must be main- sclerosing osteomyelitis, selection and use of anti-
tained. Just as we have made many advances in the biotics, and the changing microbiology of infections
management of these infections, an equal number of of the head and neck.
new and serious issues have arisen to test our resolve. The impressive ability of bacteria and viruses to
Newly recognized bacterial and viral strains, the adapt, change, and mutate in response to our phar-
effects of global antibiotic resistance to once univer- macologic bombardment is a testimony to the com-
sally effective agents, viral mutations, ‘‘flesh eating’’ plex, surreptitious, and unpredictable nature of these
bacteria causing necrotizing fasciitis, currently un- small yet hardy microbes. For every new drug we
treatable catastrophic infections, such as those caused formulate, resistance develops to an older and often-
by the Ebola virus, and even biologic warfare and used one. For every organism that we eradicate,
bioterrorism have emerged as important issues over another one suddenly emerges to take its place. To
the last 10 years, and articles about these issues flood those of us in the clinical trenches, it seems that we

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xii D.M. Laskin, R.A. Strauss / Oral Maxillofacial Surg Clin N Am 15 (2003) xi–xii

are in a war with an ever-expanding number of Daniel M. Laskin, DDS, MS*


increasingly virulent and destructive bacteria, fungi, Robert A. Strauss, DDS, MD
and viruses. At times it seems that despite our Department of Oral and Maxillofacial Surgery
advances in technology and knowledge, the out- School of Dentistry
come of that war is not as clear as we might wish. Virginia Commonwealth University
It is our hope that the information provided by Richmond, VA 23298-0566, USA
the outstanding contributors to this issue will help E-mail address: dmlaskin@vcu.edu
to resolve some of the important issues we cur-
rently face. * Corresponding author.
Oral Maxillofacial Surg Clin N Am 15 (2003) 1 – 15

The changing microbiology of maxillofacial infections


Richard H. Haug, DDS
Division of Oral and Maxillofacial Surgery, University of Kentucky College of Dentistry, D-509 Chandler Medical Center,
Lexington, KY 40536-0084, USA

Dramatic headlines in the recent news media have any changes that may have occurred over the past
provided such alarming infectious disease stories as decades in infections of the maxillofacial region. It
‘‘Five year-old girl battles flesh eating bacteria,’’ ‘‘The attempts to answer whether there actually have been
killers all around: new viruses and drug resistant any changes in the microbiology of maxillofacial
bacteria are reversing human victories over infectious infections and, if so, what those changes, patterns,
disease,’’ and ‘‘Losing the battle of the bugs’’ [1 – 3]. and trends might be.
These reports conjure up images of an almost science The availability of the ‘‘wonder drug’’ penicillin in
fiction type of horror story. Concerns among the lay the years immediately after World War II ushered in an
population regarding the perceived shifting of infec- era of complacency in infectious disease management.
tious disease patterns and their subsequent manifes- Many traditional management techniques, such as
tations have become a topic of discussion in the news isolation, quarantine, and scrupulous application of
media, often creating public alarm through misinter- aseptic methods in the office and operatory, were
pretation and occasional exaggeration of events. For minimized or discarded altogether as no longer being
example, Time magazine has suggested that antibiotics necessary because the new drugs were so effective in
are so overused that the human body has become treating common infections. Antibiotics were pre-
saturated and that the human immune system is so scribed when symptoms initially appeared, without
depressed that it provides an environment for the determining either the cause of the disease or antibiotic
creation of ‘‘bacterial monsters’’ [2]. The reports of susceptibility of the microbe. Many infectious disease
‘‘flesh-eating’’ Streptococcus strains and ‘‘killer’’ bac- and public health professionals were ready to declare
teria that are resistant to most common antibiotics raise ultimate victory over infection, being convinced that
public concerns that the normal bacterial flora is antibiotics and vaccines would solve any existing and
mutating uncontrollably and that infections are much future disease threats. Events of the last five decades
more severe than they used to be [1 – 3]. Is this actually suggest that such enthusiasm was premature.
the case, and if so, do the same principles hold true for Although there have been many dramatic improve-
oral and maxillofacial infections? The purpose of this ments in the rates of morbidity and mortality associ-
article is to review the past and present oral and ated with infectious diseases the past few decades,
maxillofacial literature, with a focus on identifying microorganisms have proved to be adaptable and have
displayed the alarming ability to reemerge in continu-
ing cycles of disease in somewhat different forms [4].
In the journal Science, Harold Neu suggested that
Portions of this article have been reprinted from Storoe
‘‘bacteria are more clever than men’’ [5]. They have
W, Haug RH, Lillich TT. The changing face of odontogenic
adapted to every environmental niche on the planet
infections. J Oral Maxillofac Surg 2001;59:739 – 48; and
Haug RH, Assael LA. Infection in the maxillofacial trauma and are assimilating to surroundings saturated with
patient. In: Hupp J, Topazian RG, Goldberg MH, editors. antibiotics [5]. This ability has been demonstrated over
Management of infections of the oral and maxillofacial the past decade in an array of infections not previously
regions. 5th edition. Philadelphia: WB Saunders Co.; 2002; recognized in humans. The reemergence of diseases in
p. 267 – 92. different forms caused by common microorganisms,

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2 R.H. Haug / Oral Maxillofacial Surg Clin N Am 15 (2003) 1–15

such as Staphylococci, Streptococci, Escherichia coli, any interaction between the microbes present
and Mycobacterium tuberculosis, further substantiates [17,19,20]. Although there is generally a normal
this observation. The reemergence is caused partly by resident flora for any particular anatomic region, a
acquisition of antibiotic resistance mechanisms, either transient flora also may be found to colonize for
through mutation or by transfer of genetic information periods ranging from hours to weeks without being
from other bacteria; thus, there has been a rise in the retained permanently. This discussion is limited to the
antibiotic resistance of important pathogenic genera indigenous flora (not transient), which, in the interest
[4 – 6]. of brevity, have been listed in Boxes 1 – 3.
The most dramatic example in the development of
resistance over the past three decades and its effects Cutaneous microflora
in terms of cost—human and economic—has been
the evolution of methicillin-resistant Staphylococcus. Skin is relatively dry, has a mildly acidic pH, and
It is estimated that methicillin resistance in certain desquamates. This is an inhospitable environment for
strains of Staphylococcus has risen from 2.4% in microbes [17,21]. In the newborn, the cutaneous flora
1975 to 29% in 1999 and that the costs of hospi- is initially that of the mother’s birth canal. With time,
talization for these types of nosocomial infections the skin develops its own unique flora (see Box 1)
could approach $3 billion annually in the United and can include one animal form, five types of yeast,
States alone [6 – 16]. One must remember, however, and multiple species of bacteria [17,19,22 – 24]. This
that the ultimate human cost is death and that post- flora is generally present on the hair follicles and
surgical patients who develop nosocomial infections stratum corneum. The types and number of micro-
from methicillin-resistant Staphylococcus are twice as organisms are relatively constant, with minimal
likely to die as patients who do not [13,15]. One must change observed in the healthy individual [17,21].
ask the question: Do oral and maxillofacial infections
follow the same principles of reemergence and res- Oral microflora
istance as those described in other areas? If so, are the
patterns and trends similar? This article attempts to The mouth, unlike the skin, is warm, has a
answer those questions using the following format. relatively constant temperature, is wet and dark,
First, the microorganisms of the maxillofacial region possesses environments with and without oxygen,
are identified in terms of indigenous flora. If this
process is not performed first, abnormalities and
outliers could not be identified. Next, oral and max-
illofacial infections are identified in terms of odonto-
genic infections, trauma-related infections, nasal and
paranasal sinus infections, and cutaneous infections. Box 1. Some of the most common
Finally, changes or similarities in the microbiology of indigenous and colonizing maxillofacial
maxillofacial infections over time are discussed in the cutaneous flora [17,19,22 – 24]
context of the previously named categories.
Aerobic and facultative isolates
Acinetobacter species
Enterobacteriaceae
Normal oral and maxillofacial microflora Corynebacterium species
Micrococcus species
Factors that affect microbial flora Staphylococcus epidermidis
Staphylococcus species
Most areas of the human body harbor an indigen- Streptococcus viridans
ous microbial flora that is specific to the anatomic Yeasts
area and the individual person. [17 – 21]. The specific Candida albicans
ecosystem helps to play a role in protecting the Malassezia furfur
individual from invasion by pathogenic organisms. Pityrosporum ovale
Numerous factors may alter the type, frequency, and Pityrosporum orbiculare
distribution of these microbes, including the anatomic Torulopsis glabrata
region, the individual host’s immune system, the Animal
relative humidity, the presence or lack of oxygen, Demodex folliculorum
local surface characteristics, available nutrition, and
R.H. Haug / Oral Maxillofacial Surg Clin N Am 15 (2003) 1–15 3

Penicillium species
Box 2. Some of the most common
Scopulariopsis species
indigenous and colonizing oral flora
Viruses
[17 – 19,22,24]
Herpes simplex virus
Aerobic and facultative isolates Cytomegalovirus
Protozoa
Diphtheroids
Lactobacilli Entamoeba gingivalis
Rothia dentocariosa Trichomonas tenax
Streptococcus faecalis
Streptococcus milleri
Streptococcus mitis and provides a constant source of nutrition [17,19 –
Streptococcus mutans 21]. The newborn’s mouth is not sterile but, like the
Streptococcus salivarius skin, contains a mixture of organisms representative
Streptococcus sanguis of the mother’s vagina, including Streptococci, Enter-
Anaerobic isolates ococci, and Microaerophilic species [17 – 21]. The
Actinobacillus newborn mouth is generally populated with aerobic
actinomycetemcomitans organisms because there are initially no crevices for
Actinomyces israelii the development of an anaerobic environment. That
Actinomyces naeslundii status changes with the eruption of teeth. In adult-
Actinomyces odontolyticus hood, the flora become more constant in composition
Actinomyces viscosus (see Box 2) and contain mostly streptococcal bac-
Bacteroides asaccharolyticus terial species (30% – 60%), other bacteria, yeasts,
Bacteroides melaninogenicus fungi, protozoa spirochetes, and viruses. Local dis-
Bacteroides oralis eases, such as caries and periodontitis, can alter the
Bacteroides ochraceus microflora [17 – 20,22,24]. Environmental agents,
Bacterionema matruchotii such as alcohol, tobacco smoke, medications, and
Branhamella catarrhalis radiation therapy, also change the microflora.
Capnocytophaga gingivalis
Capnocytophaga ochraceus
Nasal and paranasal sinus microflora
Capnocytophaga sputigena
Eikenella corrodens
Unlike the skin and mouth, the nasal passages and
Fusobacterium plauti
paranasal sinuses are sterile at birth. Within days,
Fusobacterium nucleatum
however, the infant acquires flora that are mostly
Neisseria sicca
associated with the mother, nursing staff, and hospital
Peptostreptococcus
[24 – 28]. As a human breathes, air and its contents
Veillonella alcalescens
pass through the nose. There the air is filtered, and
Veillonella parvula
most of the microorganisms are trapped by mucous
Spirochetes
secretions and swallowed. These secretions contain
Spirochaeta species
enzymes and immunoglobulins that further kill or
Christispira species
inhibit the growth of microorganisms. With time
Treponema denticola
and altered host resistance, the sinuses of the adult
Treponema orale
human acquire an indigenous microflora and occa-
Treponema macrodentium
sionally are subjected to colonization (see Box 3)
Treponema vincentii
[1,24,25,27,28].
Borrelia species
Leptospira species
Yeasts
Aspergillus species Odontogenic infections
Candida albicans
Other Candida species Although numerous articles in the surgical litera-
Geotrichum species ture discuss odontogenic infections, they do not
Hemispora species identify changes in the microbiology of these infec-
tions over time, nor do they make comparisons using
4 R.H. Haug / Oral Maxillofacial Surg Clin N Am 15 (2003) 1–15

case controlled cohorts [23,29 – 39]. A recent inves- No significant differences were found between the
tigation has attempted to identify such changes and two cohorts for age, gender, race, admission temper-
make such comparisons [40]. Although not ideal in ature, admission white blood cell count, space
design (possessing all of the imperfections inherent in involvement, or length of stay. The manner in which
a retrospective chart review), it remains the only case- the bacterial isolates were reported was limited by the
controlled cohort comparison of odontogenic infec- ability to retrieve data in a retrospective review of
tions over time. records. The reporting was performed in the follow-
The retrospective record review performed by ing manner. All isolates obtained from any one
Storoe et al [40] was conducted at the Cleveland patient, whether from a ‘‘sterile abscess,’’ multiple
MetroHealth Medical Center, a large county teaching sites, or multiple cultures, were recorded for that
hospital that serves an urban population of 1.9 million patient. Most patients from the 1980s and 1990s
and a rural population of 2 million in northeastern had multiple organisms isolated. The reporting mech-
Ohio. Hospital charts and radiographs were reviewed anism was the number of isolates per patient per
from two patient cohorts admitted to that institution; admission. 180 bacterial isolates were identified from
the first during the 81 months between March 1983 79 patients from the 1980s compared to 115 from 71
and November 1989 (1980s patients) [33] and the patients from the 1990s. For the initial analysis,
other during the 81 months between July 1992 and isolates were grouped into four broad categories:
March 1999 (1990s patients). Admission criteria were gram-positive cocci, other gram-positive bacteria,
face or neck swelling, which suggested abscess or gram-negative anaerobes, and other gram-negative
cellulitis and one or more of the following: temper- bacteria (Table 1). Gram-positive cocci and gram-
ature above 38C, white blood cell count more than negative anaerobes were isolated significantly less
10.8  103/mL, or concern about airway compromise. frequently from the 1990s patients than from the
Patient characteristics reviewed were age, gender, 1980s patients.
race, admission temperature, admission white blood Table 2 reports the number of isolates per patient
count count, fascial space(s) involved, tooth of etiol- per admission. For instance, a-hemolytic streptococci
ogy, duration of hospitalization, and bacteria isolated. were isolated in 47 patients from among 79 during
An exhaustive statistical analysis was undertaken to the 1980s and in 24 patients from among 71 during
analyze and compare the two populations and any the 1990s. When individual isolates from the cohorts
changes in their microbiology. were compared, significant differences were found
for a-hemolytic streptococci, Bacteroides melanino-
genicus, coagulase-negative staphylococci, Eikenella
corrodens, Staphylococcus epidermidis, Neisseria
Box 3. Some of the most common species, and b-lactamase – positive Bacteroides.
indigenous and colonizing nasal and Culture and antibiotic sensitivity data were avail-
paranasal sinus flora [24 – 28] able from only ten 1990s patients (14%) (Table 3). The
1980s patient data were unavailable. Of the 32 bac-
Aerobic and facultative isolates terial isolates, 26 (81%) were resistant to one or more
Corynebacterium diptheria antibiotic. 62% of the resistant bacteria were gram
Corynebacterium species positive and 38% were gram negative; Staphylococcus
Haemophilus influenzae aureus and coagulase-negative staphylococci were the
Haemophilus parainfluenza most common gram-positive antibiotic-resistant bac-
Neisseria species teria isolated. Klebsiella pneumoniae was the most
Staphylococcus species common gram-negative antibiotic-resistant isolate.
Streptococcus pneumoniae Until the mid 1970s, researchers believed that
Moraxella species odontogenic infections were caused by a single species
Micrococcus species of aerobic or facultative bacteria [37]. Subsequently, it
Neisseria meningitidis has been well established that odontogenic infections
Staphylococcus aureus are polymicrobial [23,29,30,33 – 37,39,41 – 43].
Staphylococcus epidermidis Researchers also have observed that the bacteria iden-
Streptococcus viridans tified from odontogenic infections have changed over
Streptococcus pneumonia the decades [37]. Moenning et al [37] reported that the
Anaerobic isolates bacterial flora of odontogenic infections is no longer
Propionibacterium acnes predominately facultative or microaerophilic, with
Staphylococcus and Streptococcus as the primary
R.H. Haug / Oral Maxillofacial Surg Clin N Am 15 (2003) 1–15 5

Table 1
Bacteria isolated
Number isolated from the Number isolated from the Chi-square
1980s patients (percent of total) 1990s patients (percent of total) statistic P value
Gram-positive cocci 101 (56) 80 (70) 5.357 0.021
Other gram-positive bacteria 9 (5) 5 (4) 0.066 0.8
Gram-negative anaerobes 41 (23) 15 (13) 4.323 0.038
Other gram-negative bacteria 29 (16) 15 (13) 0.520 0.5
Total isolates 180 (100) 115 (100)
From Storoe W, Haug RH, Lillich TT. The changing face of odontogenic infections. J Oral Maxillofac Surg 2001;59:739 – 48;
with permission.

genera, but is more often a mixed flora, with anaerobes been reported as either Prevotella or Porphyromonas
outnumbering aerobes 2:1. a-hemolytic streptococci in the 1990s patients [44]. Consequently, the differ-
are the most frequently isolated bacteria [23,29,35], ence between the two groups for this obligate anaer-
although Bacteroides melaninogenicus has been obe is a statistical anomaly.
reported as the most common in some studies The statistically significant difference between
[30,32]. In one study, 19 bacterial genera or species groups for S. epidermidis and coagulase-negative
were isolated in the 1980s patients, with a-hemolytic staphylococci can be explained by changes in labo-
streptococci predominating almost 2:1 over B. mela- ratory protocol. S. epidermidis is a coagulase-nega-
ninogenicus and b-hemolytic streptococci predominat- tive bacterium. During the 1980s, it was common to
ing 3:1 over S. epidermidis and almost 4:1 over S. speciate isolates, although this provided little clin-
aureus and E. corrodens (see Table 2). 24 genera or ically useful information. Consequently, protocol
species were isolated in the 1990s patients, with changes were made that resulted in all coagulase-
coagulase-negative staphylococci, a-hemolytic strep- negative staphylococci being reported as such with-
tococci, and b-hemolytic streptococci having nearly a out further identification. A more accurate picture
1:1:1 ratio and predominating equally over all other of the statistically significant differences between
bacteria by more than a 2:1 ratio (see Table 2). groups emerges by analyzing S. epidermidis and
No isolates of B. melaninogenicus were reported coagulase-negative staphylococci together. When this
in the 1990s patients; however, 13 other Bacteroides is done, there is no significant difference between the
isolates were identified. Significant differences groups. The significant decreases in Neisseria species
between the groups were found for a-hemolytic and E. corrodens from the 1980s patients to the
streptococci, B. melaninogenicus, coagulase-negative 1990s patients are most probably caused by labo-
staphylococci, E. corrodens, S. epidermidis, Neisse- ratory protocol changes and changes in therapy,
ria species, and b-lactamase – positive Bacteroides, respectively. The complete absence of Neisseria iden-
which suggests that there has been a shift in the tified in the 1990s patients suggests a decision by the
microbiologic flora involved in odontogenic infec- clinical laboratory not to seek this species in clinical
tions. a-hemolytic Streptococci were the most com- specimens from odontogenic infections. The decrease
mon isolates in both groups, which confirms previous in E. corrodens isolated from the 1990s patients may
reports of the frequency with which these bacteria are be the result of improved treatment of anaerobic
isolated from odontogenic infections [23,29,35]. It is infection with antibiotics that have been developed
clear that these common gram-positive cocci remain a in the past 10 years. Unfortunately, no data about
threat to patients with odontogenic infections. The preadmission treatment were available.
significance of the differences in the other isolates is The only other bacteria with a significant differ-
less clear because of changes in bacterial nomencla- ence between groups were b-lactamase – positive Bac-
ture and laboratory protocols in the past 10 years. For teroides, which were not reported at all in the 1980s
example, there was a statistically significant differ- patients. The reason for this change is unclear, but
ence between groups for B. melaninogenicus largely rather than reflecting some important shift in odonto-
because there were no isolates identified from the genic infection etiology, it is probably caused by a
1990s patients. This is because B. melaninogenicus change in nomenclature or protocol. For example, it
was reclassified in 1990; bacteria identified as is curious that no Prevotella or Porphyromonas
B. melaninogenicus in the 1980s patients would have species were reported in the 1990s patients despite
6 R.H. Haug / Oral Maxillofacial Surg Clin N Am 15 (2003) 1–15

Table 2
Frequency of bacteria isolated, per patient, per admission
Bacteria 1980s patients 1990s patients Chi-square statistic P value
Gram-positive cocci
a-hemolytic streptococci 47 24 9.900 0.002
b-hemolytic streptococci 22 21 0.055 0.815
Staphylococcus aureus 12 8 0.498 0.480
Coagulase-negative staphylococci — 18 22.759 0.001
Staphylococcus epidermidis 15 — 14.979 0.001
g-hemolytic streptococci 2 5 0.846a 0.358
Peptostreptococcus species 3 3 0.000a 1.000
Enterococcus species — 1 0.003a 0.957
Other gram-positive bacteria
Diphtheroids 6 4 0.023a 0.878
Actinomyces species 2 — 0.406a 0.524
Lactobacillus species 1 — 0.000a 1.000
Corynebacterium species — 1 0.003a 0.957
Gram-negative anacrobes
Bacteroides malaninogenicus 27 — 29.59 0.001
Bacteroides (b-lactamase +) — 6 4.928a 0.03
Bacteroides (b-lactamase ) — 4 2.660a 0.103
Bacteroides (not fragilis) — 2 0.622a 0.430
Eusobacterium necrophorum — 2 0.622a 0.430
Bacteroides fragilis 1 1 0.000a 1.000
Other gram-negative bacteria
Eikenella corrodens 13 3 5.870 0.02
Haemophilus influenzae 8 2 2.144a 0.143
Neisseria species 9 — 6.704a 0.01
Klebsiella species 4 3 0.000a 1.000
Enterobacter species 3 1 0.159a 0.690
Escherichia coli 3 — 1.155a 0.283
Citrobacter species 1 — 0.000a 1.000
Haemophilus hemolyticus 1 — 0.000a 1.000
Proteus mirabilis — 1 0.003 0.957
Actinobacter — 1 0.003a 0.957
calcoaceticus (Iwoffi)
Sorralia marcescens — 1 0.003a 0.957
Pseudomonas aeruginosa — 1 0.003a 0.957
Pseudomonas species — 1 0.003a 0.957
Stenotrophomonas maltophilia — 1 0.003a 0.957
Total isolates 180 115
From Storoe W, Haug RH, Lillich TT. The changing face of odontogenic infections. J Oral Maxillofac Surg 2001;59:739 – 48;
with permission.
a
Continuity adjustment. Chi-square is reported because more than 25% of the cells had expected counts less than 6.

their importance in periodontal and other odontogenic From the limited antibiotic sensitivity data avail-
infections. It has been reported that more than 50% of able, it was not possible to determine if there have
Prevotella species are b-lactamase producers [45]. It been changes between groups in the kind, number,
is possible that the significant difference seen and frequency of resistant isolates. There were no
between groups is another consequence of the data available for the 1980s patients, and only 10% of
nomenclature change in B. melaninogenicus. It can the 1990s patients had a culture and antibiotic sen-
be concluded that contrary to previous suggestions, sitivity test performed at least once during their
there has been little change in the kinds of bacteria hospitalization (Table 3). Despite their limitations,
isolated from odontogenic infections in the two the data confirm some disturbing trends. 81% of the
groups of patients 10 years apart; a-hemolytic strep- isolates were resistant to one or more antibiotics.
tococci remain the most frequently isolated bacteria. Despite the relatively low overall occurrence (see
R.H. Haug / Oral Maxillofacial Surg Clin N Am 15 (2003) 1–15 7

Table 3
Antibiotic resistance for the 1990s patient’s isolates
Isolate No. Resistant No. Sensitive Total
g- streptococci (not Enterococcus) 0 1 1
b-streptococci (non A/B) 0 1 1
Coagulase-negative staphylococci 6 0 6
Enterococcus secies 1 0 1
Staphylococcus aureus 9 1 10
Total gram positive 16 3 19
Acinetobacter calcoacelicus (Iwoffi) 1 0 1
Bacteroides species 0 1 1
Eikenella species 1 0 1
Enterobacter cloacae 1 0 1
Klebsiella pneumoniae 3 0 3
Pseudomonas aeruginosa 1 2 3
Pseudomonas species 2 0 2
Stenotrophomonas maltophilia 1 0 1
Total gram negative 10 3 13
Totals 26 6 32
From Storoe W, Haug RH, Lillich TT. The changing face of odontogenic infections. J Oral Maxillofac Surg 2001;59:739 – 48;
with permission.

Table 2), S. aureus was the most frequently identified material in the cases included in this investigation,
antibiotic resistant isolate. In addition to its innate but it is unlikely because proper surgical technique
virulence, S. aureus is of increasing concern because and rigorous preoperative antimicrobial skin prepara-
it, along with other gram-positive cocci, is becoming tion were used. One would expect surgical technique
resistant to most common antibiotics. For example, and skin preparation to improve with time, thereby
methicillin-resistant S. aureus that also exhibits inter- reducing the incidence of sample contamination
mediate resistance (minimum inhibitory concentra- from cutaneous sources. This does not seem to be
tion = 8 mg/mL) to vancomycin, the antimicrobial the case in this comparison of odontogenic infections
regarded as the ‘‘antibiotic of last resort’’ for these from the 1980s and the 1990s, however, which
bacteria, recently has been reported in Japan and the showed no change in the frequency of Staphylococ-
United States [46]. cus species isolated. Assuming that proper technique
Another trend is the number of antibiotic-resistant, was followed and that the sites were prepared
coagulase-negative staphylococci isolated. These bac- properly, it is improbable that there has been a shift
teria long have been regarded as ‘‘apathogenic’’ in the kinds of bacteria causing odontogenic infec-
members of the normal flora but are increasingly tions in the last 10 years.
becoming recognized as important causes of infec-
tions, especially those acquired in hospitals [47].
Because most of the infections they cause are noso- Trauma-related infections
comial, it should not be surprising to see increasing
multiple antibiotic resistance. Against a background Infection is a concern during the management of
of the empiricism with which many clinicians con- patients who have sustained maxillofacial trauma
tinue to treat these patients (eg, only 10% of the [48]. It may be a result of the injury itself or the
patients in the 1990s had a culture and antibiotic treatment of that injury. Infection may cause systemic
sensitivity test performed), one may predict that there sepsis, fracture nonunion, failure in cutaneous wound
will be more initial treatment failures and a con- healing, and the need for a prolonged hospitalization
sequent increase in patient morbidity and total cost or additional surgery [49,50]. Infection in the trauma
of care. patient also may produce irreversible damage, includ-
Moenning et al [37] suggested that wounds or ing disfigurement, dysfunction, and death. From the
cavities could become contaminated with normal most empirical standpoint, infection subsequent to
skin microflora, including Staphylococcal species, trauma involves the introduction or inoculation of
through external drainage. It is possible that such microorganisms that routinely exist as normal flora
contamination occurred during the harvest of culture (Boxes 1 – 3, Table 1) beyond the body’s external
8 R.H. Haug / Oral Maxillofacial Surg Clin N Am 15 (2003) 1–15

protective media (the skin or mucosa) and the altera- the use of a rigorous protocol of tetanus globulin
tion of the homeostatic relationship between the and toxoid administration, the incidence of wartime
individual and his or her environment. Nothing more clostridial infection (in US casualties) was reduced
suddenly alters homeostasis than acute trauma, and from 5% in World War I, to 0.7% in World War II,
the major organ systems are mobilized to respond to and finally 0.08% during the Korean War [68].
increased demands. Because of the systemic response Civilian data are unavailable.
to injury, patients who have sustained major trauma
are far more susceptible to wound infection than
individuals who have suffered mere localized injuries
[48,51,52]. Box 4. Some of the most common
The skin and mucosa are essential barriers to the microorganisms transmitted by human
entry of microorganisms into the underlying connec- bites [53,54,56,58,59,63,64]
tive tissue and organs. The integument is normally
exposed to bacterial flora only to the depth of the Aerobic and facultative isolates
adnexa. Scalp and maxillofacial cutaneous lacerations Acinetobacter species
expose the underlying structures to the microorgan- Corynebacterium species
isms listed in Box 1. Intraoral lacerations and even Eikenella corrodens
simple fractures through the periodontal ligament Enterococcus species
expose the bone and viscera to the otherwise normal Haemophilus influenzae
flora (see Box 2). Finally, mid- and upper-facial Haemophilus parainfluenzae
fractures contaminate the victim with multiple micro- Klebsiella pneumonia
organisms from the skin, nose, and paranasal sinuses Neisseria species
(Box 3). Nocardia species
The introduction of microorganisms beyond the Proteus species
individual’s own indigenous flora also may occur Pseudomonas
with bite wounds (Boxes 4,5) or exposure to a Staphylococcus aureus
contaminated environment. Streptococcus viridans, Staphylococcus epidermidis
Bacteroides species, Peptostreptococcus species, Streptococcus
and E. corrodens are among the microorganisms most n-hemolytic
commonly isolated from humans who develop infec- p-hemolytic
tions after having been bitten by other humans, and S. Group A o-hemolytic
aureus, Pasteurella multocida, Streptococci species, Non – group A o-hemolytic
and Bacteroides species are pathogens that often have Anaerobic isolates
been isolated from mammalian bite wound infections Bacteroides fragilis group
[12,53 – 64]. The rabies virus is always a concern for Bacteroides oralis
raccoon, skunk, fox, or bat bites. Contamination also Bacteroides ureolyticus
may include debris or foreign material impacted into Bifidobacterium species
the wound, farm-related injuries that inoculate the Eubacterium species
victim with animal feces (gram-negative enteric Fusobacterium nucleatum
organisms, group D streptococci, and anaerobes) Fusobacterium necrophorus
[65], earth-borne contaminants, such as Clostridium Peptococcus niger
tetani and Actinomyces species, and contamination Peptostreptococcus
with free-standing water (E. coli). Fresh-water con- asaccharolyticus
tamination, particularly in brackish water, has caused Peptostreptococcus magnus
Aeromonas hydrophila infection [59]. This aerobic Prevotella melaninogenica
gram-negative rod can cause severe facial cellulitis Prevotella intermedia
and myonecrosis. Enteric organisms such as E. coli Veillonella species
also frequently contaminate wounds exposed to Other rare pathogens
coastal seawater. Hepatitis B virus
When burns, concussion, maceration, or avulsion Herpes simplex virus
injure muscle, myonecrosis may ensue, and if con- HIV
taminated, it frequently results in infection [66]. Mycobacterium tuberculosis
Anaerobic bacteria such C. perfringens and C. Treponema pallidum
tetani are the most frequent causes [67]. Through
R.H. Haug / Oral Maxillofacial Surg Clin N Am 15 (2003) 1–15 9

Box 5. Some of the most common Rio Bravo virus


microorganisms transmitted by animal Simian herpes virus (macaque
bites [12,53 – 64] monkeys only)
Spirillum minus
Aerobic and facultative isolates Streptobacillus moniliformis
Yersinia pestis
Acinetobacter species
Aeromonas hydrophila
Bacillus subtilis
Bordetella species
Brucella canis Neither the indigenous maxillofacial flora nor the
Capnocytophagia canimorsus introduction of common contaminants has changed
Chromobacterium species in the management of maxillofacial trauma. Rather, the
Clostridium perfringens development of nosocomial infections and the human
Corynebacterium species body’s weakened systemic response to trauma are
EF-4 responsible. Central nervous system injury sharply
EF-7 increases the risk of infection in the trauma patient,
Eikenella corrodens with gram-negative pneumonia being among the great-
Enterococcus species est adverse outcomes [52]. Serratia and Pseudomonas
Flavobacterium species species are becoming more prominent offenders in the
Haemophilus aphrophilus head-injured patient because of their frequent presence
Klebsiella in intensive care units. The emergence of new and
Moraxella catarrhalis more resistant strains of staphylococci, especially
Moraxella weaveri methicillin-resistant S. aureus, has made the manage-
Neisseria species ment of nosocomial infection tenuous, with the under-
Proteus species standing that surgical patients who develop
Pasteurella multocida nosocomial methicillin-resistant S. aureus infection
Proteus mirabilis are twice as likely to die than those who do not
Pseudomonas [13,15]. The fear of the emergence of new and resistant
Serratia marcescens strains of bacteria has prompted the trauma surgeon to
Staphylococcus aureus withhold the administration of antibiotics until after
Staphylococcus epidermidis the trauma patient has become infected (if an infection
Staphylococcus saprophyticus does develop) [7,11]. This trend also has extended to
Streptococcus species the management of maxillofacial trauma victims.
Weeksella zoohelcum Many patients with clean-contaminated wounds who
Anaerobic isolates would previously have been considered candidates for
Arachnia propionica antibiotics are no longer considered such.
Bacteroides spp
Eubacterium spp
Fusobacterium spp
Leptotrichia Nasal and paranasal sinus infections
Peptococcus
Peptostreptococcus spp Acute maxillary sinusitis
Propionibacterium acnes
Veillonella spp Sinusitis is a disease that results from an infection
Other rare pathogens of one or more of the paranasal sinuses [69,70].
Bartonella henselae Acute sinusitis is generally categorized by its etiol-
Clostridium tetani ogy: nosocomial or community-acquired and viral,
Francisella tularensis bacterial, or fungal [69,70]. Combinations of causes
Hepatitis B virus are possible. Perhaps the most common cause for
Herpes simplex virus acute maxillary sinusitis is a rhinovirus infection. The
Leptospira species ability to culture viruses accurately is a relatively
Rabies virus recent development, and changes or trends in viral
pathogenicity have not been established.
10 R.H. Haug / Oral Maxillofacial Surg Clin N Am 15 (2003) 1–15

The origin of acute community-acquired bacterial


Box 6. Some common microorganisms
sinusitis (ACABS) has been well substantiated for the
responsible for acute maxillary and
past five to six decades (Box 6) [24,69 – 74].
ethmoid sinusitis [49,69,70,72,73]
S. pneumonia and H. influenzae account for more
than half of the occurrences of this form of sinusitis.
Aerobic and facultative isolates
Other Streptococcus species—S. aureus, M. catar-
Escherichia coli
rhalis, a-hemolytic streptococci, and anaerobic bac-
Haemophilus influenzae
teria—also have been isolated. Complicating
Moraxella catarrhalis
diagnosis and treatment even more has been the
Neisseria species
observation that viruses and bacteria may be iden-
Pseudomonas aeruginosa
tified as simultaneously causing ACABS. When
Staphylococcus aureus
cultures fail to yield bacteria for ACABS (approx-
Streptococcus pneumoniae
imately 40% of the time), a viral cause should be
Streptococcus pyogenes
suspected. Fungi also may be responsible for ACABS
Streptococcus
but are more associated with nosocomial sinusitis and
n-hemolytic
sinus disease that develops in the compromised host,
o-hemolytic
such as someone with diabetes. S. aureus, P. aerugi-
Anaerobic isolates
nosa, Serratia marcescens, K. pneumonia, Entero-
Bacteroides species
bacter species, Proteus mirabilis, and Legionella
Fusobacterium species
pneumonia are also associated with nosocomial
Peptostreptococcus species
sinusitis and the compromised host [69].
Viruses
The relative distribution of microorganisms re-
sponsible for ACABS has not changed in either Adenovirus
appearance or prevalence over the past five decades Influenza virus
(Box 6) [69,73,74]. What has changed is their Parainfluenza virus
antimicrobial susceptibility. Penicillin-resistant Rhinovirus
S. aureus has emerged as a difficult offender to
manage, along with b-lactam – resistant strains of
H. influenzae and M. catarrhalis. Worse yet has
been the emergence of multiple strains of resistant Infectious rhinitis
S. pneumoniae. The changes in the microbiology of
acute maxillary sinusitis have not been in the type or Infectious rhinitis may be classified as acute, self-
frequency of microorganisms but rather the emer- limiting, or chronic, and it is the major component of
gence of resistant strains. the ‘‘common cold’’ [75]. Viruses are the most fre-
quent cause of infectious rhinitis, and rhinoviruses are
Chronic maxillary sinusitis the most frequent etiologic agent among them (Box 8)
[26 – 28,75]. Bacteria are an infrequent cause of iso-
The specific cause and pathogenicity of chronic lated nasal infections but are common as a cause of
sinusitis disease remain unanswered, and its success- combination nasal/paranasal sinus infections [75].
ful treatment modalities continue to be elusive Granulomatous nasal infections, such as rhinoscle-
[49,72,73]. Although some cases of chronic sinusitis roma, tuberculosis, syphilis, aspergillosis, and mucor-
disease exist as a separate and distinct entity, it is mycosis, are rare and are caused by numerous
believed that most cases arise from ACABS treatment microorganisms, including fungi, protozoa, and myco-
failures. S. pneumoniae, H. influenzae, and other bacterium [26 – 28,75].
streptococcal species have been isolated from patients
with chronic sinusitis disease (Box 7) [24,69 – 74]. Frontal and sphenoid sinusitis
Recent reports have identified b-lactamase – pro-
ducing strains of S. pneumonia, H. influenzae, and The microbial flora of the infected frontal and
M. catarrhalis in ACABS aspirates [65,73]. It seems sphenoid sinuses are separate and distinct from those
probable that chronic sinusitis disease is merely the of the maxillary and ethmoid sinuses. Acute sphenoid
continued manifestation of ACABS caused by inef- and frontal sinusitis is uncommon and difficult to
fective treatment. The changes in the microbiology of diagnose and carries with it a significant degree of
chronic sinusitis disease have been in the emergence morbidity but accounts for less than 5% of paranasal
of resistant strains. sinus infections [76 – 78]. Headache is the most
R.H. Haug / Oral Maxillofacial Surg Clin N Am 15 (2003) 1–15 11

consistent finding, and it may be accentuated with


Box 8. Some common microorganisms
activity. The degree of pain associated with it can be
responsible for rhinitis [26 – 28,75]
debilitating. Several organisms have been associated
with this disease (Box 9) [70,76 – 78]. S. aureus,
Aerobic and facultative isolates
S. pneumoniae, H. influenzae, and other streptococci
Klebsiella rhinoscleromatis
are the most frequent pathogens [76 – 78]. Although
Mycobacteria
changes in the microbiology of frontal and sphenoid
Mycobacterium tuberculosis
sinusitis have not been identified by case-controlled
Spirochetes
cohort investigations, changes in therapeutic trends
Treponema pallidum
point to the need for antibiotics that address b-lacta-
Fungi
mase – producing strains of organisms. Especially
problematic are b-lactamase – producing staphylo- Absidia species
cocci, streptococci, and H. influenzae. This finding Aspergillus flavus
suggests that the changes in the microbiology of acute Aspergillus fumigatus
frontal and sphenoid sinusitis are, as in other nasal and Bipolaris species
paranasal infections, not in the type or frequency of the Cladosporium species
microorganisms isolated but in the emergence of Curvularia species
resistant strains. Exophiala species
Exserohilum species
Histoplasma capsulatum
Mucor species
Cutaneous infections Rhinosporidium seeberi
Rhizopus species
A plethora of cutaneous maxillofacial infections Wangiel1la species
occur with relative infrequency in the population Protozoa
[79,80]. Many are rare and exotic, such as noma Leishmaniasis
(cancrum oris), the progressively deforming gangre- Viruses
nous stomatitis most often seen in debilitated and Adenovirus
malnourished Third World children. It is believed Enterovirus
to result from P. aeruginosa and the fusospirochetal Influenza virus
organisms, Borrelia vincentii and Fusobacterium Parainfluenza virus
nucleatum [79,80]. Other unusual cutaneous max- Respiratory syncytial virus
illofacial infections include such zoonotic diseases Rhinovirus
as cat scratch disease, caused by Bartonella hense-
lae; leptospirosis, caused by Leptospira species;
and the Bubonic Plague, caused by Y. pestis [81 –
83]. Zoonotic diseases occur from the inoculation the aforementioned diseases is characterized by
into the humans of microorganisms that exist non- raised, red, painful cutaneous lesions that are man-
pathogenically in the animal population. Each of aged with antibiotic therapy [81 – 83]. Although
exotic and unusual, changes in frequency of
appearance or virulence of these types of infections
Box 7. Some common microorganisms have not been observed.
responsible for chronic maxillary sinus- More common cutaneous infections that affect
itis [24,69 – 74] the maxillofacial region are erysipelas, caused by
group A streptococci; impetigo, the result of group A
Aerobic and facultative isolates streptococci or S. aureus; and furuncles, carbuncles,
Corynebacterium species and folliculitis, which may be caused by S. aureus,
Haemophilus influenzae C. albicans, or P. aeruginosa [79,80]. Although
Streptococcus pneumoniae associated with compromised hosts and institutional
Anaerobic isolates and regional outbreaks, there have been neither
Bacteroides species changes in the frequency of appearance of these
Peptostreptococcus species infections in the general population nor changes in
Veillonella species virulence of the organisms. Buccal cellulitis of
infancy, often confused with an odontogenic infec-
12 R.H. Haug / Oral Maxillofacial Surg Clin N Am 15 (2003) 1–15

Summary
Box 9. Some common microorganisms
responsible for sphenoid and frontal
What is considered the indigenous maxillofacial
sinusitis [44,70,76,78]
flora begins during birth with the acquisition of the
flora of the birth canal and then changes from infancy
Aerobic and facultative isolates
to adulthood as a result of the specific anatomic
o-hemolytic Streptococci
region, environmental influences, and host factors.
Citrobacter
The changes in the microbiology of infections of
Coliform bacilli
odontogenic etiology rest in changes in nomenclature
Enterococci
and in our ability to isolate organisms. The changes in
Escherichia coli
the microbiology of infections associated with max-
Haemophilus influenzae
illofacial trauma are not caused by the injuries but are
Klebsiella pneumonia
related to nosocomial systemic infection and the
Pneumococci
emergence of resistant microorganisms. The changes
Proteus
in the microbiology of nasal and paranasal sinus
Pseudomonas aeruginosa
infections are associated with the emergence or
Serratia
reemergence of strains of bacteria that are resistant
Staphylococcus aureus
to common antibiotics. Cutaneous infections appear
Staphylococcus epidermidis
infrequently, but the most common etiologic agent,
Streptococcus pneumoniae
herpes simplex virus, also has been associated with
Streptococcus viridans
the isolation of resistant strains at an alarming rate.
Anaerobic isolates
Anaerobic Streptococci
Fungi
Aspergillus References

[1] Ohira R. Five-year-old girl battles flesh-eating bacteria.


Honolulu Star-Bulletin, June 28, 2002. p. 1.
[2] Lemonick MD. The killers all around: new viruses and
drug resistant bacteria are reversing human victories
tion from the deciduous teeth, is another unusual over infectious disease. Time 1994;144:62.
cutaneous maxillofacial infection [80]. Its cause is [3] Spake A. Losing the battle of the bugs. US News and
H. influenzae, and it is cared for with constitutional World Report 1999;126:52 – 60.
support, antibiotics, and antipyretics. This condition [4] Satcher D. Emerging infections: getting ahead of the
also has shown no apparent change in virulence or curve. Emerg Infect Dis 1995;1:1 – 6.
frequency of distribution. [5] Neu HC. The crisis in antibiotic resistance. Science
Perhaps the most frequent cutaneous infection of 1992;257:1064 – 73.
the maxillofacial region is that caused by the herpes [6] Dacre J, Emmerson A, Jenner E. Gentamicin-methicil-
simplex virus [9]. Although it may produce mucocu- lin – resistant Staphylococcus aureus: epidemiology of
an outbreak. J Hosp Infect 1986;7:130 – 6.
taneous lesions of the entire face, it is mostly limited
[7] American Society of Health-System Pharmacists.
to the skin and mucosa of the oral cavity and perioral ASHP therapeutics guidelines on antimicrobial pro-
region. Conjunctival and nasal/perinasal manifesta- phylaxis in surgery. Am J Health Syst Pharm 1999;
tions are also common. The virus is introduced into 56:1839 – 88.
the body through mucosal exposure or abraded skin. [8] Barett F, McGehee R, Finland M. Methicillin-resistant
Although the initial infection may be subclinical, Staphylococcus aureus at Boston City Hospital. N
recurrence is common. More than 90% of adults have Engl J Med 1998;279:441 – 8.
antibodies to the herpes simplex virus. Prevalence [9] Corey L. Herpes simplex virus. In: Mandell GL, Ben-
increases with decreasing socioeconomic status, and nett JE, Dolin R, editors. Principles and practice of
it is more prevalent in African Americans and persons infectious disease. 5th edition. Philadelphia: Church-
ill-Livingstone; 2000. p. 1564 – 80.
living in Western Europe than in the United States.
[10] Crossley K, Loesch D, Landesman B, et al. An out-
Although relief and complacency developed in the break of infections caused by strains of Staphylococcus
medical and lay populations after the discovery of aureus resistant to methicillin and aminoglycosides. I:
acyclovir, concern has arisen again because of the clinical studies. J Infect Dis 1979;139:273 – 9.
increasing frequency of isolation of acyclovir-resist- [11] Fukatsu K, Saito H, Matsuda T, et al. Influences of
ant strains of herpes simplex virus. type and duration of antimicrobial prophylaxis on an
R.H. Haug / Oral Maxillofacial Surg Clin N Am 15 (2003) 1–15 13

outbreak of methicillin-resistant Staphylococcus aur- [27] Weiser JN, Kim JO. The respiratory tract microflora
eus and on the incidence of wound infection. Arch and disease. In: Tannock GW, editor. Medical impor-
Surg 1997;132:1320 – 5. tance of the normal microflora. Boston: Kluwer Aca-
[12] Goldstein E, Citron D, Feingold S. Dog bite wounds demic; 1999. p. 47 – 73.
and infection: a prospective clinical study. Ann Emerg [28] Volk WA, Gebhart BM, Hammarskjold M, et al. Nor-
Med 1980;9:508 – 12. mal flora, infections, and bacterial invasiveness. In:
[13] Kirkland KB, Briggs JP, Trivette SL, et al. The im- Volk WA, Gebhart BM, Hammarskjold M, et al,
pact of surgical-site infections in the 1990s: attribut- editors. Essentials of medical microbiology. 5th edition.
able mortality, excess length of hospitalization, and Philadelphia: Lippincott-Raven; 1996. p. 315 – 32.
extra costs. Infect Control Hosp Epidemiol 1999; [29] Bartlett JG, O’Keefe P. The bacteriology of periman-
20:725 – 30. dibular space infections. J Oral Surg 1979;37:407 – 9.
[14] Klimek J, Marsik F, Bartlett R, et al. Clinical, epide- [30] Chow AW, Roser SM, Brady FA. Orofacial odonto-
miologic and bacteriologic observations of an outbreak genic infections. Ann Intern Med 1978;88:392 – 402.
of methicillin-resistant Staphylococcus aureus at a [31] Dodson TB, Perrott DH, Kaban LB. Pediatric maxillo-
large community hospital. Am J Med 1976;61:340 – 5. facial infections: a retrospective study of 113 patients.
[15] Panlilio AL, Culver DH, Gaynes RP, et al. Methicillin- J Oral Maxillofac Surg 1989;47:327 – 30.
resistant Staphylococcus aureus in US hospitals, [32] Har-el G, Aroesty JH, Shaha A, et al. Changing trends
1975 – 1991. Infect Control Hosp Epidemiol 1992;13: in deep neck space abscess: a retrospective study of
582 – 6. 110 patients. Oral Surg Oral Med Oral Pathol 1994;77:
[16] Pavillard R, Harvey K, Douglas D, et al. Epidemic of 446 – 50.
hospital-acquired infection due to methicillin-resistant [33] Haug RH, Hoffman MJ, Indresano AT. An epidemio-
Staphylococcus aureus in Victorian hospitals. Med J logic and anatomic survey of odontogenic infections.
Aust 1982;1:451 – 4. J Oral Maxillofac Surg 1981;49:976 – 80.
[17] Gallis HA. Normal flora and opportunistic infections. [34] Heimdahl A, Von Konow L, Satoh T, et al. Clinical
In: Joklik WK, Willett HP, Amos DB, et al. Zinsser appearance of orofacial infections of odontogenic ori-
microbiology. 19th edition. Norwalk (CT): Appleton gin in relation to microbiological findings. J Clin Mi-
and Lange; 1988; p. 337 – 42. crobiol 1985;22:299 – 302.
[18] Koneman EW, Allen SD, Dowell VR, et al. Color atlas [35] Hunt DE, King TJ, Fuller GE. Antibiotic susceptibility
and textbook of diagnostic microbiology. 3rd edition. of bacteria isolated from oral infections. J Oral Surg
Philadelphia: Lippincott; 1988; p. 17 – 8. 1978;36:527 – 9.
[19] Schuster GS. Microbiology of the orofacial region. [36] Kannangara DW, Thadepalli H, McQuirter JL. Bacteri-
In: Topazian RG, Goldberg MH, Hupp JR, editors. ology and treatment of dental infections. Oral Surg
Oral and maxillofacial infections. 4th edition. Phila- Oral Med Oral Pathol 1980;50:103 – 9.
delphia: WB Saunders Co.; 2002. p. 30 – 42. [37] Moenning JE, Nelson CL, Kohler RB. The microbiol-
[20] Shuster GS. Oral flora and pathogenic organisms. In- ogy and chemotherapy of odontogenic infections.
fect Dis Clin N Am 1999;13:757 – 74. J Oral Maxillofac Surg 1989;47:976 – 85.
[21] Tramont EC, Hoover DL. Innate (general or nonspe- [38] Sakaguchi M, Sato S, Ishigama T, et al. Characteristics
cific) host defense mechanisms. In: Mandell GL, Ben- and management of deep neck infections. Int J Oral
nett JE, Dolin R, editors. Principles and practice of Maxillofac Surg 1997;26:131 – 4.
infectious disease. 5th edition. Philadelphia: Churchill- [39] Sethi DS, Stanley RE. Deep neck abscess-changing
Livingstone; 2000. p. 31 – 8. trends. J Laryngol Otol 1994;108:138 – 42.
[22] De Pauw BE, Donnelly JP. Infections in the compro- [40] Storoe W, Haug RH, Lillich TT. The changing face of
mised host: general principles. In: Mandell GL, Ben- odontogenic infections. J Oral Maxillofac Surg 2001;
nett JE, Dolin R, editors. Principles and practice of 59:739 – 48.
infectious disease. 5th edition. Philadelphia: Churchill- [41] Gorbach SL, Gilmore WC, Jacobus NV, Doku C, Tally
Livingstone; 2000. p. 3081 – 2. FP. Microbiology and antibiotic resistance in odonto-
[23] Labiola JD, Mascaro J, Alpert B. The microbiologic genic infections. Ann Otol Rhinol Laryngol 1991;
flora of orofacial abscesses. J Oral Maxillofac Surg 154:S40 – 2.
1983;41:711 – 4. [42] Greenburg RN, James RB, Marier RL, et al. Micro-
[24] McCarter YS. Laboratory microbiological diagnostic biologic and antibiotic aspects of infections in the
techniques. In: Topazian RG, Goldberg MH, Hupp oral and maxillofacial region. J Oral Surg 1979;
JR, editors. Oral and maxillofacial infections. 4th edi- 37:873 – 84.
tion. Philadelphia: WB Saunders Co.; 2002. p. 43 – 61. [43] Sands T, Pynn BR, Katsikeris N. Part two odontogenic
[25] Bamberger DM. Antimicrobial treatment of sinusitis. infections: microbiology, antibiotics and management.
Semin Respir Infect 1991;6:77 – 84. Oral Health 1995;85:11 – 4.
[26] Larsen HS. Host-parasite interaction. In: Mahon CR, [44] Lewis MAD, MacFarlane TW, McGowan DA. Quan-
Manuselis G, editors. Textbook of diagnostic microbi- titative bacteriology of acute dento-alveolar abscesses.
ology. 2nd edition. Philadelphia: WB Saunders Co.; J Med Microbiol 1986;21:101 – 4.
2000. p. 213 – 6. [45] Jousimies-Somer HR, Summanen PH, Finegold SM.
14 R.H. Haug / Oral Maxillofacial Surg Clin N Am 15 (2003) 1–15

Bacteroides, porphyromonas, prevotella, fusobac- [64] Tandberg D, Rusnak R. Mammalian bites. In: Schwartz
terium, and other anaerobic gram-negative rods and GR, Safar P, Stone JH, editors. Principles and practice
cocci. In: Murray PR, Baron EJ, Pfaller MA, et al, of emergency medicine. 2nd edition. Philadelphia: WB
editors. Manual of clinical microbiology. 7th edition. Saunders Co.; 1986. p. 1618 – 25.
Washington, DC: ASM Press; 1999. p. 690 – 711. [65] Brennen SR, Rhodes KH, Peterson HA. Infection after
[46] Lowy FD. Staphylococcus aureus infections. N Engl J farm related injuries in children and adolescents. Am J
Med 1998;339:520 – 32. Dis Child 1990;144:710 – 3.
[47] Huebner J, Goldmann DA. Coagulase-negative staph- [66] Schwarz M. Myositis. In: Mandel G, Douglas R,
ylococci: role as pathogens. Annu Rev Med 1999;50: Bennett J, editors. Principles and practice of infec-
223 – 36. tious diseases. 3rd edition. New York: Churchill-Liv-
[48] Haug RH, Assael LA. Infection in the maxillofacial ingstone; 1990. p. 813.
trauma patient. In: Topazian RG, Goldberg MH, [67] Burgess J, Wambaugh G, Koczarski M. Review-
Hupp JR, editors. Oral and maxillofacial infections. ing cephalic tetanus. J Am Dent Assoc 1992;123:
4th edition. Philadelphia: WB Saunders Co.; 2002. 67 – 70.
p. 267 – 92. [68] Fackler M. Wound ballistics misconceptions. JAMA
[49] Bikle DD. Effects of alcohol abuse on bone. Compr 1990;259:2730 – 6.
Ther 1988;14:16 – 20. [69] Gwaltney JM. Sinusitis. In: Mandell GL, Bennett JE,
[50] Gavin LA. Perioperative management of the diabetic Dolin R, editors. Principles and practice of infectious
patient. Endocrinol Metab Clin North Am 1992;21: disease. 5th edition. Philadelphia: Churchill-Living-
457 – 75. stone; 2000. p. 676 – 86.
[51] Abubaker AO, Rollert MK. Postoperative antibiotic [70] Sandler NA, Johns FR, Braun TW. Advances in the
prophylaxis in mandibular fractures: a preliminary management of acute and chronic sinusitis. J Oral
randomized, double blind, and placebo-controlled Maxillofac Surg 1996;54:1005 – 13.
clinical study. J Oral Maxillofac Surg 2001;59: [71] Hamory BH, Sande MA, Sydnor A, et al. Etiology and
1415 – 9. antimicrobial therapy of acute maxillary sinusitis.
[52] Helling T, Evans L, Fowler DL, et al. Infectious com- J Infect Dis 1979;139:197 – 202.
plication in patients with severe head injury. J Trauma [72] Sydnor A, Gwaltney J, Cacchetto DM, et al. Compar-
1989;28:1575 – 7. ative evaluation of Cefuroxime Axetil and Cefaclor for
[53] Brook I. Microbiology of human and animal bite treatment of acute bacterial maxillary sinusitis. Arch
wounds in children. Pediatr Infect Dis J 1987;6:29 – 32. Otolaryngol Head Neck Surg 1989;115:1430 – 3.
[54] Callaham M. Prophylactic antibiotics in common dog [73] Wald ER, Reilly JS, Casselbrant M, et al. Treatment of
bite wounds: a controlled study. Ann Emerg Med acute maxillary sinusitis in childhood: a comparative
1980;9:410 – 4. study of amoxicillin and cefaclor. J Pediatr 1984;104:
[55] Callaham M. Treatment of common dog bites: in- 297 – 302.
fection risk factors. J Am Coll Emerg Phys 1978;1: [74] Winther B, Vickery CL, Gross CW, et al. Microbiology
83 – 7. of the maxillary sinus in adults with chronic sinus dis-
[56] Doan-Wiggins L. Animal bites and rabies. In: Rosen P, ease. Am J Med Sci 1998;316:13 – 20.
Barkin RM, editors. Emergency medicine concepts and [75] Kopke RD, Jackson RL. Rhinitis. In: Bailey BJ, editor.
clinical practice. 3rd edition. Philadelphia: Mosby-Year Head and neck surgery: otolaryngology. Philadelphia:
Book; 1992. p. 864 – 5. JB Lippincott; 1993. p. 269 – 89.
[57] Feder HM, Shanley JD, Barbera VA. Review of 50 [76] Kibblewhite DJ, Cleland J, Mintz DR. Acute sphenoid
patients hospitalized with animal bites. Pediatr Infect sinusitis: management strategies. J Otolaryngol 1988;
Dis J 1987;6:24 – 8. 17:159 – 63.
[58] Goldstein EJ, Richwald GA. Human and animal bite [77] Lew D, Southwick FS, Montgomery WW, et al. Sphe-
wounds. Am Fam Physician 1987;36:101 – 9. noid sinusitis: a review of 30 cases. N Engl J Med
[59] Johnson D, Kuzmik M, Chorazy C. Aeromonas infec- 1983;309:1149 – 54.
tion following facial injury. J Oral Maxillofac Surg [78] Middleton WG, Briant TDR, Fenton RS. Frontal si-
1986;44:563 – 5. nusitis: a 10 year experience. J Otolaryngol 1985;14:
[60] Klein JD. Animal bite infections. Del Med J 1989; 197 – 200.
61:17 – 20. [79] Swartz MN. Cellulitis and subcutaneous tissue in-
[61] Morgan JP, Haug RH, Murphy MT. Management of fections. In: Mandell GL, Bennett JE, Dolin R, ed-
facial dog bite injuries. J Oral Maxillofac Surg 1995; itors. Principles and practice of infectious disease.
53:435 – 41. 5 th edition. Philadelphia: Churchill-Livingstone;
[62] Peel M. Dog-associated bacterial infection in humans: 2000. p. 1037 – 57.
isolates submitted to an Australian reference labora- [80] Topazian RG. Uncommon inflammatory conditions
tory, 1981 – 1992. Pathology 1993;25:379 – 84. and infections of the orofacial region. In: Topazian
[63] Ruskin JD, Laney T, Wendt SV, et al. Treatment of MH, Goldberg MH, Hupp JR, editors. Oral and max-
mammalian bite wounds of the maxillofacial region. illofacial infections. 4th edition. Philadelphia: WB Sa-
J Oral Maxillofac Surg 1993;51:174 – 6. unders Co; 2002. p. 423 – 38.
R.H. Haug / Oral Maxillofacial Surg Clin N Am 15 (2003) 1–15 15

[81] Butler T. Yersinia species, including plague. In: Man- 5 th edition. Philadelphia: Churchill-Livingstone;
dell GL, Bennett JE, Dolin R, editors. Principles and 2000. p. 2444 – 57.
practice of infectious disease. 5th edition. Philadelphia: [83] Tappero JW, Ashford DA, Perkins BA. Leptospira spe-
Churchill-Livingstone; 2000. p. 2406 – 13. cies (leptospirosis). In: Mandell GL, Bennett JE, Dolin
[82] Slater LN, Welch DF. Bartonella species, including cat- R, editors. Principles and practice of infectious disease.
scratch disease. In: Mandell GL, Bennett JE, Dolin R, 5th edition. Philadelphia: Churchill-Livingstone; 2000.
editors. Principles and practice of infectious disease. p. 2495 – 501.
Oral Maxillofacial Surg Clin N Am 15 (2003) 17 – 38

Antibiotic selection in head and neck infections


Thomas R. Flynn, DMDa,b,*, Leslie R. Halpern, DDS, MD, MPH, PhDa,b
a
Department of Oral and Maxillofacial Surgery, Harvard School of Dental Medicine,
188 Longwood Avenue, Boston, MA 02115, USA
b
Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA

Oral and maxillofacial surgeons see patients with The acquisition of antibiotic resistance genes by
infections as part of their everyday practice. It is bacteria allows such mechanisms to be implemented.
imperative to understand the mechanisms of antimi- There are four specific mechanisms by which bacteria
crobial resistance, its potential problems, and the acquire resistance genes:
means of overcoming it. This situation raises several
important questions with respect to antimicrobial
therapy for odontogenic infections: 1. Spontaneous mutation. This is the original
source for all antibiotic resistance, because
bacteria have maintained genes that encode
1. Is there a problem of antibiotic resistance?
for resistance of naturally occurring anti-
2. How does antibiotic resistance arise?
biotics of other species. For example, the
3. Is antibiotic resistance the fault of the bacteria
DNA encoding of b-lactamases and penicillin-
or the host or the result of treatment (ie, the
binding proteins have several homologous
medical and surgical community)?
sequences [1].
4. What can be done to remedy the problem?
2. Gene transfer. Bacteria can undergo conjuga-
tion with a transfer of genes as plasmids, which
The purpose of this article is to examine the
are a composition of cytoplasmic loops of
problem of antimicrobial resistance in the oral cavity
DNA that encode for antibiotic resistance, and
and make recommendations for antibiotic selection in
transposons, which are able to insert them-
the treatment of head and neck infections.
selves into the genome of the recipient cell. An
example of a plasmid-mediated genetic event is
acquisition of the ability to produce b-lacta-
Molecular biology of antibiotic resistance
mase by some species.
3. Bacteriophages. Viruses infect bacteria and
Generally speaking, bacteria acquire antibiotic
can insert genetic material and take control
resistance in one of four ways:
of the host’s genetic and metabolic machin-
ery, which may encode for antibiotic re-
1. Alteration of a drug’s target site
sistance mechanisms.
2. Inability of a drug to reach its target
4. Mosaic genes. Bacteria can absorb directly
3. Inactivation of an antimicrobial agent
the fragments of the virally altered genome of
4. Active elimination of an antibiotic from the cell
dead members of related species to form a
‘‘mosaic genome’’ of genetic material from
* Corresponding author. Department of Oral and
varying sources. This type of gene derivation
Maxillofacial Surgery, Harvard School of Dental Medicine, is responsible for the non – b-lactamase pen-
188 Longwood Avenue, Boston, MA 02115. icillin resistance in Streptococcus pneumoniae
E-mail address: thomas_flynn@hsdm.harvard.edu and meningococci and ampicillin resistance in
(T.R. Flynn). Haemophilus influenzae and gonococci [1].

1042-3699/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.
PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 8 2 - 1
18 T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38

Antibiotic resistance mechanisms Strategies in the prevention of antibiotic resistance

Once the genetic machinery is in place, bacteria Extending surgical prophylaxis beyond 48 hours
exert antibiotic resistance by various pathways that and inappropriately low dosing that encourages sub-
are broadly classified in four ways. populations of organisms to survive in increasing
Drug inactivation or modification. The destruc- concentrations of antibiotics can select for resistant
tion or inactivation of the antimicrobial agent is bacteria [3]. Although culture and sensitivity studies
accomplished by the induction of specific drug-inac- are crucial and should not preclude empiric therapy
tivating enzymes, such as those that inhibit b-lactams when warranted, there is also the risk that the latter
or aminoglycosides. Numerous gram-positive and can produce bacterial resistance. A case series to
gram-negative bacteria, such as Staphylococcus au- examine the bacteriology of dentoalveolar abscesses
reus, Enterococcus faecium, Escherichia coli, Pseu- in patients who received empiric antibiotic therapy
domonas aeruginosa, H. influenzae, Bacteroides, and suggested that the polymicrobial nature of the abscess
many strains of Prevotella have this capability. and the administration of empiric therapy with ampi-
Another method used by bacteria to withstand anti- cillin or cephalosporins often results in resistant
microbial attack is the ability to synthesize neutral- strains [4]. The predominant species were anaerobic
izing enzymes. The best examples are penicillinase (ie, Prevotella and Peptostreptococcus species, both
and the methylation of erythromycin and clindamy- resistant to the therapy initially given). Kuriyama et al
cin. Other antibiotics that are neutralized include [5] examined the relationship between past adminis-
vancomycin, sulfonamides, aminoglycosides and tration of b-lactamase antibiotics and an increase in
rifampin. Bacterial organisms with this capability b-lactamase – producing bacteria in patients with
include S. pneumoniae, S. aureus, Clostridium per- odontogenic infections. The algorithm of treatment
fringens, Bacteroides fragilis, Campylobacter spe- derived from their study is a course of b-lactamase
cies, and Neisseria gonorrhoeae. antibiotics for 1 to 2 days, but if the infection is
Alteration of microbial membrane permeability. unresolved by 3 days or more, one should assume
Alterations in membrane permeability can cause the presence of b-lactamase – producing organisms,
decreased uptake or increased efflux of the antibiotic. and treatment should involve a penicillinase-stable
The types of antibiotics most often affected by this b-lactam or a non – b-lactam antibiotic. No definitive
mechanism are the b-lactams, quinolones, tetracy- studies with large sample sizes clearly define ways to
clines, erythromycin, and the aminoglycosides. The manage antibiotic resistance in odontogenic infec-
gram-negative rods E. coli, P. aeruginosa, and Sal- tions, however.
monella typhimurium also have this capability. Porins The question of whether antibiotic resistance in
within the transmembrane protein matrix are specific patients with odontogenic infections who need hos-
for various antibiotics, and the loss of a specific porin pitalization is caused by the therapeutic modality
confers resistance. Lack of the D2 porin, for exam- given, the characteristics of the patient population,
ple, confers imipenem resistance in P. aeruginosa. or the ability to isolate and characterize more
Increased efflux of the antibiotic before lethal damage carefully the vector of disease is paramount because
occurs is seen in the Enterobacteriae with the mar, of the possibility that the increased incidence of
norA, and tetA genes, which convey resistance by antibiotic-resistant strains is an unavoidable direct
pumping tetracycline out of the cells. E. coli and effect of therapy. Retrospective studies that com-
Staphylococcus epidermidis also can resist tetracy- pared populations decades apart have shown that
clines, macrolides and quinolones by this mechanism although no clinically significant differences exist
[1,2]. between cohorts examined, there are differences
Alteration of target site. Enzymes responsible for in types of microorganisms in terms of their no-
cell wall synthesis, the transpeptidases, can be altered menclature [6,7]. Flynn et al [8] performed a
slightly to produce less affinity for penicillins. These prospective study of 34 hospitalized patients with
altered penicillin-binding proteins are most often seen odontogenic infections and found a 26% rate of
in S. aureus and S. pneumoniae [3]. clinical failure with penicillin therapy and a 60%
Alteration in the concentration of drug target rate of penicillin resistance.
receptors. Many of the gram-negative rods (ie, E. This finding is exemplified by data on treatment
coli and Proteus, Enterobacter, and Klebsiella spe- of upper respiratory tract infections. In a study of
cies) have the ability to alter the number of drug children with pharyngitis, Brook [9] found a 9%
receptors that bind antibiotics. The sulfonamide fam- incidence of penicillin resistance in throat swab
ily is affected by such a mechanism. cultures at the initiation of treatment. After 1 week
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38 19

of penicillin therapy, 46% of the subjects and 45% of antibiotics in early cases. Another factor is the
the subjects’ parents and siblings harbored resistant severity of the odontogenic infection. Flynn et al
strains. The number declined to 27% in the subjects [8] found a clinical failure rate of 26% for penicillin
over the ensuing 3 months. Several hospitals have in hospitalized cases. On the other hand, little or no
substituted the cephalosporins for penicillin/b-lacta- difference was found between the effectiveness of
mase inhibitor combinations, with or without an penicillin and various other antibiotics in outpatient
aminoglycoside, which in some cases has resulted odontogenic infections [11 – 14].
in dramatic recovery of antibiotic susceptibility rates The clinician must keep in mind the occasional
among pathogens such as Enterobacter cloacae, pathogen that is resistant to the usual empiric anti-
Klebsiella pneumoniae, P. aeruginosa, and Clos- biotic of choice. In odontogenic infections and dog
tridium difficile [1]. and cat bites, Eikenella corrodens is fairly resistant to
the penicillins and completely resistant to clindamy-
cin. The fluoroquinolones have become the antibiotic
Issues in antibiotic selection of choice for this pathogen. E. corrodens should be
considered a possible pathogen in treatment failure of
The selection of an appropriate antibiotic for a odontogenic infections and routinely in animal bite
given case can be complex, but usually it is a wounds [15]. The usual flora of various types of head
straightforward process. The factors that must be and neck infections are listed in Table 1.
considered can be categorized into host-specific and
pharmacologic factors. Allergy or intolerance

A history of antibiotic allergy is usually readily


Host factors in antibiotic selection obtained from the conscious patient or, alternatively,
from the family. Penicillin allergy is common, and
Usual pathogens macrolide (erythromycin family) intolerance and drug
interactions are frequent. The choice of clindamycin,
The type of infection that presents can be char- metronidazole, or newer antibiotics may be prudent
acterized by cause and location, and each has its when anamnestic information is unavailable.
own characteristic flora. Odontogenic infections are The penicillins are the antibiotics most frequently
generally characterized by a combination of faculta- prescribed for infections in the oral cavity. It is not
tive streptococci and oral anaerobes. Within the surprising that their use is associated with hypersen-
viridans group of facultative streptococci, the Strep- sitivity reactions. Between 1% and 10% of patients
tococcus milleri group, which consists of S. angino- who initially take penicillin develop an allergic reac-
sus, S. intermedius, and S. constellatus, is most tion, and persons who do not develop a reaction have
frequently associated with orofacial cellulitis and less than a 1% chance of developing an allergy with
abscess. This is fortunate because only approxi- reexposure [16]. It is judicious to clarify whether the
mately 3% of the strains of these species are resistant person has a true allergy to penicillin. Cross-sectional
to the penicillins. On the other hand, other members studies of penicillin allergy indicate that in many
of the viridans streptococci, such as Streptococcus hospital chartings of penicillin allergy, subsequent
mitis, Streptococcus sanguis, and Streptococcus sal- skin testing proved that more than 60% of pa-
ivarius, are more frequently found in endocarditis, tients were not allergic to either penicillin or other
and they can be highly penicillin resistant—up to b-lactams, which warrants more careful vigilance by
58% in one study [10]. doctors who are recording medical histories and
Among the anaerobes, anaerobic peptostreptococci allergies of their patients [17,18]. Fortunately, hyper-
and members of the genera Prevotella and Porphyro- sensitivity reaction to clindamycin, often substituted
monas predominate. Although the peptostreptococci in penicillin-allergic patients, is a rare event.
remain penicillin sensitive, approximately 25% of All clinicians should be aware of the potential for
strains of Prevotella and Porphyromonas are penicillin cross-allergy between the penicillins and other mem-
resistant [8]. bers of the b-lactam group. Approximately 10% to
The penicillin-sensitive streptococci predominate 15% of penicillin-allergic patients are also sensitive
during the first 3 days of clinical symptoms, and the to the cephalosporins. The cross-allergic group tends
more resistant gram-negative obligate anaerobes to include persons who have had an anaphylactoid
appear in significant numbers thereafter. This fact reaction to the penicillins. The cephalosporins should
suggests the selection of the penicillins over other be avoided in these patients.
20 T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38

Table 1
Major pathogens of head and neck infections
Type of infection Microorganisms
Odontogenic cellulitis/abscess Streptococcus milleri group
Peptostreptococci
Prevotella and Porphyromonas
Fusobacteria
Rhinosinusitis Acute Streptococcus pneumoniae
Haemophilus influenzae
Head and neck anaerobes (peptostreptococci, Prevotella,
Porphyromonas, fusobacteria)
Group A b-hemolytic streptococci
Staphylococcus aureus
Moraxella catarrhalis
Viruses
Chronic Head and neck anaerobes
Fungal Aspergillus
Rhizopus sp. (mucor)
Nosocomial Enterobacteriaceae (especially Pseudomonas,
(especially if intubated) Acinetobacter, Escherichia coli)
S. aureus
Yeasts (Candida species)
Osteomyelitis of the jaws Acute Odontogenic flora
S. aureus and skin flora in trauma
Salmonella in sickle cell disease
Chronic Actinomyces species
Necrotizing fasciitis Group A b-hemolytic streptococci
Regional flora (oral and sinus pathogens
in head and neck)
Fungal Mucosal or disseminated Candida species
Soft tissue Histoplasma species
Blastomyces species
Sinus Aspergillus
Rhizopus (mucor)

The newer b-lactam antibiotics, the monobactams lysis, or with nucleic acid synthesis, which arrests
(aztreonam) and the carbapenems (imipenem and vital processes. The bacteriostatic antibiotics interfere
meropenem), have much less frequent cross-sensitiv- with protein synthesis, arresting growth and mul-
ity with the penicillin group. A history of adverse tiplication. Some antibiotics, such as clindamycin,
reaction or intolerance of an antibiotic, such as seem to be bacteriostatic at lower doses and bacte-
phototoxicity with the tetracyclines or antibiotic- ricidal at higher doses.
associated colitis with clindamycin, would preclude HIV-infected individuals seem to be able to han-
its subsequent use unless strongly indicated. dle oral bacterial infections almost as well as non-
infected persons. This ability is probably caused by
the antibody-mediated immunity provided by the
Immune system compromise B-lymphocytes, which is largely responsible for com-
bating the extracellular bacterial pathogens of most
Because the immunocompromised patient is less head and neck infections. Resistance to these com-
able to kill invading pathogens by host resistance mon infections remains fairly robust until the terminal
mechanisms, a bactericidal rather than bacteriostatic stages of AIDS, when all types of lymphocytes are
antibiotic should be selected whenever possible. This severely depleted. On the other hand, fungal and viral
stratagem should result in a more rapid clinical infections, which are resisted by cell-mediated
response. The bactericidal antibiotics generally inter- immunity (T cells), are prevalent in poorly controlled
fere with either cell wall synthesis, which causes HIV-infected individuals.
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38 21

Table 2 They are discussed in the section on adverse anti-


Bactericidal and bacteriostatic antibiotics biotic reactions.
Bactericidal Bacteriostatic
b-lactams Macrolides
penicillins erythromycin Pharmacologic factors in antibiotic selection
cephalosporins clarithromycin
carbapenems azithromycin Antimicrobial spectrum
monobactams Clindamycin
Aminoglycosides Tetracyclines The most important pharmacologic consideration
Vancomycin Sulfa antibiotics in antibiotic selection is whether it is effective against
Metronidazole the likely pathogens. Table 3 describes the general
Fluoroquinolones
spectrum of selected antibiotics. Table 4 lists the
bacteria and fungi most likely to be encountered
and the antibiotics of choice for those pathogens.
Table 2 lists common antibiotics by their ability to The antibiotics effective against the highly resistant
kill bacteria or merely suppress their growth. organisms are also included in Table 4. Table 5 lists
the antibiotics to which selected highly resistant
organisms have become resistant. These data, among
Previous antibiotic therapy
others, are used in constructing the recommendations
for empiric antibiotics of choice for various head and
All antibiotic therapy inherently selects for re-
neck infections, and Tables 4 and 5 especially can be
sistant organisms. Studies of patients who are cur-
used in selecting an appropriate antibiotic for organ-
rently taking or recently have taken antibiotics
isms identified by culture, for which sensitivity data
consistently yield a higher incidence and proportion
may not be available.
of organisms resistant to that antibiotic [10,19]. On
the other hand, these effects persist for a consid-
Tissue distribution of antibiotics
erable time after antibiotic therapy and may be
permanent [19,20].
Although abscess cavities are not vascular, some
The previous use of different antibiotics during
penetration of antibiotics into these spaces does
the course of an acute infection definitely clouds the
occur. The antibiotic that best penetrates an abscess
bacteriologic picture. In this situation, the clinician
is clindamycin; the abscess concentration of clinda-
has the choice of changing the current antibiotic or
mycin reaches 33% of the serum level [22]. This fact
increasing its dose, perhaps by using the parenteral
may partially explain the usefulness of clindamycin
route. With penicillins V (oral) and G (intravenous),
in odontogenic infections.
peak serum blood levels are 5.6 mg/mL and 20 mg/mL,
Bone penetration of antibiotics is an important
respectively. The dramatic increase in efficacy
consideration, especially in osteomyelitis. The
afforded by the parenteral route of administration
antibiotics that best penetrate or even accumulate
may be more advantageous than changing to another
in bone are the tetracyclines, clindamycin, and
antibiotic that is less effective than the penicillins.
the fluoroquinolones.
The penicillin resistance rate of the endocarditis-
Cerebrospinal fluid penetration, or the ability of
associated viridans streptococci (S. mitis, S. sanguis,
an antibiotic to cross the blood-brain barrier, is
and S. salivarius) is high—up to 58% [21] in persons
paramount in the treatment of infections that threaten
with a history of prior endocarditis. Clindamycin
the central nervous system, as in actual or impending
resistance of these bacteria in such patients remains
cavernous sinus thrombosis. The antibiotics that can
low. In patients with a history of endocarditis, it may
attain therapeutic levels in cerebrospinal fluid when
be advisable to use clindamycin rather than amox-
the meninges are inflamed are listed in Table 6. The
icillin for endocarditis prophylaxis before oral proce-
antibiotics that do not penetrate the cerebrospinal
dures. This approach, however, has not been tested in
fluid well are clindamycin, the macrolides (including
a clinical study.
clarithromycin and azithromycin), cefazolin, and
most other cephalosporins (except those listed in
Special conditions Table 6), aminoglycosides, amphotericin, itracona-
zole, ethambutol, and saquinavir.
Certain temporary host conditions may affect Penicillin G in high doses reaches 5% to 10% of
antibiotic selection, such as childhood and pregnancy. the serum concentration in the cerebrospinal fluid
22 T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38

Table 3
Spectrum of selected antibiotics
Antibiotic category Antibiotic Susceptible organisms
Natural penicillins Penicillin G and V Viridans streptococci
Oral anaerobes
Actinomyces sp. (penicillin G only)
Pasteurella multocida
Semisynthetic penicillins Ampicillin As with natural penicillins, plus enterococci
Amoxicillin Actinomyces
b-lactam/b-lactamase inhibitors Amoxicillin/clavulanate As with amoxicillin, plus
Ampicillin/sulbactam S. aureus, not MRSA
S. epidermidis, not MRSE
H. influenzae
M. catarrhalis
Klebsiella species
E. coli
Bacteroides fragilis
Penicillinase-resistant penicillins Oxacillin S. aureus, not MRSA
Dicloxacillin S. epidermidis, not MRSE
Antipseudomonal penicillins Ticarcillin/clavulanate As with natural penicillins, plus
Piperacillin/tazobactam S. aureus, not MRSA
S. epidermidis, not MRSE
H. influenzae
M. catarrhalis
Klebsiella species
E. coli
Bacteroides fragilis
Enterobacteriaceae (most)
Pseudomonas aeruginosa
Carbapenems Imipenem As with antipseudomonal penicillins, plus
Meropenem Actinomyces (imipenem)
Ertapenem
Monobactam Aztreonam Enterobacteriaceae, except Salmonella
(no data) and Acinetobacter (resistant)
Cephalosporins First generation Streptococci
Cephalexin S. aureus, not MRSA
Cefazolin H. influenzae
Klebsiella
E. coli
Second generation As with first generation, plus
Cefaclor M. catarrhalis (cefuroxime)
Cefuroxime Oral anaerobes
Cefoxitin B. fragilis (cefoxitin)
Third generation As with first generation, plus
Cefotaxime M. catarrhalis
Ceftriaxone Oral anaerobes
Actinomyces (ceftriaxone)
Macrolides Erythromycin Streptococci
Clarithromycin Actinomyces
Azithromycin Peptostreptococci (azithromycin)
Clindamycin Clindamycin Streptococci
Oral anaerobes
Actinomyces
S. aureus, not MRSA
Metronidazole Obligate anaerobes
Fluoroquinolones Ciprofloxacin S. aureus, not MRSA
Enterobacteriaceae (most)

(continued on next page)


T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38 23

Table 3 (continued )
Antibiotic category Antibiotic Susceptible organisms
Moxifloxacin Streptococci
Oral anaerobes
S. aureus, not MRSA
Actinomyces
B. fragilis
Enterobacteriaceae (most)
Aminoglycosides Gentamicin S. aureus, not MRSA
Tobramycin Enterococci (gentamicin synergistic with ampicillin)
Enterobacteriaceae (many)
Pseudomonas
Glycopeptides Vancomycin Streptococci
Teicoplanin S. aureus, including MRSA
S. epidermidis, including MRSE (vancomycin)
Oxazolidinones Linezolid Streptococci
Staphylococci, including VISA, VRSE, MRSA, MRSE
Peptostreptococci
Enterococci, including VRE
Pristinamycins Quinupristin/dalfopristin Streptococci
Staphylococci, including VISA, VRSE, MRSA, MRSE
Legionella
Ketolides Telithromycin Streptococci
S. aureus (not MRSA?)
H. influenzae
M. catarrhalis
Legionella
Abbreviations: MRSA, methicillin-resistant S. aureus; MRSE, methicillin-resistant S. epidermidis; VISA, vancomycin-inter-
mediate S. aureus; VRSE, vancomycin-resistant S. epidermidis.

when the meninges are inflamed. In odontogenic For example, the t/2 of penicillin G is 0.5 hours.
infections that threaten the central nervous system, During each half hour, 50% of the remaining penicil-
the addition of metronidazole (30% – 100% penetra- lin is eliminated from the serum. By five half-lives, or
tion) to ampicillin (13% – 14% penetration) is more 2.5 hours, only approximately 3% of the peak serum
efficacious than using penicillin G alone [15]. level of penicillin remains. Because the MIC-90 of the
viridans streptococci (the concentration that kills 90%
Pharmacokinetics of the strains) is 0.2 mg/mL and because the peak
serum level achieved with 2 million U of intravenous
The effectiveness of some antibiotics, such as the penicillin G is 20 mg/mL, the serum concentration of
fluoroquinolones and aminoglycosides, is concentra- penicillin after 4 hours (eight half-lives) is approx-
tion dependent, whereas with other antibiotics, such imately 0.15 mg/mL. The serum level will have fallen
as the b-lactams and vancomycin, it is time depen- below the MIC-90 roughly for only the last 15% of the
dent. In concentration-dependent antibiotics, efficacy dosage interval. Intravenous penicillin G, 2 million U
is determined by the ratio of the serum concentration every 4 hours, should be highly effective against the
of the antibiotic to the minimum inhibitory concen- viridans group of streptococci.
tration (MIC), which is the concentration of the Using the same analysis, the peak blood level
antibiotic required to kill a given percentage of the achieved with amoxicillin, 500 mg orally, is 7.5 mg/mL,
strains of a particular species, usually 50% or 90%. In and its t/2 is 1.2 hours. The MIC-90 for the viridans
time-dependent antibiotics, it is necessary to maintain streptococci is 2 mg/mL for amoxicillin. Using an
the serum concentration above the MIC for at least 8-hour dosage interval, the remaining serum concen-
40% of the dosage interval. tration of amoxicillin should have fallen below the
It is necessary with time-dependent antibiotics to MIC-90 of the viridans streptococci at approximately
know the serum elimination half-life (t/2) of the 2.5 hours, which is only 31% of the dosage interval.
antibiotic to determine its proper dosage interval. Oral amoxicillin therapy may not kill 90% of all the
24 T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38

Table 4
Antibiotics of choice for head and neck pathogens
Pathogen Type First choice antibiotics Alternative antibiotics
Actinomyces +, R, A Penicillin G or ampicillin Doxycycline
Clindamycin
Erythromycin
Bacteroides fragilis  , R, AN Metronidazole Clindamycin
Cefoxitin, not cefotetan (DOT)
Ampicillin/sulbactam
Clostridium species +, R, AN Penicillin G F clindamycin Metronidazole
(except C. difficile) Doxycycline
Cephalosporin (1st)a
Clostridium difficile +, R, AN Metronidazole p.o. Vancomycin p.o.
Bacitracin p.o.
Eikenella corrodens  , R, A Penicillin G or V Fluoroquinolones
Amoxicillin TMP/SMX (avoid
Amoxicillin/clavulanate clindamycin)
Enterococcus faecalis +, C, F Ampicillin F gentamicin Vancomycin
(group D streptococcus) (for endocarditis or meningitis Ampicillin/sulbactam
Linezolid
Enterococcus faecium (group D +, C, F Linezolid + quinupristin/dalfopristin F Teicoplanin + aminoglycoside
streptococcus: b-lactamase +, choramphenicol F doxycycline (van B)
aminoglycoside and For some strains: no effective
vancomycin resistant) regimen (I.D. consultation)
Escherichia coli  , R, A Ticarcillin/clavulanate Meropenem for central nervous system
Cephalosporins Aztreonam
Imipenem TMP/SMX
Fluoroquinolones Tobramycin
Fusobacterium species  , R, AN Penicillin G or V Metronidazole
Clindamycin
Haemophilus influenzae  , R, F Amoxicillin/clavulanate Cefotaxime (if life threatening)
(b-lactamase positive) Cefaclor Ciprofloxacin
Azithro/clarithromycin TMP/SMX
Klebsiella pneumoniae  , R, A Cephalosporin (3rd)* Tobramycin
Fluoroquinolones Ticarcillin/clavulanate
Imipenem/cilastatin
Klebsiella pneumoniae  , R, A Imipenem/cilastatin Meropenem
(producing extended spectrum Fluoroquinolones
b-lactamases: ESBLs)
Pasteurella multocida  , R, A Penicillin G Doxycline
(eg, dog and cat bites) Amoxicillin/Clavulanate Cephalosporin (2nd)a
TMP/SMX
Peptostreptococcus +, C, AN Penicillin G or V Clindamycin
(and former Peptococcus) Doxycline
Vancomycin
Black pigmented oral  , R, AN Clindamycin PCN + metronidazole
anaerobes (Prevotella and Amoxicillin
Porphyromonas) Cefotetan
Proteus vulgaris (indole +)  , R, A Cephalosporin (3rd) Tobramycin
Fluoroquinolones Imipenem
Ticarcillin/clavulanate
Pseudomonas aeruginosa  , R, A Ciprofloxacin Aztreonam + ceftazidime
Tobramycin Piperacillin + tobramycin
Cefepime + tobramycin
Salmonella typhi  , R, A Fluoroquinolones Chloramphenicol
Ceftriaxone Amoxicillin
TMP/SMX
(continued on next page)
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38 25

Table 4 (continued )
Pathogen Type First choice antibiotics Alternative antibiotics
Serratia marcescens  , R, A Cephalosporin (3rd) Gentamicin
Imipenem Aztreonam
Meropenem
Fluoroquinolones
Shigella  , R, A Fluoroquinolones TMP/SMX + ampicillin
Azithromycin
Staphylococcus aureus +, C, A Penicillinase-resistant Cephalosporin (1st)a
(methicillin sensitive) penicillin Vancomycin
Clindamycin
Staphylococcus aureus +, C, A Vancomycin Teicoplanin
(methicillin resistant) Quinupristin-dalfopristin
TMP/SMX (some strains)
Linezolid
Staphylococcus aureus +, C, A No effective regimen Quinupristin/dalfopristin
(methicillin and Try vancomycin F rifampin Linezolid
vanco mycin resistant)
Staphylococcus epidermidis +, C, A Vancomycin (+ rifampin Quinupristin/dalfopristin
(methicillin resistant) + gentamicin
for prosthetic valve endocarditis)
Staphylococcus epidermidis +, C, A Quinupristin/dalfopristin Vancomycin (high dose)
(methicillin and Linezolid New fluoroquinolones?b
glycopeptide resistant) (rapid resistance a problem)
Streptococcus pneumoniae +, C, A Penicillin G or V Cefuroxime, cefipime
(Pneumococcus) Ceftriaxone Imipenem
(penicillin sensitive) Amoxicillin New fluoroquinolonesb
Streptococcus pneumoniae +, C, A Vancomycin + Rifampin Clindamycin
(Pneumococcus) (multiantibiotic New fluoroquinolones (in vitro)
resistant, including high-level
penicillin, erythromycin,
tetracycline, chloramphenicol,
and TMP/SMX)
Streptococcus pyogenes +, C, A Penicillin G or V (+ gentamicin Cephalosporin (1st)a
(b-hemolytic streptococcus) if serious group B infection) Erythromycin
Streptococcus viridans +, C, A Penicillin G or V Cephalosporin (1st)a
(a-hemolytic streptococcus) Macrolides
Fungal organisms
Blastomyces Fungus Amphotericin B Itraconazole (if surface)
(for systemic cases) Fluconazole (if surface)
Candida Fungus Fluconazole Nystatin (if surface)
Amphotericin B Clotrimazole (if surface)
(for systemic cases) Ketoconazole (if surface)
Itraconazole (if surface)
Coccidioides immitis Fungus Itraconazole Fluconazole
Amphotericin B
Histoplasma Fungus Amphotericin B (for systemic Itraconazole (immunocompetent)
or immunocompromised cases) Itraconazole (immunocompromised)
Mucormyces Fungus Amphotericin B Control underlying systemic disease
Abbreviations: A, aerobe; AN, anaerobe; C, coccus; DOT, distasonis, ovatus, and thetaiotamicron group of B. fragilis species;
F, facultative; PCN, penicillin; R, rod; TMP-SMX, trimethoprim-sulfamethoxazole.
Data from Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy 2002. 32nd edition. New Hyde
Park (VT): Antimicrobial Therapy Inc.; 2002.
+ = gram positive.
 = gram negative.
a
Number in parentheses after cephalosporins refers to generations within the cephalosporin family.
b
New fluoroquinoles are gati-, gemi-, lero-, moxi-, sparfloxacin.
26 T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38

strains of the viridans streptococci. Fortunately for oral


and maxillofacial surgeons, the Streptococcus milleri
group associated with odontogenic infections is highly
sensitive to the penicillins, whereas the endocarditis-
Table 5 associated strains are less so.
Highly resistant organisms and the antibiotics to which they The pharmacokinetics of the clinically available
are resistant antibiotics have been determined during drug devel-
Organism Resistant to opment. It is incumbent on the clinician to prescribe
Acinetobacter baumanii Penicillins antibiotics within the accepted ranges for dose
Third generation and interval.
cephalosporins Once-daily dosing for the aminoglycosides as a
Antipseudomonal means of reducing their ototoxicity and nephrotox-
aminoglycosides icity recently has been evaluated in a systematic
Fluoroquinolones review [23]. The available well-designed studies
Imipenem indicate that this practice results in a modest increase
Enterococcus faecalis Glycopeptides
in therapeutic advantage and possibly a decrease in
b-lactamase negative Streptomycin
Gentamicin
toxicity. The cost saving of once-daily intravenous
Enterococcus faecalis All b-lactams dosing makes this approach appealing. Caution is
b-lactamase positive Glycopeptides advised in patients with limited volumes of fluid
Aminoglycosides distribution, however.
Enterococcus faecium Glycopeptides
b-lactamase negative Streptomycin Adverse reactions
Gentamicin
Enterococcus faecium all b-lactams The adverse reactions and toxicities of the anti-
b-lactamase positive Glycopeptides biotics commonly used in head and neck infections
Aminoglycosides
are generally mild and uncommon. Table 7 lists the
Klebsiella pneumoniae Penicillins
ESBL positive Third generation
major serious adverse reactions of the commonly
cephalosporins used antibiotics. The clinician especially should note
Aztreonam allergic reactions to the penicillins and cephalospo-
Pseudomonas Penicillins rins, gastrointestinal intolerance of the erythromycins,
aeruginosa Cephalosporins nephrotoxicity and ototoxicity of the amino-
Carbapenems glycosides, and antibiotic-associated colitis with the
Staphylococcus Methicillin b-lactam/b-lactamase inhibitor combinations (eg,
aureus MRSA Augmentin, Unasyn), antipseudomonal penicillins
S. aureus VISA or GISA Methicillin (eg, ticarcillin, piperacillin), cephalosporins, and clin-
Vancomycin only
damycin, among others.
Vancomycin and
teicoplanin (both
available glycopeptides) Special conditions
Staphylococcus Methicillin
epidermidis MRSE Antibiotics that should be avoided in children
S. epidermidis VRMRSE Methicillin include the tetracyclines (under the age of 8), because
Glycopeptides of permanent intrinsic dental staining, and the fluo-
Streptococcus pneumoniae Penicillin G roquinolones, because of chondrotoxicity in growing
penicillin intermediate cartilage. Among the carbapenems, imipenem is not
or resistant recommended because of the risk of seizures. Mer-
S. pneumoniae Penicillins
openem is an acceptable alternative.
multi-antibiotic resistant Cephalosporins
Aztreonam
The use of antibiotics in pregnancy almost always
involves an evaluation of risk versus benefit. The
Abbreviations: ESBL, extended-spectrum b-lactamase;
antibiotics that must be avoided in pregnancy include
GISA, glycopeptide-intermediate S. aureus; MRSE, methi-
cillin-resistant S. epidermidis; VRMRSE, vancomycin- the antimycobacterial agent, thalidomide, and the
resistant methicillin-resistant S. epidermidis. antiparasitic agent, quinine, for which the risk clearly
Data from Gilbert DN, Moellering RC Jr, Sande MA. The outweighs the benefit.
Sanford guide to antimicrobial therapy. 32nd edition. Hyde Table 8 lists the pregnancy risk categories of
Park (VT): Antimicrobial Therapy, Inc.; 2002. selected antibiotics.
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38 27

Table 6 Antibiotic drug interactions


Selected antibiotics and the blood-brain barrier
Cerebrospinal fluid Antibiotic
Two important categories of antibiotic drug inter-
action are interference with the effectiveness of oral
Therapeutic Penicillins contraceptives and interference with the metabolism
levels achieved ampicillin
of drugs, which involves the cytochrome P450 sys-
nafcillin
penicillin G, high dose
tem. These and other selected antibiotic drug inter-
ticarcillina actions are listed in Table 9.
piperacillina Antibiotic interference with the effectiveness of
Cephalosporins oral contraceptive pills remains a controversial topic.
ceftazidime The only antibiotic that has been shown conclusively
cefuroxime to interfere with oral contraception is rifampin. The
ceftriaxone evidence that implicates ampicillin, amoxicillin, dap-
Carbapenem sone, trimethoprim/sulfamethoxazole, and the antivi-
meropenemb ral protease inhibitors is less strong. It is important to
Fluoroquinolones
note that antibiotics do not interfere with injectable or
levofloxacin
ciprofloxacinc
implantable contraceptives. Only oral contraceptives
Other antibiotics are affected [24].
metronidazole A possible mechanism for this interaction stems
trimethoprim/ from efforts to decrease the adverse effects, such as
sulfamethoxazoled thromboembolism and activation of uterine and
vancomycine breast carcinomas associated with older contracep-
Antifungal drugs tive formulations that contained higher estrogen
fluconazole doses. Currently, oral contraceptive preparations
flucytosine have minimally effective estrogen doses, and the
Antiviral drugs
serum level of the estrogen is supported by enter-
acyclovir
foscarnet
ohepatic recirculation. In this process, the liver
ganciclovir conjugates absorbed estrogen with glucuronide, and
zidovudine the estrogen-glucuronide complex is excreted in the
Therapeutic levels Cephalosporins bile. In turn, the gut flora breaks the estrogen-
not achieved cefazolin glucuronide bond, which allows the pure estrogen
cephalexin molecule to be reabsorbed by the gut, thus support-
Aminoglycosides ing the serum estrogen level. If an antibiotic kills
Macrolides enough of the gut flora, then the conjugated estrogen
erythromycin is not broken down, and the estrogen-glucuronide
clarithromycin
complex stays in the intestine until it is excreted.
azithromycin
Clindamycin
The serum estrogen level falls, which results in
Antifungal drugs breakthrough menstrual bleeding or ovulation and
amphotericin unwanted pregnancy.
itraconazole The cytochrome P450 system is a complex set
Antiviral drugs of drug-metabolizing enzymes that is responsible for
saquinavir the breakdown of many classes of drugs. Enzymes
zidovudine within this system include CYP3A4, CYP2C19, and
Data from Gilbert DN, Moellering RC Jr, Sande MA. The CYP2D6. Drugs that share this metabolic pathway
Sanford guide to antimicrobial therapy. 32nd edition. Hyde may interact. The metabolism of one or the other
Park (VT): Antimicrobial Therapy, Inc.; 2002. may be either increased or decreased as a result.
a
Levels effective for P. aeruginosa and coliforms may The adverse affect is usually caused by an increased
not be reached.
b effect of the drug whose metabolism is inhibited,
Imipenem is avoided in meningitis because of seizure
but in some of the most serious cases, life-threat-
potential. Meropenem is preferred.
c
Does not reach adequate cerebrospinal fluid levels ening or fatal cardiac dysrhythmias, such as ven-
for streptococci. tricular fibrillation and torsade des pointes, have
d
Not adequately effective against Neisseria species occurred. The most significant interactions invol-
and coliforms. ving the cytochrome P450 system are included in
e
High doses are needed for resistant streptococci. Table 9.
28
Table 7

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38
Major adverse reactions of selected antibiotics
Ampicillin,
Penicillin G amoxicillin F Ticarcillin F Gentamicin, Cephalexin,
Adverse reactions and V clavulanate clavulanate Impenem Meropenem tobramycin cefazolin Cefuroxime Cefoxitin Cefotaxime Cefaclor
Local, phlebitis +
Hypersensitivity
Rash + + + + +
Photosensitivity
Anaphylaxis +
Serum sickness +
Anemia +
Nausea, vomiting
Diarrhea +
Antibiotic-associated colitis (AAC) +
Renal: z BUN, creatinine +
Headache
Seizures +
Hypotension
Ototoxicity +
Vestibular dysfunction +
Alcohol interaction
‘‘Red man’’ flushing
Drug interactions +
Pregnancy risk C or D +
Data from Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy. 32nd edition. Hyde Park (VT): Antimicrobial Therapy, Inc.; 2002.
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38
Table 7 (continued )
Clarithromycin, Tetracycline,
Erythromycin azithromycin Clindamycin Metronidazole Ciprofloxacin Moxifloxacin Vancomycin doxycycline Linezolid Telithromycin
Local, phlebitis +
Hypersensitivity +
Rash
Photosensitivity +
Anaphylaxis
Serum sickness
Anemia +
Nausea, vomiting + + + +
Diarrhea + +
AAC + +
Renal: z BUN, creatinine
Headache +
Seizures
Hypotension +
Ototoxicity
Vestibular dysfunction
Alcohol interaction +
‘‘Red man’’ flushing +
Drug interactions + + + + + +
Pregnancy risk C or D + + + + +

29
30 T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38

Table 8
Pregnancy risk categories of selected antibiotics
Antibiotic Pregnancy risk category Pregnancy risk
Penicillins
penicillin G and V B
ampicillin B
amoxicillin B
amoxicillin/clavulanate B
ticarcillin/clavulanate B
Cephalosporins
cephalexin B
cefazolin B
cefaclor B
cefuroxime B
cefoxitin B
cefotaxime B
Carbapenems
imipenem C Spontaneous abortions in monkeys
meropenem B
Macrolides
erythromycin B
clarithromycin C Fetal defects in mice and monkeys
azithromycin B
Antianaerobic
clindamycin B
metronidazole B
Fluoroquinolones
ciprofloxacin C Spontaneous abortions in rabbits
moxifloxacin C Fetal toxicity in rodents and monkeys
Aminoglycosides
gentamicin D Ototoxicity in human fetuses
tobramycin D Ototoxicity in human fetuses
Other
vancomycin C Potential ototoxicity in human fetuses
tetracyclines D Intrinsic dental staining
doxycycline D Intrinsic dental staining
linezolid C Fetal toxicity in rodents
telithromycin B
Data from Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy. 32nd edition. Hyde Park (VT):
Antimicrobial Therapy, Inc.; 2002.
A = Studies in pregnancy; no risk.
B = Animal studies no risk, but human studies inadequate or animal toxicity, but human studies no risk.
C = Animal studies show toxicity, and human studies inadequate, but benefit of use may outweigh risk.
D = Evidence of human risk, but benefits may outweigh risk.
X = Risk outweighs benefit.

Cost cially by the intravenous route. Table 10 compares the


retail cost of a 1-week prescription of the antibiotics
Although clinical effectiveness and reduction of listed. The penicillin V cost ratio is calculated by
the morbidity of infection and treatment are of para- dividing the retail cost of the standard 1-week pre-
mount concern in the management of head and neck scription for the given antibiotic by that of penicillin V.
infections, cost is a factor that should be considered Table 11 compares the cost of intravenous anti-
when other factors do not predominate. The costs of biotics. The cost of administration assumes great
oral antibiotic therapy can be compared based on the importance. Each dose requires sterile intravenous ad-
cost for a standard prescription for the antibiotics of ministration supplies, professional labor, and hospital
interest, because there is no additional cost of admin- sterile processing and drug error prevention systems.In
istration, as there is with parenteral antibiotics, espe- Table 11, these costs are conservatively estimated at
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38 31

Table 9
Selected antibiotic interactions with other drugsa,b
Antibiotic Second drug Adverse effects Mechanism
Erythromycin, clarithromycin, Theophylline Seizures, dysrhythmias Antibiotic inhibits
ketoconazole, itraconazole cytochrome P450
metabolism of second
drug; ketoconazole
not implicated
Erythromycin, clarithromycin, Cisapride Dysrythmias (torsades) Antibiotic inhibits
ketoconazole, itraconazole cytochrome P450
metabolism of
second drug
Erythromycin, clarithromycin, Alfentanil z Respiratory depression Antibiotic inhibits
ketoconazole, itraconazole cytochrome P450
metabolism of second
drug; ketoconazole
not implicated
Erythromycin, clarithromycin, Bromocriptine z CNS effects, hypotension Antibiotic inhibits
ketoconazole, itraconazole cytochrome P450
metabolism of
second drug
Erythromycin, clarithromycin, Carbamazepine Ataxia, vertigo, drowsiness Antibiotic inhibits
ketoconazole, itraconazole cytochrome P450
metabolism of
second drug
Erythromycin, clarithromycin, Cyclosporine z Immunosuppression Antibiotic inhibits
ketoconazole, itraconazole and nephrotoxicity cytochrome P450
metabolism of
second drug
Erythromycin, clarithromycin, Felodipine, possibly other Hypotension, tachycardia, Antibiotic inhibits
ketoconazole, itraconazole calcium channel blockers edema cytochrome P450
metabolism of
second drug
Erythromycin, clarithromycin, Methylprednisolone, z Immunosuppression Antibiotic inhibits
ketoconazole, itraconazole prednisone cytochrome P450
metabolism of
second drug
Erythromycin, clarithromycin, Lovastatin, possibly Muscle pain, rhabdomyolysis Antibiotic inhibits
ketoconazole, itraconazole other -statins cytochrome P450
metabolism of
second drug
Erythromycin, clarithromycin, Triazolam, oral midazolam z Sedative depth and duration Antibiotic inhibits
ketoconazole, itraconazole cytochrome P450
metabolism of
second drug
Erythromycin, clarithromycin, Disopyramide Dysrhythmias Antibiotic inhibits
ketoconazole, itraconazole cytochrome P450
metabolism of
second drug
Erythromycin Clindamycin # Antibiotic effect Mutual antagonism
Erythromycin, tetracyclines Digoxin Digitalis toxicity, Antibiotic kills
dysrhythmias, visual Eubacterium lentum,
disturbances, which metabolizes
hypersalivation digoxin in the gut
Erythromycin, clarithromycin, Warfarin z Anticoagulation Antibiotic interferes
metronidazole Anisindione with metabolism of
the second drug

(continued on next page)


32 T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38

Table 9 (continued )
Antibiotic Second drug Adverse effects Mechanism
Tetracycline, cefamandole, Warfarin, anisindione z Anticoagulation Antibiotic kills gut
cefotetan, cefoperazone, flora that synthesize
sulfonamides, aminoglycosides vitamin K, which
antagonizes the second
drug; poor vitamin K
intake a factor
Metronidazole, cephalosporins Alcohol, ritonavir Flushing, headache, Antibiotic inhibits
palpitations, nausea acetaldehyde
dehydrogenase,
causing accumulation
of acetaldehyde;
ritonavir preparations
contain alcohol
Metronidazole Disulfiram Acute toxic psychosis
Metronidazole, tetracyclines Lithium Lithium toxicity: confusion, Antibiotic inhibits
ataxia, kidney damage lithium excretion by
kidney; tetracycline
interaction not well
established
Tetracyclines, fluoroquinolones Divalent and trivalent cations # Absorption of antibiotic Second drug interferes
(dairy, antacids, vitamins) with absorption of
didanosine antibiotic; didanosine
is formulated with
calcium carbonate and
magnesium hydroxide
buffers
Clindamycin, aminoglycosides, Neuromuscular blocking z Depth and duration Additive effect caused
tetracyclines, bacitracin agents of paralysis by inherent minor
neuromuscular
blocking effect of the
antibiotic; seen with
clindamycin in the
presence of low
pseudocholinesterase
levels and abnormal
liver function tests
Clindamycin Erythromycin # Antibiotic effect Mutual antagonism
Penicillins, cephalosporins, Estrogen- and progestin- Contraceptive failure Interference with
metronidazole, erythromycin, containing oral contraceptives enterohepatic
clarithromycin, tetracyclines, recirculation of
rifampin estrogen caused by
killing of gut flora;
rifampin is the only
antibiotic in which
this has been
clinically proven
Ampicillin, amoxicillin Allopurinol Rash Unknown, possibly
caused by hyperuricemia
in patients taking
allopurinol
Cephalosporins Aminoglycosides z Nephrotoxicity Additive or
potentiating effect
Trimethoprim/sulfamethoxazole Thiazide diuretics Purpura, bleeding in Thrombocytopenia
elderly patients
Vancomycin Aminoglycosides z Renal toxicity Additive effect
(continued on next page)
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38 33

Table 9 (continued )
Antibiotic Second drug Adverse effects Mechanism
Fluoroquinolones, sulfonamides, Oral hypoglycemic agents Hypoglycemia Antibiotic displaces
chloramphenicol, fluconazole, second drug from
itraconazole plasma proteins
Ciprofloxacin, sulfonamides, Phenytoin z Serum level of phenytoin, Interference with
chloramphenicol, fluconazole, confusion, delirium phenytoin metabolism
ketoconazole, itraconazole
Sulfonamides Methotrexate z Methotrexate concentration Antibiotic displaces
methotrexate
from plasma proteins
Protease inhibitors (ritonavir, Hydrocodone, fentanyl, z Levels of second drug, Serious interaction:
amprenavir, saquinavir, alfentanil, amiodarone, with possible toxic effects avoid using the drugs
nelfinavir, indinavir, lidocaine, anticonvulsants, in bold print
and others) loratidine, Ritonavir has high
Benzodiazepines affinity for various
b-blockers isoenzymes in the
Calcium channel blockers cytochrome P450 system
Cisapride and has the most frequent
Corticosteroids and severe drug
-statin type interactions among the
antihyperlipidemics protease inhibitors
Warfarin Warfarin reaction is
only with ritonavir
Protease inhibitors Codeine, morphine, # Levels of second drug Antibiotic enhances
contraceptives cytochrome P450
metabolism of
second drug
Delavirdine (Rescriptor) Cisapride, clarithromycin, z Levels of second drug, Antibiotic inhibits
protease inhibitors, warfarin with possible toxic effects cytochrome P450
metabolism of
second drug
Didanosine (ddl, Videx) Metronidazole z Risk of peripheral Additive effect
neuropathy
Foscarnet (Foscavir) Ciprofloxacin z Risk of seizures Additive effect
From Flynn TR. Update on the antibiotic therapy of oral and maxillofacial infections. In: Piecuch JF, editor. Oral and
maxillofacial surgery knowledge update 2001. Rosemont (IL): American Association of Oral and Maxillofacial Surgeons, 2001;
with permission.
a
Interactions among the various anti-HIV antibiotics are frequent and complex. The reader is referred to appropriate sources
on the subject.
b
This list of antibiotic-drug interactions is only partial and selected according to the interests of oral and maxillofacial
surgeons. Drug prescribers remain responsible to ascertain the complete drug interactions of any medications they may prescribe.

$4.00 per dose. Even this small additional cost can in an infection that threatens the brain, for example,
make an infrequently administered but more expensive because clindamycin does not cross the blood-brain
antibiotic more economical than a cheaper, more fre- barrier and penicillin does so only to a limited extent.
quently dosed antibiotic. An example of this effect can Metronidazole crosses the blood-brain barrier well.
be found by comparing the cost ratio of penicillin G
(analogous to the penicillin V cost ratio) with cefazolin.
Table 11 also illustrates the markedly increased New antibiotics of interest to oral and
cost of combined antibiotic therapy as compared to maxillofacial surgeons
monotherapy. For example, 1 week’s intravenous
therapy of penicillin G plus metronidazole costs New fluoroquinolones
$690, whereas 1 week’s treatment with clindamycin
costs only $375, a reduction of 46%. On the other Moxifloxacin (Avelox) and gemifloxacin are
hand, the combination approach may be advantageous two new fluoroquinolones whose spectrum includes
34 T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38

Table 10
Oral antibiotic costs
Usual dose Usual interval Pharmacy Cost for Retail cost for Penicillin
Antibiotic (mg) (h) Cost ’01 * * 24 hours 1 weekd cost ratioc
Penicillins
Penicillin V 500 6 $0.14 $0.56 $9.99 1.00
Amoxicillin 500 8 $0.31 $0.93 $13.89 1.39
Augmentina 500 8 $3.65 $10.95 $104.99 10.51
Augmentin 875 12 $4.76 $9.52 $97.59 9.77
Dicloxacillin 500 6 $0.66 $2.64 $26.69 2.67
Cephalosporins (generation)
Cephalexin caps (1st) 500 6 $1.07 $4.28 $24.89 2.49
Keftabs (1st)b 500 6 $3.11 $12.44 $104.99 10.51
Cephradine (1st) 500 6 $0.52 $2.08 $70.59 7.07
Cefuroxime (2nd) 500 8 $7.43 $22.29 $199.99 20.02
Cefaclor (2nd) 500 8 $4.00 $12.00 $77.59 7.77
Erythromycins
Erythromycin base 500 6 $0.36 $1.44 $13.89 1.39
Erythromycin stearate 333 6 $0.36 $1.44 $16.29 1.63
Erythromycin estolate 250 6 $0.31 $1.24 $13.49 1.35
Dirythromycin (Dynabec) 500 24 $12.39 $12.39 $63.99 6.41
Clarithromycin (Biaxin) 500 12 $3.57 $7.14 $71.99 7.21
Azithromycin (Zithromax) 250 24 $6.75 $6.75 $60.59 6.07
Anti-anaerobic
Clindamycin (generic) 150 6 $0.98 $3.92 $31.29 3.13
Clindamycin (2 T generic) 300 6 $1.96 $7.84 $54.86 5.49
Clindamycin (Cleocin) 300 6 $4.22 $16.88 $118.27 11.84
Metronidazole (250 mg = $0.08) 500 6 $0.72 $2.88 $10.02 1.00
Other
Trimethoprim/sulfamethoprim 160/800 12 $0.15 $0.30 $11.69 1.17
Ciprofloxacin 500 12 $4.15 $8.30 $80.59 8.07
Doxycycline 100 12 $0.08 $0.16 $9.99 1.00
Vancomycin 125 6 $5.38 $21.52 $187.99 18.82
Usual doses and intervals are for moderate infections, and are not to be considered prescriptive.
From Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy 2001. 31st edition. Hyde Park (VT):
Antimicrobial Therapy, Inc; 2001.
a
Augmentin = amoxicillin plus clavulanic acid.
b
Keftab = cephalexin hydrocloride in tablet form (Dista).
c
Penicillin cost ratio = retail cost of antibiotic for 1 week retail cost of penicillin V for 1 week.
d
Retail cost/1 week = retail price charged for a 1-week prescription at a large pharmacy chain in the Boston region. Courtesy
of Chris Gonzalez, RPh.

the viridans streptococci, oral anaerobes, and acti- gram-positive pathogens but not against the gram-
nomyces. They are also effective against sinus negative oral anaerobes. Its effectiveness against
pathogens, staphylococci, Enterobacteriaceae, and methicillin- and vancomycin-resistant staphylococci
B. fragilis. Their broad spectrum is a relative dis- and enterococci indicates that it should be reserved
advantage when the target is a fairly small range of for these highly resistant organisms [25].
bacteria. These new fluoroquinolones probably
should be reserved for situations in which a narrower Ketolides
spectrum alternative antibiotic is not available.
Telithromycin (Ketek) is the first representative of
Oxazolidinones this new class, which is related to the macrolides. Its
spectrum includes the pathogens against which the
Linezolid (Zyvox) is the prototype of this new macrolides have been historically effective, including
class of antibiotics. It is effective against virtually all S. pneumoniae, mycoplasma, H. influenzae, Chlamy-
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38 35

Table 11
Intravenous antibiotic costs
Usual Usual interval Pharmacy Pharmacy Total cost Total cost Penicillin G
Antibiotic doseb (hour)b cost ’00 cost ’01 24 hours for 7 days cost ratioa
Penicillins
Penicillin G 2 mu 6 $1.33 $1.32 $21.28 $148.96 1.00
Ampicillin 1g 6 $1.64 $1.31 $21.24 $148.68 1.00
Unasyn 2g 6 $10.18 $14.45 $73.80 $516.60 3.47
Oxacillin 1g 6 $2.68 $5.14 $36.56 $255.92 1.72
Ticarcillin 3g 4 $12.92 $13.43 $104.58 $732.06 4.91
Timentin 3.1 g 4 $15.40 $15.20 $115.20 $806.40 5.41
Cephalosporins (generation)
Cefazolin (1st) 1g 8 $1.74 $1.90 $17.70 $123.90 0.83
Cefotetan (2nd) 1g 12 $11.58 $11.60 $31.20 $218.40 1.47
Cefuroxime (2nd) 1.5 g 8 $13.93 $13.80 $53.40 $373.80 2.51
Cefotaxime (3rd) 2g 8 $21.16 $26.38 $91.14 $637.98 4.28
Ceftazidime (3rd) 2g 8 $28.45 $28.45 $97.35 $681.45 4.57
Ceftriaxone (3rd) 1g 24 $42.00 $40.18 $44.18 $309.26 2.08
Monobactam
Aztreonam 1g 8 $16.97 $16.97 $62.91 $440.37 2.96
Carbapenem
Imipenem-cilastatin 0.5 g 6 $30.32 $30.32 $137.28 $960.96 6.45
Penicillin allergy
Erythromycinc 1g 6 $22.16 $23.00 $108.00 $756.00 5.08
Azithromycin 0.5 g 24 $23.70 $24.44 $28.44 $199.08 1.34
Vancomycin 0.5 g 6 $7.80 $8.28 $49.12 $343.84 2.31
Vancomycin 1.0 g 12 $15.60 $16.56 $41.12 $287.84 1.93
Anti-anaerobic
Clindamycin 0.9 g 8 $13.88 $13.88 $53.64 $375.48 2.52
Metronidazole 0.5 g 6 $19.03 $15.34 $77.36 $541.52 3.64
Other
Doxycycline 0.1 g 12 $21.07 $4.16 $16.32 $114.24 0.77
Trimethoprim-sulfa 800 mg 6 $16.42 $16.42 $81.68 $571.76 3.84
Ciprofloxacind 400 mg 12 $30.00 $30.00 $68.00 $476.00 3.20
Total cost of therapy includes $1.00 for infusion materials and $3.00 labor cost, per dose.
From Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy 2001. 31st edition. Hyde Park (VT):
Antimicrobial Therapy, Inc; 2001.
a
Penicillin cost ratio = 24-hour cost of antibiotic/24-hour cost of penicillin G.
b
Usual doses and intervals are for moderate infections and are not to be considered prescriptive.
c
Only the brand name price is listed in the reference. Price is selected from the lowest available average whole-
sale price.
d
Cipro IV is for NPO patients only because of excellent oral absorption.

dia pneumoniae, and Legionella pneumophila. Its Empiric antibiotics of choice for head and
most frequent use probably is in respiratory tract neck infections
infections, especially pneumonia [26,27].
Odontogenic infections
Pristinamycins
Empiric antibiotics are administered before cul-
Quinupristin/dalfopristin (Synercid), a combina- ture and sensitivity test results are available; specific
tion of two pristinamycin antibiotics, is especially antibiotic therapy is selected based on culture and
effective against vancomycin-resistant staphylococci. sensitivity results. Table 12 lists the empiric anti-
Its use generally has been reserved for infections biotics of choice for selected types of head and neck
caused by these organisms. infections, including odontogenic infections.
36 T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38

In a prospective case series of 34 cases of odonto- two weeks [15]. On the other hand, a recent system-
genic infection, Flynn et al reported therapeutic atic literature review indicates that penicillin or
failure of penicillin in 26% of cases using the amoxicillin alone is as effective as the other broader
following criteria for failure: allergic or toxic reaction spectrum and more expensive antibiotics [29].
(no cases); failure of swelling, temperature, and white In chronic rhinosinusitis, the flora becomes more
blood cell count to decline after at least 48 hours of anaerobic, including B. fragilis and the peptostrep-
intravenous penicillin; and a postoperative CT scan tococci, such as Fusobacterium, Prevotella, and
that demonstrated adequate surgical drainage. If in- Porphyromonas. Antibiotics alone are not usually
adequate drainage was found on the postoperative CT effective in these cases, and corrective surgery, usually
scan, surgery was repeated. All of the patients with with otorhinolaryngology consultation, is indicated.
therapeutic penicillin failure (8 of 31 cases initially Fungal infection of the sinuses should be sus-
treated with penicillin) subsequently yielded at least pected and treated urgently with antibiotics and
one penicillin-resistant strain when culture and sen- surgery in patients with acute rhinosinusitis who have
sitivity test results became available. This finding diabetes mellitus with acute ketoacidosis, neutro-
suggests a correlation between infection severity penia, or previous treatment with deferoxamine.
and penicillin resistance and is the basis for the Amphotericin B and surgery are indicated, along with
recommendation of clindamycin as the empiric anti- discontinuation of deferoxamine, if applicable. Defer-
biotic of choice in odontogenic infections serious oxamine (Desferal) is an iron-chelating agent used in
enough to require hospitalization [8]. Alzheimer’s disease. Mucormycosis has been found
On the other hand, penicillin resistance has not yet in patients who are undergoing simultaneous defero-
been shown to be a significant problem in outpatient xamine treatment and hemodialysis.
odontogenic infections [11 – 14]. Penicillin V remains
the empiric antibiotic of choice for outpatient odon- Osteomyelitis of the jaw
togenic infections. Because of their ineffectiveness
against the oral anaerobes, the macrolides are no The microbiology of osteomyelitis of the jaws has
longer considered among the empiric antibiotics not been reported specifically in a large case series. It
of choice for odontogenic infections. Because the is increasingly apparent from case reports, however,
oral anaerobic gram-negative rods are fairly resist- that the usual odontogenic pathogens are the most
ant to most cephalosporins, especially those in the frequent cause. One also may suspect skin and soil
first generation, the cephalosporins remain second- pathogens in traumatic osteomyelitis and salmonella
line choices. in sickle-cell osteomyelitis. Actinomyces are another
prominent pathogen in chronic osteomyelitis, and
Sinus infections culture and microscopic examination may be required
to identify this organism. Molecular methods ulti-
Acute rhinosinusitis of odontogenic origin is char- mately may become the most rapid and reliable
acterized by the same flora as other odontogenic method for identifying Actinomyces [30]. Long
infections, except that not all of the species found courses of the antibiotics effective against the Actino-
in the periapical infection survive in the sinus loca- myces are required (see Table 4). Oral penicillins plus
tion [28]. Non-odontogenic acute rhinosinusitis is probenecid can be used for long-term outpatient
frequently caused by S. pneumoniae, H. influenzae, therapy. Probenecid inhibits the renal excretion of
Moraxella catarrhalis, and streptococci. S. aureus is penicillin and increases the blood level obtained by
found in only approximately 4% of cases of acute the oral route.
rhinosinusitis [15].
Antibiotic treatment should be reserved for Fungal infections
patients who already have been treated for 7 days
with only decongestants and analgesics and who have Various fungi cause a wide spectrum of infectious
maxillary or facial pain or purulent nasal discharge. manifestations in the head and neck. An excellent
Patients with severe pain or fever may need antibiotic review of the topic can be found in a recent chapter by
therapy sooner, and hospitalization may be required Bergman [30]. The major fungal infections of concern
in these cases. If antibiotics have been used in to oral and maxillofacial surgeons are histoplasmosis
the previous month or if the local incidence of and blastomycosis, which may cause granulomatous
penicillin-resistant S. pneumoniae is more than oral lesions; aspergillosis and mucormycosis, which
30%, amoxicillin and clavulanic acid or a second- tend to cause sinusitis; and candidiasis, which causes
or third-generation cephalosporin is prescribed for surface lesions in non-immunocompromised patients
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38 37

Table 12
Empiric antibiotics of choice for head and neck infections
Type of infection Empiric antibiotic of choice
Odontogenic infections
Outpatient Penicillin
Clindamycin
Cephalexin (or other first-generation cephalosporin)
Penicillin allergy Clindamycin
Cephalexin (only if nonanaphylactoid penicillin reaction)
Inpatient Clindamycin
Ampicillin + metronidazole
Ampicillin + sulbactam
Penicillin allergy Clindamycin
Moxifloxacin
Cefotaxime (only if nonanaphylactoid penicillin reaction)
Rhinosinusitis
Acute Amoxicillin
Amoxicillin/clavulanate
Cefuroxime
Moxifloxacin (over 18 years of age)
Penicillin allergy Clarithromycin or azithromycin
Telithromycin
Moxifloxacin (over 18 years of age)
Chronic Antibiotics not effective:
otolaryngologic consultation
Intubated Imipenem or meropenem
Ticarcillin or piperacillin
Ceftazidime + vancomycin
Cefepime
Fungal Amphotericin B
Osteomyelitis of Clindamycin
the jaw
Ampicillin + metronidazole
Ampicillin + sulbactam
Penicillin allergy Clindamycin
Moxifloxacin
Histoplasmosis and Itraconazole
blastomycosis
Fluconazole
Amphotericin B
(systemic or disseminated)
Candidiasis
Oral, non-AIDS Fluconazole or itraconazole
Nystatin or clotrimazole
Oral, AIDS Fluconazole or itraconazole
Amphotericin B
Data from Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy. 32nd edition. Hyde Park (VT):
Antimicrobial Therapy Inc.;2002.

and may cause disseminated and invasive disease in infections are treated with the azole-type antifungal
immunocompromised persons. Histoplasmosis, blas- agents for less severe cases and amphotericin B for
tomycosis, and mucormycosis are diagnosed by sur- disseminated and severe disease. In surface candidia-
gical sampling for culture, histologic examination sis in a patient with a healthy immune system,
with special stains, and use of molecular methods, clotrimazole is a better-tasting yet economical alter-
such as polymerase chain reaction. In general, fungal native to nystatin.
38 T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38

Summary spective double-blind evaluation of penicillin versus


clindamycin in the treatment of odontogenic infections.
Antibiotic selection remains as much of an art as it J Oral Maxillofac Surg 1988;46:1065 – 70.
[13] Lewis MA, Carmichael F, MacFarlane TW, Milligan
is a science. It requires the integration of many factors
SG. A randomised trial of co-amoxiclav (Augmentin)
that are host specific, pharmacologic, and even geo-
versus penicillin V in the treatment of acute dentoal-
graphic. Much more research is necessary in this field veolar abscess. Br Dent J 1993;175:169 – 74.
to solve the current problems with the need for more [14] Paterson SA, Curzon ME. The effect of amoxycillin
timely culture and sensitivity results, increasing anti- versus penicillin V in the treatment of acutely ab-
biotic resistance, and best practices in antibiotic usage. scessed primary teeth. Br Dent J 1993;174:443 – 9.
[15] Gilbert DN, Moellering Jr RC, Sande MA. The San-
ford guide to antimicrobial therapy, 32nd edition. Hyde
Park (VT): Antimicrobial Therapy Inc.; 2000.
References [16] Craig TJ, Mende C. Common allergic and allergic-like
reactions to mediations: when the cure becomes the
[1] Flynn TR. Update on the antibiotic therapy of oral and curse. Postgrad Med 1999;105:173 – 81.
maxillofacial infections. In: Piecuch JF, editor. Oral [17] Bowrey DJ, Morris-Stiff GJ. Drug allergy: fact or fic-
and maxillofacial surgery knowledge update 2001. tion? Int J Clin Pract 1998;52:20 – 1.
Rosemont (IL): American Association of Oral and [18] Warrington RJ, Lee KR, McPhillips S. The value of
Maxillofacial Surgeons; 2001. p. 23 – 50. testing for penicillin allergy in an inpatient population:
[2] Molinari JA. Antibiotic resistance and maxillofacial analysis of the subsequent patient management. Al-
pathogens: emerging treatment issues. J California lergy Asthma Proc 2000;21:297 – 9.
Dental Assoc 1999;27:386 – 92. [19] DeFonseca MA. Adverse reaction to amoxicillin:
[3] Neu HC. Emerging trends in antimicrobial resistance a case report. Pediatr Dent 2000;22:401 – 4.
in surgical infections: a review. Eur J Surg Suppl 1994; [20] Ebersole JL, Cappelli D. Acute-phase reactants in in-
573:7 – 18. fections and inflammatory diseases. Periodontology
[4] Kulekei G, Inane D, Kocak H, et al. Bacteriology of 2000;23:19 – 49.
dentoalveolar abscesses in patients who have received [21] Bancescu G, Skaug N, Dumitriu S, et al. Antimicrobial
empirical antibiotic therapy. Clin Infect Dis Suppl susceptibility of some streptococci strains of anginosus
1996;1:S51 – 3. group isolated from oral and maxillofacial infections.
[5] Kuriyama T, Nakagawa K, Karasawa T, et al. Past Roum Arch Microbiol Immunol 1999;58:57 – 63.
administration of b-lactam antibiotics and increase in [22] Kasten MJ. Clindamycin, metronidazole, and chloram-
the emergence of b-lactamase-producing bacteria in phenicol. Mayo Clin Proc 1999;74:825 – 33.
patients with orofacial odontogenic infections. Oral [23] Fisman DN, Kaye KM. Once-daily dosing of amino-
Surg Oral Med Oral Pathol Oral Radiol Endod glycoside antibiotics. Infect Dis Clin North Am
2000;89:186 – 92. 2001;14:475 – 87.
[6] Haug RH, Hoffman MJ, Indresano AT. An epidemio- [24] Hersh EV. Adverse drug interactions in dental practice:
logic and anatomic survey of odontogenic infections. interactions involving antibiotics. Part II. J Am Dent
J Oral Maxillofac Surg 1991;49:976 – 80. Assoc 1999;130:236 – 51.
[7] Storoe W, Haug RH, Lillich TT. The changing face of [25] Marchese A, Schito GC. The oxazolidinones as a new
odontogenic infections. J Oral Maxillofac Surg 2001; family of antimicrobial agent. Clin Microbiol Infect
59:739 – 48. 2001;7(Suppl 4):66 – 74.
[8] Flynn TR, Wiltz M, Adamo AK, et al. Predicting [26] Felmingham D. Microbiological profile of telithromy-
length of hospital stay and penicillin failure in severe cin, the first ketolide antimicrobial. Clin Microbiol In-
odontogenic infections. Int J Oral Maxillofac Surg fect 2001;7(Suppl 3):2 – 10.
1999;28(Suppl 1):48. [27] Linden PK. Treatment options for vancomycin-resist-
[9] Brook I. Microbiology of common infections in the ant enterococcal infections. Drugs 2002;62:425 – 41.
upper respiratory tract. Prim Care 1998;25:637 – 47. [28] Brook I, Frazier EH, Gher Jr ME. Microbiology of
[10] Doern GV, Ferraro MJ, Brueggemann AB, Ruoff periapical abscesses and associated maxillary sinusitis.
KL. Emergence of high rates of antimicrobial resist- J Periodontol 1996;67:608 – 10.
ance among viridans group streptococci in the [29] Williams Jr JW, Aguilar C, Makela M, et al. Antibi-
United States. Antimicrob Agents Chemother 1996; otics for acute maxillary sinusitis. Cochrane Library
40:891 – 4. 2000;3:1 – 51.
[11] Fazakerley MW, McGowan P, Hardy P, Martin MV. [30] Bergman SA. Fungal, viral, and protozoal infections
A comparative study of cephradine, amoxycillin of the maxillofacial region. In: Topazian RG, Goldberg
and phenoxymethylpenicillin in the treatment of acute MH, Hupp JR, editors. Oral and maxillofacial infec-
dentoalveolar infection. Br Dent J 1993;174:359 – 63. tions. 4th edition. Philadelphia: W.B. Saunders Co.;
[12] Gilmore WC, Jacobus NV, Gorbach SL, et al. A pro- 2002. p. 243 – 78.
Oral Maxillofacial Surg Clin N Am 15 (2003) 39 – 49

Diagnostic imaging of maxillofacial infections


Thomas E. Underhill, DDS, MDa,*, Fred J. Laine, MDa,b, John George, BSc
a
Department of Radiology, Division of Neuroradiology, VCU Health Systems/MCV Hospitals and Physicians,
1250 East Marshall Street, PO 980615, Richmond, VA 23298, USA
b
Department of Otolaryngology, VCU Health Systems/MCV Hospitals and Physicians, 1250 East Marshall Street,
PO 980615, Richmond, VA 23298, USA
c
Medical Student, 8377 NW 57th Drive, Coral Springs, FL 33067, USA

Diagnosis and management of head and neck compromise [5], cavernous sinus thrombosis [4,6],
infections are common clinical challenges for the oral cerebral empyema [4,7], internal jugular vein throm-
and maxillofacial surgeon. Symptoms, signs, and bophlebitis [8], Ludwig’s angina [9], or necrotizing
laboratory data are often suggestive of an infectious fasciitis [10 – 12], can occur.
or inflammatory process. Given the right clinical This article discusses mainly CT and MRI as they
conditions, however, several noninfectious conditions relate to localization of infectious processes and the
can mimic these processes. Based on clinical exam- evaluation of abscess cavities.
ination and occasionally laboratory data, the exam-
ining surgeon must determine the need for advanced
imaging studies. Techniques
Opinions still vary as to whether computed tomog-
raphy (CT) or magnetic resonance imaging (MRI) is Computed tomography
the best imaging modality for acute neck infections
[1 – 4]. When imaging is needed, it is the authors’ Traditional or single slice acquisition CT uses a
opinion that the least invasive and least expensive gantry that houses an x-ray tube and a row of
examination that adequately evaluates the patient detectors. Images are produced by data collected from
should be used. When an odontogenic origin (necrotic the detectors after a 360° rotation. After each tomo-
pulp) is suspected as the source of a localized infec- graphic image the patient table is moved and another
tion, intraoral films or panoramic radiographs are image obtained. A time delay of 10 to 15 seconds
usually adequate. Ultrasound also has been used in between each slice is necessary. Spiral CT involves
the evaluation of superficial neck infections, espe- the simultaneous movement of the patient table and
cially to determine fluid accumulation, but is not the x-ray tube, which results in a volume acquisition
recommended for deep neck infections because it of data from which individual tomographic images
cannot penetrate bone or the airway space. Conven- can be reconstructed. Because a volume data set is
tional films still can be used for a preliminary survey, acquired, excellent multiplanar reformations are pos-
especially of the retropharyngeal space and evaluation sible when using thin image slices (3 mm or less).
of the airway. Picture archival communication systems are becom-
Although most maxillofacial infections remain ing more common in hospitals. Some of these systems
localized and are managed successfully by antibiotic allow viewing multiplanar reformation in any plane
therapy or surgical intervention, serious and poten- desired, not just the standard sagittal and coronal
tially life-threatening complications, such as airway planes. In the past, CT reformation programs, such
as DentaScan, were recommended for true cross-
sectional images of the jaws, not only for implant
* Corresponding author. planning but also for evaluation of tumors, osteomye-
E-mail address: tunderhill@attbi.com (T.E. Underhill). litis, or other pathologic conditions [13,14]. Picture

1042-3699/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.
PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 7 5 - 4
40 T.E. Underhill et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 39–49

archival communication systems with multiplanar of clinical examination alone in identifying a drain-
reformation capability obviate the need for such pro- able collection was 63%, the sensitivity (ability of a
grams in the evaluation of pathologic conditions. test to identify correctly a disease when it is truly
Other advantages of spiral CT in applications to the present) was 55%, and the specificity (ability of a test
head and neck include one breath hold, which mini- to identify correctly the absence of disease when it is
mizes artifacts because of swallowing, and improved truly absent) was 73%. The accuracy of CECT alone
vascular opacification and lesion enhancement using a was 77%, the sensitivity was 95%, and the specificity
smaller contrast bolus [15]. Multidetector CT is yet 53%. When CECT and clinical examination were
another improvement over spiral CT. Whereas spiral combined, the accuracy in identifying a drainable
CT uses a single row of detectors, multidetector CT collection was 89%, the sensitivity was 95%, and
uses a matrix of detectors that allows the acquisition of the specificity was 80% [16].
multiple tomographic images per revolution, which
greatly increases the speed of imaging. Deep neck infections in pediatric patients
Nagy et al [3] compared the sensitivity of lateral
Accuracy of computed tomography neck films and CECT in evaluating children with a
high index of suspicion for a deep neck infection,
Deep neck infections in adult patients based on clinical presentation. More than 25% of
Miller et al [16] performed a prospective study that lateral neck radiographs were unable to determine
compared the efficacy of contrast-enhanced CT the presence of a deep neck infection, whereas CECT
(CECT) to clinical examination in detecting the pres- had a sensitivity of 100%. They concluded that CECT
ence of a drainable fluid collection in suspected deep is the study of choice in the evaluation of children
neck infections. The accuracy (frequency of a test to strongly suspected of having a deep neck infection
diagnosis correctly the presence or absence of disease) based on clinical presentation [3].

Fig. 1. (A) Chronic dentoalveolar granuloma. Axial T1-weighted MRI without contrast shows the normal bright signal from fatty
marrow in the maxillary alveolar ridge. There is a focal area with low signal surrounding the maxillary canine root (arrow),
which indicates replacement of normal fatty marrow by either a neoplastic or inflammatory process. (B) Parasagittal T1-weighted
MRI with contrast and fat saturation demonstrates enhancement of tissue surrounding the root of the right maxillary canine. The
uniform enhancement indicates a granuloma rather than an abscess, which would exhibit only peripheral enhancement.
T.E. Underhill et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 39–49 41

Wetmore et al [17] evaluated the use of CT in coils distort the uniform field, which causes only those
children with deep neck infections. CECT demonstra- hydrogen protons in a certain plane to resonate when
ted an accuracy of 92% for detection of an abscess excited by a specific radiofrequency. These excited
confirmed by surgery. In children with superficial neck protons emit a signal that, when analyzed by a two-
infections, only 24% of those who were treated sur- dimensional Fourier, is transformed into an image.
gically showed definite CT evidence of an abscess.
The decision to perform surgery was based on clinical Accuracy of magnetic resonance imaging
findings, such as palpable fluctuance and skin changes
[17]. As with adults, the combination of clinical Munoz et al [2] prospectively evaluated 47 patients
examination and radiographic data yielded the with neck infections. Each patient underwent CT and
best results. MRI with contrast of the area of interest using similar
slice thickness. MRI was superior to CT in regard to
NewTom lesion conspicuity, number of anatomic spaces
involved, extension, and source. CT was superior to
A new development in maxillofacial imaging is the
NewTom (Schick NIM S.r.l., Verona, Italy). This
machine performs axial panoramic and multiplanar
imaging of the maxillofacial region and produces
images similar to those acquired by the DentaScan
(General Electric Medical Systems, Milwaukee, WI)
as viewed in bone windows. Image acquisition by the
NewTom is fundamentally different from conventional
CT. The images are derived from a three-dimensional
data set acquired from multiple planar images (ie,
multiple digital projections), which renders excellent
high tissue contrast resolution (bony detail). Because
of this ability, the NewTom is excellent for detection of
lytic bony lesions; however, it lacks the ability to
demonstrate the low tissue contrast resolution needed
to detect subtle soft tissue changes as seen with
cellulitis, soft tissue abscess, cerebral empyema, or
retropharyngeal fluid/edema. The lower neck cannot
be imaged. For these reasons, conventional CECT is
recommended for the evaluation of head and neck
inflammatory processes.

Magnetic resonance imaging


Fig. 2. Retropharyngeal abscess. Axial image of CT scan
A disadvantage of MRI is the lack of availability.
with contrast obtained at the level of the maxilla. A 1.5-cm
Most MRI units are ‘‘tightly booked’’ with long retropharyngeal abscess is present (large arrow). This is seen
waiting periods for appointments. Even a 1-day wait as a fluid density collection surround by a rim of enhancing
is not acceptable for a patient with a potentially life- tissue. Notice that the density or attenuation of this fluid
threatening head and neck infection. Over the years, collection is the same as the cerebrospinal fluid that
MRI scanners have become more numerous and are surrounds the cord. A second area of fluid density, which
more available for emergent scans. Some imaging is not as well defined (smaller arrows), is seen in the lateral
centers have time reserved each day for emergency neck. This represents a multiloculated abscess. Notice that
scanning, and some large medical centers have MR normal fat on the soft tissue windows is dark. There is an area
scanners in the emergency department. Even with of edema or infiltration in the fat (stars). This appearance is
referred to as dirty fat. Compared to the right sternocleido-
emergency time reserved, however, maxillofacial
mastoid muscle (SCM), the left sternocleidomastoid muscle
and neck infections would have a lower priority for cannot be distinguished from the surrounding inflammatory
the MRI scanner than examinations to evaluate for process. The left jugular vein is compressed and is not
acute spinal cord compression or acute stroke. visualized. The right jugular vein and the right carotid artery
An MRI is obtained by placing the patient in a are in their normal location (J,C). The left carotid artery (c) is
strong and uniform magnetic field. Smaller gradient displaced anteriorly by the inflammatory process.
42 T.E. Underhill et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 39–49

MRI in the detection of intralesional gas and calcium whereas muscle decreases in attenuation on noncon-
and showed fewer motion artifacts. On this basis, MRI trasted CT [18]. Increased blood flow occurs in
was considered superior to CT in the initial evaluation inflamed tissue. After administration of iodinated
of neck infections. These findings suggest that MRI contrast medium, areas of increased blood flow dem-
should be used as the first and perhaps only modality onstrate enhancement. Intravenous iodinated contrast
to evaluate patients initially with neck infections [2]. is indicated for CT evaluation of a patient with
suspected cellulitis or abscess.

Interpretation Magnetic resonance imaging

Computed tomography The MRI parameters can be manipulated to pro-


duce several different appearances. As an oversim-
Computed tomography uses the differences in plification, T1-weighted images produce images in
attenuation of the x-ray beam by different tissues to which fat is bright and fluid such as cerebrospinal
form an image. The lowest attenuation occurs in air, fluid is dark. The presence or absence of the bright
and the highest attenuation occurs in bone, dentin, signal from fat can help detect pathologic processes.
enamel, or metal. Fat has a lower attenuation than Normally fatty marrow is bright. Any pathologic
water, which in turn has lower attenuation than process, such as metastatic disease or infection, that
muscle. When edema occurs, there is an increase in has replaced the normal fatty marrow appears abnor-
water content. Edematous fat increases in attenuation, mally dark (Fig. 1A). Gadolinium contrast medium is

Fig. 3. (A) Subperiosteal abscess. Axial CT image with contrast at the level of the inferior border of the mandible in a 43-year-old
man with painful swelling of the neck. There is a fluid mass density surrounding the angle of the mandible and extending along
the inferior border (arrows). This abnormal fluid collection extends on both sides of the mandible. The geniohyoid muscle
(asterisks) is displaced medially. (B) Bone window demonstrates a small periapical radiolucency around the distal root of the
mandibular right second molar. The next inferior image demonstrates a small break in the cortex. The source of the large
subperiosteal abscess was from the necrotic second molar.
T.E. Underhill et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 39–49 43

used only with T1-weighted images. When concen- such as cerebrospinal fluid, appears bright. Edematous
trated in tissues, gadolinium contrast medium dem- or inflamed tissues demonstrate increased signal
onstrates an increase in signal intensity. Unlike intensity, especially when fat saturation is used.
imaging the brain, where (usually) no fat is located,
in maxillofacial, orbital, or neck imaging, fat satura-
tion is critical when using gadolinium contrast Pathology
medium. Fat saturation makes the normal fat dark,
and normal and abnormal enhancement is much more Odontogenic infections
conspicuous (Fig. 1B). When evaluating a contrasted
T1-weighted image of the head and neck, there In a retrospective study of 210 patients with neck
should be an avid enhancement of the nasal mucosa. infections, the most common cause was dental infec-
If it does not enhance, there is a problem with the tion (43%). Dental infection was the cause of 76% of
contrast bolus and pathologic processes also would Ludwig’s angina [20]. In patients with deep neck
fail to enhance. This occurrence could lead to a false- space infections, airway compromise was more fre-
negative examination result. The ocular muscles quent and severe in odontogenic than in nonodonto-
normally enhance, but the larger muscles, such as genic deep neck space infections. The parapharyngeal,
paraspinal muscles or muscles of mastication, do submandibular, and masticator spaces are more vul-
not enhance. nerable in odontogenic deep neck space infections
With T2-weighted images, the ‘‘juicier or squish- than in nonodontogenic infections. The predilection
ier’’ [19] the tissue, the brighter it is. Stationary fluid, for certain spaces of the neck to be involved in

Fig. 4. (A) Septic thrombophlebitis. Axial CT examination with contrast performed at the level of the inferior border of the
mandible in a 31-year-old woman with a painful swollen left neck. There is an area of low attenuation surrounded by avid
enhancement (arrows). Compared to Fig. 1, this has the appearance of an abscess, but the hypodensity extends in a craniocaudal
dimension from the skull base to the level of the hyoid bone. This represents a low-density thrombus surrounded by enhancing
vasovasorum. Note the normally enhancing jugular vein on the right (JV ). (B) Axial enhanced CT scan at the level of the thyroid
gland (T ). Note the normally enhancing jugular vein at this level on the left and the normal carotid arteries (C ).
44 T.E. Underhill et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 39–49
T.E. Underhill et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 39–49 45

odontogenic deep neck space infection originates


from the intimate relationship of the mandibular
molars to the adjacent deep neck spaces [5] (Fig. 2).

Retropharyngeal abscess versus cellulitis

On CT, cellulitis appears as soft tissue swelling,


increased density of surrounding fat, enhancement of
involved muscles, and obliteration of fat planes [3,5].
An abscess is considered to be present if there is a low
(fluid) density area with a peripheral rim of enhance-
ment (Fig. 3) [3,5]. Symptoms include fever, neck
swelling, sore throat, dysphasia, and cervical rigidity.
Sometimes small children present with nonspecific
symptoms [21]. Children younger than 5 years who
Fig. 6. Periorbital abscess. Coronal CT scan with contrast in
present with poor oral intake, high fever, drooling, and
a 14-year-old boy who experienced orbital swelling and
trismus should be suspected of having a peritonsillar
pain. Notice the subperiosteal fluid collection adjacent to the
abscess. A CT scan of the neck is usually required to orbital roof on the left (arrows). There is opacification of
confirm a suspected diagnosis [22]. the maxillary sinuses and left ethmoid sinuses. Also notice is
the periorbital soft tissue swelling. The left medial rectus
Recurrent deep neck infections (asterisk) is displaced laterally from the lamina propria. The
cause for this orbital abscess was spread of infection from
Most deep neck infections are the result of sup- ethmoid sinusitis.
purative adenitis. The location of the primary focus is
usually from the mucosa of the upper aerodigestive
tract or from an odontogenic source. Recurrence in [24]. Cervical tuberculous lymphadenitis is also an
these situations is unusual. Less commonly, congen- important cause of a neck mass in many countries.
ital lesions can present as deep neck infections, and Multilocular low densities with peripheral enhance-
recurrences are common. In patients with recurrence ment and a large confluent low density with a lesser
of deep neck infections, the possibility of an under- degree of fat plane obliteration than a pyogenic
lying congenital lesion, such as branchial cleft cyst, abscess are suggestive features of advanced cervical
infected lymphangioma, or thyroglossal duct cyst, tuberculous lymphadenitis.
should be considered [23].
Septic thrombophlebitis
Nontuberculous and tuberculous
mycobacteria infection Septic thrombophlebitis of the jugular vein
(Lemierre’s syndrome) is an uncommon cause of
Nontuberculous mycobacteria infection most painful neck swelling [8]. On CT, a thrombus within
often presents in children as an asymmetric adenop- the jugular vein appears as an area of low attenuation
athy with contiguous low-density ring-enhancing with peripheral enhancement (Fig. 4), which easily
masses, minimal or absent inflammatory stranding could be mistaken for abscess. Normal enhancing
of the subcutaneous fat, and cutaneous extension vascular structures of the neck must be identified

Fig. 5. (A) Sialadenitis with abscess formation. The patient presented with painful swelling in the left floor of the mouth.
Clinically, an odontogenic source of infection was suspected. Axial CT scan performed at the level of the submandibular gland
showed multiple small locules of gas present as low attenuation or dark areas (arrows). Notice that gas has extended into the
submandibular space, buccal space, and parapharyngeal space. Compare to the normal submandibular gland (SMG) on the right.
(B) Axial CT image performed superior to the submandibular gland at the level of the floor of the mouth. Note the presence of
gas in the fascial plane of the floor of the mouth, with some crossing the midline. The gas is the product of gas-producing
organisms. The appearance is concerning for early development of Ludwig’s angina. (C) Axial CT scan performed at the level of
the maxillary sinuses. Gas in the parapharyngeal space (black arrow) has tracked up toward the skull base. There is also a large
amount of gas in the buccal space (white arrow), anterior to the left masticator space.
46 T.E. Underhill et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 39–49

for abscess/cellulitis is recommended. Frequently,


inflammatory processes in the salivary glands present
as a mass and clinically are difficult to distinguish
from malignancy. In such cases, contrasted CT or MRI
can be used to determine if the mass is intrinsic or
extrinsic to the gland [25].
Acute suppurative bacterial sialadenitis is associ-
ated with painful, swollen glands. The parotid gland is
most commonly involved [1]. Salivary calculi are best
seen on CT and appear as a high-density mass along
the course of the duct. CT also demonstrates gas in the
tissue better than MRI [5].
Fig. 7. Pott’s puffy tumor. A CT image with contrast at the
level of the frontal sinus of a 14-year-old boy with painful
frontal swelling. A subperiosteal abscess is present (asterisk). Necrotizing fasciitis
There is erosion of the inner wall of the frontal sinus and
abnormal dural enhancement (arrow). A bony sequestrum Craniocervical necrotizing fasciitis is a rapidly
is present. progressive, severe bacterial infection of the super-
ficial fascial planes of the head and neck. Group A
and traced in the craniocaudal direction. Tracing of beta-hemolytic Streptococcus, Staphylococcus au-
other neck structures also is important. Necrotic reus, and obligate anaerobic bacteria are commonly
lymph nodes also can mimic cervical abscesses on involved pathogens. The disease usually results
CT scans and result in negative surgical findings [22]. from a dental source or facial trauma. Extensive
fascial necrosis and severe systemic toxicity are
Sialadenitis common manifestations of craniocervical necro-
tizing fasciitis. Most patients have an underlying
In general, CT has supplanted sialography for the medical problem that created an immunocompro-
evaluation of inflammatory processes in the salivary mised state, usually diabetes mellitus or chronic
glands (Fig. 5). If salivary calculi are suspected as the alcoholism [26]. Constant CT features of necro-
cause of an inflammatory process, a noncontrasted CT tizing fasciitis are diffuse cellulitis, diffuse enhance-
to detect calculi followed by contrasted CT to evaluate ment or thickening of the superficial and deep

Fig. 8. (A) Chronic fungal sinusitis. Axial CT image without contrast at the level of the orbits. Notice the high-density material in
the ethmoid sinuses (asterisks). This is a chronic process and has caused expansion of the ethmoid sinuses, which resulted in
hypertelorism. The fungal sinusitis also caused erosion of the clivus (arrows). The high-density material in the ethmoid sinus is
characteristic of fungal sinusitis. The surrounding lower density material represents mucosa. (B) Axial T2-weighted MRI at the
same level as (A). Notice the signal void (asterisk), which corresponds to the high-density material seen on the CT examination.
This signal void could be mistaken for normal, aerated ethmoid sinus. The lack of signal is highly characteristic of fungal sinusitis.
T.E. Underhill et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 39–49 47

cervical fasciae (fasciitis), enhancement and thick- should receive an immediate noncontrasted and con-
ening of the neck muscles (myositis), and fluid trasted head CT and MRI. If CT is used, additional
collections in multiple neck compartments. thin cuts (3 mm or less) in the axial and coronal
planes of the paranasal sinuses should be obtained.
Sinusitis Because of the late development of the frontal
sinuses, frontal sinus infection in children is rare.
The paranasal sinuses are a common source of When present, it can lead to osteomyelitis associated
maxillofacial infection. Occasionally, paranasal with forehead swelling (Pott’s puffy tumor) (Fig. 7).
sinusitis can have devastating sequelae from involve- Early diagnosis and active treatment prevent progres-
ment of the orbits (Fig. 6), cavernous sinuses, or brain sion to life-threatening intracranial spread [28].
parenchyma [4]. Orbital spread is most commonly In fungal disease of the paranasal sinuses, expan-
secondary to bacterial or fungal sinus infections. sion of the bony walls occurs by increased mucus
Optic neuritis that arises from such infections requires secretion and fungal growth (Fig. 8). The fungus is
prompt recognition and aggressive treatment if vision confined to the lumen and does not invade the
is to be preserved [27]. Intracranial empyema sec- tissues. Within the lumen of the sinus, fungus
ondary to sinusitis is generally a disease of young appears as areas of high attenuation on the CT scan
adult men without an antecedent history of sinus because of the presence of calcium and traces of
disease [7]. The dominant clinical features are fever, metallic elements. On MRI, the fungus-filled lumen
intense headache, and facial swelling. The patient appears as an area of low signal intensity because of

Fig. 9. (A) Invasive fungal sinusitis. Coronal nonenhanced T1-weighted MRI in a 33-year-old immunocompromised man. There
is an oroantral fistula in the region where maxillary teeth were removed because of loss of all bony support. On removal of teeth,
there was no normal tissue with which to close the sinus opening. Abnormal tissue along the left infraorbital rim has eroded the
bone and replaced the normal bright orbital fat (asterisk). (B) Sagittal postcontrast T1-weighted MRI with fat saturation shows
the oroantral fistula (large arrows). Abnormal enhancing tissue extends back to the orbital apex along the expected route of the
infraorbital nerve (small arrows). Not imaged on this slice is the abnormal enhancing tissue that extends into the cavernous sinus.
This is an example of perineural spread of a fungus infection.
48 T.E. Underhill et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 39–49

the presence of ferromagnetic elements (Fig. 8) [29]. antibiotic and anticoagulation therapy: a case report.
Invasive fungal sinusitis involves destruction of the Angiology 2000;51:173 – 7.
bony walls and spread into surrounding structures [9] Nguyen VD, Potter JL, Hersh-Schick MR. Lud-
wig angina: an uncommon and potentially lethal
(Fig. 9) [29].
neck infection. AJNR Am J Neuroradiol 1992;13:
215 – 9.
[10] Haraden BM, Zwemer Jr FL. Descending necroti-
Summary zing mediastinitis: complication of a simple den-
tal infection. Ann Emerg Med 1997;20:683 – 6.
Computed tomography and MRI are quick and [11] Raboso E, Llavero MT, Rosell A, Martinez-Vidal A.
accurate methods for the evaluation of complex head Craniofacial necrotizing fasciitis secondary to sinusitis.
and neck infections. Because of new spiral CT J Laryngol Otol 1998;112:371 – 2.
scanners and picture archival communication sys- [12] Tsunoda R, Suda S, Fukaya T, Saito K. Descending
tems, multiplanar imaging is common with CT. CT necrotizing mediastinitis caused by an odontogenic in-
fection: a case report. J Oral Maxillofac Surg 2000;58:
has supplanted sialography for the evaluation of
240 – 2.
inflammatory processes in the salivary glands. In
[13] Abrahams JJ, Glassberg RM. Dental disease: a fre-
the search for a drainable abscess collection, MRI quently unrecognized cause of maxillary sinus ab-
is superior to CT in regard to lesion conspicuity and normalities? AJR Am J Roentgenol 1996;166:
determining the number of anatomic spaces involved 1219 – 23.
and the degree of extension and the source. MRI is [14] King JM, Caldarelli DD, Petasnick JP. DentaScan: a
also superior to CT for detection of intracranial new diagnostic method for evaluating mandibular
extension of infection. CT is superior to MRI in the and maxillary pathology. Laryngoscope 1992;102:
detection of intralesional gas, calcifications, and 379 – 87.
cortical destruction. [15] Heiken J, Brink J, Vannier M. Spiral (helical) CT. Ra-
diology 1993;189:647 – 56.
[16] Miller WD, Furst IM, Sandor GK, Keller MA. A pro-
spective, blinded comparison of clinical examination
References and computed tomography in deep neck infections.
Laryngoscope 1999;109:1873 – 9.
[1] Ginsberg LE. Inflammatory and infectious lesions [17] Wetmore RF, Mahboubi S, Soyupak SK. Computed
of the neck. Semin Ultrasound CT MR 1997;18: tomography in the evaluation of pediatric neck in-
205 – 219. fections. Otolaryngol Head Neck Surg 1998;119:
[2] Munoz A, Castillo M, Melchor MA, Gutierrez RJ. 624 – 7.
Acute neck infections: prospective comparison be- [18] Ariti E, Moriguchi S, Kuroki T, et al. Computed to-
tween CT and MRI in 47 patients. Comput Assist To- mography of maxillofacial infections. Dentomaxillofac
mogr 2001;25:733 – 41. Radiol 1991;20:147 – 51.
[3] Nagy M, Backstrom J. Comparison of the sensitivity of [19] Elster AD, Burdette JH. Introduction to nuclear mag-
lateral neck radiographs and computed tomography netic resonance. In: Questions and answers in magnetic
scanning in pediatric deep-neck infections. Laryngo- resonance imaging. St Louis: Mosby; 2001. p. 37.
scope 1999;109:775 – 9. [20] Parhiscar A, Har-El G. Deep neck abscess: a retrospec-
[4] Sahjpaul RL, Lee DH. Infratentorial subdural empye- tive review of 210 cases. Ann Otol Rhinol Laryngol
ma, pituitary abscess, and septic cavernous sinus 2001;110:1051 – 4.
thrombophlebitis secondary to paranasal sinusitis: case [21] Chan WL, Fernandes VB, Carolan MG. Retropharyng-
report. Neurosurgery 1999;44:864 – 6. eal abscess on a Ga-67 scan: a case report. Clin Nucl
[5] Kim HJ, Park ED, Kim JH, Hwang EG, Chung SHJ. Med 1999;24:942 – 4.
Odontogenic versus nonodontogenic deep neck space [22] Friedman NR, Mitchell RB, Pereira KD, Younis RT,
infections: CT manifestations. Comput Assist Tomogr Lazar RH. Peritonsillar abscess in early childhood:
1997;21:202 – 8. presentation and management. Arch Otolaryngol Head
[6] Feldman DP, Picerno NA, Porubsky ES. Cavernous Neck Surg 1997;123:630 – 2.
sinus thrombosis complicating odontogenic paraphar- [23] Nusbaum AO, Som PM, Rothschild MA, Shugar JM.
yngeal space neck abscess: a case report and dis- Recurrence of a deep neck infection: a clinical indica-
cussion. Otolaryngol Head Neck Surg 2000;123: tion of an underlying congenital lesion. Arch Otolar-
744 – 5. yngol Head Neck Surg 1999;125:1379 – 82.
[7] Fenton JE, Smyth DA, Viani LG, Walsh MA. Sino- [24] Robson CD, Hazra R, Barnes PD, Robertson RL, Jones
genic brain abscess. Am J Rhinol 1999;13:299 – 302. D, Husson RN. Nontuberculous mycobacterial infec-
[8] Nakamura S, Sadoshima S, Doi Y, Yoshioka M, Yama- tion of the head and neck in immunocompetent chil-
shita S, Gotoh H, et al. Internal jugular vein thrombo- dren: CT and MR findings. AJNR Am J Neuroradiol
sis, Lemierre’s syndrome, oropharyngeal infection with 1999;20:1829 – 35.
T.E. Underhill et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 39–49 49

[25] Conway W, Laine F, Blinder R. Newer diagnostic eases affecting the orbit. Otolaryngol Clin North Am
imaging techniques. Oral Maxillofacial Surg Clin N 1993;26:657 – 71.
Am 1991;3:259 – 72. [28] Hore I, Mitchell RB, Radcliffe G, De Casso, Moxo C.
[26] Henrich DE, Smith TL, Shockley WW. Fatal cranio- Pott’s puffy tumour: a rare cause of forehead swelling
cervical necrotizing fasciitis in an immunocompetent in a child. Int J Clin Pract 2000;54:267 – 8.
patient: a case report and literature review. Head Neck [29] Michaels L, Lloyd G, Phelps P. Origin and spread of
1995;17:351 – 7. allergic fungal disease of the nose and paranasal si-
[27] Osguthorpe JD, Hochman M. Inflammatory sinus dis- nuses. Clin Otolaryngol 2000;25:518 – 25.
Oral Maxillofacial Surg Clin N Am 15 (2003) 51 – 58

Diagnosis and treatment of cervicofacial actinomycosis


Morton H. Goldberg, DMD, MDa,b,*
a
Department of Oral and Maxillofacial Surgery, University of Connecticut, USA
b
Department of Dentistry, Hartford Hospital, Seymour Street, Hartford, CT 06107, USA

Actinomycosis is an uncommon and frequently and their reproduction by typical bacterial fission
misdiagnosed infection of the cervicofacial region rather than by budding or by spores. Actinomyces
that may be acute or indolent. The term ‘‘actino- are anaerobic (whereas fungi are aerobic) and lack the
mycosis’’ derives from the Greek aktino (ray) and nuclear membrane of fungi and yeasts. Actinomyces
mykos (fungus). Historically, Langenback may have are destroyed by antibacterial agents such as penicil-
been the first to describe the disease in humans lin and erythromycin but are not affected by antifun-
(1848), although it had been considered to be a gal medications, such as amphotericin B (see box 1)
sarcoma in cattle 20 years earlier by Leblanc. Bol- [2,3].
linger (1870) coined the term ‘‘lumpy jaw’’ in its
bovine form, whereas Harz (1877) described the
appearance of a ray-like microorganism, which he Box 1. Taxonomy of the order
named Actinomycoses bovis. In 1878, Israel and Actinomycetales [2,38]
Ponfick observed and described ‘‘sulfur granules’’
in human disease, and in 1891, Israel and Wolf Class: Schizomycetes
isolated the anaerobic filamentous organism from Order: Actinomycetales
humans. In 1898, the organism found in humans Family: Actinomycetes
was named Actinomycoses israelii, and by the Genus: Actinomyces
1940s further research had confirmed that whereas * Species:
A. bovis was responsible for ‘‘lumpy jaw’’ in cattle, A. israelii
A. israelii was the etiologic agent of human disease A. neerlundi
[1 – 3]. A. viscosus
Originally considered to be a fungus (mykos) A. odontolyticus
because of its slow growth and filamentous appear- A. meyerii
ance, it is currently generally accepted that Actino- A. bovis
myces are bacteria and are taxonomically classified Family: Mycobacteriaceae
accordingly as members of the order Actinomycetales Genus: Mycobacterium
and the family Actinomycetacae. Other orders clas- Family: Nocardiaceae
sified as Actinomycetales include Mycobacteriaceae Genus: Nocardia
and Nocardiaceae. * A. israelii is the etiologic organism of
Evidence that Actinomyces are bacteria include most human actinomycosis,
their filaments, which are narrower than the hyphae but all species except A. bovis can
of fungi, their morphology, including bacillary forms, be commensals in the normal oro-
pharyngeal flora. Human disease is
occasionally reported with species
* Department of Dentistry, Hartford Hospital, 928 other than A. israeii [4].
Farmington Avenue, West Hartford, CT 06107.

1042-3699/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.
PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 7 4 - 2
52 M.H. Goldberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 51–58

Microbiology and natural history


Box 3. Reported diagnostic sites of head
and neck infection by Actinomycoses
Actinomyces are endogenous to the human oral
[2,11,16,26 – 32,36,37,39 – 42]
cavity and cervicofacial region and are not restricted
to soil or soil contaminants as previously hypothe-
Dentigerous cyst
sized. The organism is a human commensal, but its
Dental caries
presence results only in a low incidence of clinical
Dental plaque
infection, even when tissue undergoes trauma, such
Dental pulp
as tooth extraction. This low incidence of infection,
Ear (external canal and middle ear)
despite the high incidence of oral trauma, argues for
Eye (lids, conjunctiva, lacrimal gland)
the organism’s minimal potential for invasion and its
Fascial spaces (submandibular, sub-
lack of virulence.
mental, temporal, masseteric,
Actinomyces require a polymicrobial ecosystem
buccal)
and tissue trauma to proliferate and create clinically
Gingiva
evident infection. These microflora work synergisti-
Larynx
cally to destroy vascularized aerobic tissue and create
Lip
poorly oxygenated granulation tissue, which becomes
Masseter muscle, mandible, maxilla
an environment that supports the growth and mul-
(exodontia, fracture)
tiplication of Actinomyces. The severity and chro-
Osteotomy site
nicity of tissue trauma are factors that can enhance
Palate
the development of anaerobic growth by these organ-
Parotid gland
isms, which normally exhibit low virulence. Other
Scalp
oral bacterial species involved in this ecosystem
Sinuses
include Actinobacillus, Actinomycetencomitans (fre-
Temporal bone
quent), Bacteroides, Eikenella, and Fusobacterium
Temporomandibular joint
(see box 2). Actinomyces have been isolated from
Thyroid
teeth, extraction sites, periodontal infections, jaw
Tongue
fractures, postoperative surgical sites, salivary glands,
Tonsils
the tongue, tonsils, and other areas of the orofacial
Tooth (extraction site)
and neck region (see box 3).
Trachea

Histopathology
nibacteria. The thin filaments of Actinomyces may be
Morphologically, Actinomyces may be filamen- observed to have V or Y branching and may appear in
tous or diptheroidal. If diptheroidal, they may bacillary or coccoid forms.
resemble nonpathogenic diptheroids such as Propio- Sulfur granules are macroscopic yellowish grains
of firm consistency that are visible to the eye when
on a gauze sponge. They vary in size from 100 to
Box 2. Bacterial ecosystem associated 1000 u in diameter and are visible by light micro-
with Actinomycoses infection scopy. When stained with methylene blue, Gram’s
[1,11,33 – 35] stain, periodic acid-Schiff, or silver methenamine,
gram-positive branching mycelia and filaments are
Actinobacillus actinomycetemcomitas visible (Figs. 1,2). The filaments may be mistaken
Bacteroides species (pigmented) for streptococci.
Capnocytophaga species Granules may not always be present or may be
Eikenella corrodens few in number, which necessitates multiple micro-
Fusobacterium species scopic sections of sinus tracts or abscess walls for
Haemophilus species their identification. One study found only one to three
Peptostreptococcus granules in 56% of specimens examined and none at
Porphymonas all in seven cases, which were confirmed by culture
Streptococcus [5]. Although granule formation is common in A.
Staphylococcus gingivalis israelii infection, it is not observed with A. odonto-
lyticus, a noninvader of tissue. The presence of
M.H. Goldberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 51–58 53

Fig. 1. Low magnification of sulfur granule. Note amorphous center and peripheral rosette of filaments. (Courtesy of Dr. Ellen
Eisenberg, University of Connecticut.)

granules in exudate from an infection in the cervico- Microscopic examination of an excised or biop-
facial region, although highly suggestive of actino- sied mass of tissue can reveal acute or chronic
mycosis, is not, of itself, pathognomonic, because inflammation, with loculation of neutrophils, lym-
granules may be produced by Actinobacillus ligniersi phocytes, plasma cells, macrophages, and dense fib-
and some pathogenic mycoses, such as Sporotrichum rous tissue. The number of plasma cells increases
and Phialophore [6], and are found in nocardial with the chronicity of the lesion. Fibrosis may be
infections. Although fluorescent antibody staining mild in early infections, whereas chronicity is asso-
may contribute to an accurate diagnosis, confirmation ciated with intense avascular fibrosis. This tissue is
by culture is necessary. believed to maintain the anaerobic environment that

Fig. 2. Higher magnification of edge of sulfur granule, which demonstrates individual and branching filaments. (Courtesy of Dr.
Mark Fletcher, Hartford Hospital.)
54 M.H. Goldberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 51–58

stimulates growth of the actinomyces organisms and radiographic finding. True actinomycotic osteomyel-
inhibits antibiotic penetration [7,8]. itis may demonstrate imaging evidence of cortical
erosion or localized lytic destruction in the midst of
increased bone density. Sinus tracts may develop
Clinical manifestations from the bone to the surface. Radiographically, acti-
nomycotic osteomyelitis may be diagnostically inter-
Actinomycosis is an uncommon disease. It is preted as suppurative osteomyelitis or neoplasm.
possible for an oral maxillofacial surgeon to have a
lengthy career and never encounter the disease. It
may occur at any age, however, most commonly Box 4. Differential diagnosis of osteolytic
between age 30 and 60. Cases among men outnumber lesions of the jaws associated with
cases that involve women 4:1. In the pediatric popu- ‘‘lumpy jaw’’ or sinus tracts
lation, actinomycosis is rare, and a low level of
suspicion may cause diagnostic confusion and delay Infection:
in treatment [9].  Pyogenic osteomyelitis
The disease may present as either an acute or  Periapical infection
chronic form. The less common acute form manifests  Tuberculosis
as a fluctuant swelling that resembles or mimics an  Nocardiosis or other fungal
acute odontogenic infection. It may be painful and infection
associated with temperature elevation, and it can  Infected hardware
spread rapidly through tissue [10]. More common, Tumor:
however, is the chronic lesion of actinomycosis,  Benign bone tumors
which presents as a slowly enlarging, progressive,  Primary or metastatic malignant
inflammatory mass that may or may not be painful bone tumors
and usually is associated with an afebrile course or  Gingival carcinoma invading bone
minimal elevation of temperature. The chronic or
chronic-recurring form may develop or progress or
recur over weeks, months, or even years, during The recovery of Actinomyces and Eikenella from
which time lethargy may be present, but patients do cultures of chronic diffuse sclerosing osteomyelitis
not typically complain of feeling ill. Sedimentation by Marx et al suggests that a pathogenic mutalism
rates tend to remain low or normal, whereas leuko- exists between these organisms and perhaps with
cyte counts may be normal or minimally elevated. Arachnia. This research must be repeated and
Reddish-brown discoloration of the facial skin over- expanded [17,18].
lying the jaw is common, and recurrent episodes of Although cervicofacial infection may account for
suppuration result in firm or fluctuant irregular skin 60% of all cases of actinomycosis, other anatomic
masses; hence the historic description of the infection sites or organ systems may be infected, including the
as ‘‘lumpy jaw.’’ Spread of the infection is indepen- thoracic cavity (15%) and the abdominal cavity
dent of lymphatic channels or fascial planes. Ulti- (20%), where it may surprise the unsuspecting physi-
mately, sinus tracts develop deep in the lesion, cian or surgeon. Superficial cutaneous infection and
burrowing through the dense fibrosis and discharging genitourinary tract infection also may occur. Central
onto the surface of the skin (or mucosa). These sinus nervous system infection is uncommon (2%) and can
tracts may persist or close, or new tracts may form. A originate by direct extension of cervicofacial infec-
pattern of remission and exacerbation may character- tion via the sinuses, orbits, or auditory canals and by
ize the disease, especially if the diagnosis remains perineural pathways [19]. It can gain access to the
obscure and short-term episodic antibiotic therapy is trigeminal ganglion via the foramen ovale. Meningeal
performed [2,11,12]. spread may result in diffuse meningitis or brain
A primary actinomycotic bone infection is uncom- abscess, and it may be initially misdiagnosed as a
mon but may occur in up to 12% of cases, because tumor. Central nervous system involvement may be
osseous invasion and destruction may result from the result of hematogenous spread from the oral,
spread of the infection from adjacent soft tissues, pulmonary, abdominal, or pelvic regions. Dissemi-
extraction sites, or fractures sites. Such infections nated hematogenous ‘‘sepsis’’ is rare but may be
occur more commonly in the mandible than the fatal. Focal neurologic signs and elevated intracranial
maxilla (4:1) [13 – 16] (see box 4). Periostitis with pressure should alert the examiner to this possibility.
evidence of periosteal elevation may be the earliest A delay in diagnosis of 2 months or more caries a
M.H. Goldberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 51–58 55

mortality rate of 28%, even when adequate antibiotic percentage of positive identification. Immediate
therapy is ultimately instituted. Gram stain of the specimens may yield a presumptive
The most common diseases occur most frequent- diagnosis of Actinomyces, especially if sulfur gran-
ly; therefore the diagnostician is more likely to be ules have been included [2].
correct when looking for ‘‘horses’’ rather than Culture plates must be incubated at least 14 days,
uncommon or unlikely ‘‘zebras.’’ Some diseases under completely anaerobic conditions, in a 5%
masquerade or mimic other diseases—‘‘horses wear- carbon dioxide atmosphere at 37 C. Blood agar,
ing striped pajamas’’ [20]. Actinomycosis that brain-heart infusion agar, and thioglycolate liquid
mimics tumors of the maxillary sinus or neural neo- medium are commonly used. During the incubation
plasms is an example of this phenomenon [21,22]. period, direct observation of the cultures may reveal
sulfur granules, which can be Gram stained, a tech-
nique that adds evidence to the final diagnosis [2,11].
Diagnosis The fine-needle aspiration technique permits eas-
ier anaerobic transport and rapid inoculation into
Although history and physical examination are anaerobic culture media. Gram staining of aspirated
always basic to diagnosis of any disease, the indolent material may reveal the filamentous appearance of the
but progressive natural process of actinomycotic infec- Actinomyces. Aspiration is most successful when
tion requires a high index of suspicion of what is often easily palpable tissue masses can be aspirated accu-
a diagnostic dilemma. With a history of recurrent or rately rather than when a blind attempt is made to
late infection after tooth extraction and the presence of obtain material from deep tissue.
one or more sinus tracts not associated with high fever Classic microscopic examination of excised tissue
or elevated neutrophil count, actinomycosis should be (biopsy) can be useful diagnostically but has limita-
high on the differential diagnosis list. tions, especially if intense inflammation is present in
Radiographs of bone may be helpful in recognizing the tissue in the early stages of the infection. Histo-
the extent of the osseous process but are nonspecific logically, it is difficult to differentiate Actinomyces
for actinomycosis even in the presence of soft tissue from Nocardia species. Small colonies or isolated
swelling and sinus tract. CT and gallium scintigraphy filaments of Actinomyces may be overlooked in
may be useful in differentiating between inflammatory routine hematoxylin and eosin – stained tissue sec-
and neoplastic changes. CT may reveal loculations and tions. Other diagnostic tests include fluorescent typ-
dense fibrosis, whereas scintigraphy may be useful as a ing and gel-diffusion techniques, but these are not
method to determine the efficacy of therapy; however, routinely available in many laboratories.
no single imaging modality is diagnostic. It is important for clinicians, pathologists, and
Absolute confirmation of the diagnosis depends microbiologists to consider that the presence of
on careful culturing of these fastidiously oxygen- A. israelii in tissue specimens or even in cultures does
sensitive anaerobes, preferably when the patient has not unequivocally confirm its role as the etiologic
received no antibiotics for 7 to 10 days. If culturing is agent in an infection; it may represent contamination
delayed, improperly performed, or negated by recent or commensal growth. Its presence should correlate
or concurrent antibiotic therapy, the diagnosis may with clinical findings.
remain obscure or uncertain.
Culturing may be performed directly from sinus
tract drainage, an open biopsy of tissue, or after Therapy
needle aspiration of the lesion [23]. The clinician
must be fastidious in technique to avoid contamina- Before the availability of antibiotics, treatment of
tion by skin or oral flora and prevent excessive cervicofacial actinomycosis included surgery, irra-
exposure of the specimen to room air. Even with diation, vaccination, and the use of iodides and other
these precautions, recovery of the pathogen is com- ineffective nostrums. The successful use of sulfona-
monly unsuccessful, often in more than 50% of mides in 1938 simplified the therapy. Penicillin was
specimens. All cultures should be transported imme- introduced into the therapeutic regimen for actino-
diately to the microbiology laboratory in a nonaerobic mycosis in 1948, and by 1960, prolonged high-level
medium with a carbon dioxide atmosphere. If the penicillin therapy was being used, as was the radical
laboratory has been alerted that Actinomyces is sus- excision of recalcitrant fibrotic lesions and persistent
pected as the pathogen, appropriate culture media in sinus tracts that resisted antibiotic penetration [24].
an anaerobic environment can be available, without Later, Lerner recommended the use of intravenous
unnecessary delay, which contributes to a higher antibiotics alone for early lesions, whereas resection
56 M.H. Goldberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 51–58

was advised for more mature and densely fibrotic because penicillin-resistant organisms develop in the
lesions [6,11]. Perhaps the efficacy of penicillin polymicrobial ecosystem that supports the growth of
therapy is related not only to its direct effect on A. actinomycoses. After successful therapy, pharma-
israelii but also to its antimicrobial suppression of the ceutical or surgical, secondary repair or reconstruction
other microorganisms that participate in the metabolic may be indicated. Bone loss, absence of teeth, and
ecosystem and enable Actinomyces to flourish. aesthetically unacceptable scarring from chronic si-
In actinomycotic osteomyelitis, sequestrectomy or nus tracts can be treated by bone grafting, soft
saucerization of nonvital bone is indicated. Débride- tissue procedures, or implants, but only when the sur-
ment of the dead bone, an excellent anaerobic growth geon is confident that the infection has been com-
medium that lacks any vascularity and is unpenetra- pletely eliminated.
ble by antibiotics, contributes to the healing process.
Initial therapy for actinomycosis is high-dose in-
travenous infusion of penicillin. Three to 12 million U Medicolegal considerations
daily is recommended and can be administered at
home by indwelling heparin-lock intravenous cath- Because A. israelii is an oral commensal, actino-
eter. This treatment should be followed by orally mycotic infection cannot be predicted or prevented. It
administered penicillin, 2 to 4 g daily, for an addi- would seem that malpractice claims secondary to
tional 3 to 12 months, depending on the infection’s infection are specious and without scientific validity.
response [16,25]. This therapeutic regimen may be Nonetheless, the author has reviewed such cases,
extended if central nervous system infection is pre- which are based on the claims that practitioners have
sent. If actinomycotic osteomyelitis has developed, failed to diagnose or treat appropriately.
intravenous penicillin doses may reach 20 million U The decision whether to prescribe antibiotics at
daily, given in divided doses. If potassium penicillin is the time of tooth extraction should not be based on
used in high doses for prolonged periods, potassium the statistically highly unlikely possibility that the
levels should be monitored and one should observe for patient might eventually develop actinomycosis. Nei-
hyperkalemia, especially in patients who are simulta- ther routine culturing nor routine antibiotic use after
neously taking potassium-sparing diuretics or who exodontia can be justified medically or economically.
have impaired renal function. The most common causes of early postextraction
Other antibiotics that are effective include eryth- infection are food trapping (inadequate hygiene) in
romycin, cephaloridine, minocycline, clindamycin, the operative site or the presence of a small fragment
chloramphenicol, and imipenem. Flagyl (metronida- of nonviable bone. Such infections are usually treated
zole) and aminoglycosides are ineffective against with irrigation, débridement, and antibiotics if, in the
A. israelii (Table 1). surgeon’s judgment, they are indicated. Late or mul-
If the clinical response to monoantibiotic therapy tiple infections should alert the surgeon to the pos-
is less than optimal, subsequent options include sur- sibility of actinomycotic infection, however. Failure
gical exploration and excision of undrained obscure to culture late or recurrent infections and the use of
abscesses or the use of antibiotics in combination. multiple short courses of empirical antibiotic therapy
Polyantibiotic therapy may be successful, perhaps before the eventual establishment of the correct
diagnosis are the common filaments in the fabric of
actinomycosis malpractice actions. Without a high
Table 1 index of suspicion, clinicians may be lulled into a
Antibiotic therapy for actinomycosis [2,11] false sense of security because the infections may be
Antibiotic Mode MIC mg/mL Daily dose initially subtle, nonpyogenic, and indolent and
because actinomycosis may become evident months
Penicillin G IV 0.03 – 0.5 3 – 12
after the surgery or after years of quiescence.
(soft tissue infection) million U
Penicillin G (osseous IV 0.03 – 0.5 12 – 20
and central million U
nervous system) Summary [5,7,8]
Penicillin V PO 0.03 – 0.5 2–4 g
Erythromycin PO 0.12 2g Actinomyces israelii is an anaerobic commensal
Clindamycin PO 2.0 – 8.0 1200 mg microorganism of the human oral cavity. It infre-
Tetracycline PO — 2g quently causes an infection that is polymicrobial and
Minocycline PO — 2g mutalistic in nature. The infection, actinomycosis,
Abbreviations: IV, intravenous; PO, orally. has a variable clinical course, which may be acute
M.H. Goldberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 51–58 57

or indolently chronic. The differential diagnosis [16] Topazian R. Osteomyelitis of the jaws. In: Topazian R,
includes pyogenic and fungal infections, tuber- Goldberg M, Hupp J, editors. Oral and maxillofacial
culosis, and neoplasm. A high diagnostic index of infections. 4th edition. Philadelphia: WB Saunders Co.;
2002. p. 231 – 4.
suspicion for actinomycosis when late or recurrent
[17] Jacobsson S. Isolation of Actinomyces species and Ei-
postextraction infection occurs benefits the patient
chenella corrodens from patients with chronic diffuse
and the practitioner. A prolonged course of penicillin sclerosing osteomyelitis [discussion]. J Oral Maxillo-
therapy remains the contemporary treatment of fac Surg 1994;52:33 – 4.
choice. Excisional or secondary restorative surgery [18] Marx RE, Carlson ER, Smith BR, et al. Isolation of
may be necessary. Actinomyces species and Eichenella corrodens from
patients with chronic diffuse sclerosing osteomyelitis.
J Oral Maxillofac Surg 1994;52:26 – 33.
[19] Lad SD, Chandy MJ. Craniofacial actinomycosis. Br J
References Neurosurg 1991;5:361 – 70.
[20] Goldberg MH. Zebra rounds and horses wearing
[1] Holm P. Studies on the etiology of human actinomy- striped pajamas. Pharos 2001;64:53.
cosis. I: The ‘‘other microbes’’ of actinomycosis and [21] Har-El G, Prager DA, DeSoto La Paix F, et al. Actino-
their importance. Acta Pathol Microbiol Scand 1950; mycotic granuloma masquerading as infraorbital nerve
27:736 – 42. neoplasm. Head Neck 1990;12:261 – 2.
[2] Miller M, Haddad AJ. Cervicofacial actinomycosis. [22] Pradhan S, Datta NR, Prasad KN, et al. Actinomycosis
Oral Surg Oral Med Oral Pathol 1998;85:496 – 508. mimicking carcinoma of the maxillary sinus. Indian J
[3] Richtsmeier WJ, Johns ME. Actinomycosis of the Cancer 1993;30:1 – 4.
head and neck. CRC Crit Rev Clin Lab Sci 1979;11: [23] Das DK. Actinomycosis in fine-needle aspiration cy-
175 – 202. tology. Cytopathology 1994;5:243 – 50.
[4] Pordy RC. Lumpy jaw due to Actinomycoces meyerii: [24] Peabody JW, Seabury JH. Actinomycosis and nocar-
report of the first case and review of the literature. Mt diosis. Am J Med 1960;28:99 – 115.
Sinai J Med 1988;55:190 – 3. [25] Goldberg MH. Antibiotics: old friends and new
[5] Brown JR. Human actinomycosis: a study of 181 sub- acquaintances. Oral Maxillofacial Surg Clin N Am
jects. Hum Pathol 1973;4:319 – 30. 2001;13:15 – 30.
[6] Lerner PI. Actinomyces and arachnia. In: Wonsiewicz [26] Barnard NA, Magennis JPM. Intra-masseteric actino-
MJ, editor. Infectious Diseases. Philadelphia: WB Sa- mycosis: report of a case. Br J Oral Maxillofac Surg
unders Co.; 1992. p. 1626 – 32. 1992;30:190 – 1.
[7] Bennhoff DF. Actinomycosis: diagnostic and therapeu- [27] Bradley P. Actinomycosis of the temporomandibular
tic considerations and a review of 32 cases. Laryngo- joint. Br J Oral Surg 1971;9:54 – 6.
scope 1984;94:1198 – 217. [28] Carrau RL, Greenwall K, Canaan RE, et al. Actino-
[8] Dusek JJ, Howe AG, Carr RF, et al. Case 37, part II: mycosis of the infratemporal fossa. Am J Otolaryngol
cervico-facial actinomycosis [clinicopathological con- 1993;14:1 – 4.
ference]. J Oral Maxillofac Surg 1982;40:113 – 6. [29] Chuong R, Goldberg M. Case 60: preauricular mass
[9] Foster SV, Demmier GJ, Hawkins EP, et al. Pediatric (clinicopathological conference). J Oral Maxillofac
cervico-facial actinomycosis. South Med J 1993;86: Surg 1986;44:214 – 7.
1147 – 50. [30] Deloach-Banta LJ, Barber FA. Nonhealing masses of
[10] Nielsen PM, Novak A. Acute cervicofacial actinomy- the right cheek and submandibular areas. Arch Derma-
cosis. Int J Oral Maxillofac Surg 1987;16:440 – 4. tol 1991;127:1831 – 4.
[11] Lerner PI. The lumpy jaw: cervicofacial actinomycosis. [31] Fenton R, Rotenberg D. Actinomycosis of the parotid.
Infect Dis Clin N Am 1988;2:203 – 19. Is it usually a masticator space infection? J Otolaryngol
[12] Schuster GS. Bacterial and protozoal infections with 1977;6:233 – 8.
oral manifestations. In: Topazian R, Goldberg M, edi- [32] Ficarra G, DiLollo S, Pierleoni F, et al. Actinomyces of
tors. Oral and maxillofacial infections. 3rd edition. Phi- the tongue: a diagnostic challenge. Head Neck 1993;
ladlphia: WB Saunders Co.; 1994. p. 557 – 77. 15:53 – 5.
[13] Gupta DS, Gupta MK, Naidu NG. Mandibular osteo- [33] Jordan HV, Kelly DM. Persistence of associated gram-
myelitis caused by Actinomyces israelii. J Oral Max- negative bacteria in experimental actinomycotic lesions
illofac Surg 1986;14:291. in mice. Infect Immunol 1983;40:847 – 9.
[14] Lewis RP, Sutter VL, Finegold SM. Bone infections [34] Jordan HV, Kelly DM, Heeley JD. Enhancement of
involving anaerobic bacteria. Medicine (Baltimore) experimental actinomycosis in mice by Eikenella cor-
1978;57:279 – 305. rodens. Infect Immunol 1984;46:367 – 71.
[15] Schaal KP, Beaman BL. Clinical significance of actino- [35] Lerner PI. Susceptibility of pathogenic Actinomycetes
mycetes. In: Goodfellow M, Mordarski M, Williams to antimicrobial compounds. Antimicrob Agents Che-
ST, editors. The biology of the Actinomycetes. New mother 1974;5:302 – 9.
York: Academic Press; 1983. p. 389 – 424. [36] Nakamatsu K, Shinohara M, Takenoshita Y, et al. Two
58 M.H. Goldberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 51–58

cases of actinomycosis of the submandibular region. sinuses: a case report and review. Otolaryngol Head
Jpn J Oral Maxillofac Surg 1986;32:68 – 74. Neck Surg 1996;114:818 – 21.
[37] Ozaki W, Abubaker AQ, Sotereanos GC, et al. Cervi- [40] Shaheen S, Ellis F. Actinomycosis of the larynx. J R
cofacial actinomycosis following sagittal split ramus Soc Med 1983;76:226 – 8.
osteotomy: a case report. J Oral Maxillofac Surg [41] Weir J, Buck W. Periapical actinomycosis. Oral Surg
1992;50:649 – 52. 1982;54:336 – 40.
[38] Rippon JW. Medical mycology. In: The pathogenic [42] Zajac I, Oribovac Z, Bagatin M. Temporal actinomy-
fungi and the pathogenic actinomycetes. 3rd edition. cosis: report of a case. J Oral Maxillofac Surg 1999;57:
Philadlphia: WB Saunders Co.; 1988. p. 30 – 52. 1370 – 2.
[39] Roth M, Montone KT. Actinomycosis of the paranasal
Oral Maxillofacial Surg Clin N Am 15 (2003) 59 – 67

Diagnosis and treatment of necrotizing fasciitis in the head


and neck region
Mark McGurk, MD, FRCS, DLO, FDSRCS
Department of Oral and Maxillofacial Surgery, Guy’s, King’s, and St. Thomas’ Dental Institute, Floor 23 Guy’s Tower,
Guy’s Hospital, London Bridge, London SE1 9RT, UK

A rare event encountered in current medical prac- cal infections are monitored nationally, and in the
tice is necrotizing fasciitis. Its presence is occasionally 5-year period from1989 to1994, 160 cases of necro-
brought to public attention by the press through head- tizing fasciitis were reported in England and Wales.
lines such as ‘‘Killer or Flesh-Eating Bug’’ [1], when Most were attributed to group A streptococci [1].
the impression is conveyed of the advent of a newly Because many cases are caused by polymicrobial
discovered disease. Nothing could be further from the infection, however, this was almost certainly an
truth because the condition was well known to the underestimate. In the United States, an estimated
military surgeons of past centuries. In his book ‘‘Lec- 10,000 to 15,000 cases of invasive group A strep-
tures on Inflammation,’’ J. Thomson, the Regius tococcal infections occur annually, of which 5% to
Professor of Military Surgery at Edinburgh [2], attri- 10% are necrotizing fasciitis, with a case fatality of
buted the first description of the disease to L. Gillespie, 28% [5]. A prospective population-based study of
who was a surgeon in the Royal Navy [3]. The group A streptococcal necrotizing fasciitis conducted
condition was known to Amboise Pare and can be in Ontario between November 1991 and May 1995
found in the writings of most army surgeons who kept showed that the incidence increased from 0.085 per
careful records of their experiences. Knowledge of the 100,000 population in the first 12 months to 0.4 per
disease can be traced back to Hippocrates, who gave a 100,000 population in the last year of the study [6].
classic description of the disease process: This pattern mirrors a world trend increase in group A
streptococcal infections since 1980 [7].
‘‘Sometimes a very small wound broke out and if Typically, necrotizing fasciitis occurs on the abdo-
such an accident was neglected great inflammation
men/perineum or lower limbs after trauma or surgery.
took place. In most of them the abscess ended in
suppurations and there was great falling off of the In a few cases (1% – 10%), however, it occurs in the
flesh, tendons and bones; and the defluxion which head and neck region, particularly when the patient’s
seated in the parts was not like pus, but a sort of health is already compromised. Delayed diagnosis is
putrefaction and the running was large and of various a common event because the condition can arise
characters. About the head these things were unexpectedly out of a seemingly trivial infection or
accompanied by falling off of the hairs of the head injury. The defining characteristic is rapid, progress-
and chin, the bones were laid bare and separated and ive tissue destruction that is disproportionate to the
there were excessive runnings; and these symptoms initial clinical signs and symptoms.
happened in fevers and without fevers.’’ [4] Despite modern advances in medicine, this dis-
ease presents similar problems currently just as it did
In modern practice, necrotizing fasciitis occurs
200 years ago. Necrotizing fasciitis is a clinical
sporadically, which makes a true estimate of its
syndrome rather than a pathologic entity. Mortality
prevalence difficult to ascertain. Invasive streptococ-
rates have been reported in the region of 40%.
Success depends on prompt diagnosis and treatment
E-mail address: mark.mcgurk@kcl.ac.uk without delay for microbiologic confirmation.

1042-3699/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.
PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 8 3 - 3
60 M. McGurk / Oral Maxillofacial Surg Clin N Am 15 (2003) 59–67

An historical perspective

The identification of disease entities from histor-


ical texts can be difficult because of changing nomen-
clature and vague clinical descriptions that lack
diagnostic detail; however, necrotizing fasciitis was
described clearly in the late eighteenth century by
Claude Pouteau, chief surgeon to the Hotel Dieu in
Lyon in 1783 [8]. At that time the disease complex
was given many names, such as ‘‘malignant ulcer,’’
‘‘gangrenous ulcer,’’ ‘‘putrid ulcer,’’ ‘‘phagedenis
ulcer,’’ ‘‘phagedena gangraenosa,’’ and ‘‘hospital
gangrene.’’ In the late eighteenth century, a series
of outbreaks affected the British Home Fleet. In Fig. 1. Private Milton Warren, aged 41 years, of the 1st
confined quarters the disease could spread quickly. Kentucky Cavalry was captured in August 1863 at the
Cumberland River. While in captivity at Richmond he was
On HMS San Josef the surgeon observed ‘‘. . .an ulcer
shot in the right elbow. An amputation was required on June
that had devoured the one side of a sailor’s face, 1, 1864. On June 20, the stump looked inflamed, and by
which had followed a blow on the ear, that was June 24, the whole stump and bone were exposed. He was
attended by a very slight wound’’ [9]. In the early treated with charcoal and yeast poultices, a generous diet,
nineteenth century, the disease was reported from and ale. By August the sloughing process had stopped and
military hospitals by the name of ‘‘hospital gan- he survived to claim his pension in 1873.
grene’’ or ‘‘phagedena gangraenosa.’’ In one case,
’’half the cranium was denuded, the bones having ease was also present at the Douglas hospital in
become as black as charcoal; in another the neck was Fredricksburg [13].
denuded to expose the trachea.’’ The characteristic In civilian life it was much less common and
features of the disease were as follows: occurred sporadically in clusters, being much less
contagious. The hospital surgeon of London knew a
 extreme rapidity with which the disease pro- form of it as a genital disease that was said to be
gressed (measured in hours), which distin- confined to prostitutes and the destitute, and a few
guishes it from standard gangrene; cases were admitted to St. Bartholomew’s Hospital
 a tendency to turn soft parts into a putrid, pulpy London [14], where the disease was aggressive and if
substance; unchecked ‘‘. . .involves in its ravages the vagina,
 severe pain together with a smell, which was perineum and anus and sometimes even the bladder
peculiar and extremely offensive; and uterus.’’ Fournier’s classical description of the
 starting at the site of a wound or following a condition was of phagedena of the penis and scrotum
trivial scratch and attacking young and healthy [15], but case histories demonstrated that it was the
persons and debilitated soldiers. same disease process as reported by the military
surgeons [16].
The disease was recorded in the Gendarmerie Sporadic cases continued to be reported into the
Hospital at Brussels after Waterloo [10], and Miss early twentieth century. An American surgeon
Nightingale noted 80 cases in 1 month at Scutari reported a hospital outbreak in Peking, where it was
[11]. The disease was well known to the surgeons more common than in the West [17]. Melaney iso-
in the American Civil War (Fig. 1), and Joseph lated a hemolytic Streptococcus from the wounds,
Jones (Confederate Army surgeon) is credited with and his name subsequently was associated with the
the first clear investigation and characterization of disease (Melaney’s gangrene). In 1952, Wilson
hospital gangrene [12]. It is not possible to discrim- coined the name ‘‘necrotizing fasciitis,’’ which
inate between the different types, but 2642 cases described the main feature of the disease and empha-
were reported, of which 1142 were fatal (Table 1). sized the polymicrobial nature of some of the infec-
A serious outbreak occurred in September 1862 in tions. Currently, it occurs as unexpected isolated
the hospitals at Fredrick and West Philadelphia after attacks so that few oral and maxillofacial surgeons
the battles of South Mountain and Antietam. In have any experience with it. The effects remain as
January 1863, because of the poor prisoner of war devastating as ever if not checked, however. This fact
sanitation in Richmond, three outbreaks occurred is illustrated by the aftermath of the Nevado del Ruiz
as the sick were transferred to Annapolis. The dis- volcano eruption in Colombia, where 38 patients
M. McGurk / Oral Maxillofacial Surg Clin N Am 15 (2003) 59–67 61

Table 1 mycosis that was particularly virulent and proved


Cases of gangrene by site and mortality recorded in the War lethal in 70% of cases [23].
of Rebellion Streptococcus pyogenes produce several virulence
No. of cases Fatal cases of factors that are likely to be involved in necrotizing
Site of gangrene (n) gangrene (n) fasciitis, including the extracellular pyrogenic exo-
Head and neck 60 23 (38%) toxins A, B, and C together with other exotoxins
Trunk 216 129 (60%) and superantigens [24]. Given this powerful viru-
Upper extremity 844 295 (35%) lence armory, it is perhaps surprising that invasive
Lower extremity 1522 695 (46%) S. pyogenes infections are relatively rare. One reason
From Barnes J. Gangrene. In: Medical and surgical history of for this might be the demonstration that mutations in
the War of Rebellion. 1867; Part III, Vol II Surgical History. the two-component CsrS/CsrR 2-component regula-
Government Printing Office. Washington, DC. p. 823 – 51. tory system led to increased virulence in a mouse
model [25]. It could be hypothesized that exotoxin
developed necrotizing fasciitis, and the disease proved production by S. pyogenes is normally tightly regu-
fatal in 47.7% of those people. lated but that when that control is lost through
mutation in the regulatory gene, a hypervirulent
Microbiology phenotype results. The pathogenesis of the polymi-
crobial form of the infection is unclear, although it is
Melaney was the first to associate group A strep- well known that consortia of bacteria work together
tococcal infections with severe necrotizing condi- to evade the host defenses and cause tissue damage.
tions, and this organism should be the principal Host factors may predispose to the rapid spread of
suspect in any rapidly progressive necrotizing infec- some infections.
tion. Because culture techniques have improved,
however, it has become clear that most necrotizing
wounds sustain a mixture of bacteria working syn- Classification, pathogenesis, and clinical features
ergistically. Various bacterial strains may dominate of necrotizing fasciitis
different wounds, but essentially necrotizing fasciitis
may be categorized into three types according to The history of necrotizing fasciitis has been domi-
the causative organism. (1) In cool and temperate nated by bacteriology. Pruitt [26] and Gorbach et al
climates it tends to be associated with group A [27] produced a bacterial classification, each of which
b-hemolytic streptococci (Streptococcus pyogenes) comprised five entities, and Simmons [28] produced
[6] alone or with Staphylococcus aureus. They are a third classification, which incorporated seven. Even
the only bacteria that seem to be able to generate a simplified clinical classification based on necro-
solely this clinical picture. Serotypes M1 and M3 are tizing cellulitis, necrotizing fasciitis, and myonecrosis
the most common S. pyogenes serotypes associated [23] is difficult to adopt because these entities are rare
with invasive disease [7], but multilocus sequence and clinical experience is unavailable to distinguish
typing has confirmed that a genetically diverse range between them. In practice this is not important
of strains is associated with these infections [18]. (2) because the initial treatment for all rapidly progres-
In many cases (up to 60%) the necrotizing fasciitis sive necrotizing infections is the same: wide surgical
may be polymicrobial, including one or more obligate débridement. Attempts to subclassify the disorder are
anaerobes [19,20]. Brook and Frazier [21] reviewed unnecessary [29] and may be a disadvantage if it
87 cases of necrotizing fasciitis over a 17-year period. leads to delay in surgery (even 24 – 48 hours) to
Of these cases, only 4 were monoinfections with obtain culture results. This principle greatly simpli-
S. pyogenes. In the remaining cases, anaerobic bac- fies the approach to clinical management. Ultimately,
teria were predominant, with Peptostreptococcus, success depends on rapid diagnosis of the early lesion
Prevotella, Porphyromonas, Bacteroides, and Clos- and prompt treatment.
tridium the commonest genera isolated. Facultative
anaerobic bacteria, such as Enterobacteriacae, are Pathogenesis
also important. Up to 11 bacterial species have been
cultured with various streptococci (groups B and F) in The overarching feature of necrotizing fasciitis is
attendance, not just group A [21]. (3) In tropical a rapid, progressive liquefaction of the subcutaneous
climates, the condition can be caused by members fat and connective tissue below a relatively normal
of the family Vibrionacae, which are of seawater looking skin surface. The fascial planes disintegrate,
origin [22]. In Colombia, the dominant genus was a and with the ensuing necrosis come edema and the
62 M. McGurk / Oral Maxillofacial Surg Clin N Am 15 (2003) 59–67

Fig. 2. (A,B) Necrotizing fasciitis arising from an infected tooth. The infection spread relentlessly, first into the neck and then the
chest wall. (C) The patient became systemically unwell. (D,E) After wide débridement the patient made a full recovery and is
married, with her own family. (Courtesy of Mr. P. McAndrew.)

release of tissue fluid. Early in the development of ardized and the skin becomes pale, which leads to
the disease the veins that traverse the liquefying necrosis and wet (coliquative) gangrene. The bacteria
subdermal fat become inflamed and start to throm- initiate an acute local inflammatory response within
bose, which gives the skin first a red and then a the dermis that is characterized by an intense poly-
mottled color. Later the arterial supply is also jeop- morphonuclear infiltrate, focal necrosis, and micro-
M. McGurk / Oral Maxillofacial Surg Clin N Am 15 (2003) 59–67 63

whereas a few cases involved the trunk and perineum.


The head and neck were involved in 1% to 10% of
cases. The condition even has been reported after
routine dental surgery or dental sepsis (Fig. 2).
The variable clinical picture means that delay in
diagnosis is common, because the prodromal period
in which the synergistic consortia of bacteria are
evolving may be only 3 or 4 days before the phase
of rapid acceleration. Diagnosis depends on being
alert to the possibility of the disease and recognizing
the pattern of clinical events, the main feature of
which is a rapidly progressive necrotizing infection.
The area is acutely painful, and the surrounding
tissues are red (the signs depend on the specific
mix of bacteria), but on close inspection a central
portion of skin is pale and toxic (Fig. 3). The skin
subsequently develops a slightly mottled appearance
as it becomes congested through venous stasis. As the
perfusion is further reduced through arterial failure,
the skin starts to blister. Sensory perception is lost as
nerves are destroyed and the wound weeps fluid from
the underlying liquefaction. Gross edema is a feature
of the disease, and gas may be present in up to 40%
Fig. 2 (continued ).
of cases [21]. The presence of gas is neither a reliable
abscess formation. The histologic picture is one of nor discriminatory sign for clostridial infections
arteriolar and venous thrombosis of the subcutaneous because it can be absent in gas gangrene and present
fat, whereas the adjoining muscle shows compara- in various nonclostridial infections [20]. Gas simply
tively little inflammation. denotes the presence of anaerobic bacteria [29]. A
marked leukocytosis (median 16,000 leucocytes/mm)
Clinical features is common, but 20% of patients have a normal white
cell count, and in some cases the count even may be
The rate of necrosis is disproportionate to the low. Fever is not always present, especially in the
signs and symptoms of infection. A small wound early stages of the disease.
can be painful. Early systemic symptoms may be With advancing disease the patient becomes pro-
subtle and amount to little more than a feeling of gressively unwell, with a general malaise and tachy-
malaise or tachycardia. If there are systemic symp- cardia. More than 50% of patients develop significant
toms in the presence of an apparently innocuous hypotension. In 10% to 30% of cases the disease is
wound, however, necrotizing fasciitis should be con- complicated by one or more of the following con-
sidered early. The incidence of this disease increases ditions: acute renal failure, coagulopathy, abnormal
with age (median age, 57 years) and most adult cases liver function, acute respiratory distress syndrome, or
(70%) occur in patients with at least one underlying hemolytic anemia. The rapid progression of the
chronic illness (immunosuppression, diabetes, alco- disease is a distinguishing feature.
hol/drug abuse, malignancy, or chronic systemic dis-
ease). Children by contrast tend not to have chronic Diagnosis
illness, but necrotizing fasciitis may complicate
chickenpox. Occasionally the disease afflicts appa- If the clinical features are suggestive of necro-
rently healthy individuals. It has been suggested tizing fasciitis, the diagnosis should not wait for the
(unconvincingly) that antiinflammatory medication results of bacterial culture. Clinical inspection of the
might predispose to these spreading infections by wound demonstrates that the subcutaneous fat has no
interfering with granulocyte function [30], but Kauls structural integrity and offers little resistance to the
et al [6] could find no such association. In two thirds exploring finger. The skin is widely undermined by
of cases, the necrosis followed either a skin lesion or the progressing infection. Histologic criteria have
trauma. In an otherwise normal Western population, been described for the early diagnosis of necrotizing
more than 50% of episodes occurred in the limbs, fasciitis by frozen section [31], and the typical pattern
64 M. McGurk / Oral Maxillofacial Surg Clin N Am 15 (2003) 59–67

Fig. 3. An emaciated patient presented with a large oral carcinoma (A) and a history of alcoholism with associated liver failure,
pancreatitis, and diabetes. Necrosis of the skin flaps occurred abruptly 72 hours after surgery (mixed flora) despite antibiotic
prophylaxis (B). Surgical débridement was followed by a regimen of dressing changes every 4 hours (C). Healthy granulating
tissue developed eventually (D) and the skin flaps reattached. The patient remains disease free 2 years after surgery (E).

of a dense polymorphonuclear infiltrate in the dermal Management


layers of the skin clinches the diagnosis. Samples of
necrotic tissue are uninformative; a biopsy should be Shock and multiorgan failure are relatively com-
taken from normal-looking adjacent tissue. A Gram’s mon, so resuscitation and general supportive mea-
stain may be helpful in selecting first-line antibiotics, sures are vital in the established case. Two treatments
and blood cultures typically produce positive results. are recommended: (1) surgery and (2) antibiotics, to
M. McGurk / Oral Maxillofacial Surg Clin N Am 15 (2003) 59–67 65

which hyperbaric oxygen might be added. Of these from beneath the yellow slime. The undermined skin
treatments, the single most important modality is at the edge of the wound reattaches to the underlying
surgery. There is no controversy regarding the initial granulation tissue and the packing can be withdrawn
management of spreading necrosis, the extent of slowly day by day. Regular dressing still should be
débridement being determined clinically [29]. Under- maintained at 8-hour intervals, which demands a
lying muscle can be preserved, but all necrotic tissue heavy nursing commitment.
and overlying skin must be removed. Resected tissue Ultimately, antibiotic therapy is dictated by the
(skin, muscle, connective tissue) should be sent for cultures, but intravenous penicillin is the initial drug
culture and antibiotic sensitivity (aerobic and anaer- of choice. If the Gram’s stain shows a mixed flora, a
obic), and Gram’s stain results should be obtained. broad-spectrum antibiotic also should be used (gen-
Time is of the essence at this stage, because mortality tamycin), and it can be supplemented as appropriate
is associated with delayed intervention. Even if information is obtained. Finally, hyperbaric oxygen
recognized promptly, significant necrosis usually has been suggested as a supportive measure, but
has taken place before resection is undertaken. More there is no definitive evidence of efficacy and there
than one débridement may be necessary and it is are obvious logistic problems if this technology
considered prudent to make a second operative is contemplated.
inspection of the wound after 24 to 36 hours.
Management is similar to that of an extensive
burn. The wounds should be washed (hydrogen Results
peroxide is useful for débridement) and packed
regularly (every 4 hours) (Fig. 4), a procedure best Despite proper management of necrotizing fascii-
done personally by the attending surgeon. Slowly the tis, mortality remains high. A collective review [32]
slough clears and shiny granulation tissue emerges [Janevicious, Han & Batt 1982] of 146 cases reported

Fig. 4. During the preparation of this article a 27-year-old man presented with a recent history of third molar infection (A). He
was otherwise healthy. The tooth was removed manually by the patient himself on a Sunday, he was admitted with low-grade
cervical infection the following Thursday, and submental necrosis developed overnight (B). Note the ring of ischemia around the
ulcer and the congestion in the surrounding tissue. Fluid can be seen leaking from the ulcer. The infection (mixed flora) settled
quickly after débridement (C) and standard antibiotic therapy. The wound was allowed to granulate before repair with a split
skin graft (D).
66 M. McGurk / Oral Maxillofacial Surg Clin N Am 15 (2003) 59–67

a 38% mortality rate. In a prospective study, Kaul [6] AE, Simor AE. Population based surveillance for
record ed a case fatality rate of 34%. Pessa and group A streptococcal necrotizing fasciitis: clinical
Howard [33] applied severity of illness scoring sys- features, prognostic indications and microbiological
analysis of seventy seven cases. Am J Med 1977;
tems to predict outcome. They found that the scores
103:18 – 24.
continued to rise after débridement in patients who
[7] Schlievert PM, Aris P, Assimacopoulos Cleary PP. Se-
were to die, and accurate prediction of survival could vere invasive group A streptococcal disease: clinical
be made as early as the third postoperative day. description and mechanism of pathogenesis. J Lab Clin
Mortality rates increase with age ( > 50 years of Med 1996;127:13 – 22.
age), concomitant illness (diabetes), delay in diag- [8] Blackadder HH. Observations on phagedena gangrae-
nosis or treatment [20], inadequate débridement, nosa. Edinburgh: David Brown; 1818.
lesions of the abdomen, and mucormycosis [23,32]. [9] Trotter T. Medicina nautical. London: Longman, Hurst,
In a multivariate analysis, age, hypotension, and Rees and Orme; 1797. p. 1 – 111.
bacteremia were independent variables that predicted [10] Henne J. Principles of military surgery. Edinburgh:
Constable; 1820.
mortality. Patients can die from systemic problems
[11] Nightingale F. Notes on hospitals, 3rd edition. London:
some days or weeks after the infection, and in
Longman, Green; 1863.
historical texts there are reports of fatal arterial bleeds [12] Jones J. Investigation upon the nature, causes and treat-
occurring approximately 10 days after surgery, just as ment of hospital gangrene as it prevailed in the Con-
the infective process is settling. federate armies 1861 – 1865. In: Hamilton FH, editor.
United States Sanitary Commission memoirs: surgical
II. New York: Riverside Press; 1871. p. 146 – 70.
[13] Barnes J. Gangrene. In: Barnes J, editor. Medical
Summary
and surgical history of the War of Rebellion. 1867.
p. 823 – 51.
Necrotizing fasciitis is a dramatic but rare disease. [14] Welbank R. On sloughing phagedaena. London: Long-
In the head and neck it often strikes unexpectedly. mans Brown and Green; 1844.
Early diagnosis and radical treatment are important to [15] Fournier JA. Gangrene fourdroyant de la verge. Sem-
maximize the chances of a good outcome. The aine Medicale 1883;3:345 – 7.
outcome depends on the clinician having a high [16] Travers T. Two cases of slough ulceration. London
threshold of suspicion when rapidly progressive local Medical and Physical Journal 1824;122 – 34.
and systemic symptoms appear in the presence of [17] Melaney F. Hemolytic Streptococcus gangrene. Arch
what was initially an apparently innocuous wound. Surg 1924;9:317 – 64.
[18] Enright MC, Spratt BG, Kalia A, Cross JH, Bessen
Diagnosis is achieved principally by inspection and
DE. Multilocus sequence typing of Streptococcus pyo-
manual examination during explorative surgery but genes and the relationships between emm type and
can be supported by frozen section examination. clone. Infect Immunol 2001;69:2416 – 27.
Treatment is mainly surgical, helped by general [19] Giuliano A, Lewis F, Hadley K, Blaisdell FW. Bacteri-
measures of support to combat the systemic effects ology of necrotizing fasciitis. Am J Surg 1977;
of circulating toxins. The key to success is captured 134:52 – 7.
in a line by Shakespeare in Macbeth: ‘‘Be bloody, [20] Freischlag JA, Ajalat G, Busuttil RW. Treatment of
bold and resolute.’’ necrotizing soft tissue infections. Am J Surg 1985;
149:751 – 5.
[21] Brook I, Frazier EH. Clinical and microbiological fea-
tures of necrotizing fasciitis. J Clin Microbiol 1995;
References 33:2382 – 7.
[22] Joynt GM, Gommersall CD, Lyon DJ. Severe necrot-
[1] Deans M. Flesh-eating bugs scare. Lancet 1994; izing fasciitis of the extremities caused by Vibrionacae:
343:1418. experience of a Hong Kong Territory referral hospital.
[2] Thomson J. Hospital gangrene or malignant ulcers. In: Hong Kong Med J 1999;5:63 – 8.
Lectures on inflammation. Edin: James Ballantyne and [23] Patino J, Castro D, Valencia A, Morales P. Necrotizing
Co.; 1813. p. 456 – 500. soft tissue lesions after a volcanic cataclysm. World J
[3] Gillespie L. Observations on the putrid ulcer. London Surg 1991;15:240 – 7.
Medical Journal 1785;6:373 – 400. [24] Cunningham MW. Pathogenesis of group A streptococ-
[4] Adams F. The genuine works of Hippocrates. London: cal infections. Clin Microbiol Rev 2000;13:470 – 511.
Sydenham Society; 1771. p. 400 – 1. [25] Engleberg NC, Heath A, Miller A, Rivera C, Di Rita
[5] Anonymous. Invasive group A streptococcal infec- VJ. Spontaneous mutations in the CsRS two compo-
tions. JAMA 1994;272:16. nent regulatory system of Streptococcus pyogenes re-
[6] Kauls R, McGeer A, Low DE, Green K, Schwartz sulting in enhanced virulence in a murine model of
M. McGurk / Oral Maxillofacial Surg Clin N Am 15 (2003) 59–67 67

skin and soft tissue infection. J Infect Dis 2001;183: multiple disease entities requiring a common approach.
1043 – 54. JAMA 1981;246:1717 – 21.
[26] Pruitt BA. Burns and soft tissues. In: Polk Jr HC, [30] Brun-Buisson CJL, Saada M, Trunet P, Rapin M, Rou-
editor. Infection and the surgical patient: clinical sur- jeau J, Revuz J. Haemolytic streptococcal gangrene
gery international. London: Churchill-Livingstone; and non-steroidal anti-inflammatory drugs. BMJ
1982. p. 113 – 31. 1985;290:1786.
[27] Gorbach SL, Bartlett JG, Nichols RL. Manual of sur- [31] Stamenkovic I, Lew PD. Early recognition of poten-
gical infections: skin and soft tissue infections. Boston: tially fatal necrotizing fasciitis: the use of frozen sec-
Little Brown and Co.; 1984. tion biopsy. N Engl J Med 1984;310:1689.
[28] Simmons RL, Ahrenholz DH. Infections of the skin [32] Janevicius RV, Hann SE, Batt MD. Necrotizing fascii-
and soft tissues. In: Howard RJ, Simmons RL, editors. tis. Surg Gynecol Obstet 1982;154:97 – 102.
Surgical infections diseases. 2nd edition. Norwalk: Ap- [33] Pessa ME, Howard RJ. Necrotizing fasciitis. Surg Gy-
pleton and Lange; 1988. p. 404 – 8. necol Obstet 1985;161:357.
[29] Dellinger EP. Severe necrotizing soft-tissue infections:
Oral Maxillofacial Surg Clin N Am 15 (2003) 69 – 78

Diagnosis and treatment of diffuse sclerosing


osteomyelitis of the jaws
Marjut Montonen, MD, DDSa,*, Christian Lindqvist, MD, DDS, PhDa,b
a
Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Surgical Hospital,
P.O. Box 263, Fin-00029 HUS, Finland
b
Department of Oral and Maxillofacial Surgery, Helsinki University Central Hospital, Institute of Dentistry,
P.O. Box 263, Fin - 00029 HUS, Helsinki, Finland

Diffuse sclerosing osteomyelitis of the jaws is an myelitis by its more insidious onset, which is char-
inflammatory condition that is a consequence of acterized by acute exacerbations of pain and swelling
vascular changes and nonspecific bacterial infection but a general lack of purulent drainage.
in which bone deposition rather than bone resorption Most investigators believe that diffuse sclerosing
occurs [1 – 3]. Diagnosis is based on clinical and osteomyelitis is caused by bacteria that are not
radiologic findings and histopathologic findings relat- particularly virulent; however, no specific causative
ing to bone specimens. Histopathologic findings in micro-organisms have yet been identified. Various
the maxilla and in the mandible are similar, but the bacteria have been reported in some studies, but
symptoms—which are characterized by intermittent contamination of the culture specimen by organisms
pain resistant to almost all treatment—and specific on the skin or oral mucosa could not be excluded
radiological changes relate almost exclusively to the [11 – 13]. It has been suggested that a hyperactive
mandible [3 – 10]. immunologic reaction to the bacterial toxins may be
responsible for the chronic inflammatory response.
There is generally no identifiable bacterial port of
Etiology and pathogenesis entry, but chronic periodontal disease has been impli-
cated as a possible source. Diffuse sclerosing osteo-
In osteomyelitis of the jaws following pulpal or myelitis is difficult to eradicate and may persist for
periodontal infections, there is inflammation of both years, with intermittent symptoms of pain and swell-
the cortical and cancellous bone. In the acute form, ing of the face [5,11,14].
there is pain, swelling, and purulent discharge. The
condition is generally curable by antibiotics, drain-
age, and removal of the offending teeth; however, if Differential diagnosis
the condition is untreated or inadequately treated, the
infection becomes chronic and eradication may Diffuse sclerosing osteomyelitis should be distin-
require extensive sequestrectomy as well as antibiotic guished from secondarily infected florid osseous
therapy. Diffuse sclerosing osteomyelitis differs from dysplasia. In the latter, apart from inflammation and
the acute and chronic suppurative forms of osteo- reactive changes, histological studies reveal a fibro-
blastic stroma with bone and cementum-like struc-
tures that have been formed as a result of metaplasia
[15]. Diffuse sclerosing osteomyelitis may even
* Corresponding author. indicate the mandibular location of SAPHO (syn-
E-mail address: marjut.montonen@hus.fi ovitis, acne, pustulosis, hyperostosis, osteitis) syn-
(M. Montonen). drome [16 – 19].

1042-3699/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.
PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 7 3 - 0
70 M. Montonen, C. Lindqvist / Oral Maxillofacial Surg Clin N Am 15 (2003) 69–78

Clinical findings left edge of the line indicates no pain, and the right
edge indicates the worst possible pain [22]. The
The most important criteria for diagnosis of dif- McGill Pain Questionnaire involves the patient
fuse sclerosing osteomyelitis of the jaws are history choosing words from various categories that describe
of intermittent pain, swelling, trismus, pressure and the nature of the pain as well as its intensity [21].
paresthesia. These symptoms can appear at any age
and often persist for years. Exacerbations are charac-
terized by a marked inflammatory reaction in the Radiologic findings
bone marrow leading to sensitization and stimulation
of primary afferent nociceptive nerves, which results Radiographic and scintigraphic investigations are
in intense, sometimes unbearable pain, particularly in used to increase diagnostic accuracy and improve
the lower jaw [8,9,20]. prognostic and therapeutic judgements [7,23 – 26].
Because pain is the most important symptom of Whereas a typical feature of suppurative osteomye-
diffuse sclerosing osteomyelitis, standardization of litis of infectious origin is a radiolucent lesion spread-
measurement of pain and employment of a question- ing through the cancellous bone, with cortical bone
naire detailing the history of the pain are useful in perforation and a lamellated periosteal reaction, in
clinical examination. Using such means, the nature chronic sclerosing osteomyelitis, intermingled scle-
and intensity of pain can be classified. Classification rotic and osteolytic lesions with a solid periosteal
is necessary from a differential diagnostic point of reaction or external bone resorption are common
view, and in deciding treatment and evaluating its findings [24]. However, with the passage of time,
effects [20]. Pain can be measured using a visual sclerosis becomes increasingly marked, and normal-
analogue scale, the McGill Pain Questionnaire,a pain- ization of bone structure is rare [7].
relief scale, or a pain diary [21,22]. The visual Panoramic and intraoral radiographs and 99mTc-
analogue scale involves the patient drawing a mark scintigraphy are most often used for diagnosis, deter-
on a 100-mm horizontal line on a piece of paper. The mination of disease activity, and follow-up [7,9]. CT

Fig. 1. (A) Vertical and horizontal osteotomies over the osteomyelitic lesion. (B) Removal of the lateral cortical bone to the
exposed cancellous bone. (C) Bur holes have been drilled through lingual cortex.
M. Montonen, C. Lindqvist / Oral Maxillofacial Surg Clin N Am 15 (2003) 69–78 71

scans and MRI techniques can also be used to deter-


mine extent of disease, especially when planning
primary surgical therapy [2,24,27,28]. However,
MRI techniques may be less useful during follow-up
after surgery because of disturbing artifacts related to Table 1
the use of metallic instruments. Yoshimura et al [28] Unpublished data on patients with diffuse sclerosing
osteomyelitis treated in the Department of Oral and
showed by CT scan a close interaction between cortical
Maxillofacial Surgery at Helsinki University Central Hospital
plate disruption and muscle inflammation. Compared
with plain film, the extent of the soft tissue involve- Characteristics Years Number
ment could be better appreciated with CT scans, Sex
especially in mixed pattern cases [28]. Along with Female 59
this, detecting and localization of active sequestra will Male 43
be improved by the use of MRI, CT scans, or single Age at onset of symptoms Mean 27.5
Range 5 – 77
photon emission computerized tomography (SPECT)
Dental status
with 99mTc hydroxymethylene diphosphonate (HDP)
Edentulous 10
when planning surgical debridement [2,29]. Dentate 92
Location of symptoms
Maxilla 2
Histologic findings Mandible 100
Dentate area 102
Histologic examination and various enzyme Other regions 98
immunohistochemical investigations of bone speci- Symptoms
mens are necessary to establish diagnosis. These can Pain 102
Swelling 100
be obtained by using an accurate biopsy technique.
Trismus 100
Use of a rotating trepan bur is preferred in attempting
Duration of disease Mean 13.5
to obtain representative bone specimens [30]. Scler- Range 0.5 – 42
otic changes have been described mainly in the Diagnosis
subperiosteal parts of biopsy specimens from the Clinical 102
lower jaw using this technique. Coarse trabeculae Radiologic 102
and necrotic foci, partly calcified, thin trabeculae Histologic 102
reminiscent of fibrous dysplasia, and granulation Conservative treatment
tissue with chronic inflammatory cell and foreign- Outpatients 102
body giant cells have been found in cancellous bone Inpatients 77
Inpatients in pain clinic 36
[8,9,30 – 32]. The histopathology of diffuse sclerosing
Systemic antibiotics 102
osteomyelitis in the maxilla and mandible is probably
Nonsteroidal 102
the same; however, diffuse sclerosing osteomyelitis antiinflammatory drugs
of the maxilla has been mentioned in only a few Systemic steroids 42
reports [1,33,34]. Disodium clodronate 36
Weak or strong opioids 102
Anticonvulsants 10
Laboratory findings Antidepressants 8
Physiotherapy 67
In general, there are no specific laboratory tests Hyperbaric 9
oxygen treatment
for determining the stage of diffuse sclerosing osteo-
Surgery
myelitis except for the mean erythrocyte sedimenta-
Dentoalveolar surgery 28
tion rate, which can be slightly elevated during Revision, removal 15
exacerbations. In attempts to discover a suitable tool of sequestrum
for evaluation of the results of treatment, the serum Decortication 47
levels of alpha-1-antitrypsin, orosomucoid, and hap- Partial resection 2
toglobin have been measured during different stages; Resection and 1
however, caution must be exercised when general- reconstruction with
izing from results of single measurements. Serum microvascular bone craft
levels of C-reactive proteins seem to reflect the Combination of conservative 94
therapy and surgery
clinical activity of the disease, but a certain ‘‘mass
72 M. Montonen, C. Lindqvist / Oral Maxillofacial Surg Clin N Am 15 (2003) 69–78

of inflammation’’ is necessary before elevated values chronicity of the disease cannot be explained by
of these proteins can be detected [35]. Leukocyte and immunologic findings [11,36].
platelet counts, as well as serum levels of osteocalcin,
parathyroid hormone, creatinine, calcium, phosphate,
aspartate aminotransferase, alanine aminotransfer- Bacteriologic findings
ase, albumine, and alkaline phosphatase, remained
within normal limits [20]. Various attempts have been made to determine the
Because the synthesis of immunoglobulins only causes of diffuse sclerosing osteomyelitis. Bacterio-
reflects inflammatory activity indirectly, immunoglo- logic investigations of specimens from diseased bone
bulines are not regarded as appropriate markers of have been undertaken, paying particular attention to
inflammation. However, their concentration in serum anaerobic culture techniques. Few studies involving
can vary with clinical activity [35]. Immunological healthy controls have been performed. Some bac-
findings suggest that most patients with diffuse scle- teria—including Propionibacterium acnes, Pepto-
rosing osteomyelitis have normal humoral and cel- streptococcus intermedius, Eikenella corrodens,
lular responses. The inflammatory events and Actinomyces species, Streptococcus sanguis, Strep-

Fig. 2. (A) Panoramic radiographs of a 17-year-old female with a 9-month history of pain and swelling on the right side of the
mandible preceded by prolonged endodontic treatment of the second molar. (B) Wide lytic areas can be seen in connection with
the teeth and in the body of the mandible. (C) Uptake of 99mTc-diphosphonate corresponding to the radiographic changes.
M. Montonen, C. Lindqvist / Oral Maxillofacial Surg Clin N Am 15 (2003) 69–78 73

tococcus mitis, and Fusobacterium nucletum—have the disease, its causes, and its natural history is not
been found, but in very small numbers [11 – 13]. known. Long-term antibiotic therapy can have a
However, contamination with skin or oral flora cannot beneficial effect on the course of the disease in its
be avoided despite improvements of sampling techni- early stages, while corticosteroid therapy and some-
ques. The results of bacteriological and serological times decortication can be more effective once the
investigations indicate that Propionibacterium acnes condition has become chronic [37]. The type of
and Peptostreptococcus intermedius may be of sig- antibiotics and the exact duration of treatment are
nificance in relation to the disease but cannot explain difficult to establish [40]. The clinical efficacy of
its chronicity [11]. One bacteriologic study comparing long-term roxithromycin treatment (300 mg/day
patients with diffuse sclerosing osteomyelitis of the orally for 68 days to 66 months) in patients with
mandible with healthy controls has been done, and this diffuse sclerosing osteomyelitis of the mandible has
study found no difference in the quantity or quality of been studied [41]. In seven of nine cases (77.8%)
bacteria in the bone samples [13]. No particular group the symptoms disappeared 1 month to 1 year after
of bacteria was unequivocally associated with disease. the start of therapy. Radiography showed that
Thus, the findings probably reflected contamination. osteolysis had decreased but that osteosclerosis
had persisted or increased by the end of therapy.
The optimum duration of treatment should be
Therapy determined based on the amelioration of symptoms
and the disappearance of osteolytic findings on
Nonsurgical treatment radiographs. The mechanism of action of roxithro-
mycin is not yet fully understood, but long-term
There is no cure for diffuse sclerosing osteomye- roxithromycin treatment may be useful before sur-
litis [37 – 39]. The main reason is that knowledge of gical treatment is considered [41].

Fig. 3. (A) Two years after onset of the disease, an exacerbation occurred with swelling of the mandible and severe pain. (B)
Predominantly sclerotic areas are seen in the right body and angle and new lytic areas as present in the ramus of the mandible.
(C) An intensive uptake of 99mTc-diphosphonate corresponds to the swollen and painful area of the mandible.
74 M. Montonen, C. Lindqvist / Oral Maxillofacial Surg Clin N Am 15 (2003) 69–78

The inflammatory nature of the disease has been Surgery


demonstrated by alleviation of ostomyelitic pain
through administration of glucocorticosteroids [37]. Surgical treatment of diffuse sclerosing osteomye-
Hyperbaric oxygen has often been recommended as litis involves decortication and removal of any foci of
an adjunct to treatment of diffuse sclerosing osteo- infection and sequestra [37,40,46]. The results of
myelitis of the jaws with antibiotics and surgery decortication have been described by Hjørting-Hansen
[37,39]. The results of hyperbaric oxygen treatment [47], Jacobsson and Hollender [37], and Montonen et
of chronic osteomyelitis of the jaws have been al [38]. They reported a success rate in relation to to
described by van Merkesteyn et al [39]. mandibular decortication of about 50%. Symptoms
Disodium clodronate, a bisphosphonate, is a generally recurred within a year of surgery. Advanced
potent anti-osteolytic agent which has been used to age at the time of decortication and the presence of
treat diseases of bone and calcium metabolism [42 – carious or poorly endodontically treated teeth in the
44]. It has also been found to be useful for treatment decorticated area correlated with recurrence [14].
of recurrent pain of diffuse sclerosing osteomyelitis Decortication can be performed intraorally or
unresponsive to conservative or surgical therapy extraorally and should be preceded by intravenous
[13,45]. In a randomized, placebo-controlled, dou- antibiotics and hyperbaric oxygen treatment for opti-
ble-blind study, patients received disodium clodro- mial results. After horizontal and vertical burr cuts
nate (300 – 900 mg) or placebo intravenously. have been made in the lateral cortex covering the
Disodium clodronate administration resulted in no diseased area, pieces of cortical and cancellous bone
better immediate pain relief than administration of can be removed using a chisel. Perforations can then be
placebo. However, 6 months after treatment there was drilled into the bleeding marrow cavity before closure
a statistically significant difference in pain intensities of the wound to improve bone nutrition (Fig. 1) [38].
between the groups, with the disodium clodronate In cases in which decortication fails, resection of
group experiencing significantly less pain [13]. affected areas has been recommended [48 – 50]; how-

Fig. 4. (A) The patient was symptom-free 6 months after combined conservative treatment consisting of removal of the third
molar, intravenous antibiotics, hyperbaric oxygen, and disodium clodronate. (B) There was remodeling of the mandible bone
along with increasing sclerosis of the angle and the body of the mandible.
M. Montonen, C. Lindqvist / Oral Maxillofacial Surg Clin N Am 15 (2003) 69–78 75

ever, resection should be limited to severe, therapy- subacute suppurative osteomyelitis and osteoradio-
resistant cases because of potential disadvantages necrosis were excluded. Thirty-three patients are still
such as loss of function of the inferior alveolar nerve being followed and are receiving therapy as neces-
and problems related to mandibular reconstruction sary. All patients had been clinically and radiograph-
[14]. It would therefore seem preferable to choose ically examined, and the diagnoses have been verified
saucerization combined with particulate cancellous by histological investigation (Table 1). All patients
bone and marrow grafting as a relatively conservative had typical symptoms with intermittent pain, swell-
surgical treatment for diffuse sclerosing osteomyelitis ing, trismus, and radiological changes.
of the mandible [51]. The topical application of a A typical example is a young woman with a
broad spectrum antibiotic to the surgical bed after 6-year history of the disease whose radiographs are
removal of the affected jaw bone has been reported in shown in Fig. 2. Her symptoms first occured in the
only two case reports [46,52]. The outcome of this right second molar area at the age of 17. The location
therapy was not better than decortication alone. of symptoms varied subsequently between the ramus
and symphysis of the mandible. Erupting third molars
were considered to be the infectious foci and were
Personal experience extracted. Hyperbaric oxygen treatment was under-
taken before and after the operation, and antibiotics
Records relating to 102 patients (59 women, were administered intravenously (Fig. 3). Bone –
43 men) with diffuse sclerosing osteomyelitis treated tissue specimens were taken from the affected man-
between 1962 and 2002 in the Department of Oral dible by means of minor decortication. They exhibited
Maxillofacial Surgery at Helsinki University Central typical histologic changes, namely subcortical scle-
Hospital were retrospectively analyzed (unpublished rosis and moderate chronic medullar inflammation
data, M. Montonen, 2002). Patients with acute and with mononuclear cell infiltration. Microbial findings

Fig. 5. (A) After a symptom-free period of 13 months, increased pain and swelling occurred in the right ramus, body, and
symphysis of the mandible. (B) Panoramic radiograph showing sclerotic changes in the body, angle, and ramus of the mandible
and lytic lesions in the coronoid process (arrow) and adjacent to the right first premolar and central incisors, which had a positive
response to electrical stimulation. (C) Intense uptake of 99mTc-diphosphonate corresponds in the dentate area of the mandible.
76 M. Montonen, C. Lindqvist / Oral Maxillofacial Surg Clin N Am 15 (2003) 69–78

Fig. 6. (A) Panoramic radiograph of a 22-year-old woman with a 3-year history of diffuse sclerosing osteomyelitis of the
mandible taken 2 weeks before surgery. Mixed lytic radiographic lesions are present in the mandibular body, ramus, and condylar
process. The teeth with periapical lesions had a positive response to electrical stimulation. (B) Panoramic radiograph taken
6 years after surgery. The mandible appears radiologically normal and the patient is symptom-free.

with spare oral flora were equal from the diseased and Summary
the contralateral side of the mandible bone, resem-
bling the results from the previous study with mis- Early clinical and radiological diagnosis of diffuse
taken contamination [13]. Seven months after surgery sclerosing osteomyelitis and effective, combined con-
the patient was symptom-free, but sclerosis in the servative and surgical treatment, including meticu-
body and the ramus of the mandible was increasing lous dental care by a specialist, may improve the
(Fig. 4). Despite operative treatment; long-term ad- chance of avoiding a poor outcome. There should be
ministration of antibiotics, anti-inflammatory drugs, regular follow-up by a specialist in a facial pain clinic
and disodium clodronate; and hyperbaric oxygen where there are possibilities of oral and maxillofacial
treatment, symptoms recurred after 1.5 years in the consultation. Such an approach should facilitate rapid
right premolar and incisor regions. There were lytic and efficient evaluation of pain and treatment of
radiological changes and increased uptake in the exacerbations. To minimize the likelihood of exacer-
99m
Tc-scintigram (Fig. 5). The teeth in the affected bations, even regular dental checkups and treatments
area were vital and were not endodontically treated. If should be performed.
symptoms persist despite continued medical treat-
ment, either the new endodontic therapy of the right
second molar should be performed or the tooth
should be extracted, because it may act as the focus References
of infection despite an apparently satisfactory
root filling. [1] Bell WH. Sclerosing osteomyelitis of the mandible and
Only two cases of maxillary diffuse sclerosing maxilla. Oral Surg Oral Med Oral Pathol 1959;12:
391 – 402.
osteomyelitis have been reported; the disease mostly
[2] Schuknecht BF, Carls FR, Valavanis A, Sailer HF.
affects the mandible. The pain in the maxilla differed Mandibular osteomyelitis: evaluation and staging in
from that associated with diffuse sclerosing osteo- 18 patients, using magnetic resonance imaging, com-
myelitis of the mandible. These patients had neuro- puted tomography and conventional radiograps. J Cra-
pathic pain with a burning sensation or a feeling of nio-Maxillofacial Surg 1997;25:24 – 33.
dull, deep pressure. In both cases there was a dental [3] Thomas DW, Shepherd JP. Paget’s disease of bone:
problem before symptoms occurred. Radiologically, current consepts in pathogenesis and treatment. J Oral
the disease was characterized by mixed sclerotic and Pathol Med 1994;23:12 – 6.
osteolytic changes of the mandibular bone, but there [4] Adekeye EO, Cornah J. Osteomyelitis of the jaws:
were few radiological findings in the upper jaw. a review of 141 cases. Br J Oral Maxillofac Surg
1985;23:24 – 35.
Only 1 of 100 patients with mandibular diffuse
[5] El-Mofty S. Chronic diffuse sclerosing osteomyelitis.
sclerosing osteomyelitis experienced complete clin- Oral Surg Oral Med Oral Pathol 1973;36:898 – 904.
ical and radiological recovery from the disease. This [6] Hudson JW. Osteomyelitis of the jaws. J Oral Maxil-
patient had suffered typical intermittent symptoms lofac Surg 1993;51:1294 – 301.
with typical findings for 9 years but has now been [7] Jacobsson S, Hollender L. Chronic sclerosing osteo-
free from symptoms for over 10 years (Fig. 6) [38]. myelitis of the mandible. Scintigraphic and radio-
M. Montonen, C. Lindqvist / Oral Maxillofacial Surg Clin N Am 15 (2003) 69–78 77

graphic findings. Oral Surg Oral Med Oral Pathol rating scale and the visual analogue scale. Pain 1975;1:
1978;45:167 – 74. 379 – 84.
[8] Jacobsson S. Diffuse sclerosing osteomyelitis of the [23] Rohlin M. Diagnostic value of bone scintigraphy in
mandible. Int J Oral Surg 1984;13:363 – 85. osteomyelitis of the mandible. Oral Surg Oral Med
[9] van Merkesteyn JP, Groot RH, Bras J, Bakker DJ. Dif- Oral Pathol 1993;75:650 – 7.
fuse sclerosing osteomyelitis of the mandible: Clinical, [24] Suei Y, Taguchi A, Tanimoto K. Radiographic evalua-
radiographic and histologic findings in twenty-seven tion of possible etiology of diffuse sclerosing osteo-
patients. J Oral Maxillofac Surg 1988;46:825 – 9. myelitis of the mandible. Oral Surg Oral Med Oral
[10] Wannfors K, Hammarström L. A proliferative inflam- Pathol Oral Radiol Endod 1997;84:571 – 7.
mation in the mandible caused by implantation of an [25] von Wowern N, Hjørting-Hansen E, Edeling CJ. Bone
infected dental root: a possible experimental model for scintigraphy of benign jaw lesions. Int J Oral Surg
chronic osteomyelitis. Int J Oral Maxillofac Surg 1978;7:528 – 33.
1989;18:179 – 83. [26] Tsuchimochi M, Higashino N, Okano A, Kato J. Study
[11] Jacobsson S, Dahlén G, Möller Å. Bacteriologic and of combined technetium 99m methylene diphoshonate
serologic investigation in diffuse sclerosing osteomye- and gallium 67 citrate scintigraphy in diffuse scleros-
litis (DSO) of the mandible. Oral Surg Oral Med Oral ing osteomyelitis of the mandible. J Oral Maxillofac
Pathol 1982;54:506 – 12. Surg 1991;49:887 – 97.
[12] Marx R, Carlson E, Smith B, Toraya N. Isolation of [27] Orpe EC, Lee L, Pharoah MJ. A radiological analysis
Actinomyces species and Eikenella corrodens from of chronic sclerosing osteomyelitis of the mandible.
patients with chronic diffuse sclerosing osteomyelitis. Dentomaxillofac Radiol 1996;25:125 – 9.
J Oral Maxillofac Surg 1994;52:26 – 33. [28] Yoshiura K, Hijiya T, Ariji E, Sa`do B, Nakayama E,
[13] Montonen M, Jousimies-Somer H, Lindqvist C. Higuchi Y, et al. Radiographic patterns of osteomyelitis
Quantitative microbial findings in diffuse sclerosing in the mandible. Plain film/CT correlation. Oral Surg
osteomyelitis (DSO) of the mandible. Presented at Oral Med Oral Pathol 1994;78:116 – 24.
the 15th Congress of European Association for Cra- [29] Robinson CB, Higginbotham-Ford EA. Determination
nio-Maxillo-Facial Surgery. Edinburgh, Scotland, Sep- of sequestrum activity by SPECT with CT correlation
tember 5 – 9, 2000. in chronic osteomyelitis of the head and neck. J Oto-
[14] Panders AK, Hadders HN. Chronic sclerosing inflam- laryngol 1986;15:279 – 81.
mations of the jaw. Oral Surg Oral Med Oral Pathol [30] Jacobsson S, Heyden G. Chronic sclerosing osteomye-
1970;30:396 – 412. litis of the mandible. Histologic and histochemical
[15] Shakenovsky BN, Ripamonti U, Lownie JF. Chronic findings. Oral Surg Oral Med Oral Pathol 1977;43:
osteomyelitis of the jaws. Int J Oral Maxillofac Surg 357 – 64.
1986;15:352 – 6. [31] Shafer WG. Chronic sclerosing osteomyelitis. J Oral
[16] Eyrich GK, Harder C, Sailer HF, Langenegger T, Surg 1957;15:138 – 42.
Bruder E, Michel BA. Primary chronic osteomyelitis [32] Wannfors K, Hammarström L. Infectious foci in
associated with synovitis, acne, pustulosis, hyperosto- chronic osteomyelitis of the jaws. Int J Oral Surg
sis and osteitis (SAPHO syndrome). J Oral Pathol Med 1985;14:493 – 503.
1999;28:456 – 64. [33] Deane CE. Chronic diffuse sclerosing osteomyelitis of
[17] Kahn MF, Hayem F, Hayem G, Grossin M. Is diffuse the maxilla and mandible. Oral Surg Oral Med Oral
sclerosing osteomyelitis of the mandible part of the Pathol 1978;46:872 – 3.
synovitis, acne, pustulosis, hyperostosis, osteitis (SA- [34] Tooley M, Towns BS. Chronic sclerosing osteomyelitis
PHO) syndrome? Analysis of seven cases. Oral Surg of maxilla and mandible: review of the literature and
Oral Med Oral Pathol 1994;78:594 – 8. report of case. J Oral Surg 1972;30:903 – 5.
[18] Suei Y, Taguchi A, Tanimoto K. Diffuse sclerosing [35] Wannfors K, Hansson LO. Plasma protein changes in
osteomyelitis of the mandible: its characteristics and chronic osteomyelitis of the jaws. J Oral Pathol Med
possible relationship to synovitis, acne, pustulosis, hy- 1991;20:81 – 5.
perostosis, osteitis (SAPHO) syndrome. J Oral Maxil- [36] Malmström M, Fyhrquist F, Kosunen TU, Tasanen A.
lofac Surg 1996;54:1194 – 200. Immunological features of patients with chronic scle-
[19] Valleala H, Montonen M, Lindqvist C, Kahn M-F, rosing osteomyelitis of the mandible. Int J Oral Surg
Konttinen YT. Tuntematon SAPHO [The unknown 1983;12:6 – 13.
SAPHO]. Duodecim 2000;116:1985 – 9. [37] Jacobsson S, Hollender L. Treatment and prognosis of
[20] Montonen M, Kalso E, Pylkkänen L, Lindström BM, diffuse sclerosing osteomyelitis (DSO) of the mandi-
Lindqvist C. Disodium clodronate in the treatment of ble. Oral Surg Oral Med Oral Pathol 1980;49:4 – 14.
diffuse sclerosing osteomyelitis (DSO) of the mandi- [38] Montonen M, Iizuka T, Hallikainen D, Lindqvist C.
ble. Int J Oral Maxillofac Surg 2001;30:313 – 7. Decortication in the treatment of diffuse sclerosing os-
[21] Melzack R. The McGill Pain Questionnaire: major teomyelitis of the mandible. Oral Surg Oral Med Oral
properties and scoring methods. Pain 1975;1:277 – 99. Pathol 1993;75:5 – 11.
[22] Onhaus EE, Adler R. Methodological problems in the [39] van Merkesteyn JP, Bakker DJ, van der Waal I, Kusen
measurement of pain: a comparison between the verbal GJ, Egyedi P, van den Akker HP, et al. Hyperbaric
78 M. Montonen, C. Lindqvist / Oral Maxillofacial Surg Clin N Am 15 (2003) 69–78

oxygen treatment of chronic osteomyelitis of the jaws. pregnated polymethylmethacrylate (PMMA) beads in
Int J Oral Surg 1984;13:386 – 95. the treatment of primary chronic osteomyelitis of the
[40] Ord RA, El Attar A. Osteomyelitis of the mandible in mandible. Br J Oral Maxillofac Surg 1990;28:367 – 74.
the children: clinical presentation and review of man- [47] Hjørting-Hansen E. Decortication in treatment of os-
agement. Br J Oral Maxillofac Surg 1987;25:204 – 17. teomyelitis of the mandible. Oral Surg Oral Med Oral
[41] Yoshii T, Nishimura H, Yoshikawa T, Furudoi S, Yosh- Pathol 1970;29:641 – 55.
ioka A, Takenono I, et al. Therapeutic possibilities of [48] Glahn M. The surgical treatment of chronic osteo-
long-term roxithromycin treatment for chronic diffuse myelitis of the mandible. J Maxillofac Surg 1974;2:
sclerosing osteomyelitis of the mandible. J Antimicrob 238 – 41.
Chemother 2001;47:631 – 7. [49] Head MD, Sanger JR, Matloub HS, Yousif NJ, Rooney
[42] Ascaari E, Attardo-Parrinello G, Merlini G. Treatment GE. Bilateral microvascular free iliac grafts for man-
of painful bone lesions and hypercalcemia. Eur J Hae- dibular reconstruction in intractable osteomyelitis: re-
matol 1989;51(Suppl):135 – 9. port of case. J Oral Maxillofac Surg 1986;44:724 – 7.
[43] Ernst DS, McDonald RN, Paterson AH, Jensen J, [50] Obwegeser HL, Sailer HF. Experiences with intraoral
Brasher P, Bruera E. A double-blind, crossover trial partial resection and simultaneous reconstruction in
of intravenous clodronate in metastatic bone pain. cases of mandibular osteomyelitis. J Maxillofac Surg
J Pain Symptom Manage 1992;7:4 – 11. 1978;6:34 – 40.
[44] Fleich H. Bisphosphonates in bone disease. From the [51] Ogawa A, Miyate H, Nakamura Y, Shimada M, Seki S,
laboratory to the patient. 2nd edition. New York: The Kudo K. Treating chronic diffuse sclerosing osteomye-
Parthenon Publishing Group; 1995. litis of the mandible with saucerization and autogenous
[45] Jokinen J, Lindqvist C, Elomaa I, Tasanen A. Treat- bone grafting. Oral Surg Oral Med Oral Pathol Oral
ment of recurrent diffuse sclerosing osteomyelitis of Radiol Endod 2001;9:390 – 4.
the mandible with clodronate. Presented at the Euro- [52] Chisholm BB, Lew D, Sadasivan K. The use of tobra-
pean Association for Cranio- Maxillo-Facial Surgery, mycin-impregnated polymethylacrylate beads in the
9th Congress. Athens, Greece, September 5 – 9, 1988. treatment of osteomyelitis of the mandible. Report of
[46] Grime PD, Bowerman JE, Weller PJ. Gentamicin im- three cases. J Oral Maxillofac Surg 1993;51:444 – 9.
Oral Maxillofacial Surg Clin N Am 15 (2003) 79 – 89

Diagnosis and treatment of viral infections


Sol Silverman, Jr, MA, DDSa,*, Craig S. Miller, DMD, MSb
a
Department of Stomatology, University of California School of Dentistry, Box 0422 S-612, 513 Parnassus Avenue,
San Francisco, CA 94143, USA
b
Department of Oral Medicine, Microbiology, Immunology, and Molecular Genetics,
University of Kentucky College of Dentistry, College of Medicine, MN-118,
Lexington, KY 40536-0297, USA

Viral infections are of concern to dental profes- occurring at a disproportionately higher rate in Afri-
sionals because of ease of transmission, the oral, can Americans. In reversal since the late 1990s, the
latent, recurrent, and systemic diseases they can number of new cases and deaths is increasing once
produce, their association with opportunistic infec- again because of viral resistance to multiple drug
tions and malignant transformation, and their influ- therapy, apathy toward barrier techniques, the
ence on infection control. In this article, information increasingly large number of individuals living with
regarding the following viruses is provided: (1) HIV, HIV who serve as a reservoir for transmission, and
(2) human herpesviruses, (3) human papillomavi- widespread drug abuse and prostitution.
ruses, (4) enteroviruses, and (5) hepatitis C virus. The HIV epidemic is an important concern to the
dental profession for many reasons. First, infection
control measures are required in the dental office.
HIV Second, many oral and systemic manifestations occur
in immunocompromised individuals who have falling
We are currently in the third decade of an RNA numbers of physiologically incompetent lymphocytes
virus pandemic. There are approximately 40 million and rising viral loads. Third, recognition of the signs
people throughout the world infected with HIV. It is and symptoms of HIV infection should lead to referral
estimated that more than 16,000 new infections occur of the patient to a physician for diagnostic testing.
each day. HIV is spread predominantly by sexual con- Acute HIV infection in most cases produces flu-
tact, blood or blood products, or perinatal exposure. like symptoms that develop 2 to 6 weeks after the
Infection also results from high-risk activities, such as initial infection. Soon thereafter, persistent general-
sharing needles with infected drug users, having ized lymphadenopathy occurs, which is followed by a
unprotected sexual activity with one or more infected latent phase. Initially the latent phase is asympto-
partners, receiving infected blood or blood products, or matic. Later as the viral loads rise and the CD4+ cell
being accidentally exposed to infected materials. count drops, lymphadenopathy, weight loss, fever,
In the United States, almost 500,000 persons are diarrhea, fatigue, skin anergy, neurologic decline,
reported to be living with HIV and AIDS. More than parotid enlargement, and opportunistic infections
2 million persons are believed to be infected, how- develop. Many of the numerous oral lesions that
ever. Approximately 98% of infections occur in develop are caused by increased individual suscep-
adults and adolescents, and approximately one third tibility to viral transmission and proliferation. These
of new cases occur in women. New infections are infections, which involve the herpes family viruses
and human papillomaviruses, are more prevalent in
HIV-seropositive patients and are usually concurrent
* Corresponding author. and recurrent. An increasing number of HIV patients
E-mail address: ssjr@itsa.ucsf.edu (S. Silverman). are coinfected with the hepatitis C virus.

1042-3699/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.
PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 7 2 - 9
80 S. Silverman, C.S. Miller / Oral Maxillofacial Surg Clin N Am 15 (2003) 79–89

The final stage of the disease (AIDS) is often exposed to HSV and have developed circulating
marked by fatal respiratory infections, lymphoma, or antibodies. The virus incubates and replicates for 2
cancer. Treatment involves the use of highly active to 12 days within epithelium and then penetrates local
antiretroviral agents, such as nucleoside, nucleotide, nerve endings [1]. After the primary infection, the
and nonnucleoside reverse transcriptase inhibitors, virus travels to regional ganglia, where it remains
and protease inhibitors, which are used in combina- latent indefinitely. Asymptomatic shedding and reac-
tion to block virus replication and maturation. tivation are common [2]. Although population studies
are variable, clinical recurrences are estimated to
occur in up to 40% of cases [3].
Human herpesviruses More than 67% of initial exposures are asympto-
matic subclinical infections [4]. The remaining indi-
The human herpesvirus (HHV) family includes viduals who acquire the primary infection experience
herpes simplex viruses (HSV-1 and -2), varicella- marked signs and symptoms that last up to 2 weeks
zoster virus (HVV, HHV-3), Epstein-Barr virus (Fig. 1). Features include gingivostomatitis, lip ves-
(EBV, HHV-4), cytomegalovirus (CMV, HHV-5), icles and coalescing ulcerations, fever, lymphade-
lymphotrophic viruses (HHV-6 and -7), and Kaposi’s nopathy, and oropharyngeal pain. Approximately
sarcoma virus (HHV-8). These large DNA viruses 10% of adults are not exposed to or do not obtain
have the hallmark of establishing latent infection. The adequate level of antibodies. These persons are at risk
latent infection serves as a reservoir for the periodic for developing adult-onset acute herpetic gingivosto-
activation of virus. Although the molecular factors matitis. Although the signs and symptoms in adults
that regulate activation of HHVs are still undefined, are usually more severe, the attack is usually com-
aging, immunosuppression, stress, and tissue damage plete in 2.5 weeks. The initial HSV infection incurs
predispose HHVs to reactivation. Reactivation occurs permanent immunity from a similar future attack;
despite cell-mediated and humoral HHV immunity. however, it does not prevent reactivation and recur-
Clinical manifestations are diverse and are more rent mucosal and labial flares.
severe during immunosuppression. Recurrent mucosal (intraoral herpes) and labial
(cold sores) infections create a lifetime problem in
Herpes simplex viruses persons who are susceptible to reactivation of latent
HSV (Fig. 2). These lesions recur near the point of
HSV-1, the most common of the HHV oral infec- entry into the body and are usually caused by HSV-1,
tions, must contact mucosa or abraded skin to initiate although HSV-2 (usually associated with genital
infection. By puberty, most individuals have been herpes) occasionally can be identified. The signs,

Fig. 1. Primary adult-onset herpetic gingivostomatitis in a 28-year-old man. It was manifested by sudden onset, pain, fever,
lymphadenopathy, and gingivitis. There had been no similar previous attacks, and the signs and symptoms resolved completely
in 2 weeks.
S. Silverman, C.S. Miller / Oral Maxillofacial Surg Clin N Am 15 (2003) 79–89 81

Fig. 2. Typical recurrent oral herpes manifested by irregular, shallow gingival ulcerations that tend to coalesce and usually
resolve within 7 to 10 days. The lesions are often mistaken for trauma.

symptoms, and treatment are similar for both sero- to sunlight, cold, fever, trauma, and immunosuppres-
types. Lesions are often preceded by prodromal sion [5 – 7]. There are reports that HSV infection can
symptoms of burning, tingling, itching, or pain. precede, or be subclinically involved in, an attack of
Recurrent intraoral HSV is often mistaken for erythema multiforme, which indicates a possible
some form of traumatic injury, because lesions antigenic role [8].
appear on periosteal bound mucosa as small, irregu- Diagnosis of HSV infections is usually based on
lar, erosive areas or ulcers that usually disappear the history and clinical findings. Cultures, cytologic
within 1 week. An important implication is trans- smears that show multinucleation, and special immu-
mission, because vesicular and ulcerative lesions nofluorescent processing can be helpful when clinical
shed virus during the first 2 to 3 days, during which recognition is uncertain. Serologic diagnosis is of
time HSV can be transmitted. Common sites of value only to determine past exposure.
spread are the eye (herpetic keratitis) and fingers Definitive treatment includes the use of systemic or
(herpetic whitlow) (Fig. 3). ‘‘Cold sores’’ are a topical antiviral drugs [9 – 12] (Table 1). Precursor
problem because of aesthetics, pain, and source of antiviral agents, such as valacyclovir and famciclovir,
transmission. The nature of HSV recurrences varies have better oral bioavailability than acyclovir and pen-
and often is preceded by stress, irritation, exposure ciclovir. If not used early in the infection (first 3 to

Fig. 3. Herpetic whitlow of the finger contracted by contact with a cold sore.
82 S. Silverman, C.S. Miller / Oral Maxillofacial Surg Clin N Am 15 (2003) 79–89

Table 1 Epstein-Barr viruses


Antiviral drugs
Generic (trade name) Suggested dosage Epstein-Barr virus is associated with infectious
(days)a mononucleosis, hairy leukoplakia, nasopharyngeal
Systemic: acyclovir (Zovirax) 400 mg 3  carcinomas, and lymphomas [13]. The primary infec-
daily (7) tion, referred to as infectious mononucleosis, usually
famciclovir (Famvir) 125 mg 1  causes a sore throat, fever, cervical lymphadenopathy,
daily (5) malaise and pain, and occasional hepatosplenome-
valacyclovir (Valtrex) 500 mg 2  galy. It occurs chiefly in adolescents and young
daily (5) adults. The disease is of low contagiousness, and
Topical: acyclovir (Zovirax) 5% ointment transmission is through exchange of EBV-contami-
penciclovir (Denavir) 1% cream
nated saliva. Affected patients often demonstrate
docosanol (Abreva) 10% cream
multiple petechiae located on the soft palate or lips.
(over-the-counter)
The lymphadenopathy is often bilateral and affects
Apply topical medications to oral lesions at least four
the posterior cervical nodes. Blood studies reveal
times daily.
a atypical lymphocytes, heterophile antibodies, and
Dosage levels are adjusted according to clinical
severity and response. For severe infection: acyclovir 5 – mildly elevated transaminase levels. Treatment in
10 mg/kg IV q8h for 7 – 10 days, famciclovir 500 mg t.i.d., most cases is palliative and supportive. Recovery
or valacyclovir 1000 – 2000 mg b.i.d. For acyclovir-resistant usually occurs within 1 to 2 months; however, the
cases: foscarnet (Foscavir) 40 – 60 mg/kg IV q8h for 7 – 10 virus enters latency in lymphocytes.
days, or cidofovir (Vistide) 5 mg/kg. Epstein-Barr virus is associated with hairy leuko-
plakia, which is a benign manifestation of epithelial
hyperplasia and hyperkeratosis that primarily occurs
4 days), antiviral drugs are usually ineffective. Anti- on the lateral border(s) of the tongue. It appears as a
septic, analgesic, and antiinflammatory medications corrugated white lesion that does not rub off (Fig. 4).
can be beneficial in reducing pain and transmission of Hairy leukoplakia is predominately seen in individuals
the disease. Systemic antiviral agents are used in com- infected with HIV; however, it may be seen in non-
plicated primary infections, HSV infections in the HIV immunosuppressed patients. Hairy leukoplakia is
immunocompromised, prophylaxis for seropositive almost always asymptomatic, with the principal sig-
patients who undergo chemotherapy or transplanta- nificance being a sign of immunosuppression.
tion, HSV-associated central nervous system disease, The diagnosis of hairy leukoplakia is clinically
and recurrent erythema multiforme. Systemic antiviral suggestive and can be confirmed by biopsy. Cyto-
agents are used often as daily prophylaxis. Nephrotox- logic scrapings are somewhat characteristic by fea-
icity, although rare, is a concern with the use of high- turing nucleoprotein condensations in nuclei.
dose systemic acyclovir, valacyclovir, and famciclovir, Treatment is elective and includes high-dose antiviral
particularly if patients have renal insufficiency. drugs, topical podophyllin in 25% tincture of ben-

Fig. 4. Hairy leukoplakia in an HIV-positive patient. The lesion was asymptomatic and chronic.
S. Silverman, C.S. Miller / Oral Maxillofacial Surg Clin N Am 15 (2003) 79–89 83

tion of EBV latency membrane protein 1 and the


NF-kB pathway that alters apoptotic and growth
pathways [16]. EBV-associated lymphomas in the
head and neck region present as nontender swellings
in Waldeyer’s ring, cervical lymph nodes, salivary
glands, oral mucosa, and lytic bone lesions (Fig. 5).
Persistent fever of unknown cause, weight loss,
malaise, sweating, and abdominal or chest pain often
accompany the condition. Radiation and chemother-
apy are used for treatment. Of interest is the recent
detection of EBV DNA in the serum of patients who
have nasopharyngeal carcinoma, certain lymphomas,
and gastric carcinoma.

Cytomegalovirus

Cytomegalovirus rarely causes mouth lesions but


can be associated with persistent mucosal ulcerations
(Fig. 6) in transplant patients and immunosuppressed
persons. Transmission is person-to-person mainly
through sexual and blood contacts. The primary
infection in most persons goes unrecognized. In utero
Fig. 5. A lytic bone lesion caused by lymphoma.
and perinatal transmission can lead to deafness,
learning disabilities, and mental retardation, however.
zoin, or laser vaporization. Recurrence is common. CMV enters latency in peripheral blood mononuclear
Although the term ‘‘leukoplakia’’ has been used to cells and reactivates during immunosuppression.
describe the condition, there is no known associated CMV infection recurs commonly in HIV-infected
precancerous risk. individuals and presents as pneumonitis, retinitis, or
Epstein-Barr virus is well known for its ability to nervous system disease [17]. CMV can infect and
cause lymphocyte immortalization and malignant replicate in major salivary glands, particularly in
transformation [13,14]. Such transformation occurs immunocompromised patients, which can lead to
in a small percentage of infected persons. The trans- swelling, pain, and xerostomia, secondary to lympho-
formation process is complex and involves the upre- cytic salivary gland infiltrates.
gulation of several viral and host gene products and The diagnosis of CMV infection is established by
immunosuppression [13,15]. Critical is the upregula- special stains and immunoprocessing (polymerase

Fig. 6. A painful ulceration of the palate of 1 month duration in an HIV-positive patient. Biopsy showed this to be a CMV-
induced lesion that responded to high-dose antiviral medication.
84 S. Silverman, C.S. Miller / Oral Maxillofacial Surg Clin N Am 15 (2003) 79–89

chain reaction) of biopsy specimens and specific lesions occur on the trunk between vertebrae T3 and
serologic antibody tests. Successful treatment is L2 and on the face along the ophthalmic division of
based on establishing the diagnosis and the use of the trigeminal nerve and extend up to the midline
antiviral agents, such as acyclovir or ganciclovir. (Fig. 7). In immunocompetent patients, vesicles break
down, scab, and resolve within 2 to 4 weeks.
Herpes varicella virus or varicella-zoster virus The diagnosis of varicella-zoster virus infection is
made by history, clinical findings, and serology.
Varicella-zoster virus is well known for causing Polymerase chain reaction is used for diagnosis in
chickenpox. It is a highly contagious virus that is severe cases that may involve the central nervous
generally spread during the late winter and spring system [18]. Treatment involves antiviral drugs in
months to young children who lack antibodies against high dosages (acyclovir, 4000 mg/d in divided doses;
varicella-zoster virus. After exposure and a 2- to famciclovir, 1500 mg/d in three divided doses; vala-
3-week incubation period, mild prodromal features cyclovir, 3000 mg/d in two divided doses) given
appear. The first recognizable signs are fever, mal- within the first week [19]. Supportive treatment for
aise, and a distinctive red, itchy truncal rash. The rash pain and pruritus is also in order. The most painful
spreads quickly to the neck, face, and extremities and and discouraging complication is postherpetic neu-
is followed shortly by the eruption of papules that ropathy, which can be debilitating. Early use of
form vesicles and pustules. Occasionally, oral inflam- corticosteroids along with antiviral treatment may
matory vesicular-ulcerative lesions develop that may help minimize, or even prevent, the neuropathy.
be seen on the posterior palate or buccal mucosa. Longer standing cases benefit from the use of ami-
Anorexia, chills, fever, nasopharyngitis, and muscu- triptyline, nortriptyline, topical lidocaine patches, and
loskeletal aches may accompany the disease. Lesions gabapentin, which should be considered early in the
heal within 7 to 10 days as patient antibody titers rise course of treatment [20,21]. A live-attenuated vac-
and control the infection. Complications such as cine (Varivax) virus is currently available for the
pneumonitis and encephalitis are infrequent. prevention of chickenpox.
Varicella-zoster virus resides latently in the sen-
sory ganglia of the host after the initial infection. The Human herpesvirus-6 and -7
virus reactivates in approximately 0.2% of adults,
more often in elderly and immunosuppressed patients Human herpesvirus-6 and -7 are T-cell lympho-
and has an increasing incidence with age. The recur- tropic herpesviruses that have significance in den-
rent attack is known as ‘‘herpes zoster’’ or ‘‘shingles.’’ tistry. Like most human herpesviruses, they are
The disease is preceded by hypersensitive skin over- ubiquitous and capable of establishing a lifelong,
lying the area of attack. Within a few days, the classic latent infection in humans. HHV-6 is particularly
manifestations are painful vesicles that occur unilat- efficient at infecting infants and young children and
erally along nerve dermatomes. Most commonly, produces exanthem subitum (roseola) and febrile

Fig. 7. Varicella (herpes) zoster or ‘‘shingles’’ in a 65-year-old patient. Note the unilateral distribution. The vesicles/ulcers
formed scabs and healed after 3 weeks. Treatment was supportive and included high-dose acyclovir.
S. Silverman, C.S. Miller / Oral Maxillofacial Surg Clin N Am 15 (2003) 79–89 85

seizures. HHV-6 is present in saliva [22] and has been and elderly persons. It attacks many different organs
detected in salivary glands and tonsillar tissue [23]. and is usually multifocal. Kaposi’s sarcoma does not
Primary infection in adults can cause a mononuc- metastasize but can be the cause of death. It occurs
leosis-like illness. The virus is harbored during most commonly in the skin, with the mouth being the
latency in peripheral blood mononuclear cells, sali- second most common site. Within the mouth, the
vary glands, mucosa, and tonsils [23]. Reactivation palate and gingiva are common sites. Kaposi’s sar-
occurs in the immunocompromised host and is asso- coma is highly vascular and typically appears purple-
ciated with fever, leukopenia, encephalitis, interstitial red. The initial appearance of Kaposi’s sarcoma is a
pneumonitis, skin rash, and bone marrow suppres- purplish macule that enlarges to become a violaceous
sion. A role for HHV-6 in malignant transformation papule or nodule. Lesions are single or multifocal,
remains to be defined, although HHV-6 can trans- can cause discomfort and bleeding, and can impact
activate other viruses, such as human papillomavirus appearance (Fig. 8).
(HPV), associated with malignant disease [24]. Since the institution of ‘‘high activity anti-retro-
Human herpesvirus-7 is associated with exanthem viral therapy’’, the occurrence of Kaposi’s sarcoma
subitum and febrile seizures and is detected in the has been much less frequent. Treatment involves low-
saliva of healthy adults [25]. HHV-7 infection gen- dose radiation, chemotherapy (systemic or intrale-
erally occurs later in childhood after infection with sional), and surgery.
HHV-6. Case reports suggest that HHV-7 may reac-
tivate after immunosuppression or the flu and can
cause encephalitis, encephalopathy, and febrile con- Human papillomavirus
vulsions [26].
Human papillomaviruses are small, double-
Human herpesvirus -8 (Kaposi’s sarcoma herpesvirus) stranded, non-enveloped DNA viruses That have a
propensity for infecting epithelium. Approximately
Human herpesvirus-8 is a sexually transmitted 5.5 million new HPV infections occur every year in
herpesvirus that infects endothelial cells. A secondary the United States, and 10% to 33% of sexually active
source of infection is organ transplantation [27]. Up to individuals are infected with the virus. Current esti-
15% of the US adult population is infected [28,29]. mates indicate that 10% to 18% of adults carry HPV,
Kaposi’s sarcoma herpesvirus contains several viral with the highest rates of infection found in 19- to
oncogenes, and Kaposi’s sarcoma is the primary dis- 26-year-old individuals.
ease associated with its infection [30]. Primary effu- There are more than 100 types of HPV, and at
sion lymphoma and multicentric Castleman’s disease least 45 types are known to infect genital and oral
also have a strong association with this virus [31]. epithelium. HPVs can be harbored latently within
Kaposi’s sarcoma is a pseudomalignancy that has epithelium for the life of the host, undergo a lytic
a particularly high prevalence in immunocompro- infection and alter epithelial cell growth and replica-
mised patients, homosexual men infected with HIV, tion, or dysregulate the cell cycle, which results in

Fig. 8. Nodular Kaposi sarcoma of the palate in a patient with AIDS whose CD4 count was less than 200/mm3.
86 S. Silverman, C.S. Miller / Oral Maxillofacial Surg Clin N Am 15 (2003) 79–89

premalignant changes. Infection outcomes depend on a rough, pebbly, clefted surface and a well-demar-
the infecting HPV genotype, anatomic site, and cated border.
immune response. Benign genotypes (HPV 6, 11, Focal epithelial hyperplasia is a multipapular con-
44, 55) replicate in the lower epidermis and differ- dition associated with HPV-13 and -32 infection that
entiated cells (keratinocytes) and produce increased was originally reported in Native American Indians
numbers of epithelial cells and koilocytosis. High- and Eskimos. The infection is transmitted by kissing.
risk genotypes [16,18,31,33,35] are associated with The HPV-induced, small, flat papules occur on labial
premalignant and malignant epithelial disease. and buccal mucosa and tongue. Lesions coalesce and
Low-risk HPV types are associated with benign develop a cobblestone-like surface.
proliferations, such as the squamous papilloma, ver- Benign HPV lesions can enlarge and spread or
ruca vulgaris, condyloma acuminatum (venereal resolve spontaneously; however, most do not regress
warts), and focal epithelial hyperplasia (Heck’s dis- without treatment. Ablative and chemotherapeutic
ease). The squamous papilloma is a well-defined, approaches are useful. Surgery, laser treatment, and
pink-white, exophytic and pedunculated or stalk-like cryotherapy have good success in removing HPV
mass. This small, usually asymptomatic growth may proliferations when the basal and adjacent epithelium
occur on any mucosal surface. is removed. High-speed evacuation is recommended
Condyloma acuminata intraorally appear as small during laser surgery to prevent aspiration of viral
verrucous lesions of varying sizes or they can mimic DNA that might be contained within the plume. A
small fibromas. Condyloma acuminata occur on any useful topical pharmacologic approach involves
mucosal surface and may be single or multiple, clus- podofilox 0.5% (Condylox, Oclassen), an agent that
tered or coalesced, and widespread (Fig. 9). Condylo- causes necrosis by arresting cells in mitosis. It is
mas are more commonly seen in immunocompromised applied twice daily for 3 days followed by no
patients and are transmitted by oral sex. A higher treatment for the next 4 days; then the cycle
prevalence of oral condyloma in HIV-positive patients is repeated up to four times. Immunomodulatory
on antiretroviral drugs compared to HIV-positive approaches include intralesional interferon, imiqui-
patients not on antiretroviral drugs has been reported. mod (Aldara) 5% cream at bedtime three times per
Reports have shown a decreased occurrence of most week for up to 16 weeks (alters cell cytokines and
other HIV-associated oral lesions, however, since stimulates interferon production), and cimetidine (a
high-activity antiretroviral therapy was initiated. histamine receptor antagonist), 30 mg/kg body
The common skin wart (verruca vulgaris) is a rare weight (bw), given daily in divided doses usually
intraoral finding. It is most often seen on the com- over 8 weeks. Recurrence is seen in approximately
missures of the lips in children and adolescents and 10% to 25% of patients generally within 3 months.
is caused by autoinoculation. Occasionally it occurs Sexual partners should be examined and treated to
on the tongue, labial mucosa, or gingiva. Warts have minimize the risk of transmission and recurrences.

Fig. 9. Condyloma accuminatum associated with the human papillomavirus in a sexually active homosexual man. Treatment was
by laser surgical removal.
S. Silverman, C.S. Miller / Oral Maxillofacial Surg Clin N Am 15 (2003) 79–89 87

Infection with high-risk HPV types has an asso- Diagnosis of HPV-infected mucosa is based on the
ciation with precancerous oral leukoplakia and history, clinical findings, and cellular characteristics
squamous cell carcinoma. In one form of leukoplakia, seen in biopsy specimens (koilocytes). Confirmation
proliferative verrucous leukoplakia, HPV-16 has been can be made by immunohistochemistry, in situ hybrid-
identified frequently. This finding helps explain the ization, or polymerase chain reaction processing.
high rate of malignant transformation associated with Currently, specific identification and typing are com-
proliferative verrucous leukoplakia. It can be charac- plex and expensive. There is no effective vaccine, and
terized clinically as a progressive leukoplakic lesion antiviral medications do not eliminate latent infection.
that can vary from somewhat corrugated and flat to The most effective treatment is by surgical approaches
one that is exophytic and verrucous. Proliferative and behavior modification (eg, barrier techniques). In
verrucous leukoplakia may have a red component the future, HPV analyses may prove important for
and a variable microscopic presentation that ranges directing treatment, such as by gene therapy.
from hyperkeratosis and epithelial dysplasia to car-
cinoma. It may be asymptomatic, cause slight discom-
fort, or be painful. The lesion usually involves more Enteroviruses
than one mucosal surface. It occurs four times more
often in women than men and occurs less commonly Enteroviruses are single-stranded, small RNA
in smokers than nonsmokers. In one long-term study positive-sense, nonenveloped viruses that cause a
[32], more than half of proliferative verrucous leuko- spectrum of human disease. The family includes
plakias were reported to have transformed into car- polioviruses, coxsackieviruses (23 serotypes), echo-
cinoma less than 8 years after diagnosis. viruses (32 serotypes), human enteroviruses 68 to 71,
Human papillomavirus can be detected in approx- hepatitis virus A, and several nonhuman enteric
imately 30% of oral squamous cell carcinoma cases, viruses that are well known for causing foot-and-
which suggests that the virus may play a causative mouth disease in livestock. Most nonpolio enterovi-
role, similar to its role in anogenital carcinoma [33]. ruses infect nasopharyngeal cells and inhabit the
The role of HPV in oral cancer seems different from alimentary (enteric) tract. They are transmitted by
the carcinogenic effects of tobacco and alcohol. For ingestion (fecal-oral route) and contaminated saliva
example, HPV-positive oropharyngeal cancers occur of close contacts in poor sanitary environments and
less often among moderate to heavy alcohol drinkers warm climates. Many enterovirus infections are
and tobacco smokers. Patients in this category also endemic in Southeast Asia [35].
have improved survival from cancer when compared The bulk of enterovirus infections are benign and
with HPV-negative head and neck squamous cell self-limiting, manifested mostly by fever alone [36].
carcinoma [34]. The role of HPV in carcinogenesis The primary enterovirus infections that involve the
may involve binding to p53 suppressor protein, oropharyngeal complex are hand-foot-and-mouth dis-
which in turn enhances epithelial cell proliferation ease and herpangina. These infections occur primarily
and neoplasia. in children. Hand-foot-and-mouth disease is caused

Fig. 10. Oropharyngeal ulcers associated with coxsackievirus infection.


88 S. Silverman, C.S. Miller / Oral Maxillofacial Surg Clin N Am 15 (2003) 79–89

Fig. 11. Erosive lichen planus of the buccal mucosa developed in a patient who previously had been diagnosed as hepatitis C
virus positive. A cause-and-effect relationship has not been proved conclusively.

by various members of the Coxsackie group and deaths each year [38]. Transmission is highest among
enterovirus 71. They produce oral ulcerations and drug users, who share HCV-contaminated needles,
extraoral ‘‘rashes’’ of the hands and feet (Fig. 10). and persons who have large or repeated percutaneous
Herpangina, caused by group A and sometimes exposures. Of individuals infected, approximately
group B coxsackieviruses, has the main feature of 80% develop hepatitis, and 10% to 20% of those
erythema and multiple vesicles of the oropharynx and persons develop cirrhosis. Treatment involves com-
posterior tongue. Both conditions are accompanied bination chemotherapy and liver transplantation.
by pain, fever, headache, lymphadenopathy, and Dental implications relate to the need for
malaise. Infection by nonpolio enteroviruses can bodily fluid borne – pathogen control in the dental
produce lymphonodular pharyngitis, which is man- office, demand for proper sterilization and disinfec-
ifested mainly by nonulcerative oropharyngeal nod- tion protocols, and use of barrier techniques to protect
ules, abdominal pain, vomiting, conjunctivitis, and against contaminated blood and saliva. HCV has been
croup. Serious infections can result in meningitis, detected in saliva [39]; however, it is less infectious
encephalitis, paralysis, myocarditis, hepatitis, and than hepatitis B virus. HCV carriers often are not
death. Although there is no viral latency, patients aware of their seropositive status.
can become reinfected by one of the many serotypes. Many questionable reports [40] indicate a relation-
The diagnosis of enteroviral infection can be made ship between HCV infection and oral lichen planus.
by viral culture, serology, and nucleic acid amplifica- Although this occurrence has not been documented
tion [36]. Treatment for self-limiting oropharyngeal conclusively, there seems to be an unexplainable risk
enterovirus infections in immunocompetent individ- that may not be coincidental. Because oral lichen
uals is supportive and palliative. Immunoglobulin, planus can be a source of oral pain and interfere with
interferon-a, and the antiviral agent pleconaril are oral functions, its diagnosis and treatment are impor-
available for treatment of persons with meningitis and tant considerations. The diagnosis of oral lichen planus
an immunocompromised status [37]. is based its on clinical characteristics (Wickham striae,
erosions, ulcers) and biopsy (Fig. 11). Effective treat-
ment requires the elimination of drugs that can cause
Hepatitis C virus similar appearing lichenoid eruptions, followed by the
use of topical or systemic corticosteroids.
Hepatitis C virus (HCV) is a small, single-stranded
RNA virus of the Flaviviridae family that was pre-
viously known as one of the non-A/non-B hepatitis References
viruses. Infection by HCV is a widespread global
disease. In the United States, it is estimated that [1] Whitley RJ. Herpes simplex virus infections. Lancet
4 million Americans are infected and potential carriers 2001;357:1513 – 8.
of HCV, with 30,000 new infections and 10,000 [2] Kameyama T, Yamamoto S, Hwang CB, Shillitoe EJ.
S. Silverman, C.S. Miller / Oral Maxillofacial Surg Clin N Am 15 (2003) 79–89 89

Shedding of herpes simplex virus type 1 into saliva. [21] Watson CPN. A new treatment for postherpetic neu-
J Oral Pathol 1988;17:478 – 81. ralgia. N Engl J Med 2000;343:1563 – 5.
[3] Higgins CR, Tatnall FM, Leigh IM. Natural history, [22] Levy J. Three new human herpesviruses (HHV6,7, and
management and complications of herpes labialis. 8). Lancet 1997;349:558 – 63.
J Med Virol 1993;1:22 – 6. [23] Roush KS, Margraf LR, Krisher K, et al. Prevalence
[4] Langenberg AG, Ashley RL, Leong WP, Straus SE. and cellular reservoir of latent human herpesvirus 6 in
A prospective study of new infections with herpes sim- tonsillar lymphoid tissue. Am J Clin Pathol 2001;116:
plex virus type 1 and type 2. N Engl J Med 1999;3412: 648 – 54.
1432 – 8. [24] Dockrell DH, Paya CV. Human herpesvirus 6. Mayo
[5] Eisen D. The clinical characteristics of intraoral herpes Clin Proc 1999;74:163 – 70.
simplex virus infection in 52 immunocompetent pa- [25] Wyatt LS. Human herpesvirus 7 is a constitutive inhab-
tients. Oral Surg Oral Med Oral Pathol Oral Radiol itant of adult human saliva. J Virol 1992;66:3206 – 9.
Endod 1998;86:432 – 7. [26] Sugaya N, Miura M, Ishizuka T, et al. Influenza ence-
[6] Logan HL, Lutgendorf S, Hartwig A, et al. Immune phalopathy associated with infection with human her-
stress, and mood markers related to recurrent oral her- pesvirus 6 and/or human herpesvirus 7. Clin Infect Dis
pes outbreaks. Oral Surg Oral Med Oral Pathol Oral 2002;34:461 – 6.
Radiol Endod 1998;86:48 – 54. [27] Regamey N, Wernli M, Witschi A, et al. Transmission
[7] Miller CS. Diagnosis and management of orofacial of human herpesvirus 8 infection from renal-transplant
herpes simplex virus infections. Dent Clin North Am donors to recipients. N Engl J Med 1998;339:1358 – 63.
1992;36:879 – 95. [28] Baillargeon J, Hettler E, Harrison C, et al. Seropreva-
[8] Darragh TM, Berger TG, Yen TS. Identification of lence of Kaposi’s sarcoma-associated herpesvirus infec-
herpes simplex virus DNA in lesions of erythema mul- tion among blood donors from Texas. Ann Epidemiol
tiforme by the polymerase chain reaction. J Am Acad 2001;11:512 – 8.
Dermatol 1991;24:23 – 6. [29] Schulz T. Kaposi’s sarcoma-associated herpesvirus
[9] Abramowicz M. Drugs for non-HIV viral infections. (human herpesvirus-8). J Gen Virol 1998;79:1573 – 91.
Medical Letter 1999;41:113 – 20. [30] Jaffe HW, Pellett PE. Human herpes virus 8 and Ka-
[10] Balfour Jr HH. Antiviral drugs. N Engl J Med 1999; posi’s sarcoma: some answers, more questions. N Engl
16:1255 – 68. J Med 1999;340:1912 – 3.
[11] Horowitz E, Pisanty S, Czerninski R, et al. A clinical [31] Chadburn A, Nador RG, Liu YF, et al. Kaposi’s sarco-
evaluation of a novel liposomal carrier for acyclovir in ma-associated herpesvirus sequences in benign lym-
the topical treatment of recurrent herpes labialis. Oral phoid proliferations not associated with human
Surg Oral Med Oral Pathol Oral Radiol Endod 1999; immunodeficiency virus. Cancer 1997;80:788 – 97.
87:700 – 5. [32] Silverman S, Gorsky M. Proliferative verrucous leuko-
[12] Raborn GW, Martel AY, Grace MGA, et al. Oral acy- plakia: a follow-up of 54 cases. Oral Surg Oral Med
clovir in prevention of herpes labialis: a randomized, Oral Pathol Oral Radiol Endod 1997;84:154 – 7.
double-blind, multi-centered trial. Oral Surg Oral Med [33] Miller CS. Human papillomavirus as a risk factor for
Oral Pathol Oral Radiol Endod 1998;85:55 – 9. oral squamous cell carcinoma: a meta-analysis, 1982 –
[13] Kieff E. Epstein-Barr virus: new insights. J Infect Dis 1997. Oral Surg Oral Med Oral Pathol Oral Radiol
1995;171:1323 – 4. Endod 2001;91:622 – 35.
[14] Cruchley AT, Niedobitek G. Epstein-Barr virus: biology [34] Gillison ML, Capone RB, Spafford M, et al. Evidence
and disease. Oral Diseases 1997;S156 – 63. for a causal association between human papillomavirus
[15] Knecht H, Al-Homsi AS, McQuain C, Brousset P. Ep- and a subset of head and neck cancers. J Natl Cancer
stein-Barr virus oncogenesis. Crit Rev Oncol Hematol Inst 2000;92:709 – 20.
1997;26:117 – 35. [35] Lum LC, McMinn PC, Goh AY, et al. Echovirus 7 asso-
[16] Hatzivassiliou E. Cellular signaling pathways engaged ciated encephalomyelitis. J Clin Virol 2002;23:153 – 60.
by the Epstein-Barr virus transforming protein LMP1. [36] Sawyer M. Enterovirus infections: diagnosis and treat-
Front Biosci 2002;7:319 – 29. ment. Curr Opin Pediatr 2001;13:65 – 9.
[17] Cunha B. Central nervous system infections in the [37] Nigrovic L. What’s new with enteroviral infections?
compromised host: a diagnostic approach. Infect Dis Curr Opin Pediatr 2001;13:89 – 94.
Clin North Am 2001;15:567 – 90. [38] Lauer GM, Walker BD. Hepatitis C virus infection.
[18] Markoulatos P, Siafakas N, Plakokefalos E, et al. Lab- N Engl J Med 2001;345:41 – 52.
oratory diagnosis of common herpesvirus infections of [39] Hermida MFM, Barral S, Laredo R, et al. Detection of
the central nervous system by a multiplex PCR assay. HCV RNA in saliva of patients with hepatitis C virus
J Clin Microbiol 2001;39:426 – 32. infection by using a highly sensitive test. J Virol Meth-
[19] Kost RG, Straus SE. Postherpetic neuralgia: pathogen- ods 2002;101:29 – 35.
esis, treatment, and prevention. N Engl J Med 1999; [40] Bagan JV, Ramon C, Gonzales L, et al. Preliminary
335:32 – 42. investigation of the association of oral lichen planus
[20] Kanazi GE, Dworkin RH. Treatment of postherpetic and hepatitis C. Oral Surg Oral Med Oral Pathol Oral
neuralgia: an update. Drugs 2000;59:1113 – 26. Radiol Endod 1998;85:532 – 6.
Oral Maxillofacial Surg Clin N Am 15 (2003) 91 – 102

Diagnosis and treatment of oropharyngeal candidiasis


Joel B. Epstein, DMD, MSD, FRCD(C)a,b
a
Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, Chicago Cancer Center,
801 South Paulina, Chicago, IL 60612, USA
b
Interdisciplinary Program on Oral Cancer, College of Medicine, Chicago Cancer Center,
801 South Paulina, Chicago, IL 60612, USA

Candida, a yeast-like fungus, is present in the oral infection. Cases of superficial and invasive candidiasis
cavity of 40% to 60% of the population [1,2]. Candida are occurring more frequently because of increased
albicans is the most commonly isolated species [1,2] use of antibiotics and immunosuppressive agents and
and is the one most likely to cause disease in humans advances in medical management, such as chemother-
[3]. Other Candida species include Candida tropica- apy, solid organ transplantation and hematopoietic cell
lis, Candida krusei, (both of which are prevalent in transplantation (HCT), parenteral nutrition, and inva-
immunosuppressed and cancer patients), Candida sive surgical procedures [4]. Candidiasis of the oro-
guilliermondii, and Candida parapsilosis (of limited pharynx and esophagus is associated with HIV
pathogenicity but associated with infection of indwel- infection and is a clinical predictor of disease progres-
ling vascular access devices). The species of coloniz- sion in HIV-infected patients [5,6].
ing organism is important, because resistance to The common portals of entry of Candida are the
antifungal agents is more common in some species, oropharynx and gut, sites that are commonly colo-
including C. tropicalis and C. krusei. Reports of nized by the organisms [7]. Invasive fungal infections
resistance to systemic agents are increasing. are one of the major complications in transplant
Candida is common in the oral and gastrointestinal medicine, potentially resulting in mortality [8]. Heart
flora, and presence in the oral cavity is increased in transplant recipients develop fungal infections in
patients with dentures, individuals who smoke, per- approximately 20% of cases [8]. In renal transplant
sons with xerostomia, and patients who use broad- patients, approximately 5% of infections are caused by
spectrum antibiotics and steroids. The use of immu- Candida species that present as urinary tract infection
nosuppressive purine analogus (eg, fludarabine, cla- and fungemia [8]. Diagnosis of systemic infection is
dribine) and antithymocyte globulin increases risk of difficult, resulting in limited ability to make an early
invasion. The risk of invasive candidiasis is increased diagnosis, and invasive infection caused by Candida
in persons with neutropenia and mucosal injury. The and Aspergillus is potentially fatal in neutropenic
use of growth factors to promote recovery of white cell patients [7]. Higher rates of infection and mortality
count in neutropenic patients may reduce the risk of are seen in patients with hematologic cancer as com-
candidiasis and require further study. Age and prior pared to patients with solid tumors. Candida accounts
splenectomy increase the risk of infection. Many for up to 70% of invasive fungal infections in cancer
sedatives, tranquilizers, and some antihypertensive patients, and a doubling of the rate of fungal infections
medications may cause dry mouth, which increases in all hospitalized patients was reported in the 1980s
the risk of oropharyngeal infection. The use of den- [7]. Candida is the fourth most common pathogen in
tures and tobacco increases the frequency of coloniza- the blood [7].
tion of the oropharynx and increases the risk of clinical Fungal infections, particularly candidiasis and
aspergillosis, in HCT are common and result in
morbidity and mortality in these high-risk patients
E-mail address: jepstein@uic.edu [9]. Increasing infections with non-albicans Candida

1042-3699/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.
PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 7 1 - 7
92 J.B. Epstein / Oral Maxillofacial Surg Clin N Am 15 (2003) 91–102

have been identified and include species such as C. nosis of infection, and discuss current approaches
tropicalis, C. glabrata, C. parapsilosis, and C. krusei, to management.
which show increased resistance to a commonly used
antifungal agent, fluconazole. C. glabrata and C.
parapsilosis are more common in patients with solid Risk factors
tumors, and C. tropicalis and C. krusei are more
common in HCT recipients [7]. Intact mucosa serves Local and systemic risk factors and characteristics
as a barrier to systemic infection, but cancer therapies of the organisms increase an individual’s susceptibil-
may lead to a violation of the barrier, which promotes ity to candidiasis. Host factors include age (ie, neo-
invasive, systemic infection. Fever caused by fungi nates and elderly people), diabetes, oral prostheses
typically occurs 7 to 14 days after neutropenia and is (particularly acrylic dentures), use of broad-spectrum
the most common cause of fever of unknown origin antibiotics, steroids and other immunosuppressive
not responsive to antibiotics [7]. Aspergillus tends to drugs, hyposalivation, disruption of oral mucosa,
occur later, 20 days after HCT, and most patients have dietary factors (eg, high carbohydrate diet, iron defi-
nasal or respiratory symptoms, in contrast to invasive ciency anemia), tobacco use, cancer and cancer thera-
candidiasis, which is typical 7 to 10 days after onset of py, and HIV infection (see Box 1). Patients may have
neutropenia [7]. In transplant medicine, the risk for multiple factors that predispose them to candidiasis.
candidiasis also depends on the occurrence of graft-
versus-host disease and the use of immunosuppressive
therapy for its prevention and management [10]. Box 1. Risk factors for development of
Gradual restoration of immune function occurs after oropharyngeal candidiasis
3 months of HCT, depending on the discontinuation of
immunosuppressive therapy for graft-versus-host dis- Local factors
ease. The time to engraftment has decreased because Xerostomia (eg, because of radiotherapy,
of changes in transplantation and use of hematopoietic chemotherapy, Sjögren’s syndrome,
growth factors, reducing the risk of invasive fungal diabetes, medications)
infection, which occur more commonly during the Use of broad-spectrum antibiotics or
postengraftment period [10]. steroids
‘‘Fungal hypersensitivity syndrome,’’ a condition High carbohydrate diet
promoted by the public media, has been associated Leukoplakia, oral cancer
with multiple and nonspecific complaints, including Dentures (eg, poor fit, trauma, unclean-
fatigue, impaired concentration and memory, respi- liness)
ratory symptoms and asthma, gastrointestinal com- Cigarette use
plaints, muscle and joint pain, and skin and urogenital Systemic factors
problems. Recent support for this possible condition Neonate, advanced age
was reported in a study in which nystatin capsules to Diabetes
116 patients were provided in a 4-week randomized Nutritional deficiencies (eg, iron, folate or
controlled trial. The symptoms were assessed by vitamin B12 deficiency)
questionnaire, and the results showed nystatin to be Malignancies (eg, leukemia, agranulocy-
superior to placebo in reducing localized and systemic tosis)
symptoms [11]. Immunosuppression (eg, AIDS, steroid
Despite the various topical and systemic agents use)
available to treat patients with oropharyngeal and
systemic candidiasis, optimal management can be
elusive. Topical therapy is generally effective in
uncompromised patients with oropharyngeal candi- Microbial factors
diasis; however, the optimal treatment for immuno-
compromised patients and patients with chronic or Factors related to the organism that have been
recurrent infection is not well documented. A general implicated include cell-wall components that enhance
overview of the etiology, pathogenesis, and treatment adhesion to epithelial cells, hydrophobicity of the
of candidiasis has been presented [4]. organism, germ tube formation, presence of mycelia,
The purpose of this article is to review the local ability to persist in epithelial cells, production of
and systemic risk factors for oropharyngeal candi- enzymes and toxins, induction of tumor necrosis
diasis, review the clinical manifestations and diag- factor, and phenotypic switching [12]. Candida is a
J.B. Epstein / Oral Maxillofacial Surg Clin N Am 15 (2003) 91–102 93

dimorphic yeast that demonstrates phenotypic switch- reported that systemic candidiasis develops more
ing from the yeast form to a filamentous form (pseu- frequently in patients with leukemia who have oro-
dohyphal), and although the pseudohyphal form has pharyngeal candidiasis than in patients who are colon-
been believed to be more pathogenic, both forms may ized before treatment, and it is associated with
be associated with clinical infection. prolonged neutropenia [16,24]. Candida is present in
approximately 90% of patients with acute leukemia
who undergo chemotherapy [24]. Candidiasis in
Systemic risk factors patients with leukemia and patients who undergo
HCT causes morbidity (eg, altered taste, oral sensitiv-
Neonates are susceptible to oropharyngeal candi- ity, dysphagia caused by esophagitis, fever) and results
diasis because of their immature immune system and in considerable risk of mortality during neutropenia
exposure to the organism during or shortly after birth [18,19,21,23]. Systemic candidiasis was shown to be
[2]. Exposure to C. albicans from infected bottle increased in patients with leukemia with ulcerative
nipples or the hands of nurses or the mother also oral mucositis [18]. Oropharyngeal candidiasis also is
may lead to oropharyngeal candidiasis [2]. The infec- associated with long-lasting fever and decreased bone
tion usually can be treated effectively with topical marrow function in patients with leukemia [23].
agents [13]. Elderly patients may present with a Patients with depletion of CD4+ lymphocytes
number of risk factors related to reduced saliva because of HIV infection are at high risk for oro-
production, denture use, and immune function, which pharyngeal candidiasis. Oropharyngeal candidiasis is
result in increased risk, although age alone does not the most prevalent opportunistic oral infection in
seem to be a risk factor. AIDS, and it occurs in as many as 95% of patients
Patients with diabetes are at increased risk of [5,6,17,24 – 27]. The development of candidiasis in
oropharyngeal candidiasis [2]. They are colonized HIV-infected patients suggests progression of immu-
more commonly and with higher than normal num- nosuppression [5,6], and in patients in whom candi-
bers of C. albicans [5,12]. Elevated glucose levels, diasis has been controlled with therapy, progression or
reduced chemotactic factor in saliva, altered neutro- recurrence of the candidiasis is commonly seen in
phil function, and reduced saliva volume may play a advancing disease.
role in the pathogenesis of clinical infection [2]. The clinical manifestations of oropharyngeal can-
Patients with cancer are at high risk for developing didiasis in AIDS patients include the pseudomembra-
oropharyngeal candidiasis [3,6,14 – 24]. Oropharyng- nous and erythematous forms and angular cheilitis
eal candidiasis is reported in up to one third of patients [5,26]. Pain and change in taste that often accompany
who receive head and neck radiation therapy, and risk this infection can result in poor appetite, which leads
is increased in patients who are colonized before to weight loss [17]. Oropharyngeal candidiasis can
radiation therapy [20]. The presence of clinical oro- extend into the esophagus and cause gastrointestinal
pharyngeal candidiasis may complicate oral mucosi- bleeding and severe regional and systemic infection
tis; in patients treated with radiotherapy, risk factors [17,25,28,29]. Therapy should consider an altered
include xerostomia, mucosal damage, the presence of host response to help combat the infection, frequent
oral prostheses, and continuing tobacco and alcohol relapses, persistent infection that requires prolonged
use during treatment [20]. treatment, potential antifungal drug resistance, and
In addition to causing mucosal damage, chemo- adverse drug effects [6].
therapy may result in transient xerostomia, which may Broad-spectrum antibiotics create a favorable
result in acute oropharyngeal infections. Use of anti- environment for the proliferation of Candida species
biotics may result in overgrowth of fungi [22]. Oro- by altering the oral flora [30]. Use of corticosteroids
pharyngeal candidiasis is reported in up to one third of also places patients at increased risk [30]. Xerostomia-
patients with leukemia [1,3,4,18,20,21]. The intensive inducing medications may place the patient at risk of
radiation and chemotherapy used to treat these patients infection by affecting saliva.
can disrupt the oral mucosa and cause a shift in the oral
flora, thus favoring overgrowth of Candida [22].
Frequent treatment with broad-spectrum antibiotics Local and oral factors
in neutropenic patients also alters the normal oral flora
and predisposes to oropharyngeal candidiasis [14]. Impaired salivary gland function increases the risk
Candida infections, although generally superficial, of oropharyngeal candidiasis [1,12,30] Because of the
can become invasive or systemic in these patients decreased saliva secretion and low pH. Saliva protects
and may result in mortality [16,18]. It has been against candidiasis by diluting and moving organisms
94 J.B. Epstein / Oral Maxillofacial Surg Clin N Am 15 (2003) 91–102

from mucosal surfaces. Antimicrobial proteins in the individuals with chronic immunosuppression, because
saliva, including defensins, lactoferrin, sialoperoxi- oropharyngeal manifestations can persist for extended
dase, lysozyme, histidine-rich polypeptides, and spe- periods regardless of the clinical findings.
cific anti-Candida antibodies, interact with the
organism [4]. Lactoferrin, a nonspecific defense factor
in saliva and mucosal secretions, seems to have Box 2. Classification of oropharyngeal
fungicidal activity against Candida species. candidiasis
Drugs that cause hyposalivation predispose
patients to oropharyngeal candidiasis. Patients with Pseudomembranous (thrush)
head and neck cancer treated with radiation to the Erythematous
head and neck develop disturbances of the salivary Denture stomatitis (atrophic)
glands that may be permanent [12]. HCT recipients Angular cheilitis
and patients who receive chemotherapy also can Leukoplakia caused by hyperplastic can-
experience salivary gland dysfunction [7]. didiasis
Oropharyngeal candidiasis is reported in up to Candidal ulceration
65% of older patients who wear full upper dentures
[3]. Increased susceptibility to oropharyngeal candi-
diasis in denture wearers may be caused by enhanced The classic form of candidiasis is the pseudomem-
adherence of Candida to acrylic, reduced saliva flow branous form (thrush), which is characterized by soft,
under the denture, poorly fitted dentures, or poor oral yellowish-white plaques on the oral mucosa that can
hygiene [1,2]. be removed with vigorous rubbing and may leave red
The risk for oropharyngeal candidiasis is increased or bleeding sites after removal [3,32]. The erythema-
when there is disruption of the oral mucosa [1,12]. tous form of candidiasis frequently develops in
The oral epithelium is a physical barrier that prevents patients who take antibiotics or use steroid inhalers
invasion of microorganisms, and epithelial turnover and in patients with HIV [3,30]. This form of candi-
helps clear adherent organisms from the mouth. diasis is characterized by sensitive and painful ery-
Patients who receive chemotherapy have an altered thematous mucosa with few, if any, white plaques.
rate of mucosal regeneration, which may result in The dorsal aspect of the tongue and the palate is
increased vulnerability to infection [12]. Patients with generally involved, and the patient presents with red
mucositis, especially individuals with an immuno- mucosa with loss of papillae on the tongue and patchy
compromised system, are at high risk for invasive red changes in the palate, although any portion of the
candidiasis [9,10,17 – 19]. oral mucosa can be affected [30].
Local use of antimicrobial products and antiin- In denture stomatitis, or denture sore mouth (atro-
flammatory agents (steroids) increases the risk for phic candidiasis), the palatal mucosa in contact with
colonization and infection [31]. Other studies have the denture is affected and is chronically erythematous
shown that chronic use of oral topical steroids and and edematous. A hyperplastic response may be seen,
steroid inhalers also increases the risk of oropharyng- although patients generally experience no symptoms
eal candidiasis, possibly by suppressing cellular [3]. Treatment includes correction of denture faults,
immunity and inhibiting phagocytosis [2,30,31]. careful cleaning of dentures, and antifungal therapy
Tobacco use represents a local factor that is asso- [33]. Angular cheilitis, an inflammatory reaction at
ciated with increased risk of colonization and clinical one or both corners of the mouth, is characterized by
infection [20,30]. painful red fissures. C. albicans is a common patho-
gen, and infection is frequently accompanied by
Staphylococcus aureus infection [3]. Denture wearers
Clinical presentation and patients with HIV are predisposed to this type of
presentation. Although denture stomatitis and angular
Symptoms that may be associated with Candida cheilitis usually do not indicate serious disease, severe
infection include oral and pharyngeal burning, sensi- infections may occur in immunocompromised indi-
tivity, altered taste, and change in the sense of smell. If viduals [4].
involvement extends to the oropharynx, dysphagia and Leukoplakia caused by hyperplastic candidiasis
odynophagia may occur. Oropharyngeal candidiasis may represent a precancerous condition that presents
can be classified clinically in several ways (see Box 2) as unilateral or bilateral, elevated, white mucosal
[3,30,32]. The use of ‘‘acute’’ and ‘‘chronic’’ descrip- lesions on the buccal mucosa, tongue, lips, and floor
tors of candidiasis should be avoided, particularly in of the mouth [3,29]. Candida species are present in
J.B. Epstein / Oral Maxillofacial Surg Clin N Am 15 (2003) 91–102 95

the tissue, can be identified on biopsy, and may be Treatment


cultured from the mouth. They may not be the cause
of the lesions, however, and may be merely secondary Susceptibility testing: identification of species and
invaders [3]. Clinical signs and symptoms range from resistant strains
painless plaque-like white patches to nodular eryth-
roplakic lesions that cause the patient discomfort. Susceptibility testing of fungi to antifungal agents
Smoking seems to be a risk factor for development is not as standardized as that of bacteria but is
of hyperplastic candidiasis. evolving, and guidelines are being developed by the
National Committee for Clinical Laboratory Standards
[37]. The current applicability of in vitro antifungal
Systemic infection susceptibility tests is limited by poor standardization
and insufficient correlation of in vitro test results with
Systemic Candida infection is usually caused by clinical outcome [38 – 41]. Antifungal susceptibility
C. albicans and less frequently by C. krusei and C. studies may help clarify which strains are likely to
tropicalis in immunosuppressed patients. Patients develop resistance during long-term therapy [42].
with neutropenia caused by leukemia or from treat-
ment of their malignancy, patients with indwelling History of treatment
intravascular lines, and patients who receive antibi-
otics or parenteral nutrition are at risk for Candida Gentian violet, an aniline dye, was used for topical
septicemia. Candida endocarditis is related to intra- treatment until the first topical polyene antibiotic,
vascular trauma (eg, cardiac catheterization, surgery) nystatin, became available in 1951 [43]. The first
and is more common on prosthetic valves, where it systemic antifungal agent, amphotericin B, was
can become a life-threatening infection. Candidiasis reported in 1956 and is the standard against which
that involves the esophagus, trachea, bronchi, or lungs newer systemic therapies are compared.
is an AIDS-defining condition [28]. The azoles include the imidazoles and the tria-
All forms of systemic disease are serious and cause zoles. The first azole, benzimidazole, was discovered
morbidity and risk of mortality. Intravenous ampho- in 1944 [43]. Miconazole and clotrimazole (both
tericin B is the treatment of choice, although ketoco- identified in 1969) and ketoconazole (1977) are imi-
nazole or fluconazole is preferred for chronic dazoles. The antifungal activity of the triazoles,
mucocutaneous candidiasis [34]. including fluconazole and itraconazole, was reported
in the mid-1980s.

Diagnosis Treatment approach

The diagnosis of candidiasis is based on clinical Underlying risk factors for colonization and infec-
signs and symptoms, laboratory testing, and the tion should be managed whenever possible. For
response to antifungal treatment. Laboratory tests example, in patients with hyposalivation, treatment
include smears from the lesions using Gram’s stain with sialagogues should be considered. Oral pros-
or a potassium hydroxide preparation or cultures theses should be disinfected or topical antifungal
from the skin, mouth, vagina, urine, sputum, or stool agents should be applied to impact colonization of
[5,35]. A culture is obtained if identification of the the acrylic surface, and instructions in denture use
species or strain is desired. One must remember, should be provided. If tobacco use is identified as a
however, that the diagnosis of oropharyngeal candi- risk factor, tobacco cessation should be encouraged.
diasis cannot be based solely on the presence of In patients with diabetes, improved glucose control
Candida species because the organism is a common may reduce oral candidiasis. In patients with neutro-
commensal in the oral flora [4]. Studies have shown penia, use of hematopoietic growth factors may speed
that high colony counts of Candida species in saliva recovery of blood counts, which reduces risk of local
collections correlate with the presence of clinical and systemic Candida infection. Changes in use of
infection, and quantitative counts may be used in medications that increase the risk of Candida col-
diagnosis [36]. Occasionally, histologic evidence onization and infection should be considered (eg, it
is necessary, specifically in cases of hyperplastic may be possible to replace topical steroid use with the
candidiasis (candidal leukoplakia), mucocutaneous use of other topical immunosuppressive medications).
candidiasis, and invasive candida ulceration in immu- Various systemic and topical agents are available
nosuppressed patients. to treat oropharyngeal candidiasis (Table 1) [4,44].
96 J.B. Epstein / Oral Maxillofacial Surg Clin N Am 15 (2003) 91–102

Table 1 taste and texture may not be tolerated if they are


Routes of action of antifungal agents for the treatment of applied without an occlusive appliance. Creams are
oropharyngeal candidiasis easily applied to the corners of the mouth. A single-
Route of action dose trial of an antifungal agent provides guidance on
Class and agent Topical Systemic product acceptability by the patient.
Gentian violet was commonly used to treat oro-
Polyenes
pharyngeal candidiasis until the advent of polyene
Nystatin X
Amphotericin B X X antifungal medications [30] and was replaced quickly
Imidazoles by the polyenes because of emerging resistance and
Clotrimazole X local side effects, such as staining and irritation of the
Miconazole X oral mucosa [43,47]. Three polyenes—nystatin,
Ketoconazole X amphotericin B, and natamycin (used only for ocular
Triazoles infection)—are available. These agents act by binding
Fluconazole X to ergosterol in the cell membrane of fungi, altering
Itraconazole X cell-membrane permeability, and causing pores and
Other
leakage of cellular components, which leads to micro-
Chlorhexidine gluconate 0.2% X
bial death [43,48].
(antiseptic for denture disinfection)
Denture cleansers X Nystatin is the most widely used agent for the
initial treatment of patients with oropharyngeal candi-
diasis [1,2]. It is available in oral rinse, topical cream,
Topical agents have been the mainstay of therapy, oral pastille, and vaginal tablet and powder [1,2,5].
particularly in uncomplicated cases. If possible, top- Nystatin is not absorbed systemically and lacks serious
ical preparations should be used before systemic toxicity. Adverse effects include nausea, vomiting, and
antifungal drugs [45] because they are not absorbed diarrhea [43], which can be problematic for cancer
systemically and lack adverse systemic effects and the patients who are already nauseated from chemother-
possible drug interactions of systemic agents. Sali- apy. The oral rinse is heavily sweetened with sucrose,
vary action may dilute and rapidly eliminate topical which increases the risk of caries formation. If chosen,
drugs from the oral cavity, however, which reduces nystatin suspension should be used with precautions to
their effectiveness [46], and compliance with required reduce caries risk. The oral rinse may be useful for
repeated topical application impacts efficacy. Topical edentulous patients, but the tablets may not dissolve
agents are available in various formulations, includ- well in the mouth and may be irritating to the mucosa,
ing oral rinses, troches, powders, and vaginal tablets particularly if it is friable or damaged [1]. Although
and creams. Systemic agents are used when topical nystatin is commonly used as prophylaxis for treat-
therapy has been ineffective or not tolerated, pri- ment of oropharyngeal candidiasis in AIDS and cancer
marily in immunocompromised patients with cancer patients, several reports have cited disappointing
or HIV infection. Topical and systemic medications results in these patients, with frequent treatment failure
are used to attempt prophylaxis in patients who re- and early relapse [6,15,16,19].
ceive HCT. Antiseptic agents have been assessed for antifun-
gal effect. An in vitro study of antifungal effects of
Topical therapy ListerineR and chlorhexidine (0.12% and 0.2%, re-
spectively) [49] showed potential value in suppression
The medication chosen should be appropriate for of Candida species. Chlorhexidine rinse has been
the conditions in the oral cavity, and cost should be assessed in patients with leukemia, and suppression
considered. The taste and texture should be consid- of Candida colonization has been demonstrated [31].
ered when selecting a medication and formulation. In patients with symptomatic oral mucositis, alcohol
Unfortunately, many of the oral products include high content, the presence of phenol, and intense flavoring
concentrations of sucrose and have a high cariogenic agents may limit use of commercial antiseptic prod-
potential, which is a particularly important considera- ucts because of mucosal irritation.
tion in dentate patients with dry mouth. In patients Care should be taken when using more than one
with dry mouth, oral rinses should be used because topical agent simultaneously. Two studies that exam-
tablets not only may dissolve poorly but also may ined the compatibility of nystatin with chlorhexidine
become rough with use, which results in physical digluconate in the treatment of patients with oropha-
irritation of the oral tissue. Antifungal creams may ryngeal candidiasis found that both drugs become
be readily applied to the surface of dentures, but their ineffective when combined [50,51]. Several studies
J.B. Epstein / Oral Maxillofacial Surg Clin N Am 15 (2003) 91–102 97

have compared various topical and systemic agents topical treatment, in patients who cannot tolerate
(eg, nystatin and amphotericin B with fluconazole or topical agents, and in patients at high risk for systemic
ketoconazole) to determine what is best tolerated, infection. It may be chosen for convenience of use and
most effective, and least expensive in different pa- ease of patient compliance (Table 2).
tients [19,52 – 55].
The azoles are fungistatic and interfere with syn- Amphotericin B
thesis of ergosterol in the fungal organism, which
causes an increased permeability of the cell membrane Intravenous amphotericin B has been shown to be
[1]. Clotrimazole, an imidazole, was the first broad- effective in patients with severe oropharyngeal candi-
spectrum antifungal agent of its class [1]. Clotrima- diasis and in patients with infection refractory to other
zole troches are more palatable than nystatin oral agents [2,6]. Low-dose, prophylactic use has been
suspension and may be used in patients who cannot shown to be effective in neutropenic HCT recipients
tolerate the taste of nystatin [12,56]. Clotrimazaole [60]. Amphotericin B also has been used prophylacti-
has been reported to be effective for prophylaxis and cally in solid organ transplant recipients [61]. Ampho-
treatment of oropharyngeal candidiasis in cancer tericin B is used primarily in patients at risk for
patients, in whom it may prevent the development progressive and potentially fatal fungal infections
of esophagitis [57], but it seems to be less effective because of the potential toxicity of the medication.
than fluconazole in treating HIV-infected patients with Potential toxicities include general toxicities (eg,
oropharyngeal candidiasis [5,58]. Like nystatin oral fever, shaking chills, malaise, weight loss), renal
troches, however, clotrimazole troches may be poorly toxicity, gastrointestinal effects (eg, nausea, vomiting,
tolerated by AIDS patients or patients with xerostomia diarrhea, cramping, altered liver function), neurologic
caused by cancer therapy [12]. Miconazole also has symptoms (eg, headache, hearing loss, dizziness,
been shown to be effective in patients with oropha- visual changes, peripheral neuropathy), muscle/joint
ryngeal and esophageal candidiasis [59]. pain, dermatologic reactions (eg, rash, itching), hem-
When topical agents cannot effectively control atologic effects (eg, anemia), and cardiovascular and
oropharyngeal candidiasis, combining topical therapy pulmonary toxicity. Despite its toxicity, amphotericin
with a systemic agent may eradicate the infection B remains the ‘‘gold standard’’ of antifungal medica-
while allowing a lower dose and shorter course of tions because of its broad spectrum of action, clinical
the systemic agent [1]. efficacy, and limited evidence of fungal resistance.

Systemic therapy Azoles

Systemic therapy may be necessary in patients The azoles (eg, miconazole, clotrimazole, ketoco-
with oropharyngeal candidiasis that is refractory to nazole, fluconazole, and itraconazole) have been

Table 2
Strategy for managing fungal infections in high-risk neutropenic patients
Risk factor Oral Parenteral
Oral colonization Topical antiseptic/polyene
Fluconazole 400 mg/d 200 mg/d if no po
Oral candidiasis Topical and oral/parenteral
Fluconazole 400 mg/d 200 mg/d if no po
Probable or proven aspergillosis Itraconazole 400 mg/d Ambisome 200 mg/d
Itraconazole 200 mg/d if no po
Possible fungal infection (fever of unknown origin) Itraconazole 400 mg/d Ambisome 200 mg/d
Itraconazole 200 mg/d if no po
Infection by Candida Fluconazole 400 mg/d Fluconazole 400 mg/d for treatment
for maintenance
Infection by Aspergillus Intraconaole 400 mg/d Ambisome 200 mg/d
for maintenance
Oral route for prophylaxis and maintenance, parenteral for treatment; dose range 200 – 400 mg/d for fluconazole, with higher
doses in North America.
Modified from Wingard JR. Approach to invasive fungal infection after blood or marrow transplantation. Transplant Proc
2000;32:1543 – 4.
98 J.B. Epstein / Oral Maxillofacial Surg Clin N Am 15 (2003) 91–102

widely used to treat patients with superficial and 76]. Therapeutic failure caused by fluconazole-resist-
systemic fungal infections. Ketoconazole was the first ant strains in AIDS patients is increasingly reported
imidazole found to have systemic activity, and [26,68,69,73 – 76], although one study found flucona-
although it is effective in the treatment of oropha- zole effective when other agents were not [77]. Risk of
ryngeal candidiasis in patients with cancer and HIV, resistance seems to develop in patients with advanced
several studies have shown that ketoconazole is less HIV disease or after repeated or long-term fluconazole
effective than fluconazole [5,14,30,62,63]. Ketocona- therapy [26,68,69,73]. Resistant species, specifically
zole requires gastric acidity for absorption, which may C. krusei, have been increasingly identified in HCT
reduce its effectiveness in patients with AIDS or other patients and patients with leukemia because of effec-
gastrointestinal disorders and persons with limited tive killing of C. albicans and selection for C. krusei
food intake [1]. The most frequent adverse effects [18] and have been described with ketoconazole [68].
described for ketoconazole include nausea, vomiting, A study by Fan-Havard et al [78] did not find large-
abdominal pain, and itching [1,62]. The adverse event scale resistance in the Candida populations isolated
of greatest concern is hepatotoxicity, which may result from patients who receive long-term azole therapy.
in hepatitis and, rarely, hepatic failure [1,40,43,45,62]. There are reports of fluconazole selecting more re-
Ketoconazole is less costly than the newer azoles. A sistant strains of Candida species and of cross-resist-
study by Donnelly et al [54] found ketoconazole to be ance between the azoles [30,47,62,72,79]. The
no more effective than amphotericin B in preventing optimal management of fungal infections in children
yeast infection in neutropenic patients, and use was with HIV remains to be determined [80].
not recommended [64]. The azoles, particularly ketoconazole, can interact
The triazoles, fluconazole and itraconazole, are in with many other agents, including antacids, omepra-
common use. Both medications have been shown to be zole, histamine-2 antagonists, rifampin, phenytoin,
effective in the treatment of oropharyngeal candidiasis oral anticoagulants, insulin, cyclosporine, and cortico-
in patients with cancer and HIV infection, and they are steroids [5,43,62]. Such interactions may result in
widely used in these patients [15,30,55,57,63,65]. either increased or decreased blood levels of these
Itraconazole and fluconazole have fewer side effects agents, thus altering their potential efficacy or toxicity.
than the azoles, and are available in oral formulations.
Fluconazole offers no protection against Aspergillus New therapies
species and has been associated with fungal resistance
[27], although this may be overcome in many cases by Unlike with the azoles, resistance to polyenes,
increasing the dose. Fluconazole is useful in patients including amphotericin B, rarely develops during
who require prolonged antifungal therapy, because it is therapy [41]. The drug’s principal limitation is its
well tolerated and is taken only once a day [25]. toxicity when used systemically [41,82]. The use of
Fluconazole prophylaxis against candidiasis in HCT amphotericin B oral suspension as a topical antifungal
patients and patients with leukemia has been con- agent was first studied nearly 40 years ago and has
ducted, and it is used in some centers [18,66]. been available commercially in Europe for the treat-
Although studies show reduction in Candida coloniza- ment of patients with oropharyngeal candidiasis
tion, not all studies have shown an effect on systemic [5,47,48]. In vitro studies have shown that amphoter-
infection [18]. Unfortunately, C. krusei is resistant to icin B is more active than nystatin against C. albicans
fluconazole, and increased infection by C. krusei in [83,84]. Virtually no amphotericin B oral suspension
patients with leukemia indicates the need for caution in is absorbed systemically, and the toxicity concerns
the use of fluconazole in these patients [18]. Further associated with intravenous amphotericin B use are
studies are needed to establish optimal doses in eliminated [47,85 – 88]. Unfortunately, the formula-
patients with HIV infection and different types of tion is poorly tolerated and the rinse has been with-
oropharyngeal candidiasis [25]; studies are also drawn from the US market [47,62,63,65]. An
needed regarding the usefulness of fluconazole in amphotericin B lozenge/chlorhexidine combination
and HCT patients and patients with leukemia [18,66]. has been used in Scandinavia to treat patients with
denture stomatitis [81]. Amphotericin B lozenges are
Resistance to antifungal agents effective in patients susceptible to Candida infection,
because long-lasting concentrations of the drug in the
Resistance of Candida to polyenes is virtually saliva can be achieved [81,82].
unknown despite years of common clinical use [67]. New formulations of systemic amphotericin B
Reports of resistance to the azoles, however, particu- have been developed with the goal of reducing tox-
larly among AIDS patients, are increasing [26,65,68 – icity. Systemic amphotericin B has been studied in
J.B. Epstein / Oral Maxillofacial Surg Clin N Am 15 (2003) 91–102 99

lipid complex, colloidal dispersion, and liposomal wearers are also at increased risk for candidiasis.
forms. Although there are limited data on the thera- The clinical presentation of this infection may vary
peutic advantage of new formulations, toxicity seems and may be asymptomatic or cause severe, persistent
to be reduced [8]. symptoms. Common oral findings may include white
New triazoles in late stage development (vorico- plaques that can be wiped off, erythema, and, less
nazole, posaconazole, ravuconazole) have increased commonly, leukoplakia.
the spectrum of antifungal activity, including against Treatment of uncomplicated oropharyngeal can-
Aspergillus and additional Candida species, and didiasis in the non-immunocompromised patient is
safety seems excellent. New classes of antifungal usually straightforward. Selecting the form of a
agents, including echinocandin agents that affect the topical medication requires consideration of the oral
fungal cell membrane (versus cell wall), are in devel- condition, the length of contact time with the medi-
opment [7]. These agents, with different mechanisms cation, and the taste, texture, and cost of the product.
of action, offer the future potential to manage cases In patients with severe oropharyngeal candidiasis,
with new drug combinations. particularly individuals with a compromised immune
system, or in patients with refractory oropharyngeal
Combination therapy antifungal agents candidiasis, treatment is often more difficult. Relap-
ses are common, and unless the underlying condi-
Combined therapies have been evaluated to seek tions that predispose to infection are managed
synergy of different agents for use in potentially fatal effectively, long-term or frequent intermittent therapy
fungal infections, including Cryptococcus, C. albi- is often required.
cans, and Aspergillus, in immunocompromised and Topical agents are generally effective in uncom-
neutropenic patients [89]. In vitro study of possible plicated cases but may be inadequate in some cases,
synergy of fluconazole and granulocyte-colony stimu- including complicated infections in patients with
lating factor (G-CSF), granulocyte-macrophage-col- AIDS or neutropenic cancer patients. The most effec-
ony stimulating factor (GM-CSF), human serum tive regimen for fungal prophylaxis in patients with
treated neutrophils, showed that the combination protracted neutropenia has yet to be determined.
caused increased killing by the antifungal agents Systemic agents, such as amphotericin B, ketocona-
[89]. Monoclonal antibodies also were shown to zole, fluconazole, and itraconazole, have been used
facilitate fungal cell death in combination with anti- extensively in these patients. A major concern with
fungals, as have combinations with proinflammatory these agents, particularly with fluconazole, is the
cytokines, interleukin-1, interferon, and tumor ne- increase in fungal resistance and in selection of
crosis factor-alpha [89]. Use of polyene and azole non-albicans species, particularly in patients who
antifungal agents has interfered with fungal killing in require long-term or recurrent therapy. Strategies
vitro; however, animal studies and clinical trials must be developed for preventing and managing the
suggest that dosing schedules of the drugs may be increasing prevalence of more resistant strains of C.
key, and conflicting results may be related to the albicans and selecting resistant species. Intravenous
dosing schedule and the animal model used. Although amphotericin B is the gold standard for patients with
combining azoles and polyenes may lead to enhanced systemic mycoses and, occasionally, persons with
effect, there are no clear guidelines for their combined refractory oropharyngeal candidiasis; however, its
use [89]. routine use for oropharyngeal candidiasis is limited
by its toxicity.

Discussion

Oropharyngeal candidiasis is increasingly com- References


mon because of changes in medical care, HIV
infection, and advances in medicine that allow [1] Epstein JB. Antifungal therapy in oropharyngeal my-
patients with cancer and other debilitating diseases cotic infections. Oral Surg Oral Med Oral Pathol
1990;69:32 – 41.
to live longer, although in an immunocompromised
[2] Guida RA. Candidiasis of the oropharynx and esoph-
state. Use of xerostomia-inducing medications, agus. Ear Nose Throat J 1988;67:832 – 40.
broad-spectrum antibiotics, and topical and systemic [3] Dreizen S. Oral candidiasis. Am J Med 1984;30:28 – 33.
steroids has led to increased oropharyngeal coloniza- [4] Budtz-Jörgensen E. Etiology, pathogenesis therapy and
tion and subsequent infection. Patients with xerosto- prophylaxis of oral yeast infections. Acta Odontol
mia, persons who smoke tobacco, and denture Scand 1990;48:61 – 9.
100 J.B. Epstein / Oral Maxillofacial Surg Clin N Am 15 (2003) 91–102

[5] Greenspan D. Treatment of oropharyngeal candidiasis sion-induction therapy in patients with acute myelo-
in HIV-positive patients. J Am Acad Dermatol 1994; leukemia. Scand J Infect Dis 1991;2:355 – 66.
31(Suppl):51 – 5. [22] Bergmann OJ, Andersen PL. Acute oral candidiasis
[6] Meyer RD, Holmberg K. Fungal infection in HIV- during febrile episodes in immunocompromised pa-
infected patients. In: Homberg K, Meyer R, editors. tients with haematologic malignancies. Scand J Infect
Diagnosis and therapy of systemic fungal infections. Dis 1990;22:353 – 8.
New York: Raven Press; 1989. p. 79 – 100. [23] Rodu B, Carpenter JT, Jones MR. The pathogenesis and
[7] Wingard JR, Leather HL. Empiric antifungal therapy clinical significance of cytologically detectable oral
for the neutropenic patient. Oncology 2001;15:351 – 69. Candida in acute leukemia. Cancer 1988;62:2042 – 6.
[8] de Pauw BE. Advances in the management of invasive [24] Dupont B, Graybiull JR, Armstrong D, et al. Fungal
fungal infections in organ transplant recipients: step by infections in AIDS patients. Journal of Medical and
step. Transpl Infect Dis 2000;2:48 – 50. Veterinary Mycology 1992;30(Suppl 1):19 – 28.
[9] Donnelly JP. A strategy for managing fungal infections [25] Koks CHW, Schepens MHJ, Burger DM, et al. Drug
in haematopoietic stem cell transplantation. Transplant development report (9): fluconazole in the treatment
Infect Dis 2000;3:88 – 95. and prophylaxis of oral candidosis in HIV-infected pa-
[10] Wingard JR. Approach to invasive fungal infection tients. J Drug Dev Clin Pract 1993;5:235 – 49.
after blood or marrow transplantation. Transplant Proc [26] Heinic GS, Stevens DA, Greenspan D. Fluconazole-
2000;32:1543 – 4. resistant Candida in AIDS patients. Oral Surg Oral
[11] Santelmann H, Laerum E, Roennevig J, Fagertun HE. Med Oral Pathol 1993;76:711 – 5.
Effectiveness of nystatin in polysymptomatic patients: [27] Pollock JJ, Santarpia III RP , Heller HM, et al. De-
a randomized, double-blind trial with nystatin versus termination of salivary anticandidal activities in
placebo in general practice. Fam Pract 2001;18:258 – 65. healthy adults and patients with AIDS: a pilot study.
[12] Peterson DE. Oral candidiasis. Clin Geriatr Med 1992; J Acquir Immune Defic Syndr Hum Retrovirol 1992;
8:513 – 27. 5:610 – 8.
[13] Dhondt F, Ninane J, De Benle K, et al. Oral candidosis: [28] Conant MA. The AIDS epidemic. J Am Acad Derma-
treatment with absorbable and non-absorbable antifun- tol 1994;31:847 – 50.
gal agents in children. Mycoses 1992;35:1 – 8. [29] Jewell ME, Sweet DE. Oral and dermatologic mani-
[14] Francis P, Walsh TJ. Current approaches to the man- festations of HIV infection. Postgrad Med 1994;96:
agement of fungal infections in cancer patients. Oncol- 105 – 16.
ogy 1992;6:81 – 92. [30] Edwards JE. Candida species. In: Mandell GL, Bennett
[15] Prentice AG. Oral and gastrointestinal candidosis: pro- JE, Dolin R, editors. Principles and practices of infec-
phylaxis during immunosuppressive therapy. Mycoses tious diseases. New York: Churchill-Livingstone;
1989;32(Suppl 2):42 – 6. 1995. p. 2289 – 301.
[16] DeGregorio MW, Lee WMF, Ries CA. Candida infec- [31] Epstein JB, Komiyama K, Duncan D. Oral topical ste-
tions in patients with acute leukemia: ineffectiveness of roids and secondary oral candidiasis. J Oral Med 1986;
nystatin prophylaxis and relationship between oropha- 41:223 – 7.
ryngeal and systemic candidiasis. Cancer 1982;50: [32] Crislip MA, Edwards JE. Candidiasis. Infect Dis Clin
2780 – 4. North Am 1989;3:103 – 33.
[17] Stevens DA, Green SI, Lang OS. Thrush can be pre- [33] Lewis MAO, Samaranyake LP, Lamey PJ. Diagnosis
vented in patients with acquired immunodeficiency and treatment of oral candidiasis. J Oral Maxillofac
syndrome and the acquired immunodeficiency syn- Surg 1991;49:996 – 1002.
drome-related complex. Arch Intern Med 1991;151: [34] Bissell V, Felix DH, Wray D. Comparative trial of
2458 – 64. fluconazole and amphotericin in the treatment of den-
[18] Epstein JB, Ransier A, Lunn R, Chin E, Jacobson J, Le ture stomatitis. Oral Surg Oral Med Oral Pathol 1993;
N, et al. Prophylaxis of candidiasis in patients with 76:35 – 9.
leukemia and bone marrow transplants. Oral Surg Oral [35] Berkow R. The Merck manual of diagnosis and ther-
Med Oral Pathol Oral Radiol Endod 1996;81:291 – 6. apy. 16th edition. Rahway (NJ): Merck & Co.; 1992.
[19] Epstein JB, Vickars L, Spinelli J, Reece D. Efficacy of [36] Epstein JB, Truelove EL, Izutzu KT. Oral candidiasis:
chlorhexidine and nystatin rinses in prevention of oral pathogenesis and host defense. Rev Infect Dis 1984;
complications in leukemia and bone marrow trans- 6:96 – 106.
plantation. Oral Surg Oral Med Oral Pathol 1991; [37] Epstein JB, Pearshall NN, Truelove EL. Quantitative
73:682 – 9. relationships between Candida albicans in saliva and
[20] Epstein JB, Freilich MM, Le ND. Risk factors for the clinical status of human subjects. J Clin Microbiol
oropharyngeal candidiasis in patients who receive ra- 1980;12:475 – 6.
diation therapy for malignant conditions of the head [38] Rex JH, Cooper CR, Merz WG, et al. Detection of
and neck. Oral Surg Oral Med Oral Pathol 1993;76: amphotericin B-resistant Candida isolates in a broth-
169 – 74. based system. Antimicrob Agents Chemother 1995;39:
[21] Bergmann OJ. Alterations in oral microflora and 906 – 9.
pathogenesis of acute oral infections during remis- [39] Barchiesi F, Del Poeta M, Morbiducci V, et al. Turbi-
J.B. Epstein / Oral Maxillofacial Surg Clin N Am 15 (2003) 91–102 101

dimetric and visual criteria for determining the in vitro conazole and amphotericin B for the prevention of
activity of six antifungal against Candida spp and yeast colonization in patients with acute leukemia.
Cryptococcus neoformans. Mycopathologia 1993; J Hosp Infect 1984;5:83 – 91.
124:19 – 25. [56] Menichetti F, Del Favero A, Martino P, et al. Prevent-
[40] Woods GL, Washington JA. The clinical and the mi- ing fungal infection in neutropenic patients with acute
crobiology laboratory. In: Mandell GL, Bennett JE, leukemia: fluconazole compared with oral amphoteri-
Dolin R, editors. Principles and practices of infectious cin B. Ann Intern Med 1994;120:913 – 8.
diseases. New York: Churchill-Livingstone; 1995. [57] Owens NJ, Nightingale CH, Schweizer RT, et al. Pro-
p. 169 – 99. phylaxis of oral candidiasis with clotrimazole troches.
[41] Galgiani JN. Antifungal susceptibility tests. Antimi- Arch Intern Med 1984;144:290 – 3.
crob Agents Chemother 1987;31:1867 – 70. [58] Shechtman LB, Funaro L, Robin T, et al. Clotrimazole
[42] Galls HA, Drew RH, Pickard WW. Amphotericin B: treatment of oral candidiasis in patients with neoplastic
30 years of clinical experience. Rev Infect Dis 1990; disease. Am J Med 1984;76:91 – 4.
12:308 – 29. [59] Goldstein SM. Advances in the treatment of superficial
[43] Korting HC, Ollert M, Georgii A, Fröschl M. In vitro Candida infections. Semin Dermatol 1993;12:315 – 30.
susceptibilities and biotypes of Candida albicans iso- [60] Uchida K, Yamaguchi H. Susceptibility to miconazole
lates from the oral cavities of patients infected with (base) of isolates from the oral cavity and esophagus of
human immunodeficiency virus. J Clin Microbiol patients with mycosis. Jpn J Antibiot 1991;44:109 – 16.
1988;26:2626 – 31. [61] Perfect JR, Klotman ME, Gilbert CC, et al. Prophylac-
[44] Gupta AK, Sauder DN, Shear NH. Antifungal agents: tic intravenous amphotericin B in neutropenic autolo-
an overview. Part I. J Am Acad Dermatol 1994;30: gous bone marrow transplant recipients. J Infect Dis
677 – 98. 1992;165:891 – 7.
[45] Judd G. Oral candidiasis: treatment choices. Continu- [62] Gupta KL, Ghosh AK, Kochhar R, et al. Esophageal
ing Education 1989;16:21 – 2. candidiasis after renal transplantation: comparative
[46] Datry A. Candidose digestive et infection vih: actu- study in patients on different immunosuppressive pro-
alites cliniques et therapeutiaques. Mycology Medicine tocols. Am J Gastroenterol 1994;89:1062 – 5.
1992;2(Suppl I):5 – 14. [63] van der Bijl P, Arendorf TM. Itraconazole and fluco-
[47] Samaranayake LP, Ferguson MM. Delivery of antifun- nazole in oropharyngeal candidiasis. Ann Dent 1993;
gal agents to the oral cavity. Adv Drug Deliv Rev 52:12 – 6.
1994;13:161 – 79. [64] Meunier F. Fluconazole treatment of fungal infections
[48] Dewsnup DH, Stevens DA. Efficacy of oral amphoter- in the immunocompromised host. Semin Oncol 1990;
icin B in AIDS patients with thrush clinically resistant 17(Suppl 6):19 – 23.
to fluconazole. Journal of Medical and Veterinary My- [65] Hansen RM, Reinerio N, Sohnle PG, et al. Ketocona-
cology 1994;32:389 – 93. zole in the prevention of candidiasis in patients with
[49] Meiller TF, Kelley JI, Jabra-Rizk MA, DePaola LG, cancer: a prospective, randomized, controlled, double-
Baqui A, Falkler WA. In vitro studies of the efficacy of blind study. Arch Intern Med 1987;147:710 – 2.
antimicrobials against fungi. Oral Surg Oral Med Oral [66] Goodman JL, Winston DJ, Greenfield RA, et al.
Pathol Oral Radiol Endod 2001;91:663 – 70. A controlled trial of fluconazole to prevent fungal in-
[50] Bennett JE. Antimicrobial agents, antifungal agents. fections in patients undergoing bone marrow trans-
In: Gilman AG, Rall TM, Nies AS, editors. The phar- plantation. N Engl J Med 1992;326:845 – 51.
macological basis of therapeutics. 8th edition. New [67] Hay RJ. Overview of studies of fluconazole in oropha-
York: Pergamon Press; 1990. p. 1165 – 81. ryngeal candidiasis. Rev Infect Dis 1990;12(Suppl 3):
[51] Barkvoll P, Atramadal A. Effect on nystatin and chlo- 334 – 7.
rhexidine digluconate on Candida albicans. Oral Surg [68] Conly A, Renin R, Johnson J, et al. Disseminated can-
Oral Med Oral Pathol 1989;67:279 – 81. didosis due to amphoteric B resistant Candida albi-
[52] Barkvoll P, Hurlen B. Conventional treatment or oral cans. J Infect Dis 1992;165:761 – 4.
candidiasis: new aspects. Nor Tannlaegeforen Tid [69] Rex JH, Rinaldi MG, Pfaller MA. Resistance of Can-
1989;99:116 – 9. dida species to fluconazole. Antimicrob Agents Che-
[53] Philpott-Howard JN, Wade JJ, Mufti GJ, et al. mother 1995;39:1 – 8.
Randomized comparison of oral fluconazole versus [70] White A, Goetz MB. Azole-resistant Candida albi-
oral polyenes for the prevention of fungal infection cans: report of two cases of resistance to fluconazole
in patients at risk of neutropenia. J Antimicrob Che- and review. Clin Infect Dis 1994;19:687 – 92.
mother 1993;31:973 – 84. [71] Ng TTC, Denning DW. Fluconazole resistance in Can-
[54] Egger T, Gratwohl A, Tichelli A, et al. Comparison of dida in patients with AIDS: a therapeutic approach.
fluconazole with oral polyenes in the prevention of J Infect 1993;26:117 – 25.
fungal infections in neutropenic patients: a prospective, [72] Newman SL, Flanigan TP, Fisher A, et al. Clinically
randomized, single-center study. Support Care Cancer significant mucosal candidiasis resistant to fluconazole
1995;3:139 – 46. treatment in patients with AIDS. Clin Infect Dis 1994;
[55] Donnelly JP, Starke ID, Galton DAG, et al. Oral keto- 19:684 – 6.
102 J.B. Epstein / Oral Maxillofacial Surg Clin N Am 15 (2003) 91–102

[73] Chavanet P, Lopez J, Grappin M, et al. Cross-sectional [81] de Vries-Hospers HG, Mulder NH, Sleijfer DT, van
study of the susceptibility of Candida isolates to anti- Saene HK. The effect of amphotericin B lozenges on
fungal drugs and in vitro-in vivo correlation in HIV- the presence and number of Candida cells in the oro-
infected patients. AIDS 1994;8:945 – 50. pharynx of neutropenic leukemia patients. Infection
[74] Samaranayake LP, Holmstrup P. Oral candidiasis and 1982;10:71 – 5.
human immunodeficiency virus infection. J Oral Path- [82] de Vries-Hospers HG, van der Waaij D. Salivary con-
ol Med 1989;18:554 – 64. centrations of amphotericin B following its use as an
[75] Manso E, Montillo M, Discepoli G, Leoni P. Flucona- oral lozenge. Infection 1980;8:63 – 5.
zole resistance of Candida krusei. Boli Ist Sieroter [83] Terrell CL, Hermans PE. Antifungal agents used for
Milan 1991;70:527 – 9. deep-seated mycotic infections. Mayo Clin Proc
[76] Redding S, Smith J, Farinacci G. Resistance of Candida 1987;62:1116 – 28.
albicans to fluconazole during treatment of orophar- [84] Ghosh A, Ghosh JJ. Effect of nystatin and amphoter-
yngeal candidiasis in a patient with AIDS: documenta- icin B on the growth of Candida albicans. Ann Bio-
tion by in vitro susceptibility testing and DNA subtype chem Exp Med 1963;23:29 – 44.
analysis. Clin Infect Dis 1994;18:240 – 2. [85] Lechevalier H. Comparison of the in vitro activity of
[77] Laguna F, Rodriguez-Tudela JL, Enriquez A. Funge- four polyenic antifungal antibiotics. Antibiotic Annual
mia due to fluconazole-resistant Candida albicans in a 1959;614 – 8.
patient with AIDS. Clin Infect Dis 1994;19:542 – 3. [86] Alban J, Groel JT. Amphotericin B oral suspension in the
[78] Lucatorto FM, Franker C, Hardy WD, Chafey S. Treat- treatment of thrush. Curr Ther Res 1970;12:479 – 84.
ment of refractory oral candidiasis with fluconazole: [87] Brandell R, Chase SL, Cohn JR. Treatment of oral
a case report. Oral Surg Oral Med Oral Pathol 1991; candidiasis with amphotericin B solution. Clin Pharm
71:42 – 4. 1988;7:70 – 2.
[79] Fan-Havard P, Capano D, Smith SM, et al. Develop- [88] Stough AR, Groel JT, Kroeger WH. Amphotericin B, a
ment of resistance in Candida isolates from patients new antifungal agent for the prophylaxis of antibiotic-
receiving prolonged antifungal therapy. Antimicrob induced moniliasis. Antibiot Med Clin Ther 1959;6:
Agents Chemother 1991;35:2302 – 5. 653 – 61.
[80] Akova M, Akalin HE, Uzun O, Gur D. Emergence of [89] Stevens DA, Kullberg BJ, Brummer E, Casadevall A,
Candida krusei infections after therapy of oropharyng- Netea MG, Sugar AM. Combined treatment: antifungal
eal candidiasis with fluconazole. Eur J Clin Microbiol drugs with antibodies, cytokines or drugs. Medical
Infect Dis 1991;10:598 – 9. Mycology 2000;3:305 – 15.
Oral Maxillofacial Surg Clin N Am 15 (2003) 103 – 110

Management of head and neck infections in the


immunocompromised patient
Newton C. Gordon, DDS, MS*, Stephen Connelly, DDS
Department of Dentistry/Oral and Maxillofacial Surgery, San Francisco General Hospital, 1001 Potrero Avenue,
NH-1N1, San Francisco, CA 94110, USA

The term immunocompromised has traditionally Normal immune system


been used to describe patients with a serious impair-
ment of one or more aspects of their immune defense To understand the defects in the immune system
mechanisms. As a result, these patients are more produced by these conditions, it is first necessary to
susceptible than immunocompetent hosts to the estab- discuss the immune system in the noncompromised
lishment of bacterial and nonbacterial infections [1]. host. The normal functioning immune system
The number of patients classified as immunocompro- involves a complex network of specialized cells and
mised has increased in the last 15 years. Among the defensive barriers designed to protect an individual
many factors contributing to the increased numbers of from potential pathogens. Its development begins in
such patients is the fact that people are outliving once the first month of gestation with the hematopoietic
fatal diseases because of advances in modern treat- stem cells located in the yolk sac [3]. In the third
ment strategies [2]. month of gestation, hematopoiesis occurs mainly in
The most common conditions leading to an the liver and continues up to the point when the
immunocompromised state can be divided into four skeletal elements are formed and the bone marrow
general categories: systemic conditions, congenital becomes the major site of blood cell formation. A
defects or primary immunodeficiencies, iatrogenic variety of cells differentiate from the hematopoietic
causes, and social factors (Box 1). The purpose of stem cell, including granulocytes, monocytes, lym-
this article is to review three common causes of phocytes, megakaryocytes, and erythrocytes. Two
immunosuppression in the oral surgery patient: dia- months into gestation, lymphocytic cells destined to
betes mellitus, alcoholism/substance abuse, and HIV/ become T cells emigrate from the bone marrow into
AIDS, with emphasis on their impact on head and the developing thymus for maturation. The matura-
neck infections. Each of these conditions leads to a tion of B cells occurs under the influence of stromal
host environment that is more susceptible to severe reticular cells. As the fetus continues to develop, so
pathogenic invasion, causing infections such as do the peripheral components of the immune system,
osteomyelitis, pan-facial abscesses, and necrotizing including the blood, thymus, lymphatic system,
fascitis. Management of these infections requires spleen, skin, and mucosa [4].
accurate diagnosis, aggressive incision and drainage, The immune system is often divided into the
proper antimicrobial therapy, and improved nutri- innate and adaptive, or acquired immune systems.
tional status to achieve resolution. Innate immunity consists of antigen-nonspecific
defense mechanisms activated immediately on
encounter with an antigen [5,6]. These mechanisms
include physical barriers like epithelium, fatty acids,
* Corresponding author. mucus, and cilia. Soluble factors such as proteins of
E-mail address: newtong@itsa.ucsf.edu (N.C. Gordon). the complement cascade, chemokines (proteins that

1042-3699/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.
PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 7 9 - 1
104 N.C. Gordon, S. Connelly / Oral Maxillofacial Surg Clin N Am 15 (2003) 103–110

tion because their specificity, selected during thymic


Box 1. Etiology of immunodeficiency
ontogeny, is retained for self – nonself discrimination.
The adaptive immune system can form memory of
Systemic conditions
antigenic exposure, decreasing the time for the sub-
sequent immune response to re-exposure to an anti-
AIDS
gen. The antigen-driven clonal expansion of T cells
Diabetes mellitus
and B cells is central to adaptive immunity and is the
End-stage renal disease
basis for immunologic memory.
Leukemia/lymphoma
The innate and adaptive immune systems are
Systemic lupus erythematous
complementary. For example, the chemokines and
Advanced age
cytokines produced by macrophages in an inflamma-
tory reaction serve to attract and modulate T cell and
Primary immunodeficiencies
B cell activation and function. In addition, the
complement cascade can be activated via the classic
X-linked severe combined immunode-
pathway by Ig stimulation [12].
ficiency
The central cellular elements of the immune
Wiskott-Aldrich syndrome
system are the leukocytes, which consist of granulo-
Chediak-Higashi syndrome
cytes, specialized antigen-presenting cells, and lym-
DiGeorge syndrome
phocytes. Granulocytes include the neutrophils,
eosinophils, basophils, and mast cells. The neutro-
Iatrogenic causes
phils, monocytes, and macrophages are responsible
for the phagocytic destruction of antigens. Their
Immunosuppressive drugs
function is crucial in the acute inflammatory re-
Broad-spectrum antibiotics
sponse. Eosinophils play a role in the late phase of
Chemotherapy
allergic inflammation and are responsible for the
Radiation therapy
destruction of parasitic infections. Basophils and mast
Bone marrow transplantation
cells both express IgE and participate in the imme-
diate hypersensitivity immune response. Monocytes,
Social factors
macrophages, Langerhans cells, Kupffer cells, and
dendritic cells comprise the antigen processing and
Alcoholism
presenting cells [13].
Illicit drug use
There are three major types of lymphocytes:
Obesity
T cells, B cells, and natural killer (NK) cells. T cells
are phenotypically defined by the expression of the
induce leukocyte migration), cytokines (proteins that TCR heterodimeric receptor on their cell surface,
modulate leukocyte function), and leukocytes other which binds antigen displayed by antigen-presenting
than T cells and B cells are all part of the innate cells [14]. B cells express transmembrane Ig on their
system that becomes activated in response to the surface, which binds unprocessed antigen indepen-
chemical properties of the insulting agent. dent of antigen-presenting cells. NK cells are mor-
Adaptive immunity is a system that is antigen- phologically large granular lymphocytes. They are
specific. The main effector cells of this antigen- phenotypically defined by the absence of either trans-
specific system are the T cells and B cells [7,8]. This membrane cell surface expression of TCR or Ig and
system requires antigen processing, which involves by the presence of the cell surface molecules (protein
the recognition of antigenic epitopes by T cells and markers), CD16 and CD56 [15]. T cells and B cells
B cells, clonal expansion, and differentiation of these are responsible for clonally specific immune re-
antigen-specific lymphocytes into effector cells [9]. sponses, while NK cells provide innate cytotoxic
In addition, random rearrangement of genes that immune responses directed against virus-infected
encode T-cell receptors (TCRs) on T cells and immu- cells and tumor cells. There is also cooperation
noglobulins (Ig) on B cells results in a vast repertoire between the NK cells and the adaptive immune
of antigen-specific receptors. This enables the host to response through Fc-bound IgG and the production
react to thousands of foreign substances [10,11]. of cytokines [4,5].
Ig genes have the ability to increase specificity and All nucleated cells of the body display the trans-
affinity of antibodies by undergoing further somatic membrane class I human leukocyte antigen (HLA)
mutation. TCR genes do not undergo somatic muta- molecule on their surface, which is encoded by the
N.C. Gordon, S. Connelly / Oral Maxillofacial Surg Clin N Am 15 (2003) 103–110 105

major histocompatability complex. The class I HLA are produced when a specific antigen binds to the
molecule is restricted to presenting linear peptides of membrane Ig receptor, which transduces an intra-
8 to 25 amino acids long to CD8+ T cells [16]. They cellular signal stimulating clonal expansion to pro-
present endogenous antigens, proteins synthesized duce more cells and secretes Ig specific for that
within the antigen-presenting cells. These proteins antigen. This production is a T cell – dependent pro-
are derived from the processing of genetic informa- cess, in which these cells direct immunoglobulin
tion from either viral, intracellular bacterial, or tumor isotype switching through a series of cell surface
sources. This is consistent with the specificity of molecular interactions with B cells, resulting in
CD8+ T cells. Only macrophages, monocytes, den- reciprocal intracellular signaling and T cell elabora-
dritic cells, and B lymphocytes present the class II tion of cytokines [22]. Repetitive antigen stimulation
HLA molecule. However, any nucleated cell stimu- is associated with somatic hypermutation within the
lated with interferon-g may also express the class II Ig gene segments, encoding the heavy and light chain
HLA molecule [17]. The specific antigen-presenting variable regions, resulting in Ig with greater antigen
cells present only the class II HLA molecule to CD4+ specificity. The daughter clones are preferentially
cells. The antigens are exogenous peptides, derived expanded and produce antibody with higher affinity,
from phagocytized bacteria, parasites and virus par- all occurring within the germinal centers of the
ticles. Class I and II HLA molecules are cell surface lymphoid organs.
heterodimeric structures with a groove for presenta- The complement system facilitates antibody-medi-
tion of linear peptides only. However, there is also a ated immunity. The complement system consists of
mechanism for the presentation of polysaccharides. plasma proteins activated along an enzymatic cascade,
CD4 and CD8 T-cells are responsive to lipoglycan resulting in a spectrum of bioactive molecules that
antigens presented by CD1 molecules, which are facilitate opsonization, osmotic lysis of targeted cells,
expressed on most antigen presenting cells [18]. and recruitment of phagocytic cells [23]. Through the
The TCR is responsible for the specificity and classic complement pathway, antigen – antibody com-
sensitivity of T cell recognition of antigens presented plexes efficiently activate the complement cascade.
by the HLA molecule [19]. T cells go through a The alternative pathway involves independent activa-
process of positive and negative selection that occurs tion of cascade protein C3.
in the thymus during T cell development. Positive Cell adhesion molecules are also very important to
selection occurs in the cortical region of the thymus. the proper functioning of the immune system. Selec-
T cells whose antigen receptor fails to bind to self- tins, integrins, and Ig superfamily adhesion molecules
HLA molecules are programmed to die by apoptosis, are the three families of adhesion molecules that
whereas T cells whose antigen receptor binds to self- allow leukocytes to attach to extracellular matrices
HLA molecules survive and migrate to the medulla. and to adhere to each other. Selectins are found on all
Negative selection occurs next when T cells whose leukocytes and function as lectins, which bind to
antigen receptor binds to self-HLA molecules with carbohydrate moieties expressed by endothelial cells
too high an affinity display auto-antigens and or other leukocytes. Selectin L, E, and P participate in
undergo apoptosis. This process creates T cells that leukocyte rolling along vascular endothelium. Integ-
can recognize HLA molecules correctly but yet not rins and Ig superfamily adhesion molecules bind
bind to those HLA molecules presenting self antigens through protein – protein interactions, which is
[20]. T cells can be further defined by their cytokine important for stopping leukocyte rolling and medi-
production and can be either T helper1 (Th1) cells ating leukocyte aggregation and transendothelial
(which generate cell-mediated immune responses) or migration [31]. The adhesion molecules are often
Th2 cells (which generate humoral allergic immune dysfunctional in patients with immunocompromising
responses). Both CD4+ and CD8+ T cells can exhibit condition, such as diabetes.
either cytokine profile.
The hallmark of the B cell is the production of Ig.
Maturation of B cells depends on bone marrow Immune defects in specific diseases
stromal cells and stromal cell-produced interleukin-
7 (IL-7) [21]. B cells can express IgM, IgD, IgG1-4, Diabetes mellitus
IgE, and IgA1-2 isotypes. IgM and IgD isotypes
characterize a naı̈ve mature B cell and switching to The negative effects of diabetes mellitus on the
the other isotypes is T cell – dependent. B cell mem- immune system have been extensively investigated.
brane Ig and secreted Ig are alternative products of These effects impact greatly on the host’s ability to
the differentially spliced Ig heavy chain gene. They prevent the establishment of, and bring resolution to,
106 N.C. Gordon, S. Connelly / Oral Maxillofacial Surg Clin N Am 15 (2003) 103–110

a variety of head and neck infections [24,25]. The Alcoholism


main etiologic factor in diabetes mellitus that leads to
dysfunction in the immune system is hyperglycemia It has been demonstrated that ingestion of large
[26,27]. All the major cell types involved in the amounts of ethanol leads to a relatively broad impair-
immune defense are affected. Cellular elements of ment of host defense mechanisms [40]. Ethanol
the innate immune system, including neutrophils and impairs phagocytic cells, including neutrophils,
monocytes/macrophages, have altered function. In monocytes, and macrophages [41]. Also, significant
the neutrophils, functions such as adherence, chemo- decreases in T cell subpopulations, including CD4,
taxis, and phagocytosis may be down- regulated. CD8, and CD3, are seen in patients with alcoholic
This results in a less effective defense against a hepatitis [42]. These abnormalities were significantly
microbial challenge [28 – 30]. The neutrophils from correlated with protein malnutrition or kwashiorkor-
diabetic patients also produce less free oxygen rad- like changes, but not with primary caloric malnutri-
icals, which reduce their ability to make toxic metab- tion or marasmus-like changes. In addition, in this
olites for release against microbes [8]. Monocytes same population, it was noted that a large percentage
and macrophages may have up-regulated catabolism of patients displayed lowered CD4 cell count num-
of pro-inflammatory cytokines as well as increased bers (250 – 300 cells/mm3), which were similar to
production of matrix metalloproteases, such as colla- counts seen in HIV-infected individuals vulnerable
genase [31 – 33]. This creates an imbalance that is to the onset of opportunistic infections. Ethanol
detrimental to the containment of head and neck seems to blunt the activation of normal human
infections. The hyperglycemic state may also lead circulating CD3 T cells in terms of their ability to
to a decrease in fibroblast proliferation and synthesis produce IL-2 and thus decreases their proliferative
of collagen, impairing tissue turnover and wound potential in response to mitogenic stimulation. The
repair [34,35]. final stages of CD4 T cell maturation may be
It has been proposed that the formation of impaired, affecting the generation of Th1 and Th2
advanced glycation end-products (AGEPs), which patterns of cytokine response [43]. It is noteworthy
form as a result of glucose irreversibly binding to that the most profound impairment in T cell prolif-
proteins and lipids in the face of prolonged hyper- eration occurred during the period after cessation of
glycemia, is a key event in the generation of the ethanol ingestion when withdrawal symptoms are
defects seen in diabetes. [29,33]. Glycation end- evident. In this period, there are high levels of
products can bind to receptors on various cells, such corticosteroids in the circulation, suggesting that this
as leukocytes, and affect their function. The up- may be the primary mode for immunosuppression in
regulation of tissue destructive cytokines produced alcoholics. An additional subset of T cells, the NK
by the monocytes and macrophages may be a result cells, have been shown to be dysfunctional in alco-
of AGEP binding. AGEPs also alter the solubility of holic patients, decreasing the hosts ability to elim-
collagen and may play a role in the changes seen in inate virus-infected cells and tumor cells [44].
small and large blood vessels. This collagen inter- B cell activation is dependent on the proper
action may result in the accumulation of AGEPs on functioning of the T cell and its ability to produce a
the basement membrane, affecting the exchange of Th2 cytokine response. If this mechanism is dysfunc-
nutrition, neutrophil migration, and the diffusion of tional, as has been demonstrated in alcoholic patients,
antibodies and oxygen. As a group, these effects then the production of antigen specific immunoglo-
should have a detrimental effect on the wound heal- bulins is greatly reduced [45].
ing apparatus.
There is a significant body of evidence that HIV-infected patients
indicates that cystolic Ca++ is elevated in many cell
types in patients with both type I and type II diabetes The characteristic immune defect in HIV infection
mellitus [36,37]. The high levels of cystolic Ca++, is the destruction of CD4+ T cells [46]. This loss of
ultimately induced by hyperglycemia, could lead to a CD4+ T cells affects a variety of immune cells and
reduced ATP content and decreased phagocytic abil- their respective functions. CD4+ T cells exhibit
ity in neutrophils [38]. Additionally, increased intra- decreased lymphokine secretion (IL-2 and inter-
cellular Ca++ may affect the cellular components of feron-g) and a decreased response to soluble antigens,
the acquired immune system. B cells may have an increasing susceptibility to opportunistic infections
impaired proliferative response to mitogen, not unlike and neoplasms. CD8+ T cells have a decreased
that seen in the altered ionic environment of chronic cytotoxic response, decreasing a host’s ability to fend
renal failure [39]. off intracellular organisms. NK cells have a decreased
N.C. Gordon, S. Connelly / Oral Maxillofacial Surg Clin N Am 15 (2003) 103–110 107

ability to kill tumor cells. Macrophages exhibit first consideration is assuming that there is no acute
diminished cytotoxic ability, decreased chemotaxis, airway compromise. If the airway is compromised,
reduced IL-1 secretion, poor antigen presentation, the first course of action is either oral or nasal
and decreased class II HLA antigen expression, endotracheal intubation. In instances where swelling
contributing to a depressed antigen response and of the oropharyngeal airway is severe, it may be
defective wound healing. B cells show depressed Ig necessary to perform a tracheostomy to establish a
production in response to new antigens, and they are competent airway.
refractory to normal signals for B cell activation [47]. Once the airway is secured, the next step should
There is also polyclonal activation of B cells resulting be to obtain a thorough history and physical exam-
in hypergammaglobulinemia and circulating immune ination. This provides information about concomitant
complexes [48]. diseases, social habits, or other processes that may be
A significant number of patients with AIDS will indications of an immunocompromised status. Such
develop neutropenia as a result of direct retroviral indicators include a positive history of HIV, a pre-
infection, use of antiretroviral drugs and other drug vious diagnosis of diabetes, or signs and symptoms of
therapy, systemic infections, and autoimmune mech- the disease, alcohol or illicit drug use, renal dialysis,
anisms [49]. In addition, the neutrophils of patients and a recent history of recurrent infections. When
with AIDS have defective bactericidal function and performing the physical examination, one should
chemotatic defects [50,51]. Consequently, it has been keep in mind that immunocompromised individuals
proposed that the impairment in neutrophil function may have an attenuated immune response resulting in
along with defective immunoglobulin synthesis are decreased signs and symptoms of inflammation.
important causes of the increased risk of bacterial Thus, a serious infection may not necessarily have a
infections in patients with advanced HIV disease [52]. dramatic clinical presentation.
Also, there has been a strong correlation between the The next step is to obtain the necessary laboratory
degree of neutropenia and risk of developing serious and imaging studies to establish the diagnosis and
bacterial infections in cancer patients [53]. determine the extent of the infection. Routine labor-
atory studies such as a white blood cell count,
hemoglobin and hematocrit determination, a platelet
Management of infections count, and measurement of electrolytes, blood urea
nitrogen, creatinine, and glucose should be per-
The management of head and neck infections in formed. It is also helpful to obtain a differential white
the immunocompromised patient should follow the cell count. A high percentage of immature neutro-
same basic steps established for immunocompetent phils would indicate that the immune system is
individuals. These steps are outlined in Box 2. The struggling to produce cells to fight the infection.
Also, a decreased lymphocyte count may be indic-
ative of an HIV infection. Imaging studies may
Box 2. Management of head and neck include plain films, CT scans with or without con-
infections in the immunocompromised trast, MRI, and radionucleotide bone scanning (skel-
patient etal scintigraphy; see elsewhere in this issue).
Empiric antibiotic treatment should be instituted
1. Airway monitoring and possible sur- as soon as possible to rapidly obtain minimum
gical airway establishment inhibitory concentrations in the plasma. A recom-
2. Comprehensive history and physical mended antibiotic regimen is outlined in Box 3.
examination The initial selection is based on the duration of the
3. Obtaining appropriate laboratory and infection and the level of immunocompetence of the
imaging studies patient. If the polymicrobial infection has been pre-
4. Empiric antimicrobial therapy sent for less than 3 days, the amount of cross-
5. Surgical debridement and irrigation, colonization or synergy that has developed is limited.
as needed After 3 days, enough time has passed so that there is
6. Culture and antibiotic sensitivity test- increased virulence of some microorganisms due to
ing of infectious organisms to appro- the changes in the environment. For example, aerobic
priately adjust antibiotic therapy bacteria may produce a more favorable environment
7. Close follow-up to monitor for reso- for anaerobic bacteria, allowing them to multiply
lution and recurrence more readily. If the infection responds well to the
empiric use of an antibiotic, the regimen should be
108 N.C. Gordon, S. Connelly / Oral Maxillofacial Surg Clin N Am 15 (2003) 103–110

mens for culture should be taken at the time of


Box 3. Empiric antibiotic treatment
surgical debridement or incision and drainage. Both
aerobic and anaerobic cultures should be done and
Early infection (first 3 days of symptoms
antibiotic sensitivity testing should be performed to
or mildly immunocompromised)
provide guidance in selecting the correct antimicro-
bial treatment. Finally, close postoperative monitor-
Penicillin
ing, including repeated imaging studies, additional
Clindamycin
surgical interventions, and long-term follow-up are
Cephalexin (or other first-generation
mandatory for resolution of the infection.
cephalosporin)
Management of head and neck infections involves
the contribution of a triad of factors: the host, the
Late infection (after 3 days of symptoms
antibiotic, and the surgical intervention. In the normal
or moderately to severely immunocom-
host, serious polymicrobial infections can be pro-
promised)
duced by organisms that may not be infectious in
pure culture but that become infectious through
Clindamycin (maximum dose)
microbial synergism. Consequently, antimicrobial
Penicillin and metronidazole
therapy aimed at one major organism may be enough
Ampicillin and sulbactam
to break the chain and change the environment
Cephalosporin (first or second
sufficiently to allow the immune system to take over
generation)
and bring about resolution of the infection. In the
normal host, surgical intervention, as well as anti-
Mild, moderate, and severe comprom-
biotic therapy, significantly alter the microbial envir-
ise is based on CD4/viral loads, glycemic
onment, allowing the patient’s immune system to
control, and the degree of alcoholic-
phagocytize the remaining bacteria. In an immuno-
related disease.
compromised patient, the host component of the triad
is weakened, leaving the surgeon to rely almost
Modified from Flynn TR. The swol-
entirely on surgical intervention and antimicrobial
len face. Severe odontogenic infec-
therapy to resolve the infection. This is the rationale
tions. Emerg Med Clin N Am 2000;18:
for recommending aggressive surgical incision and
481 – 519.
drainage, frequent irrigation of the drains, and use of
high-dose, broad-spectrum antimicrobial therapy.
Again, it must be emphasized that antimicrobial
continued even if the culture and antibiotic sensitivity therapy must be supported by aerobic and anaerobic
test indicates a change may be appropriate. However, culturing and antibiotic sensitivity testing.
in the absence of clinical improvement, the culture
and antibiotic sensitivity test results should form the
basis for continued antimicrobial therapy. Summary
If a patient is mildly immunocompromised, there
should be an adequate immune response to assist the The immunocompromised host has a potential
antimicrobial drug. However, in the moderate to increased risk for severe head and neck infections
severely immunocompromised patient there is more that usually require aggressive antimicrobial therapy
dependence on the antimicrobial drug to control the and prolonged hospitalization. The causes of the
infection. Along with the use of antibiotics, surgical immunocompromised status of patients who seek care
debridement or incision and drainage rank as the most from the oral and maxillofacial surgeon are multi-
important interventions in the management of head factorial and include diabetes, malnutrition, obesity,
and neck infections. This includes removal of all nidi alcohol abuse, tobacco abuse, intravenous drug abuse,
of infection (teeth, necrotic tissue, and nonvital bone), cocaine abuse, HIV infection, and AIDS. Patients with
exploration and irrigation of all involved fascial other diseases, such as organ transplant recipients and
spaces, and proper wound care. The lack of vascular- those receiving cancer therapy or therapy for various
ity can result in failure of immune effectors and autoimmune diseases, are not frequently encountered
antibiotics to reach the infected sites. Proper place- with severe infections of the head and neck.
ment of drains and periodic irrigation through them is The number of patients with multifaceted causes of
essential for the continuous removal of necrotic immunocompromise will clearly increase in the future
debris and enhancement of vascularization. Speci- as the population ages and medical treatments for
N.C. Gordon, S. Connelly / Oral Maxillofacial Surg Clin N Am 15 (2003) 103–110 109

previously morbid or lethal conditions are improved. [14] Germain RN, Margulies DH. The biochemistry and
Recognizing the conditions associated with decreased cell biology of antigen processing and presentation.
immune function is critical for the proper management Annu Rev Immunol 1993;11:403 – 50.
[15] Trinchieri G. Biology of natural killer cells. Adv Im-
of these patients. Concurrent with recognition of
munol 1989;47:187 – 376.
immunocompromising diseases, it is important to
[16] Salter RD, Benjamin RJ, Wesley PK, et al. A binding
have a basic understanding of the normal immune site for the T-cell-co-receptor CD8 on the alpha3 do-
system and associated defects, because advances in main of HLA-A2. Nature 1990;345:41 – 6.
therapy will undoubtedly increase in complexity. For [17] Skoskiewcz MJ, Colvin RB, Scheenberger EE, et al.
instance, new antimicrobials, as well as pharmaceut- Widespread and selective induction of major histocom-
icals that alter cytokine function and affect the gen- patibility complex-determined antigens by gamma in-
eration of progenitor cells in the bone marrow stroma, terferon. J Exp Med 1985;162:1645 – 64.
are on the horizon. Future treatment strategies will not [18] Sieling PA, Chatterjee D, Porceli SA, et al. CD1-re-
only include aggressive use of traditional management stricted T cell recognition of microbial lipoglycan anti-
gens. Science 1995;269:227 – 30.
methods but also these new approaches. Ultimately,
[19] Bjorkman PJ, Davis MM. Model for the interaction of
this should provide a shorter course of treatment and
T-cell receptors with peptide/MHC complexes. Cold
improved outcomes for immunocompromised patients Spring Harb Symp Quant Biol 1989;54:365 – 73.
with head and neck infections. [20] Haynes B, Denning SM, Le PT, et al. Human intra-
thymic T cell differentiation. Semin Immunol 1990;2:
67 – 77.
References [21] Goodwin RG, Lupton S, Schmierer A, et al. Human
interleukin 7. Proc Natl Acad Sci U S A 1989;86:
[1] Klastersky J. Infections in immunocompromised pa- 302 – 6.
tients I. Pathogenesis, etiology, and diagnosis. Clin [22] Noelle RJ, Ledbetter JA, Aruffa A. CD40 and its li-
Ther 1985;8:90 – 9. gand, an essential ligand-receptor pair for thymus de-
[2] Kumate J. Infectious diseases in the 21st century. Arch pendent B cell activation. Immunol Today 1992;13:
Med Res 1997;28:155 – 61. 431 – 3.
[3] Lewis D, Harriman GR. Cells and tissues of the im- [23] Frank MM, Fries LF. The role of complement in in-
mune system. In: Rich RR, Fleisher TA, Schwartz flammation and phagocytosis. Immunol Today 1991;
BD, et al, editors. Clinical immunology principles and 12:322 – 6.
practice. St. Louis: Mosby-Year Book Inc.; 1996. [24] Harrison GA, Schultz TZ, Schaberg SJ. Deep neck
p. 15 – 38. infection complicated by diabetes mellitus. Oral Surg
[4] Huston DP. The biology of the immune system. JAMA Oral Med Oral Pathol 1983;55:133 – 7.
1997;278:1804 – 14. [25] Sugata T, Fujita Y, Myoken Y, Fujioka Y. Cervical
[5] Fearon DT, Locksley RM. The instructive role of in- cellulitis with mediastinitis from an odontogenic infec-
nate immunity in the acquired immune response. Sci- tion complicated by diabetes mellitus: report of a case.
ence 1996;272:50 – 3. J Oral Maxillofac Surg 1997;55:864 – 9.
[6] Fleisher TA. Immune function. Pediatr Rev 1997;18: [26] Leibovici L, Yehezkelli Y, Porter A. Influence of dia-
251 – 6. betes mellitus and glycemic control on the character-
[7] Kishimoto TK, Anderson DC. The role of integrins in istics and outcome of common infections. Diabet Med
inflammation. In: Gallin JI, Goldstein IM, Snyderman 1996;13:457 – 63.
R, editors. Infammation: basic principles and clinical [27] Vernillo AT. Diabetes mellitus: relevance to dental
correlates. New York: Raven Press; 1992. p. 353 – 406. treatment. Oral Surg Oral Med Oral Pathol Oral Radiol
[8] Weissmann IL, Cooper MD. How the immune system Endod 2001;91:263 – 70.
develops. Sci Am 1993;269:64 – 71. [28] Cianciola LJ, Park BH, Bruck E, et al. Prevalence of
[9] Brodsky FM, Guagliardi L. The cell biology of antigen periodontal disease in insulin-dependent diabetes mel-
processing and presentation. Annu Rev Immunol litus. J Am Dent Assoc 1982;104:653 – 60.
1991;9:707 – 44. [29] Mattson J, Cerutis D. Diabetes mellitus: a review of the
[10] Davis MM. T cell receptor gene diversity and selection. literature and dental implications. Compendium
Annu Rev Biochem 1990;59:475 – 96. 2001;22:757 – 72.
[11] Schatz DG, Oettinger MA, Schlissel MS. V(D)J re- [30] Naghibi M, Smith R, Baltch A, et al. The effect of
combination. Annu Rev Immunol 1992;10:359 – 83. diabetes mellitus on chemotatic and bactericidal activ-
[12] Roitt IM. Immunology. 4th edition. Barcelona: Mosby; ity of human polymorphonuclear leukocytes. Diabetic
1998. Research and Clinical Practice 1987;4:27 – 35.
[13] Rodgers JR, Rich RR. Antigens and antigen presenta- [31] Campbell MJ. A light and electron microscope study
tion. In: Rich RR, Fleisher TA, Schwartz BD, et al, of blood vessels from the gingival tissues of non-
editors. Clinical immunology principles and practice. diabetic and diabetic patients. Aust Dent J 1971;16:
St. Louis: Mosby-Year Book Inc.; 1996. p. 114 – 31. 235 – 9.
110 N.C. Gordon, S. Connelly / Oral Maxillofacial Surg Clin N Am 15 (2003) 103–110

[32] Grossi SG, Genco RJ. Periodontal disease and diabetes experimental data. Alcohol Clin Exp Res 1995;19:
mellitus: a two-way relationship. Ann Periodontol 551 – 4.
1998;3:51 – 61. [43] Chiappelli F, Kung M, Lee P, et al. Alcohol modulation
[33] Lalla E, Lamster IB, Schmidt AM. Enhanced interac- of human normal T-cell activation, maturation, and
tion of advanced glycation end-products with their migration. Alcohol Clin Exp Res 1995;19:539 – 44.
cellular receptor for RAGE: implications for the patho- [44] Saxena QB, Mezey E, Adler WH. Regulation of natu-
genesis of accelerated periodontal disease in diabetes. ral killer activity in vivo. II: The effect of alcohol
Ann Periodontol 1998;3:13 – 9. consumption on human peripheral blood natural killer
[34] Golub LM, Nicoll GA, Iacono VJ, et al. In vivo activity. Int J Cancer 1980;26:413 – 7.
crevicular leukocyte response to a chemotatic chal- [45] Smith KA. Interleukin-2: inception, impact, and impli-
lenge: inhibition by experimental diabetes. Infect cations. Science 1988;242:1169 – 76.
Imm 1982;37:1013 – 20. [46] Fichtenbaum CJ, Dunagan WC, Powderly WG. Bac-
[35] Ryan ME, Ramamurthy NS, Sorsa T, et al. MMP-medi- teremia in hospitalized patients infected with human
ated events in diabetes. Ann N Y Acad Sci 1994;878: immunodeficiency virus: a case-control study of risk
311 – 34. factors and outcome. J Acquir Immune Defic Syndr
[36] Draznin B, Lewis D, Houlder N, et al. Mechanism of Hum Retrovirol 1995;8:51 – 7.
insulin resistance induced by sustained levels of cyto- [47] Janeway CA, Travers P, Hunt S, Walport M. Immu-
solic free Ca in rat adipocytes. Endocrinology 1989; nobiology. 3rd edition. New York: Garland Publish-
125:2341 – 9. ing; 1997. p. 153 – 75.
[37] Rapoport Y, Himelfarb MZ, Zikk D, et al. Cervical [48] Lane HC, Masur H, Edgar LC, et al. Abnormalities of
necrotizing fasciitis of odontogenic origin. Oral Surg B-cell activation and immunoregulation in patients
Oral Med Oral Pathol 1991;72:15 – 8. with the acquired immunodeficiency syndrome.
[38] Alexiewicz J, Kumnar D, Smogorzewski M, et al. N Engl J of Med 1983;309:453 – 8.
Polymorphonuclear leukocytes in non-insulin depend- [49] Murphy MF, Metcalfe P, Waters AH, et al. Incidence
ent diabetes mellitus: abnormalities in metabolism and mechanism of neutropenia and thrombocytopenia
and function. Ann Intern Med 1995;123:919 – 24. in patients with HIV. Br J Haematol 1987;66:337 – 40.
[39] Gaciong Z, Alexiwcz JM, Linker-Israeli M, et al. In- [50] Murphy PM, Clifford LH, Fauci AS, et al. Impairment
hibition of immunoglobulin prodution by parathyroid of neutrophil bactericidal capacity in patients with
hormone: implications in chronic renal failure. J Am AIDS. J Infect Dis 1988;158:627 – 30.
Soc Nephrol 1990;1:236 – 44. [51] Nielsen H, Kharazmi A, Faber V. Blood monocyte and
[40] MacGregor RR. Alcohol and immune defense. JAMA neutrophil functions in acquired immune deficiency
1986;256:1474 – 9. syndrome. Scand J Immunol 1986;24:291 – 6.
[41] Brayton RG, Stokes PE, Schwartz MS, et al. Effect of [52] Moore RD, Keruly JC, Chaisson RE. Neutropenia and
alcohol and various diseases on leukocyte mobiliza- bacterial infection in acquired immunodeficiency syn-
tion, phagocytosis and intracellular bacterial killing. drome. Arch Intern Med 1995;155:1965 – 70.
N Engl J Med 1970;282:123 – 8. [53] Chanock S. Evolving risk factors for infectious com-
[42] Roselle GA, Medenhal CL, Chedid A, et al. Alco- plications of cancer therapy. Hematol Oncol Clin North
hol modulation of immune function: clinical and Am 1993;7:771 – 93.
Oral Maxillofacial Surg Clin N Am 15 (2003) 111 – 122

Diagnosis and treatment of recurrent aphthous stomatitis


Ellen Eisenberg, DMD
Division of Oral and Maxillofacial Pathology, University of Connecticut School of Dental Medicine,
University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA

What is recurrent aphthous stomatitis (RAS)? Is it aphthous-like oral ulcers often occur in conjunction
appropriate to regard it as an infectious disease? Are with diverse conditions of a systemic nature. Included
there effective measures for managing aphthous among those conditions are cyclic neutropenia [5],
ulcers? These are just a few of the questions that selected anemias [6], inflammatory bowel diseases [7],
are continually asked about this benign but highly Behçet’s disease (see Box 1) [8,9], gluten-sensitive
symptomatic oral problem. enteropathy (celiac sprue) [10,11], relapsing poly-
Although it is one of the most common recurrent chondritis syndromes (including the so-called
oral ulcerative conditions of adults and children ‘‘MAGIC’’ syndrome, which consists of mouth and
recognized throughout the world, RAS is also one genital ulcers with inflamed cartilage) [12], HIV
of the least understood oral diseases and is among the infection [13], the purported symptom complex of
most vexing problems faced by affected patients and recurring fevers, aphthous stomatitis, pharyngitis, and
clinicians alike [1]. The triggering factors that pre- lymphadenopathy (FAPA syndrome) [14], and others
cipitate recurrent episodes in RAS patients seem to be [2,4 – 6,15]. Given the various presentations of RAS
as diverse and unique as the affected individuals as either an exclusively local oral phenomenon or as a
themselves [2], which has posed a challenge for systemically related oral condition, it is not surprising
scientists in their attempts to identify a specific that the search for its origin has proved frustrating.
causation for this disease. Although the origin of In recent years a body of evidence has emerged to
RAS remains obscure, there is growing lucidity with suggest a genetic and an immunologic basis for RAS.
regard to its pathogenesis, and that enlightenment has These revelations largely have eclipsed speculation
influenced contemporary approaches to its manage- that RAS is caused by an infectious microorganism
ment significantly [3]. or one of the other previously suspected etiologic
factors. They also have led to more rational and ef-
fective contemporary approaches to the management
Etiology and pathogenesis of RAS [16].

Historically, conjecture about the origin of RAS


focused on a wide spectrum of potential local and Genetic factors
systemic factors that encompassed microbial agents,
hematologic and hormonal disturbances, physical There is an apparent familial predisposition for
injury, emotional stress, and other influences [4]. To aphthous stomatitis. As compared to the general
date, however, despite years of collective effort on the population, the prevalence of RAS is higher when
part of many researchers, the precise cause of RAS there is a positive family history, especially when both
continues to elude disclosure. Also confounding the parents are affected [17]. There is also increased
search for a singular cause is the observation that disease correlation observed in identical twins as
compared to fraternal twins [18]. In familial cases of
RAS, the onset of disease is earlier and attacks tend to
E-mail address: eeisenberg@nso2.uchc.edu occur more frequently than in nonfamilial cases [19].

1042-3699/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.
PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 7 0 - 5
112 E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122

which there is immune-induced gluten sensitivity and


Box 1. Behçet’s disease
resultant intestinal malabsorption), and patients with
inflammatory bowel diseases (specifically Crohn’s
A recurrent, multisystemic, immuno-
disease and ulcerative colitis) and oral aphthae [7,10].
logically mediated vasculitic syndrome

Essential diagnostic component:


Immunologic factors
Oral aphthous ulcers (three or more
recurrences in one 12-month period)
Although findings have not been entirely consist-
accompanied by any two of the following:
ent and conflicting theories persist, mounting scien-
tific testimony supports immune dysregulation as a
Skin
 Pustular or nodular cutaneous lesions
key mechanism underlying the pathogenesis of RAS.
 Positive cutaneous pathergy (ie, pus-
It is believed that the altered immune reactivity arises
perhaps in response to, or in concert with, a state of
tule formation at injection site 24 to
presumably heightened antigenic stimulation [16]
48 hours after injection of sterile
exacted on a diminished mucosal barrier [2].
solution of inert substance)
 Superficial thrombophlebitis, ery-
A constellation of cell-mediated immunologic
phenomena seems to be a consistent factor in the
thema, ulcerations, acneiform lesions
disease. Serologic studies that compared RAS
patients and unaffected controls revealed diminished
Ocular ratios of circulating CD4+ helper cells to CD8+
 Uveitis
suppressor cells in the former group [20,21]. It has
 Retinal vasculitis
been proposed that in RAS some unspecified anti-
Genital genic influence [2,22] is at the epicenter of an
 Recurring ulcers of penis, scrotum, antibody-dependent, T cell-mediated immune re-
or vulva sponse that involves a shift in local lymphocytic
subpopulations that eventuates in tissue damage
Less common manifestations: [23 – 25]. From the observations of several investiga-
tors it has been hypothesized that the entire process of
Inflammatory bowel disease-related aphthous ulceration, from initiation through progres-
symptoms sion, is instigated by the expression on oral epithelial
Arthritis cells of not only normally found HLA class I antigens
Neurologic disturbances but also HLA class II antigens [26]. Presumably, this
 Psychiatric disorders renders the cells antigenically ‘‘foreign’’ and conse-
 Meningoencephalitis quently they become the targets of a cell-mediated
 Brain stem abnormalities immune reaction perpetrated by lymphocytes and
Langerhans cells [26]. It has been shown that in
Data from International Study Group patients with aphthous stomatitis there is a heightened
for Behçet’s Disease. Criteria for diagnosis lymphocytotoxic effect directed against oral epithelial
of Behçet’s disease. Lancet 335:1078, cells when compared to unaffected controls [25 – 27].
1990. Evidence for this pathogenetic mechanism is also
inferred from observations that tissue biopsies of
newly erupted aphthous ulcerations demonstrate
The likelihood that RAS is a genetically grounded agglomeration of activated T lymphocytes at the
disease is further supported by the recognized, periphery of the lesions, whereas in well-established
although not entirely consistent, identification of aphthae the initially predominant CD4+ helper/sup-
certain histocompatibility antigen (HLA) types (eg, pressor cell population is subsumed and succeeded by
HLA B12, B51, Cw7), among some groups of cytotoxic CD8+ lymphocytes [24,25].
aphthous patients [2]. The latter type includes the Additional indirect support for primary immune
largest group of individuals whose aphthous ulcers dysregulation is reflected in the long-recognized cor-
(‘‘canker sores’’) are isolated to the oral cavity relation between stress and outbreaks of aphthous
exclusively, without an attendant underlying systemic ulcers that is reported by many RAS patients, in con-
disease, individuals with the mucocutaneous form of trast to the notable decrease in frequency of episodes
Behcß et’s disease [8], persons with celiac disease (in during periods of reduced stress [28]. This observed
E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122 113

association is not entirely surprising, because stress is consideration also could be applied to the other human
known to affect immunologic function [2]. It also has herpes viruses, varicella-zoster virus and cytomegalo-
been observed that HIV-infected patients experience virus, which are known to affect such subclinical
oral aphthous-like ulcerations with relatively high phenomena as asymptomatic viral shedding and ele-
frequency. With advancing immune depletion, their vated viral titers, similar to HSV [35,36].) It must be
aphthous outbreaks are often dominated by larger emphasized, however, that regarding most aphthous
ulcers that run a more protracted course [13,29,30]. patients, any suggestion of a causative nexus between
Attempts to explore the possibility that RAS is RAS and HSV seems to represent unsubstantiated
fundamentally an antibody-driven disorder have dis- conjecture rather than proven fact [16].
closed findings that are at best inconsistent and
largely unsupportive. It seems that any previously
held conjecture that aphthous ulcers stem from a Nutritional factors
centrally generated humoral immune mechanism
rather than from local cellular immune responses to Other issues explored in the quest to determine a
an antigenically modified oral mucous membrane cause for RAS include the possible relationship of
was predicated on assumptions that have since been attacks to excess or deficiency of various nutritional
discredited [3,18,31 – 33]. factors, such as serum iron, folate, and vitamin B12,
and speculation that aphthous ulcers represent the
manifestation of an allergic reaction to certain foods
Microbial factors or other ingested or contacted substances. Apart from
variably favorable responses to the avoidance of
To date, investigations have yielded little, if any, gluten products in aphthous patients with docu-
consistent evidence to support the hypothesis that mented intestinal malabsorption disease (compared
RAS represents an infectious disease. In particular, to controls [37]) and in some aphthous stomatitis
from studies to determine whether there might be a patients with normal intestinal function [38], evi-
connection between previously suspect L-forms of dence that RAS primarily represents an allergic
streptococci and RAS, or the adenoviruses, herpes response or is etiologically linked to diminished
simplex virus (HSV), varicella-zoster virus, or cyto- serum iron, vitamin B12, or folate levels is lacking
megalovirus and RAS, the available evidence sug- or, at best, equivocal [6,16,24,28,39].
gests that none of these microorganisms seems to be For any RAS patient who exhibits physical signs
directly culpable for RAS despite continued specu- and symptoms that suggest the possibility of an
lation about their possible role [2,6]. One should note underlying malabsorption or nutritional deficiency
that an antiviral agent, acyclovir, offers no beneficial state or a blood dyscrasia, it is prudent to obtain a
effect in preventing or attenuating episodic flares of complete blood count and assays for serum folate,
the condition [34], which serves to weaken arguments vitamin B12, and ferritin. Should any of these tests
in favor of a possible viral causation for RAS [16]. yield findings that suggest an underlying systemic
From occasional anecdotal cases in which patients abnormality, referral to an internist or a hematologist
report an apparent consistent temporal relationship is indicated [6].
between their aphthous outbreaks and an immediately
antecedent reactivated (recurrent) HSV infection, it is
tempting to postulate that in a narrow subset of Clinical features
individuals who get RAS, the herpes virus may serve
as an antigenic ‘‘trigger’’ that initiates the cascade of The classic clinical features of RAS are generally
immunologic events that result in ulceration [2]. In a well known and usually suffice for diagnostic pur-
limited subset of RAS patients, it is possible that this poses [6]. The lesions affect the oral cavity exclu-
is actually the case. Presumably, such patients would sively and, with the occasional exception of the
benefit from appropriate therapeutic and prophylactic dorsal aspect of the tongue, overwhelmingly favor
antiviral therapy, coupled with treatments specifically nonkeratinizing, freely moveable mucosal surfaces.
aimed at lessening the severity and frequency of the From the latter characteristic, one might infer that the
RAS episodes by modulating their supposedly height- abridged mucosal barrier of these attenuated epithe-
ened immune responses to the viral ‘‘trigger’’ [6]. lial surfaces allows for intensified antigenic stimu-
Such therapeutic strategies probably would be best lation, which in turn launches the autoimmune
carried out in consultation with an infectious disease reaction that results in mucosal disruption. Involve-
specialist [6]. (Analogous speculation and therapeutic ment of keratinized epithelial surfaces is distinctly
114 E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122

uncommon and almost always represents extension of tends to experience a similar phenomenon with
ulceration from its origin on an adjacent nonkeratin- relation to the location of at least some of their
ized epithelial surface [2]. When a cluster of ulcers is aphthous lesions in the context of some, if not all,
confined to a single keratinized mucosal location (eg, of their outbreaks.
hard palate, attached gingiva), the possibility that Unlike the ulcerations seen in primary or recurrent
they represent ruptured vesicles of a recurrent HSV oral HSV infections, aphthous ulcers are not preceded
infection (Table 1) or are traumatic ulcers must be by vesicles [6]. Although individual aphthae are often
considered in the differential diagnosis as more likely categorized into one of three possible subtypes (minor,
than aphthous ulcers [6,40,41]. major, and herpetiform) based primarily on their
Aphthous ulcers’ preference for buccal and labial respective size differences, this classification is purely
mucosa and the lateral-ventral tongue surfaces also descriptive rather than substantive. Regardless of an
lends oblique support to the condition’s immune- individual lesion’s dimensions, all of the subtypes
related nature, because these sites are especially seem to represent mere superficial variations of a
susceptible to friction and prone to trauma. It is not single disease entity [2]. Any individual recurrence
uncommon for some patients to report that their may feature as few as one or two isolated ulcers or
aphthous ulcers typically arise on such locations upwards of virtually dozens of aphthous lesions. Any
shortly after a preceding minor traumatic event, such one of the subtypes or various combinations of each of
as an accidental self-inflicted bite, frictional irritation the three subtypes can occur in the course of a single
or injury from tooth clenching or bruxing, or after an RAS outbreak [16]. Notwithstanding size, all aphthous
inadvertent nonpenetrating ‘‘stab’’ from a utensil ulcers are painful, and in many cases, patients also
during a meal [42]. These events are examples of relate histories of prodromal discomfort or other symp-
the so-called ‘‘Koebner phenomenon,’’ in which toms that routinely augur impending recurrences [40].
lesions that are characteristic of a specific immuno- The frequency and severity of recurrences vary
logically mediated mucocutaneous disorder (eg, widely among affected individuals. Some patients
psoriatic plaques in psoriasis) develop on sites of experience recurrences at fairly regular intervals,
recently traumatized but previously lesion-free skin whereas for others the episodes occur with less
or mucosa [43]. ‘‘Koebnerization’’ also occurs in predictability. In many cases the attacks are precipi-
individuals with diseases such as lichen planus [44], tated by a particular identifiable factor (eg, intense
various types of lupus erythematosus, and others stress [15] or, as reported by some women, in tem-
[45]. It seems that a subset of individuals with RAS poral relation to their menstrual cycles [46]), whereas

Table 1
Distinctions: Recurrent aphthous ulcers and recurrent (‘‘reactivated’’) intraoral HSV lesions
Factor Recurrent aphthous ulcers Recurrent HSV
Etiology Focal immune dysregulation HSV-I (HSV-II rarely)
Antecedents Commonly stress, trauma; other factors diverse Local trauma, stress, systemic
and unique as the affected individuals immune alteration
Prodromal awareness Sporadic Typical
Location of lesions Non-keratinizing ‘‘moveable’’ mucosa and Keratinizing (‘‘bound down’’)
tongue dorsum mucosa only
Distribution Unifocal or multifocal throughout oral cavity Unifocal only
(in immunocompetent individuals)
Lesions Ulcers of varying size and number possible Unifocal cluster of vesicles
per episode that ulcerate
Symptoms Pain (regardless of lesion size) Pain
Diagnostic Confirmation History, clinical features; negative cytology for History, clinical features; positive viral
virally-modified epithelial cells; biopsy usually cytopathic changes on smear; biopsy
not necessary usually not necessary
Clinical course 7 to 14 days, no scarring (minor and herpetiform types); 7 to 14 days
greater than 14 days, scarring possible (major types) (in immunocompetent individuals)
Management Palliative agents, corticosteroids, other immune Antiviral agents
modulating agents
Modified from Regezi JA, Sciubba JJ. Vesiculo-bullous diseases: Herpes simplex infections. In: Regezi JA, Sciubba JJ, editors.
Oral pathology: Clinical-pathologic correlations. 2nd edition. Philadelphia: W.B. Saunders; 1993; p. 9; with permission.
E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122 115

by slightly raised, erythematous, halo-like borders.


Several ulcers in close apposition to one another may
become confluent and result in a larger area of
mucosal disruption [2].
So-called ‘‘minor’’ (‘‘typical’’) aphthous ulcers are
smaller than 1 cm in diameter and tend to heal within
10 to 14 days (Fig. 1). Their larger counterparts, so-
called ‘‘major’’ aphthous ulcers (Mickulicz’s aphthae,
periadenitis mucosa necrotica recurrens, Sutton’s aph-
thae), are not as common. They are 1 cm in diameter or
larger, with edematous borders, and classically involve
a greater depth of submucosal tissue destruction. For
this reason, these types of aphthous ulcers tend to run a
Fig. 1. Minor aphthous ulcers, lower labial mucosa. more extended clinical course; they can take signifi-
cantly longer than 2 weeks to resolve and sometimes
heal with scar formation (Figs. 2,3). Herpetiform
some patients’ outbreaks arise without any identifi- aphthous ulcers, the least common type, tend to be
able triggering factor [16]. Episodes may occur rarely distributed in tight clusters of small ulcers, 1 to 3 mm
or with some frequency, accompanied by a range of in diameter, that bear superficial resemblance to the
symptomatic intensity. Most troubling for a small ruptured vesicles of oral HSV infections [2,4,6,36].
subset of individuals is the experience of overlapping Frequently, close crops of these ulcers coalesce to
recurrences for periods of time that can involve weeks involve a broad surface area (Figs. 4,5). Although
or months or, rarely, a year or more of almost their small size allows for resolution of herpetiform
perpetual mucosal disruption from aphthous ulcer- aphthae within a 7- to 10-day period, some patients
ations. During such periods of seemingly relentless experience recurrences that flare at relatively close
outbreaks, a patient’s ability to function comfortably intervals. Although herpetiform aphthae also exhibit a
and even their emotional stability may be compro- strong predilection for nonkeratinized epithelium,
mised drastically because of protracted oral mucosal unlike their minor and major counterparts they
pain [2]. Under such circumstances, patients are coalesce readily and can occur on any oral mucosal
occasionally suspected of having Behcß et’s disease surfaces, including those that are keratinized [2].
[8] or some other major systemic disorder. Accord-
ingly, they are often referred to appropriate medical or
dental specialists for a diagnostic consultation and Histopathology
evaluation. One should note that in most cases even
the most exacting and thorough systemic evaluation Once an aphthous ulcer has emerged onto the oral
fails to reveal evidence that supports a diagnosis either mucosa, biopsy is usually not required for diagnostic
of Behcßet’s or any other identifiable systemic disease.
Instead, such evaluations only serve to confirm that
the condition is confined to the oral cavity and is
simply an extreme expression of RAS alone [2,6].
Commonly, RAS patients report sensations of
burning, tingling, or other mucosal discomfort just
before an outbreak of aphthous ulcers, similar to the
prodromal symptoms that frequently precede recur-
rent HSV infections [40]. During the prodromal phase
of RAS it may be possible to observe a transient
erythematous macule or papule at the site of mucosal
discomfort. Such lesions typically emerge onto move-
able oral mucosal surfaces or the dorsal aspect of the
tongue and can antecede the actual aphthous ulcer-
ations by at least several hours or longer. These
preulcerative lesions are succeeded by characteris- Fig. 2. Major aphthous ulcer of longer than 8 weeks’
tically painful ulcers with round, symmetrical, yel- duration. Located on anterior buccal-labial mucosa, the
low-white or gray fibrinonecrotic centers surrounded lesion had been secondarily traumatized.
116 E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122

Fig. 3. Hyperplastic scar tissue from healed major Fig. 5. Herpetiform aphthous ulcers on the soft palate and
aphthous ulcer, lower right vestibular mucosa adjacent to uvula. These clusters of small ulcerations have coalesced to
mandibular canine and first premolar tooth. Scar resembles form extensive lesions that resemble major aphthae.
epulis fissuratum.

confirmation because there are no defined pathogno- may be seen [2]. As an aphthous ulcer ‘‘ages,’’ the
monic microscopic features of this disorder. At the histopathologic findings become increasingly non-
tissue level, the clearly nonvesicular nature of the specific [16]. Biopsy of any long-standing, nonheal-
ulcerative lesion and the absence of virally modified ing oral ulcer may be indicated, however, to determine
epithelial cells may serve to distinguish an early whether the lesion is benign or malignant or repres-
aphthous ulcer from an herpetic lesion in cases in entative of some unsuspected unusual diagnostic
which there is clinical diagnostic ambiguity [4,40]. entity, such as a granulomatous infection or inflam-
Relatively early in their course, aphthous lesions matory disease.
demonstrate an ulcer base covered by a fibrinopuru-
lent pseudomembrane. The marginal epithelium may
appear spongiotic with attendant lymphocytosis, Management of recurrent aphthous stomatitis
especially in the basal-most strata. At the marginal
epithelial-stromal interface, ‘‘tagging’’ of lympho- General considerations
cytes is prominent, and throughout the superficial
stroma polymorphonuclear leukocytes and chronic Conventional wisdom and clinical experience
inflammatory infiltrates dominated by lymphocytes strongly suggest that most cases of RAS are isolated
and histiocytes prevail. Within the deeper submucosa, to the oral cavity and are neither attributable to nor
perivascular infiltrates of lymphocytes and histiocytes associated with an underlying systemic disease or
some other generalized pathologic condition. If the
medical history is positive for or suggestive of any of
the systemic conditions known to be linked to oral
aphthae, however, and the patient experiences severe
bouts or unusually frequent recurrences of aphthous
stomatitis, it may be prudent to rule out the possibility
that the oral flare up reflects an exacerbation of the
systemic disease. Should that suspicion be confirmed
through an appropriately focused evaluation in con-
sultation with the patient’s primary care provider or
an appropriate medical specialist, the apparent incit-
ing condition must be addressed and treated accord-
ingly. The expectation is that once the underlying
systemic problem is brought under control, at least
temporary remission or regression of the RAS can be
achieved [2,6,16].
Fig. 4. Minor, major, and herpetiform aphthae occurring Whether it is of value to include complete hem-
synchronously on right soft palatal mucosa. atologic screening of RAS patients as part of the
E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122 117

standard diagnostic and treatment planning evalu-


Box 2. Recurrent aphthous stomatitis:
ation is debatable. Although low serum iron and
treatment options
ferritin levels have been documented in some
patients by some investigators [47,48], others have
found that RAS patients generally have normal No treatment
erythrocyte counts and hemoglobin levels, similar Palliative approach
 Topical agents: home remedies, over-
to those of controls [49,50]. Some researchers recom-
mend that children with RAS be screened hemato- the-counter medications, prescribed
logically because in approximately 20% of children analgesics, cauterizing agents
who get aphthous ulcers, dormant serum iron defi- Antiinflammatory and antimicrobial
ciencies unaccompanied by anemia have been dis- agents
closed [51]. Regardless of the patient’s age, if Immunomodulation*
 Topical: corticosteroid creams, oint-
hematologic testing reveals a deficiency state or
other abnormality, management of the blood dyscra- ments, gels, rinses; ‘‘intralesional’’
sia also may constitute a key strategy for managing (perilesional) corticosteroid injections
 Systemic: corticosteroids, nonsteroi-
the oral lesions.
dal immunosuppressive agents, anti-
inflammatory agents
Objectives, principles, and caveats Combined therapy: topical and sys-
temic agents, systemic agents in com-
Treatment is targeted at reducing the duration bination
and expediting the resolution of ulcers, alleviating
pain, lessening the frequency of attacks, and fore- * Most efficacious approaches.
stalling recurrences. Management decisions should
be dictated by each patient’s perceptions of the
severity of the oral lesions, the frequency of recur- odic flares and can be used on an intermittent basis as
rences, and the degree of debilitation that attends the a preemptive strategy for attenuating an incipient
outbreaks. All treatment efforts must be applied in attack or they can be used to abort an imminent
balance with the safest, most judicious use of aphthous outbreak in its prodromal stage. The unre-
therapeutic agents available. mitting use of immunomodulating agents for this
In patients with strictly oral manifestations of essentially benign disease, whether topical, systemic,
RAS and no concomitant systemic abnormality, a or combined, is contraindicated, given these agents’
broad scope of possible treatment options is avail- recognized potential for pernicious side effects
able. At the extremes, choices range from doing [2,3,6].
essentially nothing other than to confirm the diag-
nosis to prescribing major therapeutic agents aimed at
prevention and control of the immunologic mecha- First-line therapeutic choices
nisms that produce aphthous ulcers. In between these
extremes several relatively conservative strategies are When a recurrent episode consists of a relatively
available for alleviating symptoms exclusively, cur- limited number of aphthous lesions that are either
tailing the duration and pain of a single episode, small or large, closely apposed to one another, and
attenuating an active outbreak that may be part of a distributed on readily accessible oral surfaces such
series of overlapping or frequent outbreaks of RAS, as the labial or vestibular mucosa or the anterior
and preventing future episodes (see Box 2). It is portion of the tongue, first-line therapeutic manage-
vitally important for the patient and the clinician to ment should involve regimens based on conserva-
bear in mind that any and all interventions for RAS, tive topical therapy [2 – 4,6,16]. Among the options
regardless of severity, are neither curative nor intend- available are any of the over-the-counter nonsteroi-
ed for persistent use [16]. Rather, they are prescribed dal occlusive preparations, such as Orabase, with or
to effect temporary respite from a disease with a without topical analgesic (usually benzocaine) that
proclivity for recurrences [1 – 4,6,16,28,40]. may be applied primarily for symptomatic relief or
Because aphthous stomatitis is an immunologi- nonsteroidal antiinflammatory preparations, such
cally mediated disease, therapies centered in as amlexanox 5% paste (Aphthasol oral paste).
immunomodulation are most appropriate. They can Applied directly to active lesions, amlexanox pro-
be applied successfully for managing individual epis- motes pain reduction by inhibiting release of his-
118 E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122

tamine and leukotrienes. It has been shown that drink for 30 minutes after application is advised to
aphthous ulcers treated with amlexanox resolve in promote adherence of the preparation to the ulcer-
less time (by 1 day) than their untreated counter- ations. To prevent or address corticosteroid-induced
parts [2 – 4,6]. candidiasis, an antifungal medication can be com-
Topical corticosteroid gels, creams, or ointments pounded into the corticosteroid cream or ointment,
that are selectively prescribed and judiciously applied with or without a tissue adhesive base when indi-
to active lesions constitute an effective conservative cated [40].
modality for managing RAS. The cream or ointment For aphthous ulcers that are difficult to reach with
preparations are preferred, because some patients a finger—predominantly ulcers that involve the most
report stinging or burning with the use of cortico- posterior oral regions—or are so numerous and widely
steroid gels [3,40]. distributed as to render the direct application of
Some patients who wish to use topical cortico- creams or ointments impractical, corticosteroid rinses
steroid gels, creams, or ointments are reluctant to do are an excellent topical therapeutic alternative [2 – 4,
so or fail to comply because of the fear that attends 6,16,28,40]. Rinsing over a period of several days
reading the warning on prescription packaging inserts with betamethasone (Celestone) syrup 0.6 mg/5 mL,
or receiving pharmacists’ admonishments that topical dexamethasone (Decadron) elixir 0.5 mg/5 mL, or a
corticosteroid preparations are for external use only. specially compounded aqueous suspension of 0.1% or
Clinicians should reassure their patients that the use 0.2% triamcinolone acetonide accelerates resolution
of these topical agents strictly as prescribed for of the ulcers and alleviates discomfort. Three to four
limited periods of time is not likely to produce times daily and before retiring for the night, 1 tea-
untoward effects and is safe [3,40,52]. spoonful of the liquid is held and swished in the
Over the course of several days, starting as early mouth for 2 to 3 minutes and then expectorated. The
as possible from the onset of the outbreak, direct rinse regimen is followed by avoidance of food and
application of a thin film of the corticosteroid agent drink for 30 to 60 minutes afterward. This is not only
three to five times daily and at bedtime after gentle an effective method for addressing active RAS out-
drying of the affected area alleviates discomfort and breaks but also may be useful for aborting an immi-
reduces the duration of ulcers so that they heal within nent attack in its prodromal phase [16]. The author
several days, rather than linger for a week or more, as also has found that ‘‘customized’’ prophylactic corti-
is typical of untreated lesions [6]. Among the recog- costeroid rinse regimens can be adapted to an indi-
nized vagaries inherent in using creams or ointments vidual patient’s needs, particularly in cases in which it
on oral mucous membranes is the likelihood that they is necessary to intercept and prevent episodes known
rapidly wash away from the site of application and to occur with some regularity or frequency. Triamcin-
thereby diminish the therapeutic efficacy of the olone acetonide suspension can be compounded with
medication. This problem can be addressed either nystatin (Nystatin oral suspension USP) for individu-
by prescribing a topical corticosteroid compounded als predisposed to oral candidiasis or with 2% lido-
with tissue adhesive (eg, 0.1% or 0.5% triamcinolone caine (Xylocaine 2% viscous solution) if there is a
acetonide [Aristocort A, Kenalog] in Orabase) or, need for expedient pain relief (Karen A. Baker, MS
as an alternative, by prescribing more potent topical Pharm, personal communication, 2001).
corticosteroids, such as 0.05% betamethasone dipro- Another method for applying topical corticoste-
pionate cream or ointment (Diprolene; Lotrisone), roid medication to active lesions (particularly major
0.05% fluocinonide cream or ointment (Lidex), aphthous ulcers or other types of aphthae located
or 0.05% clobetasol propionate ointment or cream primarily in intertriginous-like regions of the oral
(Temovate) alone, without tissue adhesive [2 – 4,6]. mucosa, such as the upper or lower buccal or labial
The latter three topical agents seem to provide greater vestibules or the sublingual vestibule) involves
therapeutic efficacy than those compounded in an using a gauze sponge either soaked in corticosteroid
occlusive or adherent base, despite their limited time rinse preparation or on which a small amount of
in contact with active lesions [3]. There seems to be corticosteroid cream or ointment has been applied
no appreciable therapeutic advantage to applying for delivery. By laying the gauze sponge directly
corticosteroid in a base preparation (ie, compounded onto the lesion or lesions and holding it in place for
in Orabase or some other inert mucous membrane 15 to 20 minutes two or three times daily during
dressing) as compared to applying a base preparation waking hours, the concentrated contact method for
alone (ie, without corticosteroid) [53]. Regardless of delivery of the medication requires fewer applica-
whether a base preparation or corticosteroid alone or tions and promotes more expeditious healing of
a compound of both is applied, avoidance of food and ulcers [3,4].
E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122 119

Perilesional injection fold. The first goal is to remedy the current attack.
The second goal is to attempt to break the apparent
Perilesional injection of corticosteroid medication cycle of recurrence to achieve at least a temporary
is another therapeutic alternative. Such injections can period of remission or an interim in which recur-
be highly efficacious for treating major aphthous rences are less frequent, ulcerations are fewer, and
ulcers that have been resistant to other more conserv- symptoms are less intense. Achieving this goal may
ative topical approaches or are unresponsive to sys- require an approach that briefly couples systemic
temic treatment [2]. The author has found that this corticosteroid ‘‘burst therapy’’ with topical cortico-
route of corticosteroid administration can reduce steroid therapy initially, followed by a ‘‘prophy-
significantly the diameter of either a newly erupted lactic maintenance’’ regimen with continuance of
or a long-standing major aphthous lesion within the the topical corticosteroid alone. The author has
24- to 48-hour postinjection period and dramatically found that individual case-centered modifications
shorten healing time. of the therapeutic approach reported by Vincent
The procedure the author uses is based on a and Lilly [16] can be effective in most cases for
modification of the adjuvant intralesional cortico- accomplishing these goals. They recommend using
steroid injection regimen described for use in treat- a ‘‘burst’’ therapeutic regimen of prednisone (40
ing recalcitrant pemphigus lesions [54]. After mg taken 1 hour after rising in the morning for
administration of local anesthesia (with vasocon- 5 days, followed by 20 mg every other day for an
strictor), 10 to 40 mg of sterile triamcinolone additional week) along with oral rinses with com-
acetonide injectable suspension, USP (Kenalog-40) pounded 0.1% triamcinolone acetonide aqueous
40 mg/mL diluted to 10 mg/mL strength, is injected suspension (5 mL of liquid swished four times
into the perilesional tissue immediately adjacent to daily for 2 to 3 minutes and expectorated ; NPO
the ulcer border. The lesion is clinically evaluated for 1 hour afterward). If the triamcinolone suspen-
48 hours after injection to determine whether the sion is not available, dexamethasone elixir used
treatment was adequate. If there seems to be neither similarly three to four times daily at outset also
improvement in symptoms nor evidence of progres- can be effective.
sion toward healing, it may be necessary to repeat In the author’s experience, ‘‘burst therapy’’ also
the procedure. Usually a single administration of can be used safely over a 3-week period if necessary
corticosteroid is sufficiently therapeutic, however, (eg, 40 mg prednisone every morning for 7 days
so that even large, painful, or stubbornly recalcitrant followed by 20 mg every morning for 7 additional
major aphthous lesions that were present for many days followed by 20 mg every other morning for
weeks before the injection resolve within 5 to another 7 days) and does not require any further
7 days. tapered doses [16]. Coupled with the initial four-
times-daily corticosteroid rinse regimen, burst ther-
apy is more effective than 5 to 7 days of abbreviated
Indications for second-line therapy systemic corticosteroid (dosepak) therapy alone for
obtaining control of an active outbreak and intercept-
Prednisolone (Prelone) or betamethasone (Celes- ing and preventing subsequent recurrences [16].
tone) syrup preparations can be used exclusively as Once the systemic corticosteroid regimen is com-
rinses or as several times daily rinse-and-swallow pleted, a prophylactic rinse regimen (eg, either one to
regimens for cases that are recalcitrant to the topical three times daily or one to three times on alternate
approach alone. The latter combined route of admin- days as needed; NPO for 30 minutes to 1 hour after
istration can be helpful for treating major aphthae and rinsing) can provide long-term preventive mainte-
is especially effective in cases in which the aphthous nance. Although systemic complications from using
ulcers are concentrated in the posterior oral cavity, soft attenuated corticosteroid rinse regimens over ex-
palate, and tonsillar fauces and are attended by con- tended periods of time do not seem to be a significant
siderable pain. Used in this manner, the corticosteroid problem [16], oral candidiasis can be a potential
agent provides topical and systemic immunomodula- problem for some individuals on this therapy, par-
tory benefits and is considered to be a second-line type ticularly individuals whose cell-mediated immune
of therapy [2]. responses are compromised by an underlying medical
For the occasional patient plagued by frequent condition, such as diabetes. In such cases, inter-
or overlapping RAS attacks over a protracted vention with ketoconazole (Fluconazole, Nizoral)
period of time and whose quality of life has been tablets or clotrimazole (Mycelex) troches may be
eroded as a result, the goal of treatment is two- indicated [2,3].
120 E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122

Other medications origin and pathogenesis, combined with ongoing


research directed toward the development of safer,
Various other medications and methods too numer- more effective immunomodulating agents, render the
ous to mention in this article and of highly variable prospect of a cure for RAS increasingly plausible.
efficacy have been used for managing aphthous sto-
matitis. These medications include inert and more
active prescribed preparations (antimicrobial agents, Acknowledgment
cauterizing solutions, monoamine oxidase inhib-
itors, tissue films, and others) and myriad home
The author wishes to express sincere gratitude to
remedies [2,4]. When cases are resistant to cortico-
Marilyn R. Holt, MS, for her technical expertise and
steroid-based immunomodulatory regimens exclu-
invaluable assistance in preparing the manuscript.
sively, other nonsteroidal immunosuppressive agents,
such as cyclosporine (Sandimmune, Neoral), dapsone,
or azathioprine (Imuran) given systemically in com-
bination with adrenal-sparing doses of prednisone and References
other agents with antiinflammatory, immunomodula-
tory properties alone (eg, pentoxyphylline [Trental] or [1] Ship JA. Recurrent aphthous stomatitis: an update. Oral
colchicine) may or may not prove useful as alternative Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81:
141 – 7.
second- or third-line therapies [2 – 4,6,16,28,40]. Their
[2] Neville BW, Damm DD, Allen CM, Bouquot JE. Al-
potential for producing serious side effects does limit lergies and immunologic diseases: recurrent aphthous
case selection for their use. stomatitis. In: Oral and maxillofacial pathology.
Recently, thalidomide (Thalomid), a potent immu- 2 nd edition. Philadelphia: W.B. Saunders; 2002.
nosuppressive medication, was found to be effective p. 285 – 90.
for treating HIV-infected patients with severe RAS [3] Eisen D, Lynch DP. Selecting topical and systemic
when prescribed at daily doses of 100 to 200 mg [55] agents for recurrent aphthous stomatitis. Cutis 2001;
and for managing oral aphthae in immunocompetent 68:201 – 6.
individuals with Crohn’s disease [56] and Behcßet’s [4] Reich RF, Kerpel SM, Freedman PD. Differential diag-
disease [8,57]. Because of thalidomide’s recognized nosis and treatment of ulcerative, erosive, and vesicu-
lobullous lesions of the oral mucosa. Oral Maxillofac
potential for profound side effects, however, its use
Surg Clin N Am 1998;10:95 – 129.
must be reserved only for patients whose aphthous [5] Wright DG, Dale DC, Fauci AC. Human cyclic neu-
ulcers have been so unrelenting and sufficiently tropenia: clinical review and long-term follow-up of
symptomatic as to significantly compromise quality patients. Medicine (Baltimore) 1981;60:1 – 13.
of life and who, after exhaustive efforts, also have [6] Ship JA, Chavez EM, Doerr PA, et al. Recurrent aph-
failed to respond to other, more conservative thera- thous stomatitis. Quintessence International 2000;31:
peutic measures. Use of this systemic agent requires 95 – 112.
strict adherence to guidelines for patient selection. [7] Glickman RM. Inflammatory bowel disease: ulcerative
Patients who take thalidomide must be monitored colitis and Crohn’s disease. In: Fauci AS, Braunwald
frequently to intercept and prevent its potential toxic E, Isselbacher KJ, et al, editors. Harrison’s principles
of internal medicine. 14th edition. New York: McGraw-
effects [2,6].
Hill; 1998. p. 1633 – 45.
[8] Ghate JV, Jorizzo JL. Behcßet’s disease and complex
aphthosis. J Am Acad Dermatol 1999;40:1 – 18.
Summary [9] International Study Group for Behcßet’s Disease. Criteria
for diagnosis of Behcß et’s disease. Lancet 1990;335:
Currently, RAS is recognized as an immunologi- 1078 – 80.
cally mediated, inflammatory oral condition rather [10] Magro C, Crowson AN, Mihm M. Cutaneous manifes-
than an infectious disease. Contemporary approaches tations of nutritional deficiency states and gastrointes-
to its management are focused on modulating the tinal disease: Behcßet’s disease, inflammatory bowel
aberrant immune responses that underlie its pathogen- diseases (Crohn’s disease, ulcerative colitis, celiac dis-
ease). In: Elder D, Elenitsas R, Jaworsky C, Johnson B,
esis. Immunomodulation has been applied with great
editors. Lever’s histopathology of the skin. 8th edition.
success for managing existing episodes and prevent- Philadelphia: Lippincott-Raven; 1997. p. 359 – 63.
ing recurrences of RAS. Safe, effective, and reliable [11] Rizzi R, Bruno S, Dammacco R. Behcß et’s disease: an
therapies for actually curing this disease remain elu- immune-mediated vasculitis involving vessels of all
sive at this time. It is reasonable to suggest that for the sizes [review]. Int J Clin Lab Res 1997;27:225 – 32.
future, anticipated new insights into the condition’s [12] Orme RL, Nordlund JJ, Barich L, et al. The MAGIC
E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122 121

syndrome (mouth and genital ulcers with inflamed car- thous-like ulcers in patients with AIDS. Oral Surg Oral
tilage). Arch Dermatol 1990;126:940 – 4. Med Oral Pathol 1991;71:68 – 72.
[13] Ficarra G. Oral ulcers in HIV-infected patients: an up- [31] Cohen L. Etiology, pathogenesis and classification of
date on epidemiology and diagnosis [review]. Oral aphthous stomatitis and Behcßet’s syndrome. J Oral Path-
Diseases 1997;3(Suppl 1):S183 – 9. ol 1978;7:347 – 52.
[14] Marshall GS, Edwards KM, Butler J, et al. Syndrome [32] Lehner T. Immunologic aspects of recurrent oral ul-
of periodic fever, pharyngitis and aphthous stomatitis. cers. Oral Surg Oral Med Oral Pathol 1972;33:80 – 5.
J Pediatr 1987;110:43 – 6. [33] Ben Aryeh H, Malberger E, Gutman D, et al. Salivary
[15] Rogers III RS. Recurrent aphthous stomatitis: clinical IgA and serum IgG and IgA in recurrent aphthous
characteristics and associated systemic disorders. stomatitis. Oral Surg Oral Med Oral Pathol 1976;42:
Semin Cutan Med Surg 1997;16:278 – 83. 746 – 52.
[16] Vincent SD, Lilly GE. Clinical, historic, and therapeu- [34] Wormser GP, Mack L, Lenox T, et al. Lack of effect of
tic features of aphthous stomatitis: literature review and oral acyclovir on prevention of aphthous stomatitis.
open clinical trial employing steroids. Oral Surg Oral Otolaryngol Head Neck Surg 1988;98:14 – 7.
Med Oral Pathol 1992;74:79 – 86. [35] Kameyama T, Sujaku C, Yamamoto S, et al. Shedding
[17] Ship JA. Inheritance of aphthous ulcers of the mouth. of herpes simplex virus type I into saliva. J Oral Pathol
J Dent Res 1965;44:837 – 44. 1988;17:478 – 81.
[18] Miller MF, Garfunkel AA, Ram CA, et al. Inheritance [36] Neville BW, Damm DD, Allen CM, Bouquot JE. Viral
patterns in recurrent aphthous ulcers: twin and pedi- infections: HSV, VZV, CMV. In: Oral and maxillofa-
gree data. Oral Surg Oral Med Oral Pathol 1977;43: cial pathology. 2nd edition. Philadelphia: W.B. Saun-
886 – 91. ders; 2002. p. 213 – 24.
[19] Miller MF, Garfunkel AA, Ram CA, et al. The inher- [37] Veloso FT, Saleiro JV. Small-bowel changes in recur-
itance of recurrent aphthous stomatitis. Oral Surg Oral rent ulceration of the mouth. Hepatogastroenterology
Med Oral Pathol 1980;49:409 – 12. 1987;34:36 – 7.
[20] Landesberg R, Fallon M, Insel R. Alterations of [38] Wray D. Gluten-sensitive recurrent aphthous stomati-
T-helper/inducer and T-suppressor/inducer cells in pa- tis. Dig Dis Sci 1981;26:737 – 40.
tients with aphthous ulcers. Oral Surg Oral Med Oral [39] Olson JA, Feinberg I, Silverman Jr S, et al. Serum
Pathol 1990;69:205 – 8. vitamin B12, folate and iron levels in recurrent aph-
[21] Savage NW, Mananonda R, Seymour GJ, et al. The thous stomatitis. Oral Surg Oral Med Oral Pathol
proportion of suppressor-inducer T-lymphocytes is re- 1982;54:517 – 20.
duced in recurrent aphthous stomatitis. J Oral Pathol [40] Regezi JA, Sciubba JJ. Ulcerative conditions: condi-
Med 1988;17:293 – 7. tions associated with immunologic dysfunction. Aph-
[22] Schroeder HE, Muller-Glauser W, Sallay K. Stereolog- thous ulcers. In: Regezi JA, Sciubba JJ, editors. Oral
ical analysis of leukocyte infiltration in oral ulcers of pathology: clinical-pathological correlations. 2nd edi-
developing Mickulicz aphthae. Oral Surg Oral Med tion. Philadelphia: W.B. Saunders; 1993. p. 52 – 60.
Oral Pathol 1983;56:629 – 40. [41] Rodu B, Mattingly G. Differential diagnosis of oral
[23] Greenspan JS, Gadol N, Olson JA, et al. Antibody- mucosal ulcerations. J Am Dent Assoc 1992;123:
dependent cellular cytotoxicity in recurrent aphthous 83 – 6.
ulceration. Clin Exp Immunol 1981;44:603 – 10. [42] Wray D, Graykowski EA, Notkins AL. Role of mu-
[24] Pedersen A, Hougen P, Kenrad B. T-lymphocyte sub- cosal injury in initiating recurrent aphthous stomatitis.
sets in oral mucosa of patients with recurrent aphthous BMJ 1981;283:1569 – 70.
ulceration. J Oral Pathol Med 1992;21:176 – 80. [43] Murphy GF, Mihm Jr MC. The skin: chronic inflamma-
[25] Savage NW, Seymour GJ, Kruger BJ. T-lymphocyte tory dermatoses. In: Cotran RS, Kumar V, Robbins SL,
subset changes in recurrent aphthous stomatitis. Oral editors. Robbins pathologic basis of disease. 5th edition.
Surg Oral Med Oral Pathol 1985;60:175 – 80. Philadelphia: W.B. Saunders; 1994. p. 1198.
[26] Savage NW, Seymour GJ, Kruger BJ. Expression of [44] Boyd AS, Neldner KH. The isomorphic response to
class I and class II major histocompatibility complex Koebner. Int J Dermatol 1990;29:401 – 10.
antigens on epithelial cells in recurrent aphthous sto- [45] Domonokos AN. Cutaneous symptoms, signs and di-
matitis. J Oral Pathol Med 1986;15:191 – 5. agnosis: Koebner’s phenomenon. In: Domonokos AN,
[27] Rogers RS, Sams WM, Shorter RG. Lymphocytotox- editor. Andrews’ diseases of the skin: clinical derma-
icity in recurrent aphthous stomatitis. Arch Dermatol tology. 6th edition. Philadelphia: W.B. Saunders; 1971.
1974;109:361 – 3. p. 26.
[28] Woo S-B, Sonis ST. Recurrent aphthous ulcers: a re- [46] Ferguson MM, Carter J, Boyle P. An epidemiological
view of diagnosis and treatment. J Am Dent Assoc study of factors associated with recurrent aphthae in
1996;127:1202 – 13. women. J Oral Med 1984;39:212 – 7.
[29] MacPhail LA, Greenspan JS. Oral ulceration in HIV- [47] Porter SR, Scully C, Flint S. Hematologic status in
infection: investigation and pathogenesis. Oral Dis- recurrent aphthous stomatitis as compared with other
eases 1997;3(Suppl 1):S190 – 3. oral disease. J Oral Pathol 1978;7:418 – 23.
[30] Phelan JA, Eisig S, Freedman PD, et al. Major aph- [48] Rogers III RS . Screening for hematinic deficiencies in
122 E. Eisenberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 111–122

patients with recurrent aphthous stomatitis. Australas J study. Oral Surg Oral Med Oral Pathol 1993;75:
Dermatol 1986;27:98 – 103. 181 – 5.
[49] Challacombe SJ, Barkhan P, Lehner T. Hematological [54] Bystryn J-C, Steinman NM. The adjuvant therapy
features and differentiation of recurrent oral ulceration. of pemphigus: an update. Arch Dermatol 1996;132:
Br J Oral Surg 1977;15:37 – 48. 203 – 12.
[50] Porter SR, Kingsmill V, Scully C. Audit of diagnosis [55] Jacobson JM, Greenspan JS, Spritzler J, et al, for the
and investigations in patients with recurrent aphthous National Institute of Allergy and Infectious Diseases
stomatitis. Oral Surg Oral Med Oral Pathol 1993;76: AIDS Clinical Trials Group. Thalidomide for the treat-
446 – 52. ment of aphthous ulcers in patients with human immu-
[51] Field EA, Rotter E, Speechley JA, et al. Clinical and nodeficient virus infection. N Engl J Med 1997;336:
hematological assessment of children with recurrent 1487 – 93.
aphthous ulceration. Br Dent J 1987;163:19 – 22. [56] Weinstein TA, Sciubba JJ, Levine J. Thalidomide for
[52] MacPhail L. Topical and systemic therapy for recurrent the treatment of oral aphthous ulcers in Crohn’s dis-
aphthous stomatitis. Semin Cutan Med Surg 1997;16: ease. J Pediatr Gastroenterol Nutr 1999;28:214 – 6.
301 – 7. [57] Eisenbud L, Horowitz I, Kay B. Recurrent aphthous
[53] Voute AB, Schulten EA, Langendijk PN, et al. Fluocin- stomatitis of the Behcßet’s type: successful treatment
onide in an adhesive base for treatment of oral lichen with thalidomide. Oral Surg Oral Med Oral Pathol
planus: a double-blind, placebo-controlled clinical 1987;64:289 – 92.
Oral Maxillofacial Surg Clin N Am 15 (2003) 123 – 128

The surgical treatment of periodontal infections


Norman Trieger, DMD, MD*
Department of Dentistry, Oral and Maxillofacial Surgery, Albert Einstein College of Medicine, Montefiore Medical Center,
111 E. 210th Street, Bronx, NY 10467, USA

Identification of the specific pathogenic micro- well as topical antibiotics are cytotoxic [1]. They
organisms responsible for periodontal destruction has provoke the death of healthy cells and elicit their own
led to newer treatment methods. The basis for this inflammatory reactions.
approach has been the application of well-established The field of periodontal disease has undergone
surgical principles of infection management: the rapid expansion of basic information with respect to
identification of the responsible pathogens; mechan- microbiology and the origin and characterization of
ical débridement of the infected sites to decrease the endotoxins produced by gram-negative anaerobes,
bacterial load as well as products of the inflammatory which are responsible for various kinds of periodon-
immune response; and the introduction of systemic titis. The endotoxins (lipopolysaccharides) from the
antibiotics known to be effective against the offend- outer cell wall of the specific anaerobes are now
ing bacteria. known to be water soluble, and their localization on
Experience has shown that eradication of the the cementum of the root is superficial and not deeply
infection is possible and regeneration of attachment imbedded [2 – 5]. Smart et al [6] and others have
and bone regrowth in vertical defects is accomplished reported that endotoxin can be washed away or
when several important guidelines are followed. The brushed away without resorting to root planing,
oral cavity is regarded as one ecosystem, with micro- which destroys the cementum. Recently, the treat-
organisms readily transported to multiple sites by ment concept has changed from aggressive root
saliva, food, and the toothbrush. Treatment by debrid- planing to debridement. It also has been shown that
ing only one quadrant at a time allows reinfection of connective tissue regrowth in the periodontal crevice
the site within the ecosystem from other untreated is positively influenced by the presence of adjacent
quadrants. The usual pattern of multiple oral hygiene cementum. In the absence of cementum, reattachment
visits before definitive full mouth debridement meant to dentin does not readily occur. Following peri-
to ‘‘prepare’’ the mouth for surgery does not elim- odontal connective tissue reattachment, bone fills
inate the infection that is harbored in biofilms in deep the vertical defects, and the mobility of teeth
pockets. Eliminating the deep infection should take decreases when the infection is resolved.
precedence over the repeated superficial scalings. It is difficult to identify the origin of the practice
Brushing, flossing and various mouth rinses do not of root planing. There is no scientific evidence to
reach pockets deeper than 4 to 5 mm despite the show that root planing is any more efficacious than
diligence of enhanced home care. The periodontal debridement, without destroying cementum. The
attachment continues to secrete extracrevicular fluid shibboleth of ‘‘scaling and root planing’’ with which
that inactivates and rapidly washes away any sub- we were taught to begin every treatment plan
stances squirted into the pocket. It should be noted deserves to be seriously questioned. In addition to
that topical antimicrobials (eg, chlorhexidine) as being destructive, the removal of cementum also
leads to thermal hypersensitivity and more postoper-
ative pain. It is likely that the original intent to
* 55 Lakeside Drive, Larchmont, NY 10538. remove scale, formed from salivary calculus, was
E-mail address: n.triege@verizon.net extended down onto the exposed root surface and

1042-3699/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.
PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 6 9 - 9
124 N. Trieger / Oral Maxillofacial Surg Clin N Am 15 (2003) 123–128

continued even in the absence of calculus deposits. Borrelia vincenti and Prevotella intermedia are two
Calculus deposits come from saliva and are most major pathogens readily identified in this condition
pronounced opposite the openings of Wharton’s and which is often associated with susceptible individuals
Stensen’s ducts. Calculus does not cause periodontitis who have been subjected to major psychologic stress,
but may constitute a mechanical irritant and be such as a divorce, familial death, or dismissal from
aesthetically objectionable. Calculus, when iden- college. Under these circumstances, direct invasion
tified, is best removed using an ultrasonic cleaner by the periopathogens has been demonstrated, lead-
or by discrete curetting, which clears away just the ing to necrosis, loss of interdental papillae, lympha-
deposit and does not strip the cementum. denitis, gingival bleeding, and fetid odor. Treatment
should be directed first to using a systemic antibiotic,
such as penicillin or amoxicillin, to control the acute
Diagnosis of periodontitis phase before launching into painful manipulations,
such as curettage.
A major contribution was made by Loesche [7],
who introduced the ‘‘specific plaque hypothesis.’’ Chronic adult periodontitis
Other investigators have identified several periopath-
ogens associated with patterns of bone loss, primarily Several specific organisms have been associated
by using the techniques of deep-pocket sampling and with the localized areas of periodontal bone destruc-
rapid anaerobic subculturing. Periodontitis was thus tion (Table 1). These organisms include Porphyromo-
identified not as a single entity but as a series of nas gingivalis, Bacteroides forsythus, Prevotella
infections based on microbiologic sources, host intermedia, Capnocytophaga species, Campylobacter
immunocompetency, and the interaction between rectus, Eikenella corrodens, and Fusobacterium
these factors. Various syndromes of periodontal infec- nucleatum. Other periopathogens will undoubtedly
tions have been identified. be identified as the field expands. Many of these
organisms produce an endotoxin (ie, lipopolysac-
Rapidly progressive periodontitis charide) that provokes the release of host-tissue fac-
tors, contributing to further breakdown. Cytokines
This is seen in children, young adults, and adults such as interleukin-1b and tumor necrosis factor-a
who are immunocompromised, especially by virtue from host lymphocytes and other mononuclear phago-
of impaired cell-mediated immunity (eg, neutropenia, cytes are released. These and other substances can
cancer chemotherapy, acquired immunodeficiency destroy collagen and bone, causing advancing de-
syndrome, etc.). struction of the periodontium. Bacteriologic culturing

Juvenile periodontitis
Table 1
Formerly known as periodontosis, this is a disease Species identified in refractory or recurrent periodontitis
of late childhood and early adolescence caused by (n = 196)
Actinobacillus actinomycetemcomitans, a gram-nega- Organism Percentage of sites
tive facultative organism that produces a potent Bacteroides forsythus 84
leukotoxin. Early in childhood the organism is found Spirochetes 83
in the tonsillar crypts and may cause repeated bouts Motile rods 76
of tonsillitis. Later on, in addition to dental pathology Fusobacterium species 68
it may be found on damaged heart valves, causing Porphyromonas gingivalis 63
infective endocarditis. This organism is susceptible to Campylobacter rectus 47
Capnocytophaga species 38
the tetracyclines and not consistently to the penicillin
Prevotella intermedia 23
derivatives or clindamycin. Another important aspect
Peptostreptococcus micros 18
of this syndrome is that there is usually a qualitative Actinobacillus actinomycetemcomitans 16
inherited defect in the behavior of the patient’s Candida species 14
neutrophilic leukocytes. Enteric rods 9
Resistance to penicillin, tetracycline, and metronidazole
Acute necrotizing ulcerative gingivitis was high.
Adapted from Listgarten MA, Lai C-H, Young V: Micro-
This uncommon infection, once called ‘‘trench biota and antibiotic resistance (abstract). J Dent Res
mouth,’’ is most often noted in young smokers. 1993:72:819. [8]
N. Trieger / Oral Maxillofacial Surg Clin N Am 15 (2003) 123–128 125

and the use of specific DNA probes (eg, University


of Pennsylvania Microbiological Testing Laboratory,
Philadelphia, PA) have served to identify putative
organisms. Other tests have been proposed based on
the enzymatic characteristics of the particular patho- Box 1. A summary of guiding surgical
gens. Loesche et al [9] have reported on the use of the treatment of periodontal infections
benzoyl-DL-arginine naphthylamide (BANA) test at
chairside. BANA identifies three known pathogens: 1. Periodontitis is an infectious dis-
P. gingivalis, B. forsythus, and Treponema denticola. ease attributable to a relatively
The ultimate aim is to develop a chairside test that will small number of gram-negative
identify the predominant organisms and guide treat- oral pathogenic bacteria that pro-
ment and follow-up monitoring. duce endotoxins.
Periodontitis is readily transmissable between 2. Piecemeal mechanical treatment
spouses and other cohabitants [10,11]. In the author’s (by quadrant or sextant) via scal-
experience, 80% of patients requiring treatment have ing and root planing above is
mates with similar organisms. To prevent ‘‘ping- incomplete and invites relapse.
ponging’’ the disease, both partners should be placed 3. The mouth is one ecosystem that
on antibiotics while the primary patient undergoes must be treated as a comprehen-
surgical débridement and proceeds into a mainte- sive unit to eradicate the infection,
nance phase. preferably under intravenous seda-
Radiographs reflect the bone level (ie, bone loss) tion and local anesthesia.
but do not indicate the current status of the infection. 4. Periodontitis may be considered a
Bone loss does not necessarily translate into mobility sexually transmitted disease.
or condemn a tooth to extraction. Satisfactory resolu- 5. Soft tissue débridement of perio-
tion of the infection leads to reduction in bleeding, dontal pockets without destruction
pocket depth, and mobility, and new bone often forms of root cementum (planing) is the
and fills vertical defects [12 – 14]. goal, in conjunction with systemic
antibiotics effective against the
specific bacterial pathogens.
Surgical techniques 6. Topical irrigants, including antibi-
otic and antimicrobial agents, are
Current management of periodontitis has moved cytotoxic and jeopardize healing
away from some of the prior practices (see Box 1). and regeneration.
The gingivectomy is passé, as is the practice of bony 7. Regrowth of bone follows reattach-
recontouring. The author prefers early, one-stage, ment when the infection is resolved
full-mouth débridement guided by the severity of and the cementum is intact. It is a
attachment and bone loss. Pockets deeper than 4 or curable disease.
5 mm merit use of a conservative access flap reflected 8. Reinfection is possible, and con-
just to the bone margin (Fig. 1). tinued vigilance and follow-up care
This provides visibility for surgical curettage of are important.
the granulation tissue and avoids the postoperative 9. Individual immune status affects
edema and pain caused by excessive exposure of the incidence and long-term re-
labial bone. Pockets that measure less than 4 or 5 mm sponse to therapy. Examples of
are debrided and curetted at the same appointment immunocompromised status in-
without flap reflection. clude diabetes, HIV, and qualita-
With the patient under intravenous sedation and tive and quantitative white blood
local anesthesia, the crevicular incisions are made in cell abnormalities.
areas where pocket depths exceed 4 to 5 mm, 10. Calculus has a minimal role in
preserving the interdental papillae and marginal gin- the initiation and progression of
givae. Bony crypts are debrided with a large Prichard periodontitis.
curette followed by use of Gracey curettes to reach The periodontal literature supports each
into and under bony defects. Copious saline irrigation of these principles and should lead to a
is used during debridement instead of cytotoxic modification of practice.
agents such as chlorhexidine and topical antibiotic
126 N. Trieger / Oral Maxillofacial Surg Clin N Am 15 (2003) 123–128

Fig. 1. (A) Crevicular incision reflected just to bony margin for débridement. (B) New bone regrowth in absence of infection.

solutions, which damage healthy cells [15,16]. It is ily controlled by frequent periodic debridement
important to remove the granulation tissue that probably because it disrupts the colonies that re-form
adheres to the underside of the mucoperiosteal flap in the pocket. When bone loss has advanced beyond
either by curettage or with a soft-tissue rongeur 4 to 5 mm, however, it does not make good sense to rely
(Nipro Medical, Miami, FL) or nipper. With the flap only on conservative treatment and wait until the
reflected, deposits on the cemental surface can be infection recurs and is finally classified as refractory.
discretely removed with a scaler or Cavitron. Treatment should be comprehensive and aim to debride
Another important component of the recommend- with the least possible damage to cementum, bone, and
ed technique is to avoid root planing. The peri- mucoperiosteum. This should be accompanied by the
odontal literature is finally recognizing that root administration of systemic antibiotics known to be
planing is destructive and compromises reattachment. effective against gram-negative anaerobes. Clindamy-
Cementum is necessary to induce and enhance fibro- cin, metronidazole, or amoxicillin/clavulanic acid have
blastic proliferation and reattachment [4,5]. The been used for 7 to 10 days with rewarding results. The
apparent indication to remove diseased cementum is tetracyclines usually are prescribed for 2 to 3 weeks to
predicated on the presence of endotoxin [2,3]. Endo- treat juvenile periodontitis [12 – 14,17,18].
toxin, a product of gram-negative anaerobic orga- Flaps are closed with interrupted sutures, avoiding
nisms, is water soluble and not deeply imbedded in apical repositioning (Fig. 1). Healing and bony
the cementum. It is limited to 40 – 50 mm of the sur- regrowth are favored by adequate mucoperiosteal
face cementum and can be washed or even brushed covering. The surgeon should not try to eliminate
away. Cementum has specific growth-enhancing fac- the pocket. The cervical defect fills initially with a
tors that stimulate the fibroblasts necessary for repair blood clot, which then differentiates into connective
and reattachment of the periodontal membrane. tissue and subsequently into new bone. Periodontal
Therefore, planing the cementum is a waste of time packs are never used; they retard healing and are
and effort. Furthermore, root planing jeopardizes soft- cumbersome, difficult to clean, and inappropriate
tissue regeneration and bone support and often leads when treating an anaerobic infection (Fig. 2).
to thermal hypersensitivity. Even in the advanced periodontitis cases, the oper-
The surgical objectives should be to clear the ating time for this procedure is usually 1 to 2.5 hours.
infection by mechanical debridement and to use anti- Very few patients undergo repeated sessions with the
biotics effectively. Minimal periodontitis can be read- hygienist before the main surgical debridement. It is
N. Trieger / Oral Maxillofacial Surg Clin N Am 15 (2003) 123–128 127

Fig. 2. (Left) Preoperative first molar bone loss. (Right) One year postoperative bone regeneration.

the primary intent to reduce the bacterial load in deep or use of a toothpaste with 1.1% sodium fluoride on a
pockets that are beyond the reach of the patient’s home daily basis at home is effective in preventing reinfec-
care or the hygienist’s scaling. tion from a supragingival source. The use of a
Postoperatively, the patient is given a prescription chlorhexidine mouth rinse is also helpful in control-
for a nonsteroidal antiinflammatory agent and ling supragingival organisms.
instructed to continue the prescribed antibiotic for Concern has been expressed about the devel-
7 to 10 days. Brushing is avoided in the sutured areas, opment of enterocolitis caused by Clostridium diffi-
and either saline irrigation or a chlorhexidine rinse is cile, a gram-positive organism that produces exotoxin
recommended for home hygiene. A new brush is and damages the cells lining the intestinal tract. This
provided on the 1-week return visit and a simple Bass complication is seen with a number of antibiotics,
brushing technique is demonstrated. such as clindamycin, the cephalosporins, and amox-
Patients are maintained on a soft diet and rarely icillin. Patients are routinely alerted to this possibility
report pain or swelling after the first day. The pockets when postoperative instructions are given. They are
are reprobed at 1 month to evaluate healing and pocket advised that approximately 10% of patients may
reduction. At this time, the patient can be referred develop diarrhea after taking the antibiotic for at least
back to his or her dentist for definitive restorative care. 4 to 5 days. If this occurs, they are instructed to
Individual persistent deep pockets may now be ad- discontinue the drug and call the office. The diarrhea
dressed if pocket elimination is requested by the usually abates within 24 to 48 hours. If it persists,
restorative dentist. Successive 3-month follow-up oral metronidazole is recommended as the drug of
visits are scheduled during the first year to evaluate first choice (250 mg four times per day).
the long-term results. Reprobing characteristically The success rate of combined mechanical and
finds pockets significantly reduced, with no bleeding antibiotic therapy has been cited by others [11 – 14,
on probing or brushing. If this is not the case, ad- 17,18] to be superior to that of periodontal therapy
ditional antimicrobial therapy is pursued after cultur- alone. When treating a destructive infectious disease
ing or taking a sample for DNA probe analysis [14]. in the year 2002 it does not make sense to avoid using
Periodic (every 3 months) disruption of reforming effective antibiotics. This technique also has distinct
colonies by deep scaling has been shown to provide advantages in the salvage of failing implants. The
adequate control if the case has been refractory to principles of debridement and irrigation and the ef-
previous treatment. Topical application of fluoride gel fective use of systemic antibiotics can enhance the
128 N. Trieger / Oral Maxillofacial Surg Clin N Am 15 (2003) 123–128

repair of endosseous implants that are losing bone [6] Smart JJ, Wilson M, Davies EH, et al. The assessment
support. No one knowingly root planes an implant. A of ultrasonic root débridement by determination of re-
soft-tissue debridement is indicated instead [12]. sidual endotoxin levels. J Clin Periodontol 1990;
17:174.
The recognition that specific cytokines, prosta-
[7] Loesche WJ. The bacterial etiology of periodontal dis-
glandins, growth factors, and interleukins, are active
ease: the specific plaque hypothesis. In: Clark JW, ed-
participants responding to the elaboration of bac- itor. Clinical dentistry. Philadelphia: Harper & Row;
terial lipopolysaccharide sheds new light on methods 1987. p. 11 – 20.
that may influence the clinical outcome. Golub and [8] Listgarten MA, Lai C-H, Young V. Microbiota and
coworkers [19] have shown that the tetracyclines, in antibiotic resistance [abstract]. J Dent Res 1993;
low doses, also inhibit matrix metalloproteinases 72:819.
such as collagenase and prevents damage to the [9] Loesche WJ, Giordano J, Hujael PP. The utility of the
attachment apparatus. BANA test for monitoring anaerobic infections due to
Perhaps most intriguing is the realization that spirochetes (Treponema denticola) in periodontal dis-
ease. J Dent Res 1990;69:1696.
immune-mediated injury is not only an integral part
[10] Asikainen S, Chen C, Aloluusua S, et al. Can one
of the host response to periodontitis, but it has also
acquire periodontal bacteria and periodontitis from a
been shown to be a significant contributor to myo- family member? J Am Dent Assoc 1997;128:1263.
carditis [20]. Cytokines released from activated [11] Offenbacher S, Olsvik B, Tonder A. The similarity of
T-lymphocytes have been identified as releasing periodontal microorganisms between husband and wife
tumor necrosis factor- a and other injurious mole- cohabitants. J Periodontol 1985;56:317 – 23.
cules that also cause myocardial and vascular injury. [12] Trieger N, Mark L, McKittrick J, et al. Clindamycin v.
Subsequent myocardial fibrosis correlates with the tetracycline in the surgical treatment of advanced pe-
presence of T-lymphocytes and macrophages, which riodontitis: a double blind study with applicability for
release fibrogenic cytokines such as fibroblast growth implant salvage. Int J Oral Maxillofac Implants
1991;7:31.
factor and tissue growth factor-b Our knowledge base
[13] Trieger N. Surgical treatment of periodontal infections.
is growing rapidly, and the future will bring fasci-
Atlas of Oral and Maxillofacial Surgery Clinics of
nating new therapies for the management of peri- North America 2000;8:127 – 34.
odontal infections. [14] Loesche WJ, Giordano JR, Soehren S, Kaciroti N. The
nonsurgical treatment of patients with periodontal dis-
ease-results after five years. J Am Dent Assoc
References 2002;133:311 – 20.
[15] Pucher JJ, Daniel JC. The effects of chlorhexidine di-
[1] Shahan M. The effect of chlorhexidine irrigation on gluconate on human fibroblasts in vitro. J Periodontol
tensile wound strength [abstract]. J Periodontol 1992; 1992;63:526.
63:1012. [16] Dahlen G, Wennstrome JL, Grondahl K, Heijl L. Mi-
[2] Hughes FJ, Auger DW, Smales FC. Investigation of crobiological observations at periodic subgingival anti-
the distribution of cementum-associated lipopolysac- microbial irrigation of periodontal pockets. J Dent Res
charides in periodontal disease by scanning electron 1989;68:1714 – 5.
microscope immunohistochemistry. J Periodontol Res [17] Loesche WJ, Schmidt E, Smith BA, Morrison EC,
1988;23:100. Caffesse R, Hujael PP. Effects of metromidazole on
[3] Nakib NM, Bissada NF, Simmelink JW, Goldstine SN. periodontal treatment needs. J Periodontol 1991;
Endotoxin penetration into root cementum of perio- 62:247 – 57.
dontally healthy and diseased human teeth. J Periodon- [18] Trieger N, Chomenko A. New concepts in the treat-
tol 1982;368 – 78. ment of periodontitis. J Oral Maxillofac Surg 1982;
[4] Fukazawa E, Nishimura K. Superficial cemental curet- 40:701 – 8.
tage: its efficacy in promoting improved attachment on [19] Golub LM, Wolff M, Roberts S, et al. Treating perio-
human root surfaces previously damaged by periodon- dontal diseases by blocking tissue destructive enzymes.
titis. J Periodontol 1994;65:2, 168. J Am Dent Assoc 1994;125:163.
[5] Cobb CM. Non-surgical pocket therapy. Mechanical [20] Beck J, Garcia R, Heiss G, et al. Periodontal disease
Annals of Periodontology 1996;1:472. and cardiovascular disease. Periodontol 1996;27:1123.
Oral Maxillofacial Surg Clin N Am 15 (2003) 129 – 138

Management of peri-implantitis
R. Gilbert Triplett, DDS, PhDa,*, J. Adam Andrews, DDS, MDa,
William W. Hallmon, DDSb
a
Department of Oral and Maxillofacial Surgery and Pharmacology, Baylor College of Dentistry,
TAMUSHSC and Baylor University Medical Center, 3302 Gaston Avenue, Dallas, TX 75246, USA
b
Department of Periodontics, Baylor College of Dentistry, TAMUSHSC, 3302 Gaston Avenue, Dallas, TX 75246, USA

Failure of osseointegrated dental implants is a the indisputable evidence that linked bacteria to
frustrating problem for the patient and dentist. Peri- periodontal disease and was later repeated in several
implantitis and occlusal overload are the most com- experimental mucositis/implantitis models [1]. The
mon causes of implant failure after osseointegration, evidence compiled from these well-designed studies
and they often require removal of the involved identified bacteria as the primary culprit in the
implant. A single failed implant can result in com- development of peri-implantitis. Large numbers of
plete prosthetic failure when load-sharing mechanics gram-negative anaerobic bacteria (A. actinomycetem-
of the prosthesis depend on the health and integrity of comitans, P. gingivalis, P. intermedia) tend to be
each individual implant. Peri-implantitis, which is an found around implants with objective signs of peri-
inflammatory process around an osseointegrated den- implantitis, whereas healthy implants are most often
tal implant in function with resulting bone loss, colonized with flora dominated by gram-positive
affects approximately 5% to 10% of osseointegrated cocci [1]. Endotoxins produced by gram-negative
implants [1]. Peri-implant mucositis refers to revers- bacteria have the capability to adhere to the implant
ible inflammation of the peri-implant soft tissues surface and produce inflammation and resulting bone
without bone loss [1,2]. Accurate diagnosis and loss around implants in a similar fashion to peri-
appropriate intervention are essential if implant sal- odontitis [1]. Several studies have demonstrated the
vage techniques are to be successful in preventing ability of periodontal pathogens to infect peri-implant
implant failure. This article focuses on the methods tissues in partially edentulous patients (Fig. 1). This
available for diagnosis and treatment of peri-implant- observation may account for the higher implant
itis that involve various implant systems. success rates reported in several studies when
implants were placed in edentulous mouths versus
partially edentulous mouths.
The role of bacteria in the development The convincing evidence that suggests a bacterial
of peri-implantitis cause of peri-implantitis provokes several interesting
clinical scenarios regarding the optimal restorative
The experimental gingivitis model of Löe and treatment of the partially edentulous patient. Extra-
Silness elegantly displays the interaction between polation of research data, which suggest that implant
bacterial plaque and gingivitis in a human model failures may be significantly higher in partially
[3]. This landmark study provided the foundation for edentulous patients with a history of periodontitis,
may lead to the possible recommendation of extrac-
tion of questionable teeth before implant placement.
A possible alternative is treatment of the periodon-
* Corresponding author. tally diseased tissues before implant placement in
E-mail address: gtriplett@tambcd.edu (R.G. Triplett). persons with a history of severe periodontal prob-

1042-3699/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.
PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 7 8 - X
130 R.G. Triplett et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 129–138

Fig. 1. (A) Peri-implantitis in the partially edentulous patient. (B,C) Peri-implant mucositis demonstrated by soft tissue
inflammation and increased probing depths without bone loss.

lems. Edentulous mouths tend to host a more benign ture (rough versus smooth, commercially pure tita-
flora because of the lack of deep pockets and nium versus titanium alloy). It seems evident, based
crevices that commonly harbor gram-negative an- on sound clinical and experimental data, that the
aerobes and spirochetes in patients with periodontal same surface implant characteristics that enhance
disease. Restoration of a more benign oral microbiota osseointegration may possibly increase the risk of
seems to be a logical goal before implant placement peri-implantitis when placed under certain unfavor-
if long-term implant and prosthetic success is to be able conditions.
achieved. Several protocols for local and systemic Patient selection is as important as the type of
decontamination of periodontal tissues have been implant used if favorable long-term success rates are
published; however, the overall long-term benefit to be expected. Implant selection should be based on
depends on many variables and is often unpredict- a combination of patient-dependent clinical and bio-
able [4]. logic considerations. Several recent studies have
concluded that rough surface implants demonstrate
a significantly higher percentage of bone-to-implant
Titanium implant surface characteristics and the contact and faster and stronger osseointegration when
relationship with implant success and failure compared to machined surface titanium implants
[5 – 7]. A study by Trisi et al [5] evaluated differences
The implant market has been inundated with in the rate of osseointegration between smooth and
various systems that use different materials, surface rough surface implants in low-density human jaw
coatings, and manufacturing processes. Implants can bone. At 12 months, the implant-to-bone contact rates
be categorized by differences in macrostructure (eg, for smooth and rough surface titanium implants were
cylindrical, threaded, screw design) and microstruc- noted to be 6.7% and 76.75%, respectively. The study
R.G. Triplett et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 129–138 131

concluded that although a rough surface may enhance prevents soft tissue attachment to the implant surface
the rate of osseointegration, it is not able to improve [10]. Recently published results that evaluated differ-
bone density [5]. ent surface coatings on rough surface implants con-
The surface oxide layer on commercially pure cluded that titanium nitride or zirconium nitride can
titanium and titanium alloy (Ti-6Al-4V) determines reduce the accumulation of plaque by coating the
the biocompatibility of a particular implant because it underlying more reactive titanium surface (indepen-
is the only portion of the implant in contact with host dent of surface roughness), which may reduce peri-
tissues [6]. The same surface oxide layer has been implant mucositis and peri-implantitis [10].
shown to exist on rough titanium surfaces, which
may contribute to enhanced osseointegration when
compared to machined surfaces of the identical Considerations with hydroxyapatite-coated
material [6]. Several other studies have reported titanium implants
significantly better bone anchorage with titanium-
oxide-blasted (TiO2-blasted) screw implants than Hydroxyapatite is a bioactive material with osteo-
with machined implants of similar composition and conductive properties [11]. Hydroxyapatite-coated
higher torque removal for implants with increased titanium alloy implants were first introduced in
surface roughness [6]. Schwartz et al demonstrated 1984 for use in restoring partially or totally edentu-
that as the surface roughness of titanium implants lous maxillas and mandibles [12]. Plasma-sprayed
increases, the cytokine and growth factor production hydroxyapatite-coated implants demonstrate greater
by host osteoblast-like cells also increases and could tolerance to unfavorable healing conditions and pro-
account for improved bone formation around the mote bone growth into gaps that measure less than
roughened implant surface [6,8]. Osteoblasts also 1 mm [11]. Early reports of faster osseointegration
have been found to display a more mature phenotype (biointegration), a stronger bone-to-implant interface
when grown on rougher surfaces [6]. Studies that (compared to titanium surfaces), and vertically direct-
compared different types of roughened titanium sur- ed bone growth along the implant surface were met
faces concluded that rougher titanium plasma- with optimism among the implant community
sprayed surfaces, corundum-blasted surfaces, and [12,13]. Short- and long-term studies have demon-
sandblasted surfaces alone are inferior to surfaces strated higher implant-to-bone contact in hydroxy-
that are treated with a combination of sandblasting apatite implants at 6 weeks when compared to
and acid-etching [5,6,9]. titanium implants. At 12 weeks, however, the tita-
Despite the convincing evidence that rough tita- nium implants displayed superior implant-to-bone
nium surfaces may enhance osseointegration and contact compared to hydroxyapatite-coated implants
implant stability, several studies have suggested that and had an increase in total implant-to-bone contact
a rough surface may contribute to plaque formation surface area after 1 year. The hydroxyapatite-coated
and higher implant failure rates from peri-implantitis. implants showed a reduction in the implant-bone
Tillmanns et al [9] experimentally induced peri- contact area over the same period with a significant
implantitis in a canine model with three different decrease in shear strength [12,14,15].
types of implant surfaces (smooth, blasted, and A combination of clinical observation and pro-
hydroxyapatite coated). The results after 3 and spective research suggests that hydroxyapatite-coated
6 months revealed plaque accumulation and the same implants may be more prone to enhanced plaque
amount of peri-implant bone loss among all implant growth and peri-implantitis because of the question-
surfaces studied. The study concluded that the three able long-term quality of the hydroxyapatite-to-bone
implant surfaces are equally susceptible to ligature- bond and the affinity of microorganisms for the
induced peri-implantitis [9]. The conclusion is in hydroxyapatite surface [12]. Johnson reported sudden
direct contrast to most experimental results that and rapid bone loss around hydroxyapatite-coated
compared implant surfaces. The finding seems to be implants ‘‘after an initial period of apparent success’’
well supported that bacterial plaque formation (Fig. 2A) [12]. Several clinical reports claim that
depends on the surface properties of the implant failure of hydroxyapatite-coated implants involves
material. A surface roughness (Ra) more than 0.2 mm ‘‘significant morbidity and permanent destruction of
facilitates early plaque formation in an experimental bone tissue,’’ whereas titanium implants tend to fail
model but may be favorable to soft tissue sealing with minimal loss of bone volume and typically
around transmucosal abutments. Anything below this regenerate to the original dimension of the alveolus
Ra value (smoothening) seems to be ineffective in (Fig. 2B) [12]. Despite the claims of higher long-term
reducing the amount of plaque formation, but it failure rates with hydroxyapatite-coated implants,
132 R.G. Triplett et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 129–138

Fig. 2. (A) Hydroxyapatite-coated implants with significant bone and attachment loss. (B) Threaded, machined surface titanium
implants with significant attachment and bone loss.

many clinicians have found them valuable in situa- Diagnosis of the failing implant
tions that involve unfavorable bone quantity or quality and peri-implantitis
[16]. Recommendations and special considerations
regarding the salvage of infected hydroxyapatite- Much debate exists regarding the definition of
coated implants are discussed in this article. implant failure. The endeavor to define implant
failure should be preceded with a definition of
success. The First European Workshop on Periodon-
Retrograde peri-implantitis tology defined success as absence of implant mobil-
ity, an average radiographic marginal bone loss of
Radiolucencies around the apical aspect of dental less than 1.5 mm during the first year of function and
implants have been attributed to several causes, less than 0.2 mm annually thereafter, and absence of
including contamination of the implant surface, over- pain and paresthesia [2]. Because this definition was
heating of bone, occlusal overload, preexisting bone based on the mean marginal bone loss around Bråne-
pathology, presence of residual root fragments or mark implants, it seems presumptuous to conclude
foreign bodies in implant sites, lack of biocompati- that different implants would behave in a similar
bility, placement of the implant in poor quality bone, manner. Much attention has been given to the terms
and drilling through the inferior border of the man- ‘‘ailing’’ and ‘‘failing’’ when referring to implant
dible or lingual cortex [17]. The term ‘‘retrograde health. It has been proposed that an ‘‘ailing’’ implant
peri-implantitis’’ was first used to describe radio- demonstrates radiographic evidence of bone loss and
graphic periapical bone loss around a dental implant probing depths more than 5 mm that are stable when
without evidence of peri-implant soft tissue inflam- reevaluated at 3 to 4 months. A ‘‘failing’’ implant
mation [16]. It was proposed that a radiolucent lesion demonstrates increasing probing depths, suppuration
found on plain film radiography was caused by or bleeding when probed, and progressive bone loss
traumatic or premature implant loading that resulted [18]. A failed implant no longer is osseointegrated or
in microfractures of the peri-implant bone and sub- never achieved osseointegration. These implants dis-
sequent resorption. Because the microflora around play peri-implant radiolucency caused by fibrous
implants that suffered from retrograde peri-implantitis tissue encapsulation, are clinically mobile, and dem-
have been shown to be similar to the microflora onstrate dullness to percussion. Failed implants must
around healthy implants, one can assume that infec- be removed to prevent chronic bone loss and the
tive failure is not experienced with this type of possibility of osteomyelitis (Fig. 3) [18].
implant lesion [3,16]. Because bacteria do not seem Esposito et al [19] concluded that radiographic
to be a causative factor in this type of implant failure, examination and mobility testing were the most
normal probing depths without bleeding are often reliable parameters in determining the prognosis of
observed, and resolution of the periapical radiolu- osseointegrated implants. Marginal bone loss around
cency may be observed if traumatic loading of the the neck of the implant can be evaluated radiograph-
implant is relieved. ically and by peri-implant probing. Reproducing the
R.G. Triplett et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 129–138 133

bacterial contamination of this interface has been


demonstrated [22].
Peri-implant probing may provide valuable
information regarding implant health or progression
of disease. Healthy implants generally have probing
depths less than 4 mm, with interproximal probing
depths normally 0.5 to 1 mm more than the buccal
and lingual probing depths [20]. Peri-implant pockets
of 5 mm or more should be considered an indicator of
peri-implantitis because deep pockets have been
shown to harbor a microflora consistent with inflam-
mation and bone loss [1].
There has been much debate over the location of
Fig. 3. Failed implant with fibrous tissue encapsulation and the probe tip and the effect on the peri-implant tissues
clinical mobility. during peri-implant probing in disease and health.
Several studies suggest that there is a resilient soft
tissue collar in peri-implant health and mucositis. The
exact radiographic exposure geometry is difficult and tip of the probe may travel without impedance to the
can lead to clinically significant variability. Despite alveolar crest in peri-implantitis, however [20]. It has
the latter finding, it seems that serial radiographs are been demonstrated experimentally that the probe tip
more reliable in monitoring peri-implant conditions penetrates apically to the laterally displaced junc-
than probing, particularly in the setting of inflamed tional epithelium with Brånemark implants, resulting
peri-implant tissues and bony defects [19]. Digital in the probe tip approaching the alveolar crest [18].
subtraction radiography eventually may prove to be This is in contrast to the findings around ITI dental
superior to traditional radiographic techniques in implants, which demonstrate the probe tip location at
evaluating subtle changes in peri-implant bone den- the apical termination of the junctional epithelium
sity, and it is highly recommended, if available (0.05 mm in healthy sites and 0.02 mm in diseased
[19,20]. If no clinical evidence of inflammation is sites) [19]. Issues regarding the practicality and
present, radiographs should be obtained 1 year after reproducibility of probing depths have brought the
implant placement and not more than every 2 years entire practice of peri-implant probing into question.
thereafter [1]. Radiographs should be taken more Several studies have concluded that peri-implant
frequently if clinical evidence of peri-implant inflam- probing damages the peri-implant soft tissues, but
mation (increased probing depths) raises suspicion of the magnitude and long-term effects have yet to be
peri-implantitis [1]. determined [19].
Differences among implant systems make the task It can be said that there is a positive correlation
of quantitatively defining the normal amount of between peri-implant probing depths and the degree of
marginal bone loss difficult. Several studies have peri-implant mucosal inflammation, but not necessar-
demonstrated that marginal bone loss and biologic ily bone loss [19]. More important than a single
width are determined largely by the implant system measurement at a single point in time is documentation
and the host response. Gargiulo [21] demonstrated of progressive peri-implant bone loss as evidenced by
that natural teeth have a normal biologic width of increasing probing depths. It is recommended that
2.73 mm. Hermann et al [22] evaluated the anatomic baseline probing depths be acquired at the time of
location of the biologic width around various types of prosthetic reconstruction to account for the predictable
dental implants and determined that the one-piece marginal bone loss during the first several months after
(single-stage) nonsubmerged implant with a rough/ implant placement. Assuming that probing has been
smooth border placed at or 1 mm apical to the accepted by the surgeon as a method of providing
alveolar crest resulted in a biologic width that most beneficial clinical information that exceeds the poten-
closely resembled that of natural teeth (2.84 mm). tial for harming the peri-implant tissues, the frequency
They also concluded that the presence of a microgap and interval must be tailored to each individual patient
(component interface) in two-piece implant systems based on compliance, oral hygiene, and other risk
significantly affects the level of crestal bone and soft factors. Probing attachment levels relate probing
tissue dimensions. The presence of a microgap in depths to a fixed reference point on the implant or
two-stage implant systems may play an important abutment and provide valuable information regarding
role in the development of peri-implantitis because attachment loss over time. Probing attachment level
134 R.G. Triplett et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 129–138

increases of 2 mm or more should be interpreted as end of an instrument and the sound is interpreted. A
marginal bone loss [19]. ‘‘ringing’’ sound in considered favorable for osseo-
In addition to providing information regarding integration, whereas a ‘‘dull’’ sound suggests fibrous
attachment level and bone loss, peri-implant probing tissue encapsulation [18]. Finally, OSSTELL (Integra-
can demonstrate peri-implant inflammation clinically. tion Diagnostics, Inc., Sävedalen, Sweden) is a new
Bleeding on probing is another controversial issue Food and Drug Administration – approved device that
regarding the diagnosis of peri-implantitis. No cor- uses resonance frequency analysis to assess implant
relation has been shown between bleeding and the stability. The reliability and usefulness of the device in
histologic or radiographic changes associated with implant dentistry still are being evaluated.
peri-implant mucositis or peri-implantitis around A systematic approach should be used when
smooth surface threaded implants [19]. Another study evaluating implants for possible disease. It is often
demonstrated that the absence of bleeding on probing more prudent to evaluate the implant by assuming
around ITI implants was associated with implant disease and proving health because this mode of
health, whereas bleeding on probing correlated highly reasoning tends to eliminate the possibility of false-
with peri-implant mucositis and peri-implantitis [19]. negative screening results. If probing is to be per-
Because the reason for these differences may be formed at the recall visit, the new probing depths
caused by inconsistent probing forces or other fac- should be compared to baseline measurements and
tors, bleeding on probing is not scientifically sup- the overall trend observed. Attachment levels also
ported as a method of diagnosing peri-implantitis should be recorded because peri-implant pockets
[19]. Several authors still maintain that ‘‘probing potentially can remain normal as marginal bone loss
depth measurements related to a fixed landmark on progresses and the attachment and marginal tissue
the implant and examination of the bleeding tendency level follows. If no attachment loss is evident and
of the peri-implant tissues seem to be well-suited for probing depths are normal, one can assume that the
the longitudinal monitoring of peri-implant stability’’ implant is associated with a nonpathogenic micro-
[1]. It has been recommended that nonmetallic probes flora and that the peri-implant tissues are not clin-
(eg, plastic) with a calibrated constant probing force ically inflamed [1].
be used for more reliable, less traumatic measure-
ments. A probing force of 0.25 N has been recom-
mended by several authors to fulfill the previously Implant salvage
mentioned criteria [1,20]. Mombelli and Lang [1]
recommend the use of standardized probes, such as The type of intervention for implant salvage
the Audio Probe, titanium plasma-sprayed probe, or depends largely on clinical findings and implant
the HAWE Click Probe, for consistent measurements. characteristics. Peri-implant mucositis is a reversible
Implant mobility in a previously healthy implant process that often responds well to conservative,
should be considered a sign of failure. Even implants noninvasive treatment because increased probing
that show significant bone loss usually are immobile if depths are usually caused by soft tissue inflammation
any direct implant-to-bone contact remains. Several and not crestal bone loss. Implants that show evi-
devices and methods have been proposed for evalu- dence of mucosal inflammation, plaque, and accu-
ating implant mobility. Periotest (Siemens AG, Ben- mulation of calculus but lack suppuration and
sheim, Germany) is a device used for measuring the probing depths more than 3 mm are often treated
damping effect of the supporting tissues to a stand- effectively with mechanical débridement. Special
ardized force as an indicator of slight changes in nonmetallic instruments should be used for débride-
implant mobility. Although several studies have ment to minimize surface defects and the theoretical
reported its success in detecting subtle changes in possibility of galvanic corrosion. Special rubber cups
the bone-to-implant interface, its usefulness and accu- and implant polishing paste can be used to remove
racy are still being evaluated [1,18]. A torque wrench plaque [20]. Subgingival chlorhexidine irrigation may
that delivers a set amount of force is another method be added to the regimen for cases in which probing
for determining implant osseointegration. An implant depths have increased to 4 to 5 mm and inflammation
is considered to be osseointegrated if a torque of 10 to and plaque/calculus deposits are noted. Generally,
20 Ncm is applied to the implant without resulting treatment for 3 to 4 weeks with chlorhexidine as a
mobility [18]. Although not scientifically supported, daily rinse or gel is required to achieve the desired
the percussion test is reported to be a simple and result [20].
sensitive method of determining osseointegration. The Lang et al [20] recommend antibiotic treatment in
implant abutment interface is percussed with the blunt addition to mechanical débridement and antiseptic
R.G. Triplett et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 129–138 135

treatment for peri-implant probing depths more than endotoxin on both types of implant surfaces when
6 mm. Tetracycline has been used for many years in compared with controls, whereas treatment with
treating periodontally involved teeth because of its chlorhexidine gluconate, tetracycline HCl, hydrogen
antibiotic properties and facilitating effect on fibro- peroxide, and chloramine T is less effective at
blastic growth and attachment on root surfaces [16]. decreasing levels of endotoxin than saline burnishing
The decision to use tetracycline in implant therapy alone. Charge interactions have been proposed as the
may depend on the type of implant surface because reason for endotoxin having a greater affinity for
of the possibility of tetracycline altering the com- hydroxyapatite-coated surfaces than grit-blasted tita-
position of the hydroxyapatite coating [16]. Treating nium alloy surfaces [24]. Studies also have shown
titanium implant surfaces with topical tetracycline that chlorhexidine and stannous fluoride can result in
(50 mg/mL) for 3 minutes before regenerative tech- the binding of endotoxin to the hydroxyapatite
niques has been reported as successful [23]. Actisite implant surface because of the inherent charge char-
(Alza, Palo Alto, CA) is a local delivery system that acteristics of these two compounds [16].
consists of nonresorbable tetracycline fibers for local Surgical treatment should be considered for any
use around periodontally involved teeth. It has been implant that displays radiographic evidence of pro-
supplanted largely by resorbable delivery systems. gressive crestal bone loss that still has adequate
Several case reports have documented the effective- residual bony anchorage. If surgical treatment is to
ness of the tetracycline fibers around infected dental be initiated, the patient first should be placed on
implants [20]. antibiotics, then a mucoperiosteal flap is elevated to
Some authors advocate systemic antibiotics expose the defect, and the implant surface is decon-
before and during implant salvage techniques. Three taminated by one of the methods described previ-
recommended regimens are (1) clindamycin, 150 mg ously. Any granulation tissue should be removed with
orally three times a day, (2) doxycycline hyclate, instruments that do not scratch or contaminate the
100 mg orally twice daily, and (3) amoxicillin with titanium surface so that it is more favorable for
or without clavulonic acid, 500 mg four times a day. regenerated tissue or osseointegration. Hydroxyapa-
Some authors recommend the addition of metroni- tite implants should be inspected for evidence of
dazole if amoxicillin is selected for systemic treat- surface pitting, cracking, or color changes. If the
ment. All regimens should be started 2 days before hydroxyapatite shows wear or contamination, the
implant salvage treatment and continued for 10 days entire layer should be removed mechanically and
after [18]. the underlying titanium surface decontaminated in
Peri-implantitis has been shown to be an endo- the manner described previously.
toxin-mediated host response that progresses to Guided bone regeneration (GBR) also can be used
implant failure if not treated. Differences among to treat osseous defects around failing implants (Fig. 4)
implant surface characteristics are important when [16]. Decontamination of the diseased implant surface
selecting appropriate interventional techniques for is paramount if this technique is to be used. The
implant salvage. Zablotsky et al [24] published a process for GBR involves placing a resorbable or
landmark study in 1992 that compared the abilities nonresorbable membrane over an osseous defect to
of various chemotherapeutic modalities to detoxify permit new bone growth into the defect while inhib-
endotoxin-contaminated implant surfaces (grit-blast- iting soft tissue infiltration [26]. GBR has been per-
ed titanium alloy and grit-blasted titanium alloy with formed around peri-implant osseous defects with and
a hydroxyapatite plasma spray coating). The study without grafting; however, bone fill and attachment
concluded that detoxification of hydroxyapatite- gain seem to be better achieved when a grafting
coated implants is best accomplished with anhydrous material is used in conjunction with a barrier mem-
citric acid reconstituted to a 40% pH 1 (supersatu- brane [16]. Several different materials, including
rated) solution that is applied to the implant surface demineralized freeze-dried bone, autologous bone,
for 30 seconds to 1 minute [24]. This effect is caused and resorbable bovine-derived hydroxyapatite, have
by a demineralization of the superficial hydroxyapa- been used in various forms as grafting material in
tite layer. The titanium grit-blasted surface was effec- GBR. It has been proposed that an alloplast, such
tively decontaminated by burnishing with saline or as nonresorbable hydroxyapatite or bioactive glass,
citric acid for 1 minute. Air powder abrasives, such as be used if the implant surface is difficult to decontam-
sodium bicarbonate mixed with sterile water, also inate because of the presence of vents, holes, or tor-
have been shown to be effective in decontaminating tuous osseous defects [18]. Alloplasts do not achieve
implant surfaces [25]. Stannous fluoride treatment biologic healing in these cases but are effective in
seems to result in significantly greater levels of filling bony defects and minimizing peri-implant
136 R.G. Triplett et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 129–138

Fig. 4. Guided bone regeneration around a failing implant. (A) Large bony defect of a rough surface implant with increased
probing depths and radiographic evidence of bone loss. (B) Bony defect covered with graft material after surface débridement
and decontamination with tetracycline HCl paste. (C) Resorbable collagen membrane prepared to cover the graft material and
necks of implants. (D) Collagen membrane in place. (E) Water-tight closure around implants and surgical site (some authors
advocate burying single-stage implant systems after this procedure). (Courtesy of Dr. Tinou Roncone.)

pockets [18]. Although studies have demonstrated that cluded that ‘‘re-osseointegration’’ could not be
GBR is effective around implants, questions have achieved with a smooth (turned) surface but was
been raised regarding the ability of the regenerated consistently successful with a decontaminated sand-
bone to ‘‘re-osseointegrate’’ with the implant surface. blasted, large grit, acid-etched surface [27]. If bone
Persson et al [27] published a study investigating loss has progressed to the apical one third of the
whether ‘‘re-osseointegration’’ could be accomplished implant, removal is indicated because there is little
after the treatment of peri-implantitis. The study con- chance of successful salvage [25].
R.G. Triplett et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 129–138 137

The membrane selected for GBR should be bio- lead to increased failure rates when these implants are
compatible and easy to place, maintain its original affected by peri-implantitis. In the presence of
shape, and be capable of functioning as a barrier for at adequate apical osseointegration, compromised
least 6 weeks [16]. A commonly used nonresorbable implants that present with peri-implantitis must
material, expanded-polytetrafluorethylene, has pro- undergo thorough débridement and be decontami-
vided good results for many years. Several resorbable nated before any attempt at GBR. GBR may be
membranes recently have gained popularity, however, accomplished successfully with many different types
because of a reduced number of complications from of membranes and grafting materials if the implant
infection or exposure and because they do not require surface is thoroughly decontaminated before regen-
retrieval surgery. Although it is acceptable to leave a erative therapy. Implant salvage is an important, yet
membrane exposed during immediate implant place- often ignored, component of clinical practice that can
ment in fresh extraction sites, primary closure over the prevent implant and prosthetic failure if the principles
membrane is necessary in implant salvage to prevent of decontamination, biomodification, and guided tis-
contamination and infection of the involved area. If sue regeneration are understood and followed.
GBR is to be used as a salvage procedure for implants,
it is imperative that a nonresorbable membrane remain
covered for as long as possible because premature
References
removal decreases the chances of success and results
in less-than-optimal bone fill [16]. Many authors
[1] Mombelli A, Lang N. The diagnosis and treatment of
recommend a minimum of 6 weeks before removal peri-implantitis. Periodontology 2000;17:63 – 76.
of a nonresorbable membrane [23]. If a resorbable [2] Albrektsson T, Isidor F, et al. Consensus report of ses-
membrane is to be used, it should provide barrier sion IV. In: Lang NP, Karring T, editors. Proceedings
function for at least 6 weeks. It has been suggested of the First European Workshop on Periodontology.
that all patients remain on an antiseptic mouth rinse, London: Quintessence; 1994. p. 365 – 9.
such as chlorhexidine gluconate 0.12%, for 6 weeks or [3] Löe H, Morrison E. Epidemiology of periodontal dis-
until the membrane is retrieved to minimize the ease. In: Genco RJ, Goldman HM, Cohen DW, editors.
chance of membrane infection [28]. If the membrane Contemporary periodontics. St. Louis: CV Mosby Co.;
becomes prematurely exposed, however, immediate 1990. p. 106 – 16.
[4] Hammond BF, Genco RJ. Sensitivity of periodontal
removal is indicated to prevent contamination of the
organisms to antibiotics and other antimicrobial agents.
regenerating tissues [16]. Single-stage implant sys- In: Genco RJ, Goldman HM, Cohen DW, editors. Con-
tems ideally should be submerged during GBR sal- temporary periodontics. St. Louis: C.V. Mosby Co.;
vage procedures to minimize contamination of the 1990. p. 161 – 9.
membrane and regenerating tissues. [5] Trisi P, Rao W, Rebaudi A. A histometric comparison
of smooth and rough titanium implants in human low-
density jawbone. Int J Oral Maxillofac Implants 1999;
Summary 14:689 – 98.
[6] De Leonardis D, Garg A, Pecora G. Osseointegration
Peri-implantitis is a treatable disease that affects of rough acid-etched titanium implants: 5-year follow-
up of 100 Minimatic implants. Int J Oral Maxillofac
functioning osseointegrated implants. Although
Implants 1999;14:384 – 91.
unfavorable mechanical loading may play a con- [7] De Leonardis D, Garg A, Pecora G, et al. Osseointe-
tributing role, peri-implantitis seems to be mediated gration of rough acid-etched implants: one-year fol-
primarily by the endotoxins from gram-negative low-up of placement of 100 Minimatic implants. Int
bacteria and the host response around the implant J Oral Maxillofac Implants 1997;12:65 – 73.
site. Many patients who were previously considered [8] Schwartz Z, Kieswetter K, Dean DD, Boyan BD.
unfavorable candidates for implant therapy are Underlying mechanisms at the bone-surface interface
being treated successfully when certain treatment during regeneration. J Periodont Res 1997;32:166 – 71.
considerations and implant maintenance programs [9] Tillmans HW, Hermann JS, Tiffee JC, et al. Evaluation
are implemented. of three different dental implants in ligature-induced
peri-implantitis in the beagle dog. Part II. Histology
It is essential that implant surgeons have a firm
and microbiology. Int J Oral Maxillofac Implants
understanding of the favorable aspects of implant 1998;13:59 – 68.
design and the potential liabilities when these systems [10] Gröbner-Schreiber B, Griepentrog M, Haustein I, et al.
are placed in unfavorable clinical conditions. Studies Plaque formation on surface modified dental implants:
have demonstrated that the same potential benefits of an in vitro study. Clin Oral Implants Res 2001;12:
implant materials and surface characteristics also may 543 – 51.
138 R.G. Triplett et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 129–138

[11] Strnad Z, Strnad J, Povysil C, et al. Effect of plasma- cations with dental implants: their prevention, diagno-
sprayed hydroxyapatite coating on the osteoconductiv- sis and treatment. Clin Oral Implant Res 2000;11:
ity of commercially pure titanium implants. Int J Oral 146 – 55.
Maxillofac Implants 2000;15:483 – 90. [21] Garqinto AW, Wentz FM, Orban B. Dimensions and
[12] Johnson BW. HA-coated dental implants: long-term relations of the dontogingival junction in humans.
consequences. CDA Journal of the California Dental Journal of Periodontology 1961;32:261 – 7.
Association 1992;20:33 – 41. [22] Hermann J, Buser D, Schenk RK, et al. Biologic width
[13] Meffert RM, Block MS, Kent JN. What is osseointe- around one- and two-piece titanium implants: a histo-
gration? International Journal of Periodontics and Re- metric evaluation of unloaded nonsubmerged and sub-
storative Dentistry 1987;7:9 – 21. merged implants in the canine mandible. Clin Oral
[14] Cook SD, Kay JF, et al. Interface mechanics and his- Implants Res 2001;12:559 – 71.
tology of titanium and hydroxyapatite-coated titanium [23] Mellonig JT, Griffiths G, Mathys E, et al. Treatment of
for implant applications. Int J Oral Maxillofac Implants the failing implant: case reports. International Journal
1987;2:15 – 22. of Periodontics and Restorative Dentistry 1995;15:
[15] Gottlander M, Albrektsson T. Histomorphometric stud- 385 – 95.
ies of hydroxyapatite-coated and uncoated CP titanium [24] Zablotsky MH, Diedrich DL, Meffert RM. Detoxifi-
threaded implants in bone. Int J Oral Maxillofac Im- cation of endotoxin contaminated titanium and hy-
plants 1991;6:399 – 404. droxyapatite-coated surfaces utilizing various
[16] Meffert RM. Periodontitis vs. peri-implantitis: the chemotherapeutic and mechanical modalities. Im-
same disease? The same treatment? Crit Rev Oral plant Dentistry 1992;1:154 – 8.
Biol Med 1996;7:278 – 91. [25] Jovanovic SA. The management of peri-implant break-
[17] Scarano A, Di Domizio P, Petrone G, et al. Implant down around functioning osseointegrated dental im-
periapical lesion: a clinical and histologic case report. plants. J Periodontol 1993;64:1176 – 83.
J Oral Implantol 2000;26:109 – 13. [26] Rominger JW, Triplett RG. The use of guided tissue
[18] Martin RM, Carter JB, Barber HD. Surgical implant regeneration to improve implant osseointegration.
failures. In: Fonseca R, Powers MP, Barber HD, edi- J Oral Maxillofac Surg 1994;52:106 – 12.
tors. Oral and maxillofacial surgery: reconstructive and [27] Persson LG, Berglundh T, Sennerby L, et al. Re-os-
implant surgery. Philadelphia: W.B. Saunders Co.; seointegration after treatment of peri-implantitis at dif-
2000. p. 275 – 308. ferent implant surfaces: an experimental study in the
[19] Esposito M, Hirsch J-M, Lekholm U, et al. Biological dog. Clin Oral Implant Res 2001;12:595 – 603.
factors contributing to failures of osseointegrated oral [28] Lehmann B, Bragger U, Hammerle CHF, et al. Treat-
implants (I). Success criteria and epidemiology. Eur J ment of an early implant failure according to the prin-
Oral Sci 1998;106:527 – 51. ciples of guided tissue regeneration (GTR). Clin Oral
[20] Lang NP, Wilson TG, Corbet EF. Biological compli- Implant Res 1992;3:42 – 8.
Oral Maxillofacial Surg Clin N Am 15 (2003) 139 – 146

Management of posttraumatic soft tissue infections


A. Omar Abubaker, DMD, PhD
Department of Oral and Maxillofacial Surgery, School of Dentistry, Virginia Commonwealth University,
521 North 11th Street, PO Box 980566, Richmond, VA 23298, USA

Between 10 and 12 million traumatic wounds are include the epithelium of the skin and mucous
treated annually in emergency departments in the membranes. The skin also grants chemical protection
United States [1,2]. More than 50% of these lacer- in the form of surface lipids, and the mucous mem-
ations are caused by blunt trauma. The others are branes provide protection by surface Ig A and an
caused by sharp objects, such as metal, glass, and acidic pH. The skin and oral mucosal surfaces are
wood. Only a small percentage of these wounds is also inhabited by normal flora that can compete with
caused by mammalian and nonmammalian bites potential microbial pathogens.
[3,4]. Most of these lacerations occur on the face, Biologic protection is provided in the form of
scalp, and arms, mostly in young men [2]. Because of various internal mechanisms that are induced by local
these locations, an important goal of management of tissue damage. These mechanisms are triggered when
these wounds is to avoid infection, which can lead to the mechanical line of defense is violated. Once this
cosmetically and functionally unacceptable scars [5]. damage ensues, an intense chemical activity is trig-
The current management of traumatic soft tissue gered, which involves activation of the kallikrein-
injuries incorporates many of the surgical principles kinin system, the release of amines, and an increase in
developed over the past century. These principles vascular permeability that allows for influx of hu-
include a thorough understanding of the pathophysi- moral and cellular immunologic elements. These
ology of wounding, the risk factors for infection, the elements are ultimately responsible for recognition
basic mechanisms by which posttraumatic sepsis of the organisms involved and their subsequent
develops, and the appropriate methods for treatment phagocytosis [6].
of these injuries and the prevention of complications. Traumatic wounds carry with them a higher
This article reviews the defense mechanisms involved degree of contamination because the mechanical
in soft tissue wound healing, describes the risk factors protective features of the skin and mucous membrane
for posttraumatic wound infections, and discusses the are disrupted, which allows direct invasion of micro-
prevention and treatment of such infections. organisms into the deeper tissues. The internal sys-
temic biologic mechanisms of host defense are also
compromised by the effects of the trauma. For
Physiologic effects of wounding example, with major trauma there is a decrease in
cellular immune functions, intracellular killing, and
The human body has evolved several defense endothelial system function [7,8]. There is also a
mechanisms body to protect itself from the micro- decrease in humoral factors, such as the immunoglob-
biologic invasion that causes wound infection. These ulins and the complement system [8]. If traumatic
mechanisms include efficient mechanical barriers to shock develops, there is also a decrease in systemic
bacteria and competent biologic protection mecha- perfusion, which, in the presence of local tissue
nisms. The mechanical barriers to bacterial invasion damage, may reduce blood flow to the wounded area
and further compromise containment of invading
E-mail address: Abubaker@vcu.edu bacteria [9,10].

1042-3699/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.
PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 6 8 - 7
140 A.O. Abubaker / Oral Maxillofacial Surg Clin N Am 15 (2003) 139–146

Risk factors for posttraumatic wound infections 1:100,000 or 1: 200,000 epinephrine). Inserting the
needle through the open part of the laceration can
Studies on management of traumatic wounds have decrease the pain of the injection [18,19]. Use of a
shown that the rate of infection ranges between 2.5% field block is beneficial in reducing distortion of the
and 11.5% [11 – 13]. This rate is influenced by several operative site when accurate approximation of the
variables, which are often referred to as risk factors. wound edges is necessary. If there are skin or tissue
Some of these factors are related to the host, the flaps of doubtful viability, the use of lidocaine with-
environment, and the type of wound, whereas others out epinephrine is desirable to avoid further impairing
are related to the techniques used to manage the circulation [20].
wounds [12,14 – 16]. Factors related to the wound Local anesthesia can be supplemented with anal-
and patient include (1) size, configuration, and depth gesics or sedatives, if necessary. General anesthesia is
of the wound, (2) location of the injury, (3) mech- preferable for uncooperative or combative patients
anism of injury, (4) type and amount of contamina- and for children. General anesthesia is also often
tion, including presence of a foreign body, (5) time indicated in patients who require prolonged proce-
between injury and wound closure, (6) care of the dures, as in extensive lacerations, lacerations that
wound between injury and definitive care, and (7) age require flap rotation or grafts for closure, and con-
and systemic condition of the patient. The technical comitant repair of facial bones fractures [21]. Patients
risk factors for development of wound infection with confirmed or suspected involvement of impor-
include (1) inadequate débridement of foreign bodies, tant structures, such as joints, nerves, or tendons, also
further bacterial contamination, and presence of devi- may be better treated in an operating room setting
talized tissues, (2) inadvertent introduction of foreign [5,19,22].
materials into the wound during cleansing, (3) inad-
equate hemostasis and failure to eliminate dead space, Wound preparation
which provides an environment for bacterial col-
onization, (4) using an excessive number of sutures Once the patient is comfortable and the wound is
to close the wound, and (5) placing excessive tension adequately anesthetized, a complete and methodical
on the sutures used to approximate the tissue edges cleansing of the wound should be achieved. The
and compromising local tissue perfusion. process involves irrigation and débridement of the
wound before draping of the operative site in prep-
aration for wound closure. Irrigation is essential in
Prevention of posttraumatic wound infection by preventing infection because it removes debris, dirt,
proper wound care microorganisms, and devitalized tissue from the
wound, which results in a reduction in infection rate
The greatest deterrent to posttraumatic wound [3]. Irrigation with normal saline solution using a
infection is a healthy wound. This status can be 50-mL syringe and a 16-gauge needle is adequate for
accomplished by (1) thorough cleansing, (2) identifica- most lacerations [23,24]. In general, 250 to 500 cc of
tion, assessment, and atraumatic débridement of all solution provides adequate irrigation for small
devitalized tissues, (3) removal of all foreign materials, wounds [24]. High-pressure irrigation is occasionally
and (4) careful handling of the tissues. Evacuation of indicated for large wounds and when a high degree of
any hematoma and obliteration of all potential dead contamination is present [17]. High-pressure irriga-
spaces by proper wound repair and approximation of tion has been shown to decrease the bacterial count of
all tissue layers are also essential elements in the wounded tissues and decrease the rate of infection
prevention of soft tissue infections. Appropriate use [25]. Vigorous irrigation in general, however, and
of prophylactic antibiotics and tetanus prophylaxis are high-pressure irrigation in particular may force debris
also important preventive measures [17]. into the wound and can cause further tissue damage
[26,27]. For these reasons, high-pressure irrigation
Anesthesia should be used with discretion and reserved for
heavily contaminated wounds in which its benefits
Before one begins definitive wound management, may outweigh its risks [17]. Similarly, use of con-
adequate patient comfort should be ensured not only centrated povidone-iodine, hydrogen peroxide, and
to permit maximum wound repair but also to allow detergents may cause significant tissue damage and
thorough examination, cleansing, and débridement of should be avoided [28]. Some authors even ques-
the wound. In most patients, comfort can be accom- tioned the value of any form of wound irrigation in
plished with local anesthesia (lidocaine with noncontaminated facial and scalp wounds [29].
A.O. Abubaker / Oral Maxillofacial Surg Clin N Am 15 (2003) 139–146 141

Decontamination of the skin around the wound is method is generally based on the assessment for risks
another step in preventing wound infection. Decon- of infection. It is often difficult to determine which
tamination can be accomplished effectively with mild treatment to use for a given wound, and the length of
soap and water or with a providone iodine or hexa- the ‘‘golden period’’ within which it can be closed
chlorphene solution. Use of chemical solutions should primarily varies [31]. In general, there is a direct
be limited to the adjacent skin surface, and caution correlation between the time from injury to closure of
should be used to avoid getting them into the wound the wound and the risk of infection. It is generally
because these agents are noxious to tissues. Because accepted that wounds with a high risk of infection
shaving may damage hair follicles and allow for should be closed as soon as possible (within the first
bacterial access and increase the risk of wound infec- 6 – 8 hours), whereas wounds with low risk of infec-
tion, it should be kept to a minimum. In areas such as tion, such as those in the head and neck area, can be
the eyebrows, it should be avoided totally [23]. closed primarily within the first 18 to 24 hours after
Débridement is considered by many to be the injury [17,24]. After 24 hours, for most wounds,
most important step in avoiding infection. One goal consideration should be given to packing them open
of wound débridement is to remove all foreign and performing a secondary repair 4 to 8 days later
materials that may be attached to, or embedded in, [17,30].
the edges of the laceration or abrasion. Removing
foreign material can be accomplished by thorough
irrigation of the wound, vigorous scrubbing, or even Postoperative wound care
surgical excision using a surgical blade or small
curette. The second goal of débridement is the For most wounds, patients should be instructed to
removal of devitalized tissue. The general rule keep them covered with a nonadherent dressing for at
regarding débridement of devitalized tissue is that least 24 to 48 hours to protect the wound from gross
all crushed or frayed edges that may become necrotic, contamination. After this period, the patient should
all obviously nonviable tissue, and all grossly con- wash, but not scrub or soak, the wound. Once the
taminated tissue should be removed. Exceptions to wound is left open, it should be cleaned two to three
this rule involve certain anatomic areas, such as the times a day with a cotton applicator stick and hydro-
eyebrow and vermilion border of the lip, where such gen peroxide or soap and water. The patient also
débridement may compromise accurate realignment should be instructed to place a topical antibiotic
of the tissues and in instances in which tissue ointment on the wound. Prospective and retrospective
débridement would result in excessive tension on studies have shown the value of topical antibiotic
the suture line. In these instances, it is preferable to agents in decreasing infection in certain wounds
avoid extensive trimming of the tissue and to approx- [32,33]. Their benefit beyond day 5 of wound closure
imate the irregular edges without tension [30]. In the remains controversial, however [19]. A topical anti-
management of facial wounds, only minimal débride- biotic ointment also keeps the wound moist, which
ment is generally required because of the excellent speeds the rate of wound epithelialization [34].
blood supply. When tissue loss is present, it is The routine use of systemic prophylactic anti-
recommended to save all tissue that has a chance to biotics to prevent infection of soft tissue wounds is
survive to provide the basis for secondary reconstruc- not recommended [35]. Because traumatic wounds
tion at a later time [22]. are, by definition, contaminated wounds, however,
some of them are prone to infection despite all
Wound closure attempts to follow the principles of appropriate
wound care. In such instances, and when the con-
Once the devitalized tissue has been removed, a sequences of wound infection may be devastating,
decision must be made regarding the timing and type prophylactic antibiotics may be indicated [16]. The
of wound closure. There are at least three major use of prophylactic antibiotics should be tailored
choices [16]: (1) primary closure and healing by individually based on factors such as the degree of
primary intention, (2) leaving the wound open, treat- bacterial contamination and the presence of the pre-
ing it with frequent dressing changes, and allowing it disposing risk factors discussed previously. Several
to heal by secondary intention and wound contrac- studies suggest that the administration of an antibiotic
ture, and (3) using delayed primary closure, in which to prevent infection of the soft tissues after trauma
the wound is splinted in a position of rest with an may be of more value when given prophylactically
occlusive dressing and is closed in 3 to 5 days when it within the first 3 to 4 hours of the injury and
is free of infection and necrotic tissue. The choice of continued until the wound is sutured than when given
142 A.O. Abubaker / Oral Maxillofacial Surg Clin N Am 15 (2003) 139–146

for a therapeutic course postoperatively [16]. Some Regardless of the mechanism of injury and the degree
authors recommend that prophylactic antibiotics be of suspected wound contamination, once the signs
continued for 24 hours [36], however, with additional and symptoms of wound infection become clinically
doses if the operative procedure is prolonged. evident, the goals of treatment should be to optimize
Tetanus continues to occur worldwide despite the tissue perfusion and nutrition, remove devitalized
availability of an effective vaccine. Consideration tissue, prevent further spread of the infection or
always should be given to administration of tetanus further tissue destruction, and achieve wound closure
prophylaxis at the time of initial wound examination. [38]. To attain these goals, Fields et al described a
A summary guide to tetanus prophylaxis is available five-phase unified approach to treatment of posttrau-
through the Centers for Disease Control (Table 1) [37]. matic soft tissue infections [6]. The phases of this
systematic approach that are applicable to wounds in
the head and neck are phase 1: early recognition of
Treatment of posttraumatic soft tissue infection; phase 2: rapid initiation of empiric anti-
wound infections biotics; phase 3: immediate surgical incision and
drainage or débridement, when necessary; and phase
Because traumatic wounds are caused by different 4: early wound closure.
types of trauma, the resulting soft tissue damage often
ranges from blunt damage to penetrating and complex Early recognition
tissue injuries. The spectrum of microbiologic soft
tissue contamination also varies and ranges from Early recognition and diagnosis are essential to
simple wound colonization without invasion to frank treating wound infections successfully and minimizing
tissue infection and necrosis. Contamination of post- morbidity [16]. The diagnosis of infection should be
traumatic wounds can occur from introduction of based on the clinical signs and symptoms, the labo-
endogenous normally nonpathogenic bacteria into ratory findings, and identification of predisposing
the wound, from missiles or other objects, or from factors. A definitive diagnosis can be made later based
contact with various surfaces at the time of injury. on culture of the microorganisms and examination of
The variation in degree of tissue injury and microbial histologic specimens if débridement was performed.
invasion can result in a wide spectrum of wound Because a minor inflammatory reaction, pain, and
infections, including general inflammation, a cel- swelling are normal components of the early stages of
lulitis or simple abscess, a diffuse inflammation and wound healing, recognition of infection based on
spreading cellulitis with or without signs of systemic these cardinal signs can be difficult and wound
toxicity, or a progressive necrotizing soft tissue infections can be missed [16]. Changes in these signs
infection [16]. Once wound infection occurs, it results on frequent examination of the wound and obser-
in the immediate release of inflammatory cytokines vation of increased swelling, tenderness, induration,
from the monocytes and macrophages, which causes discoloration, and fluctuation should increase the
a delay in wound healing. These cytokines also may index of suspicion [6,16,39]. Systemic signs of infec-
result in the release of growth factors that stimulate tion, such as malaise, fever, tachycardia, and leuko-
fibrosis and result in localized scar hypertrophy [20]. cytosis, may be present in patients with infected

Table 1
Recommendations for prophylaxis against tetanus
After clean, minor wounds After all other woundsa
Tetanus-diphtheria Tetanus Tetanus-diphtheria Tetanus
History of tetanus immunization toxoid immunoglobulin toxoid immunoglobulin
Number of previous Yes No Yes Yes
doses < 3 or not known
Number of previous doses  3
Timing of last dose
Within 5 y No No No No
Within 5 – 10 y No No Yes No
> 10 y ago Yes No Yes No
a
Examples of these wounds include contaminated wounds, puncture wounds, avulsions, burns, and crush injuries.
A.O. Abubaker / Oral Maxillofacial Surg Clin N Am 15 (2003) 139–146 143

wounds. Severe infections also may be associated likelihood of sepsis from bacterial infection. Viral
with altered glucose metabolism, respiratory distress, infections should be treated with such agents as
altered mental status, and hypotension [40]. These systemic acyclovir.
signs and symptoms are nonspecific, however, espe-
cially in critically ill patients. When such signs and Débridement
symptoms and local signs of wound infection are
present, they are indicative of a serious problem and The sine qua non of treatment of wound infection
may be associated with progression of the infection is to provide wide drainage of any purulent material
into deeper tissue. Bacterial growth on culture pro- and débride all necrotic tissue [16]. Devitalized
vides essential information for treatment, although tissue acts as a culture medium for bacteria, creates
this is not essential for the diagnosis of posttraumatic an anaerobic environment, and impairs the cellular
wound infection. Because bacteria can colonize trau- and humoral immune defenses [6,45]. It is imper-
matic wounds even in the absence of infection, ative that débridement be performed if nonviable
interpretation of culture results must be conducted tissue is present on the margins of the wound. In
with care. Finally, when there is an associated open instances in which tissue necrosis continues beyond
fracture, differentiation between infection that origi- the time of injury, such as in blast gun shot wounds,
nates in soft tissues and infection that is related to the repeated débridement may be necessary. Frequent
fracture should be made by surgical exploration, cleansing of the wound and repeated dressing
microscopic examination of tissue samples, culture changes should be instituted to assist in removal of
of organisms from the bone, or radiographic exam- bacteria, exudate, and devitalized tissue. It is impor-
ination [41]. tant that a representative tissue specimen or a sample
Also important in the recognition and diagnosis of of purulent discharge be submitted for microbiologic
posttraumatic infection is differentiation between identification of the offending organisms and for
superficial, or local soft tissue infection, and deep diagnosis of the extent of tissue necrosis. These
infections that involve fascia and muscle. Risk fac- specimens are best obtained from beneath the intact
tors for the presence of deep soft tissue infection skin, away from the wound, because bacteria recov-
include systemic diseases, such as diabetes, immuno- ered from these sites are more likely to represent the
compromised status, underlying malignancy, and true pathogens and not part of the wound coloniza-
local factors, such as gross contamination and delay tion [6].
of wound closure.
Wound closure
Empiric antibiotics
Wound closure should be performed when all the
The choice of empiric antibiotics should be based infection is resolved and healthy granulation tissue is
on the location and depth of the wound and the present [6,46]. This goal usually can be accomplished
systemic status of the patient. For most posttraumatic by secondary intention or primary closure if the
head and neck soft tissue infections, first-generation, wound is small. Large wounds may require split-
second-generation, and third-generation cephalospo- thickness skin grafting or flaps, however.
rins remain the drugs of choice for Staphylococcus
aureus [42,43]. In most of the severe posttraumatic
soft tissue infections, a combination of antibiotics is Management of bite wounds
often used until data from culture and antibiotic
sensitivity testing become available on day 2 or 3 [6]. Each year 1% of all visits to emergency rooms
Fungal infections are uncommon in posttraumatic (approximately 300,000 visits) are related to bite
wounds. Candida albicans and, less commonly, Phy- injuries [47,48]. Ninety percent of these injuries are
comycetes are opportunistic organisms that may dog and cat bites, and the rest are human or other
cause secondary infection after systemic antibiotic animal bites. Although most of these bites involve the
therapy, however. Fluconazole and amphotericin B hand, a significant percentage (16%) of dog bites are
are the most commonly used agents for treatment of in the face and scalp, whereas only a small percentage
these fungal infections [33,43]. Viral infections are (2%) of cat bites are in these regions [4,48].
also rare in posttraumatic wound infections but can be Approximately 3% to 18% of dog bites and 28%
present in immunocompromised patients, patients to 80% of cat bites become infected [48,49]. The risk
with major multisystemic trauma, and burn patients of infection is greatest for crush injuries, puncture
[44]. The presence of these infections increases the wounds, and wounds to the hand [47]. Human bites,
144 A.O. Abubaker / Oral Maxillofacial Surg Clin N Am 15 (2003) 139–146

although less common than dog and cat bites, were therapy for outpatients includes penicillin or diclox-
believed to be more prone to infection than those acillin, ampicillin, or a first-generation cephalo-
inflicted by animals. Such reports are biased by sporin [49,54,55]. A recent multicenter study of
emphasis on human bites of the hand that present infected animal bites concluded that optimal thera-
late with infection already present, however [50]. The peutic agents for this purpose include a combination
generally reported poor prognosis in such cases is of a b-lactam antibiotic and b-lactamase inhibitor, a
probably caused by the delay in treatment and loca- second-generation cephalosporin with anaerobic
tion of the wound rather than the cause of injury. activity, or combination therapy with either penicil-
Human bites to the face, lips, and ears have a lower lin and a first-generation cephalosporin or clinda-
risk of infection (less than 3%), than human bites mycin and fluoroquinolone [48]. Based on their in
elsewhere (10% – 12%) if treated properly [50,51]. vitro activity, azithromycin, trovafloxacin, and keto-
With proper wound care, the rate of dog bite infec- lide antibiotics are also effective against all of the
tions in the head and neck is also as low as 1.4%, common aerobic and anaerobic isolates from these
even when prophylactic antibiotics were not used bites [56 – 58]. For treatment of high-risk human
[52]. Wound infection from cat bites to the face is bites, empiric therapy includes penicillin and anti-
3%, whereas it is 19% in the hand and 18% in the staphylococcal agents, such as dicloxacillin and
lower extremities [53]. nafcillin [59]. An alternative to this combination is
The management of bite wounds remains some- oral amoxicillin-clavulanic acid, which provides
what controversial because there is considerable excellent in vitro coverage of the suspected patho-
variation in the patients studied and in wound gens [57,60]. Ertapenem also has an excellent
severity, and there is a relatively small number of potency against the full range of animal and human
cases in the studies reported [47]. There is general bite pathogens [58].
agreement, however, that the most effective method Use of prophylactic antibiotics for prevention of
for preventing infection of these wounds is through bite wound infection remains an area of considerable
proper initial management, which should include controversy. Some authors argue that such use is cost
thorough irrigation with a copious volume of normal effective in selected cases. These cases include
saline, débridement when necessary, and closure of wounds seen more than 8 hours after injury, wounds
the wound when appropriate. The wound also that affect the hand, wounds that involve bone and
should be cultured. Radiographic examination of joints, cat bite puncture wounds, especially near a
the adjacent facial bones may be indicated in cases joint or joint prosthesis, and wounds in patients with
in which a fracture is suspected. Proper selection a compromised immune system. In such cases, the
and administration of antimicrobial therapy, which is use of prophylactic antibiotic may decrease the rate of
based on the suspected flora and the risk of the infection from 15% to 20% to approximately 5%
wound for infection, are also important elements [47,49,54,61]. Excluding these instances, most
of treatment. authors believe that prophylactic antibiotics are not
The most commonly isolated organism from indicated, especially for patients with bite wounds in
infected dog and cat bites is Pasteurella species, the head and neck and patients who present within the
50% and 75%, respectively [48,49]. Pasteurella canis first few hours after injury and show no evidence of
is the most common isolate from dog bites, whereas infection [51,53,54,62,63]. This conclusion is based
P. multocida subspecies multocida and septica are the on the fact that most studies that showed a benefit of
most common isolates from cat bites. Other common prophylactic antibiotics used diverse treatment proto-
aerobic organisms isolated from dog and cat bites cols for wounds that were not of similar severity.
include streptococci, staphylococci, Moraxella, and Most of these studies also were biased by inclusion of
Neisseria [48]. Common anaerobic organisms that hand wounds, which have a higher incidence of
are isolated from mixed infections include Fusobac- infection. Several studies have shown that with early
terium, Bacteroides, Porophyromonas, and Prevo- surgical intervention using irrigation, débridement,
tella. Isolates from human bites include S. aureus, and primary closure, the wound infection rate in the
Eikenella corrodens, Haemophilus influenzae, and face, with and without the use of prophylactic anti-
beta-lactamase – producing oral anaerobic bacteria biotics, is similar and routine antibiotic prophylaxis is
[48,49]. not justified [52,53,55,64,65].
Based on this spectrum of organisms, the empir- The timing of closure of bite wounds also con-
ical therapy for animal bites should be directed tinues to be controversial. In general, the time of
against Pasteurella, streptococci, staphylococci, wound closure is influenced by the period between
and anaerobes Commonly used empiric antibiotic injury and presentation for care. Researchers gen-
A.O. Abubaker / Oral Maxillofacial Surg Clin N Am 15 (2003) 139–146 145

erally agree that bite wounds in the face, where [12] Hollander JE, Singer AJ, Valentine SM, et al. Risk
cosmesis is a major concern, can be closed primarily factors in patients with traumatic lacerations. Acad
or covered with skin graft when necessary—even Emerg Med 2001;8:716 – 20.
[13] Stamou SC, Maltezou HC, Psaltopoulou T, et al.
4 days after injury—with an acceptably low risk
Wound infection after minor limb laceration: risk fac-
for infection because of the rich blood supply
tors and the role of antimicrobial agents. J Trauma
[51,63,66]. 1999;46:1078 – 81.
[14] Cruse PJE, Foord R. A five-year prospective study of
23,649 surgical wounds. Arch Surg 1973;107:206 – 10.
Summary [15] Fernandoz AM, Herruzo CR, Gomez-Sanch F, et al.
Four year study of the risk factors of surgical wound
With improvements in surgical techniques and the infection in 5260 traumatological patients. Minerva
availability of effective systemic antibiotics, the Med 1996;87:189 – 94.
incidence of posttraumatic soft tissue wound infec- [16] Molnar JA, Burke JF. Prevention and management of
tions is relatively low. When such infections occur, infection in trauma. World Surg 1983;7:158 – 63.
however, they can result in significant morbidity. [17] Curtin JW. Basic plastic surgical techniques in repair of
facial lacerations. Surg Clin North Am 1973; 53:33 – 46.
These complications can be reduced by prompt initial
[18] Kelly A-M, Cohen M, Richards D. Minimizing the
management of the wound and proper treatment if pain of local infiltration anesthesia for wounds by in-
infection occurs. jection into the wound edges. J Emerg Med 1994;12:
593 – 5.
[19] Leach J. Proper handling of soft tissue in the acute
References phase. Facial Plast Surg 2001;17:227 – 38.
[20] Key SJ, Thomas DW, Shepherd JP. The management
[1] Edlich RF, Rodeheaver GT, Thacker JG. Wounds, bites of soft tissue facial wounds. Br J Oral Maxillofac Surg
and stings. In: Moore EE, Mattox KL, Feliciano DV, 1995;33:76 – 85.
editors. Trauma. 2nd edition. Norwalk (CT): Appleton [21] Sacchetti A, Schafermeyer R, Geradi M, et al. Pediatric
& Lange; 1991. p. 715 – 50. analgesia and sedation. Ann Emerg Med 1995;23:
[2] Stussman BJ. National Hospital Ambulatory Medical 237 – 50.
Care Survey: 1994 emergency department summary. [22] Dickinson JT, Jaquiss GW, Thompson JN. Soft tissue
Advance data from vital and health statistics. No trauma. Otolaryngol Clin North Am 1976;13:130 – 4.
275. DHHS publication no. (PHS, 96 – 1250). Hyatts- [23] Singer AJ, Hollander JE, et al. Pressure dynamics of
ville (MD): National Center for Health Statistics; 1996. various irrigation techniques commonly used in the
[3] Edlich RF, Rodeheaver GT, Morgan RF, Berman DE, emergency department. Ann Emerg Med 1994;24:
Thacker JG. Principles of emergency wound manage- 36 – 40.
ment. Ann Emerg Med 1988;17:1284 – 302. [24] Stuzin JM, Engrav LH, Buchler PK. Emergency treat-
[4] Hollander JE, Singer AJ, Valentine S, et al. Wound ment of facial lacerations. Postgrad Med 1982;71:
registry: development and validation. Ann Emerg 88 – 94.
Med 1995;25:675 – 85. [25] Madden J, Edlich RF, Schauerhamer R, et al. Applica-
[5] Singer JA, Hollander JE, Quinn JV. Evaluation of man- tion of principles of fluid dynamics to surgical wound
agement of traumatic lacerations. N Engl J Med 1997; irrigation. Curr Top Surg Res 1971;3:85.
337:1142 – 8. [26] Feng LJ, Eaton C. Soft tissue infection in lower ex-
[6] Fildes J, Bannon MP, Barrett J. Soft tissue infections tremity trauma. Clin Plast Surg 1986;13:735 – 45.
after trauma. Surg Clin North Am 1991;71:371 – 84. [27] Wheeler CB, Rodeheaver GT, Thacker JG, et al. Side
[7] Howard RJ. Effect of brain injury, mechanical trauma effects of high pressure irrigation. Surg Gynecol Obstet
and operation on immune defense. Surg Clin North 1976;143:775 – 8.
Am 1979;59:199 – 211. [28] Oberg MS, Lindsey D. Do not put hydrogen peroxide
[8] Miller SE, Miller CL, Trunkey DL. The immune con- or povidone iodine into wounds! Am J Dis Child
sequences of trauma. Surg Clin North Am 1982; 1987;141:27 – 8.
62:167 – 81. [29] Hollander JE, Richman PB, Werblud M, Miller T,
[9] Miles AA, Miles EM, Burke J. The value and duration Huggler J, Singer AJ. Irrigation in facial and scalp
of defense reactions of the skin to the primary lodg- lacerations: does it alter outcome? Ann Emerg Med
ment of bacteria. Br J Exp Pathol 1957;38:79 – 84. 1998;31:73 – 7.
[10] Miles AA, Niven JSF. The enhancement of infection [30] Zook EG. The care of facial lacerations. J Fam Pract
during shock produced by bacterial toxins and other 1978;6:1089 – 95.
agents. Br J Exp Pathol 1950;31:73 – 81. [31] Berk WA, Osbourne DD, Taylor DD. Evaluation of the
[11] Dire DJ, Hogan DE, Riggs MW. A prospective evalu- ‘‘golden period’’ for wound repair: 204 cases from a
ation of risk factors for infections from dog bite Third World emergency department. Ann Emerg Med
wounds. Acad Emerg Med 1994;1:258 – 66. 1988;17:496 – 500.
146 A.O. Abubaker / Oral Maxillofacial Surg Clin N Am 15 (2003) 139–146

[32] Halasz NA. Wound infection and topical antibiotics. [50] Callahan M. Prophylactic antibiotics in common dog
Arch Surg 1977;112:1240 – 4. bite wounds: a controlled study. Ann Emerg Med
[33] Teepe RG, Koebrugge EJ, Lowick C, et al. Cytotoxin 1980;9:410 – 4.
effects of topical antimicrobial and antiseptic agents [51] Chen E, Hornig S, Shepherd SM, Hollander JE. Pri-
on human keratinocytes in vitro. J Trauma 1993;35: mary closure of mammalian bites. Acad Emerg Med
8 – 19. 2000;7:156 – 61.
[34] Dire DJ, Coppola M, Dwyer DA, Lorrette JJ, Karr JL. [52] Guy JR, Zook EG. Successful treatment of acute head
A prospective evaluation of topical antibiotics for pre- and neck dog bite wounds without antibiotics. Ann
venting infections in uncomplicated soft-tissue Plast Surg 1986;17:45 – 58.
wounds repaired in the ED. Acad Emerg Med 1995; [53] Dire DJ. Cat bite wounds: risk factors for infection.
2:4 – 10. Ann Emerg Med 1991;20:973 – 9.
[35] Cummings P, Del Beccaro MA. Antibiotics to prevent [54] Callahan M. Controversies in antibiotic choices for bite
infection of simple wounds: a meta-analysis of wounds. Ann Emerg Med 1988;17:1321 – 30.
randomized studies. Am J Emerg Med 1995;13: [55] Wolff KD. Management of animal bite injuries of the
396 – 400. face: experience with 94 patients. J Oral Maxillofac
[36] Robson MC, Heggers JP. Delayed wound closure Surg 1998;56:838 – 43.
based on bacterial count. J Surg Res 1970;2:379 – 83. [56] Goldstein EJC, Citron DM, Gerardo SH, Hudspeth M,
[37] Centers for Disease Control. Diphtheria, tetanus and Merriam CV. Activities of HMR 3004 (RU 64004) and
pertussis: Recommendations for vaccine use and other HMR 3647 (RU 66647) compared to those of eryth-
preventive measures. Recommendation of the Immu- romycin, azithromycin, clarithromycin, roxithromycin,
nization Practices Advisory Committee (ACIP). Mor- and eight other antimicrobial agents against unusual
bidity and Mortality Weekly Report 1991;40:1 – 22. aerobic and anaerobic human and animal bite patho-
[38] Klein DG, Fritsch DE, Amin SG. Wound infection gens isolated from skin and soft tissue infections in
following trauma and burn injuries. Critical Care Nurs- humans. Antimicrob Agents Chemother 1998;42:
ing Clinics of North America 1995;7:627 – 42. 1127 – 32.
[39] Esrig BC, Frazee L, Stephenson SFS, et al. The pre- [57] Goldstein EJC, Citron DM, Hudspeth M, Gerardo SH,
disposition to infection following hemorrhagic shock. Merriam CV. In vitro activity of BAY 12 – 8039, a new
Surg Gynecol Obstet 1977;144:915. 8-methoxyquinolone, compared to the activities of 11
[40] Pruitt BA, Yurt RW. Treating burn and soft tissue in- other oral antimicrobial agents against 390 aerobic and
fections. Infections in Surgery 1983;2:625 – 8. anaerobic bacteria isolated from human and animal bite
[41] Garner JS, Harvis WR, Emori TG, et al. CDC defini- sound skin and soft tissue infections in humans. Anti-
tions for nosocomial infections. Am J Infect Control microb Agents Chemother 1997;41: 1552 – 7.
1988;16:128 – 40. [58] Goldstein EJC, Citron DM, Merriam CV, et al. Com-
[42] Seligman M, Martyn JAJ. Burn wound infections. In: parative in vitro activity of ertapenem and 11 other
Martyn JAJ, editor. Acute management of the burned antimicrobial agents against aerobic and anaerobic
patient. Philadelphia: WB Saunders; 1990. p. 288 – 305. pathogens isolated from skin and soft tissue animal
[43] Vitale P. Antimycotic and antifungal agents. In: Wil- and human bite wound infections. J Antimicrob Che-
liams BR, Baer CL, editors. Essentials of clinical phar- mother 2001;48:641 – 6.
macology in nursing. Springhouse (PA): Springhouse [59] Fallouji MA. Traumatic love bites. Br J Surg 1990;77:
Corp.; 1994. p. 451 – 62. 100 – 1.
[44] Kagan RJ, Naragi S, et al. Herpes simplex virus and [60] Lindsey D, Christopher M, Hollenbach J, et al. Natural
cytomegalovirus infections in burned patients. J Trau- course of human bite wound. J Trauma 1987;27: 45 – 8.
ma 1985;25:40 – 5. [61] Bunzli WF, Wright DH, Hoang AT, et al. Current man-
[45] Haury B, Rodeheaver G, Vensko J, Edgerton MT, Ed- agement of human bites. Pharmacotherapy 1998;18:
lich RF. Débridement: an essential component of trau- 227 – 34.
matic wound care. Am J Surg 1978;135: 238 – 42. [62] Chidzonga M. Human bites of the face. S Afr Med J
[46] Fratianne R, Papay F, Housini I, et al. Keratinocyte 1998;88:150 – 2.
allografts accelerate healing of split-thickness donor [63] Donkor P, Bankas DO. A study of primary closure of
sites: applications for improved treatment of burns. human bite injuries to the face. J Oral Maxillofac Surg
J Burn Care Rehabil 1993;14:148 – 54. 1997;55:479 – 81.
[47] Goldstein EJC. Bite wounds and infection. Clin Infect [64] Medeiros I, Saconato H. Antibiotic prophylaxis for
Dis 1992;14:433 – 8. mammalian bites. Cochrane Database Syst Rev 2001;
[48] Talan DA, Citron DM, Fredrick AM, et al. Bacterio- 2:CDO1738.
logic analysis of infected dog and cat bites. N Engl J [65] Venter TH. Human bites of the face: early surgical
Med 1999;340:8592 – 7. management. S Afr Med J 1988;74:277 – 9.
[49] Goldstein EJC, Citron DM, Finegold SM. Dog bite [66] Agrawal K, Mishra S, Panda KN. Primary reconstruc-
wounds and infection: a prospective clinical study. tion of major human bite injuries to the face. Plast
Ann Emerg Med 1980;9:508 – 12. Reconstr Surg 1992;90:394 – 8.
Oral Maxillofacial Surg Clin N Am 15 (2003) 147 – 153

Management of infections associated with laser-assisted


cosmetic skin resurfacing
Robert A. Strauss, DDS, MD
Department of Oral and Maxillofacial Surgery, Virginia Commonwealth University, Medical College of Virginia,
PO Box 980566, Richmond, VA 23298, USA

The last decade has seen a large increase in the skin care has made the procedure easily and safely
number of cosmetic surgical procedures performed in performed by various practitioners. Thousands of
the United States. New operations, techniques, and these procedures have been performed with generally
technologies seem to appear each year. Although the excellent aesthetic results.
exact reason for this increase is not totally clear, Although currently well accepted as a useful
cultural and social factors have played a role. Once surgical procedure in the cosmetic surgeon’s arma-
limited only to older women, cosmetic surgery is mentarium, CSR has had its share of controversy. As
currently sought by younger people, men, and even with many technology-based procedures, the rapid
children. Much controversy has been generated con- availability of the ever-changing types of hardware,
cerning the wisdom of our society seeking the coupled with the need and desire of the practitioner to
performance of totally elective surgery. Proponents generate a positive cash flow from these expensive
make arguments based on psychological well-being devices, has brought with it an immediate influx of
and the relative safety of these procedures, whereas practitioners of varying backgrounds, surgical exper-
critics point out that even with all the technologic tise, and laser experience. Unfortunately, the rapid
advances, cosmetic surgery is still associated with a advances in laser technology and widespread use of
low, but inevitable, degree of morbidity and even CSR preceded the ability of researchers to provide a
occasional mortality. clear understanding of the pathophysiology involved,
Among the more recent advances in aesthetic facial the mechanism of laser action, the indications and
surgery has been the development of laser-assisted contraindications for their use, and some of the
cosmetic skin resurfacing (CSR), which has become potential and inevitable complications that were to
one of the most popular procedures performed by be expected. As a consequence, CSR has been
maxillofacial cosmetic surgeons [1]. Similar in effect associated with several serious and occasionally di-
to chemical peeling and dermabrasion (which also are sastrous complications.
associated with the same incidence and types of With time and much scientific research, many of
infections), CSR has gained in popularity because of the unknowns that led to some of the initial problems
new advances in laser technology that allow precise, have been answered. Reasonable technique and patient
targeted, tissue ablation and the fact that these devices selection protocols, based on defensible science, have
are relatively affordable and portable enough for decreased the incidence of complications dramatically.
office-based use. Combining this technology with a They do occur, however, and the wise surgeon always
better understanding of the physiology of skin wound should be wary and diligent in looking for early
healing and the availability of new scientifically based evidence of untoward intraoperative and postoperative
pharmaceuticals for preoperative and postoperative sequelae. Some of the complications seen to date
include scarring, hypopigmentation and hyperpigmen-
tation, blotchiness, pruritis, ectropion, and infection.
E-mail address: rastrauss@vcu.edu Of these complications, infection associated with CSR

1042-3699/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.
PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 8 1 - X
148 R.A. Strauss / Oral Maxillofacial Surg Clin N Am 15 (2003) 147–153

has proved to be one of the more controversial areas in not surprisingly, aerobic or facultative anaerobes (eg,
terms of prophylaxis and treatment. Staphylococcus epidermidis and other Staphylococcus
species, Streptococcus viridans, and Corynebacterium
species). As would also be expected, the most common
Normal healing of the skin fungal organism seen is Candida albicans, although
species of Pityrosporum, Malassezia, and Torulopsis
When a wound is created in skin, a series of are also present. Not only does CSR result in loss of the
important biochemical and histopathologic changes protective epidermal barrier but it also changes the
occurs. Shortly after injury, the adjacent basal cell postoperative environment. This result, plus the me-
layer ceases its normal role of vertical migration dicaments used after surgery, produces a dramatic
and maturation and begins the process of horizontal change in the local immune system and allows for
migration to cover the exposed tissues. Any overgrowth of the normal inhabitants and infection by
adnexal epithelial structures that remain in the organisms from adjacent areas, such as the oral cavity
wound also begin to form surface epithelium and and nares.
proliferate in all directions. Simultaneously, col-
lagen formation is accelerated in the wound to fill
the defect. The more rapid the reepithelialization of Bacterial infections
the wound from external and internal sources, the
less collagen formation that occurs and the less Numerous studies have examined the incidence
likelihood there is of any significant scarring. The and microbiology of postoperative infections after
main goal in all of the skin resurfacing methods is CSR [5 – 10]. The incidence seems to be variable,
to remove the epidermis and papillary dermis and ranging from near zero in some studies to alarming
preserve the reticular dermis with its intact epithe- rates in others, even with the use of prophylactic
lial adnexal structures to allow for speedy internal antibiotics. Weinstein et al, in a study of more than
and external reepithelialization. 1900 patients, showed an overall rate of bacterial
The skin is a fundamental physical barrier to the infection of only 0.5% [10]. Similarly, in a study of
entrance of microorganisms into the body and a 500 consecutive patients, Nanni and Alster reported
vitally important functioning member of the overall an overall rate of infection of less than 1% [7].
immune system [2]. CSR, by its very design, Conversely, Walia and Alster reported an infection
removes the entire epidermis and a significant por- rate of 24% in a subset of their population who
tion of the dermis, thereby altering the immune received intraoperative and postoperative antibiotics
mechanism and enhancing the ability of various [9]. Gaspar et al also reported that 4 of 14 patients
microorganisms to colonize the exposed surface. (28%) not given prophylactic antibiotics also
For this reason a calculable incidence of infection developed postoperative bacterial infections [5]. Sev-
after CSR is to be expected. eral other studies have shown rates generally in the
range of 4% to 8% [6,8].
There seem to be multiple reasons for such
Normal microbiology of the skin diverse findings, and understanding this is important
to critically analyzing the literature in this area. One
Unlike the oral cavity, the skin of the face is of the main obstacles to studying the incidence of
generally not a particularly good place for the postoperative infections is the difficulty in defining
habitation of microorganisms. The skin, being dry the term ‘‘infection.’’ It is variably defined in
and having a slightly acidic pH, makes a hostile different studies as a positive culture associated with
environment, and the constant desquamation makes signs and symptoms, a positive culture regardless of
it difficult for organisms to attain sufficient num- signs and symptoms, or the presence of clinical
bers to cause clinical infection [3]. Various bacteria signs and symptoms with or without any culture
and yeasts consistently inhabit the skin in predict- results. Even more nonspecific, some studies defined
able and stable numbers, typically residing in the the patient as being ‘‘infected’’ whenever the cli-
stratum corneum or along the hair shafts and nician, in his or her judgment, decided to institute
follicles [4]. Patients with acute or chronic acne systemic antibiotics regardless of the culture results
present a much more diverse and complicated [11]. Such variations render interstudy comparisons
microbiologic picture. difficult or impossible.
Because the epidermis is constantly exposed to the Other reasons for the diversity of findings likely
environment, most of the bacteria found on skin are, include the wide variations in the use of prophy-
R.A. Strauss / Oral Maxillofacial Surg Clin N Am 15 (2003) 147–153 149

lactic antibiotics, the differences in postoperative Factors that affect the rate of bacterial infection
dressing management, and even when the study
was performed, because differences in these ever- One interesting factor regarding postoperative
evolving techniques and technologies must play a infection is the time of presentation. Although most
role in the incidence of infection. Other factors that infections occur in the first 3 to 10 days after surgery,
have been shown to make significant and dramatic when the wound has not yet epithelialized [8,13],
differences in infection rate are the size and location some studies have shown that infections can occur
of the operative site. Full-face resurfacing seems to several weeks after surgery [14]. This occurrence can
have a much higher incidence of infection than be explained by the concept that there may be at least
resurfacing restricted to only one or two cosmetic two different mechanisms of infection. One is related
units. Anunt et al, in their study of 396 patients, to the immediate loss of the protective immunity
showed an eightfold decrease in infection when only supplied by the epidermal covering and the type of
partial resurfacing was performed, and no infections initial postoperative management, and the other is
occurred in patients who received resurfacing of related to the long-term medicaments applied to the
only a single cometic unit [8]. surgical site.
The clinical signs and symptoms of a postoper- Another factor that may affect the incidence and
ative infection after CSR are well recognized treatment of bacterial infection is the change in
[7,9,10]. Persistent or increasing pain (especially if local immunity caused by previous operations on
the quality of the pain differs from the initial ‘‘sun- the face. Repeated procedures, such as CSR or
burn’’ pain normally felt for the first 48 hours), chemical peeling, especially when there is diffuse
burning, erythema (localized, worse than the sur- scarring, can lead to infections that may be refrac-
rounding operated skin, and often showing crusting), tory to the normal first-line antibiotics of choice.
pruritis that lasts more than 72 hours, and a yellow Although most postoperative bacterial infections are
exudate are common findings. Papules, pustules, and community acquired, patients who undergo surgery
erosions also may be seen. There may be an asso- in the hospital environment or who have had recent
ciated fever, but this not a consistent finding. hospitalizations must be considered at risk for
Depending on the microbes involved, a foul odor nosocomial infections, such as those caused by
may be noted by the patient. Although postoperative methicillin-resistant S. aureus or Pseudomonas.
bacterial infections may be obvious and overt, one Finally, the role of the immunosuppressive effects
should remember that some individuals present with of short-term systemic or topical steroids in the
only subtle findings, such as prolonged patchy erythe- development of postoperative infections has yet to
ma. Given the consequences that can result and the be evaluated.
success rate of early treatment, the astute clinician One of the most controversial areas in CSR is
always should suspect an infection when any finding the choice of open versus closed dressings for
is out of the ordinary or there is an atypical complaint postoperative management. The advantage of open
from the patient after a CSR procedure and appro- dressings (the use of topical creams or ointments to
priately rule out this possibility. maintain a moist environment through the course of
The microbiology of postoperative bacterial reepithelialization) is that the patient and doctor
infections varies and can be altered by many have direct visual access to the wound, can perform
factors, such as the use of prophylactic antibiotics hygiene procedures often, and can recognize infec-
and the type of postoperative management (eg, tions early. The advantages of closed dressings (the
closed versus open dressings). Because the overall use of occlusive and semiocclusive materials to
infection rate is relatively low, no large-scale stud- cover the wound) are that they eliminate the need
ies have shown a statistically significant classifica- for the patient to be responsible for cleaning the
tion of the organisms most likely involved in CSR. wounds in the immediate postoperative period and
A review of the literature shows that the most they are associated with less discomfort. Researchers
prevalent organisms are Staphyloccocus aureus, S. have questioned whether the warm, moist, enclosed
epidermidis, and Pseudomonas aeruginosa, but environment created under such dressings engenders
occasionally Enterobacter, Escherichia coli, Pro- the growth of infective organisms. Although some
teus, and Serratia species are found. These orga- authors contend that there is an increased incidence
nisms are similar to the organisms typically of infection when occlusive dressings are used [15],
responsible for burn wound infections, because others claim that there is no difference [16]. It is
the wound created by CSR is essentially a par- clear that if the dressings are used, use should be
tial-thickness burn [12]. limited to 48 hours, followed by either removal or
150 R.A. Strauss / Oral Maxillofacial Surg Clin N Am 15 (2003) 147–153

thorough wound cleansing and replacement [17]. Treatment of viral infections


Even in cases in which a higher incidence of
infection followed the use of closed dressings, Among the infections seen after CSR, viral infec-
changing or eliminating the dressing early either tions are probably the most common. This finding is
dramatically decreased or eliminated the problem not unexpected given the prevalence of herpes sim-
[16,17]. Whether real or not, the general feeling plex virus-1 (HSV-1) in the population and the
that these dressings may increase the infection rates, proximity of the operative sites to the most common
along with the tendency toward smaller unit CSR place of hibernation for that organism. The virus lies
(rather than full faces), has swung the pendulum for dormant and quiescent in the trigeminal ganglion but
many surgeons in favor of open dressings. may be activated at any time throughout life by a
chemical, mechanical, or traumatic stimulus or when
the immune system is compromised significantly.
Treatment of bacterial infections Widespread herpetic infections, with subsequent
scarring of the face, have been well documented in
Once a patient’s infection by clinical examination the past in burn patients and persons who undergo
has been determined, it is imperative that the treat- dermabrasion and chemical peeling [19,20]. It is not
ment be immediate, aggressive, and appropriate. This surprising that patients who undergo perioral CSR
response is vital to limiting the chance of long-term are at high risk for an HSV reactivation. One also
scarring or other sequelae. Empirical treatment should remember that although HSV-1 is the most
should be started, but culture and antibiotic sensitiv- common cause of such infections, HSV-2 (typically
ity testing, a Tzanck stain, and a KOH preparation associated with genital lesions and transmitted by
should be performed as soon as possible to guide sexual contact) also can be the causative agent in
therapy should the infection not respond to the initial some patients.
course of drugs. Because many CSR-related infec- Herpes simplex virus infection is not an insignifi-
tions are mixed in nature (ie, they include either cant complication. The incidence of HSV reactivation
multiple bacterial organisms or combined bacterial after dermabrasion and chemical peeling, without the
and fungal or viral organisms), some authors recom- use of antiviral agents, has been reported to be as high
mend beginning treatment with an antibiotic, an as 50% [21]. Before the introduction of effective and
antifungal, and an antiviral agent [8]. These choices specific antiviral agents, trigger areas such as the
can be refined when the results of the cultures and perioral area were purposely avoided during chemical
stains are obtained. peeling or dermabrasion to decrease the risk of an
The choice of an empirical antibiotic always HSV outbreak. Alternatively, patients with chronic or
should be based on the likely organisms involved recurrent HSV were considered unacceptable candi-
in the infection. Given the proclivity for staphylo- dates for these types of procedures [22].
coccal infection, a drug that is effective against Reactivation of the perioral HSV is manifested by
treating gram-positive cocci, such as a cephalo- severe burning pain in the operated site that is
sporin, is logical, but because there is also a high different from the usual stinging felt for the first
incidence of Pseudomonas and other gram-negative 48 hours after surgery. Commonly the pain occurs
infections, most authors recommend a broader spec- just after the cessation of antiviral therapy, but in
trum agent, such as ciprofloxacin, 500 to 750 mg patients who do not receive prophylactic antibiotics,
twice daily for 7 days [8,9]. Topical antibiotics are it occurs within the first 7 to 10 days before reepi-
less effective and may alter the local flora, which thelialization. Within 24 hours of the initial infection,
results in the production of resistant organisms. They the patient develops a dermatomal erythema followed
should not be used in place of systemic antibiotics by the typical vesicular lesions associated with HSV.
when any significant infection exists. Topical agents, As the vesicles rupture, the area develops ulcerated,
such as mupiricin ointment, may be added to sys- weepy patches. The infection may be difficult to
temic treatment for local management of cutaneous diagnose because the entire surgical site is already
erosions, however. When considering therapy, one denuded by the CSR. An HSV infection should be
should remember that patients admitted to the hos- considered in any patient who develops fever or
pital for intravenous antibiotics or hydration are at malaise within the first week after surgery. Because
greater risk for developing methicillin-resistant S. of the large amount of deepithelialized skin (loss of
aureus infections or infections caused by drug-re- the normal protective epidermal barrier), the infection
sistant strains of Pseudomonas, and repeated cultur- can spread rapidly to any or all of the treated areas,
ing is appropriate [18]. with potentially disastrous consequences.
R.A. Strauss / Oral Maxillofacial Surg Clin N Am 15 (2003) 147–153 151

Initially, a history of recurrent perioral HSV Treatment of candidal infections


infection was considered a true contraindication for
CSR. With the use of prophylactic antiviral therapy Fungal infections also have been reported after
this is no longer the case. Much controversy has been CSR [1,9,27]. The postoperative environmental
generated in the literature about which drugs to conditions of the face (ie, warm, moist, denuded
administer and what protocol to follow. Questions epithelium) provide an ideal growth medium for
regarding when to begin therapy, how much to give, fungal growth. To date, Candida organisms are
and when to cease therapy are still not clear and are isolated almost exclusively. One should note, how-
being investigated. ever, that several authors have found that candidal
Because it was the first modern antiviral agent to infection is often associated with bacterial and viral
be commercially available, acyclovir has been used infections [8,9].
extensively on patients who undergo CSR proce- Candidal infection after CSR should be suspected
dures. Perkins and Sklarew showed that with typical when the skin develops a fine, white film with an
low-dose prophylaxis of 600 mg per day, break- undersurface that bleeds when wiped gently with
throughs were still common (8.3%, although not gauze. Pain, burning, and delayed healing are also
nearly as common as the 50% reactivation rate they typical signs. In some cases, yeast pustules also may
found in untreated patients) [21]. Weinstein et al form. When Candida is suspected, a KOH prepara-
showed that at 1000 mg per day the rate dropped to tion and fungal cultures confirm the diagnosis.
0.3% [10]. When Perkins and Sklarew began their The treatment for fungal infection is straightfor-
prophylactic regimen 2 days before surgery at an ward. The patient should be placed on systemic
increased dose of 2400 mg per day and continued it antifungal therapy using 200 mg per day of either
for 2 weeks after surgery, their reactivation rate fluconazole or itraconazole. A course of 2 to 4 days
dropped to zero [20]. seems to be adequate to resolve most fungal infec-
Although acyclovir has been shown to be effec- tions. Topical antifungal agents, such as ketoconazole
tive, its low absorption and bioavailability necessi- cream (Nizoral), may be used to complement the
tate high dosages for long periods. Newer agents, systemic therapy. Some authors have suggested using
such as famcyclovir and valacyclovir, have much prophylactic fluconazole therapy for 1 day before
better bioavailability and are probably better surgery in women who have a history of chronic
choices [23,24]. Valacyclovir, 500 mg twice daily, vaginal yeast infections [27]. At least one study has
started the day of or the day before surgery and suggested that prophylactic fluconazole therapy,
continued for 14 days postoperatively has been 300 mg per day given between 3 and 8 days post-
shown to be 100% effective in eliminating HSV operatively, may speed reepithelialization, although
reactivation in CSR patients [25]. Although patients this report remains controversial [28]. Manuskiatti et
with a history of recurrent HSV outbreaks or at al reported a 1.8% to 2.2% incidence of yeast
least a previous single outbreak have a documented infection in 356 consecutively operated patients, but
higher risk of infection if they do not receive this rate dropped to zero with the use of prophylactic
prophylactic antivirals, patients who deny such a antifungal therapy [6]. Each clinician must determine
history should not be considered at low risk. whether this low incidence of infection warrants the
Several studies have demonstrated a high incidence use of prophylactic therapy.
of apparent or proven HSV reactivation in patients
who denied any prior history of such lesions
[25,26]. Prevention of infections
When reactivation does occur, recognition is of
paramount importance. Tzanck stains or viral cul- Because of the grave sequelae that can accompany
tures may be useful in making the diagnosis, but infections after CSR, much emphasis has been placed
given the potential for disastrous sequelae and the on prevention protocols and treatment protocols [29].
low incidence of adverse reactions to the drugs, This has proved to be one of the most controversial
the initiation of high-dose therapy should not be issues in the still-evolving field of facial rejuvenation.
delayed pending the results of these tests. Acyclovir The wisdom of prophylactic antibiotic, antiviral, and
should be increased to 4000 mg per day in five antifungal agents, the use of closed versus open
divided doses, and valacyclovir should be increased dressings, and various postoperative wound hygiene
to 1000 mg three times per day. This high-dose techniques have come under scrutiny. The use and
therapy should be continued for at least 2 weeks type of prophylactic antibiotics, in particular, have
after the lesions disappear. become sources of discussion.
152 R.A. Strauss / Oral Maxillofacial Surg Clin N Am 15 (2003) 147–153

Prophylactic antibiotics are considered appropriate ative and postoperative antiviral therapy. This neces-
to prevent infection either when the risk is exception- sity is well documented and well accepted.
ally high or when the ramifications of the infection are One area of interest that is often overlooked but
grave. The benefits of the therapy must outweigh the must be considered in any discussion of postoperative
risks of adverse effects. CSR is considered a ‘‘clean- infection is wound hygiene. Changing or eliminating
contaminated’’ procedure because of the intimate closed dressings early, meticulous wound cleansing,
proximity of the surgical site to contaminated areas, and strict hand washing are imperative. The patient
such as the oral and nasal cavities. In general, it is also should be instructed carefully on the avoidance
anticipated that ‘‘clean-contaminated’’ surgery has an of ‘‘double dipping’’—using the fingers or the hands
expected infection rate of approximately 10%. The to apply postoperative topical agents and then placing
actual infection rate of CSR procedures reported in the them back into the container for more material. This
literature ranges from 1% to 9%. With improved practice quickly contaminates the container and leads
posttreatment protocols currently being used, the to re-inoculation. Contamination can be avoided by
current rate is likely at the low end of this range. using fresh cotton swabs and removing the entire
Despite the low incidence, many surgeons still pro- amount of agent needed at one time.
vide prophylactic coverage to their patients [30,31].
Although at least one study has shown that using
antibiotics can lead to a decreased incidence of Summary
infection (decreased from 8.2% to 4.3% using cipro-
floxacin and open dressings) [6], several other studies Infections after CSR are to be expected in a small
that showed similar results either were based on small number of patients, and they can be bacterial, viral, or
samples [13] or involved retrospective studies with fungal. Despite the low incidence, these infections
multiple variables (such as the type of postoperative can have devastating sequelae. When they occur, they
dressing applied) that could have affected the infec- should be investigated promptly and thoroughly to
tion rate [8]. If one decides to use prophylactic anti- determine their cause and the best course of treat-
biotics, it is wise to use narrow-spectrum agents. ment. The use of prophylactic antibiotics and anti-
The reasons for not giving prophylactic antibiotics fungal agents is still controversial, and their use
are also compelling, including the cost of the drugs, seems in many cases to be dictated primarily by legal
possible allergic or other untoward reactions, altera- and patient demands rather than good science. It is
tion of the normal skin flora, and selection of resistant hoped that future studies will better elucidate when
organisms or development of superinfection. Several and if these agents are necessary and what drugs
studies also have shown no decrease in infection rate should be used. Conversely, antiviral therapy is
with the use of prophylactic therapy [9,32,33]. considered vital in the prevention of herpetic out-
The use of topical antibiotics also has been breaks, and it has been well documented that failure
evaluated as a means of postoperative management to use such agents leads to an unacceptably high
and for prophylaxis. Postoperative use of antibiotic incidence of infection and subsequent scarring, even
ointments has been associated with the development in patients with no previous history of HSV. Finally,
of milia, selection of resistant organisms, and a there is still much to be learned regarding the most
significant risk of contact dermatitis, especially in ideal posttreatment protocols to minimize the inci-
deepithelialized, laser-abraded skin [13,34]. The use dence of infection. Proponents of closed and open
of antibiotics is probably best avoided. Mupirocin, an dressings must demonstrate convincing evidence to
intranasal, topical, antistaphylococcal spray, also has show that one regimen is better than the other.
been tested for prophylaxis without success [6].
Although the evidence seems to indicate that use
of prophylactic antibiotics after CSR probably is not
necessary, the use of closed dressings may alter this References
paradigm. In the opinion of many authors (even
authors opposed to antibiotic use with open dress- [1] Fitzpatrick RE. Laser resurfacing of rhytides. Dermatol
Clin 1997;15:431 – 47.
ings), the surface environment associated with closed
[2] Gilchrest BA. Skin aging and photoaging. Dermatol
dressings increases the risk of infection sufficiently to Nurs 1990;2:79 – 84.
warrant the use of prophylactic agents [14]. Although [3] Gallis HA. Normal flora and opportunistic infections.
the use of prophylactic agents to prevent bacterial or In: Joklik WK, Willet HP, Amos DB, et al, editors.
fungal infection has generated some controversy, Zinsser microbiology. 19th edition. Norwalk (CT):
there is no confusion as to the necessity for preoper- Appleton and Lange; 1988. p. 337 – 42.
R.A. Strauss / Oral Maxillofacial Surg Clin N Am 15 (2003) 147–153 153

[4] Schuster GS. Microbiology of the orofacial region. In: virus and cytomegalovirus infections in burned pa-
Topazian RG, Goldberg MH, Hupp JR, editors. Oral tients. J Trauma 1985;25:40 – 5.
and maxillofacial infections. 4th edition. Philadelphia: [20] Rappaport MJ, Kramer F. Exacerbation of facial herpes
W.B. Saunders Co.; 2002. p. 30 – 42. simplex after phenol facial peels. J Dermatol Surg On-
[5] Gaspar Z, Vincuillo C, Elliot T. Antibiotic prophylaxis col 1984;10:57 – 8.
for full face laser resurfacing: is it necessary? Arch [21] Perkins SW, Sklarew EC. Prevention of facial herpetic
Dermatol 2001;137:1251 – 2. infections after chemical peel and dermabrasion: new
[6] Manuskiatti W, Fitzpatrick RE, Goldman MP, et al. treatment strategies in the prophylaxis of patients
Prophylactic antibiotics in patients undergoing laser undergoing procedures of the perioral area. Plast Re-
resurfacing of the skin. J Am Acad Dermatol 1999; constr Surg 1996;98:427 – 33.
40:77 – 84. [22] Farber GA. Chemical peeling in the treatment of cer-
[7] Nanni CA, Alster TS. Complications of carbon dioxide tain cosmetic defects and diseases of the skin. In:
laser resurfacing: an evaluation of 500 patients. Der- Burks JW, editor. Dermabrasion and chemical peeling.
matol Surg 1998;24:315 – 20. Springfield (IL): Charles Thomas Publishing; 1979.
[8] Sriprachya-Anunt S, Fitzpatrick RE, Goldman MP, et p. 209 – 26.
al. Infections complicating pulsed carbon dioxide laser [23] Alster TS, Nanni CA. Famciclovir prophylaxis of her-
resurfacing for photoaged facial skin. Dermatol Surg pes simplex virus reactivation after laser skin resurfac-
1997;23:527 – 35. ing. Dermatol Surg 1999;25:242 – 6.
[9] Walia S, Alster TS. Cutaneous CO2 laser resurfacing [24] Wall SH, Ramey SJ, Wall F. Famciclovir as antiviral
infection rate with and without prophylactic antibiot- prophylaxis in laser resurfacing procedures. Plast Re-
ics. Dermatol Surg 1999;25:857 – 61. constr Surg 1999;104:1103 – 8.
[10] Weinstein C, Pozner JN, Ramirez OM. Complications [25] Gilbert S, McBurney E. Use of valacyclovir for herpes
of carbon dioxide laser resurfacing and their preven- simplex virus-1 (HSV-1) prophylaxis after facial resur-
tion. Aesthetic Surgery Journal 1997;17:216 – 22. facing: a randomized clinical trial of dosing regimens.
[11] Futoryan T, Grande D. Postoperative wound infection Dermatol Surg 2000;1:50 – 4.
rates in dermatologic surgery. Dermatol Surg 1995;21: [26] Rendon-Pellerano MI, Lentini J, Eaglestein WE, et al.
509 – 14. Laser resurfacing: usual and unusual complications.
[12] Husain MT, Karim QN, Tajuri S. Analysis of infection Dermatol Surg 1999;5:360 – 6.
in a burn wound. Burns 1989;15:299 – 302. [27] Kilmer SL. Laser resurfacing complications: how to
[13] Ross EV, Amesbury EC, Barile A, et al. Incidence of treat them and avoid them. International Journal of
postoperative infection or positive culture after facial Aesthetic and Restorative Surgery 1997;5:41 – 5.
laser resurfacing: a pilot study, a case report, and a [28] Conn H, Nanda VS. Prophylactic fluconazole pro-
proposal for rational approach to antibiotic prophy- motes reepithelialization in full-face carbon dioxide
laxis. J Am Acad Dermatol 1998;39:975 – 81. laser skin resurfacing. Lasers Surg Med 2000;26:
[14] Christian MM, Behroozan DS, Moy RL. Delayed in- 201 – 7.
fections following full-face CO2 laser resurfacing and [29] Strauss RA, McMunn W, Gregory BA. Cosmetic skin
occlusive dressing use. Dermatol Surg 2000;26:32 – 6. resurfacing. Selected Readings in Oral and Maxillofa-
[15] Lawrence N, Coleman WP. Postoperative care after cial Surgery 2001;9:1 – 32.
laser resurfacing. In: Coleman WP, Lawrence N, edi- [30] Friedman PM, Geronemus RG. Antibiotic prophylaxes
tors. Skin resurfacing. Baltimore: Williams and Wil- in laser resurfacing patients. Dermatol Surg 2000;26:
kins; 1998. p. 189 – 95. 695 – 6.
[16] Newman JP, Fitzgerald P, Kock RJ. Review of closed [31] Kauvar ANB. Laser skin resurfacing: perspectives at
dressing after laser resurfacing. Dermatol Surg 2000;26: the millennium. Dermatol Surg 2000;26:174 – 7.
562 – 71. [32] Alster TS. Against antibiotic prophylaxis for cutaneous
[17] Goldman MP. Pre- and postoperative care of the laser laser resurfacing. Dermatol Surg 2000;26:697 – 8.
resurfacing patient. International Journal of Aesthetic [33] Gaspar Z, Apfelberg DB. Summary of the 1997
and Restorative Surgery 1997;5: 46 – 9. ASAPRS/ASPRS laser task force survey on laser re-
[18] Bellman B, Brandt FS, Holtmann M, et al. Infection surfacing and laser blepharoplasty. Plast Reconstr Surg
with methicillin-resistant Staphylococcus aureus after 1998;101:511 – 8.
carbon dioxide resurfacing of the face: successful treat- [34] Waldorf HA, Kauvar ANB, Grossman MC, et al. Skin
ment with minocycline, rifampin, and mucipirin oint- resurfacing of fine to deep rhytids using a char free
ment. Dermatol Surg 1998;24:279 – 82. carbon dioxide laser in 47 patients. Dermatol Surg
[19] Kagan RJ, Naraqi S, Matsuda T, et al. Herpes simplex 1995;21:940 – 6.
Oral Maxillofacial Surg Clin N Am 15 (2003) 155 – 160

The use of prophylactic antibiotics for the prevention of


postoperative infections
Daniel M. Laskin, DDS, MS
Department of Oral and Maxillofacial Surgery School of Dentistry, Virginia Commonwealth University,
Richmond, VA 23298-0566, USA

Despite use of the best surgical techniques, some recommendations that are made by the authors. It also
operations still carry a high risk of wound infection. may account for some of the contradictory findings
Basic and clinical studies have shown that this risk that have been reported in the literature.
can be reduced by the administration of prophy- As the result of the basic studies of Miles and
lactic antibiotics. There are certain inherent risks Burke et al [1,2] and several well-controlled clinical
associated with the use of these agents, however, studies, the principles of proper antibiotic prophylaxis
such as toxic and allergic reactions, emergence of have been established for general surgery, and they
resistant bacteria, drug interactions, and superinfec- are applicable to the field of oral and maxillofacial
tions. Moreover, prophylactic antibiotics do not surgery. These principles are (1) that the intended
prevent all postoperative infections. For these reas- procedure must carry a significant risk of postoper-
ons, their use should be based on an understanding ative infection, (2) that the correct antibiotic must be
of certain basic principles. This article reviews these selected, and (3) that the antibiotic is administered
principles and discusses their application in specific properly. To these principles one may add a fourth
clinical situations. principle: not to rely solely on prophylactic anti-
biotics to prevent postoperative infections.

Principles of prophylactic antibiotics


Risk of infection
Antibiotic prophylaxis has been defined as the
preoperative use of antibiotics to prevent infection. Although such factors as age of the patient,
Prophylactic use of antibiotics is in contradistinction nutritional status, nature of any underlying disease,
to the therapeutic use of antibiotics, which are given presence of necrotic tissue, and a decreased blood
to treat an already existing infection. Not only are the supply can increase the potential for postoperative
purposes different but also the manner in which the infection, perhaps the most important factor is wound
drugs should be administered for an optimum effect contamination. Altemeier et al [3] developed a clas-
are different. A review of the literature clearly indi- sification of general surgical wounds relating con-
cates that, in many instances, antibiotics are given tamination to the risk of infection. In this
postoperatively rather than preoperatively, although it classification, operative wounds are categorized as
is still referred to as a prophylactic procedure. This clean, clean-contaminated, contaminated, or dirty,
difference must be taken into consideration when with contamination resulting from planned or
evaluating the conclusions that are reached and the unplanned entry into the respiratory, gastrointestinal,
or genitourinary tracts. Because of the difference in
host response to such contamination and oral con-
tamination, this classification cannot be used for
E-mail address: dmlaskin@vcu.edu intraoral wounds. It can be modified, however, to

1042-3699/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.
PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 6 7 - 5
156 D.M. Laskin / Oral Maxillofacial Surg Clin N Am 15 (2003) 155–160

establish the indications for prophylactic antibiotics pathogen that may be encountered. Expanded anti-
in other forms of oral and maxillofacial surgery. biotic coverage serves only to increase the rate of
According to this modified classification, extraoral bacterial resistance and the development of super-
wounds are still categorized in terms of increasing risk infections. The most commonly encountered orga-
of infection as clean, clean-contaminated, contami- nisms from oral contamination are the streptococci,
nated, and dirty. However, the definitions must be anaerobic gram-positive cocci, and anaerobic gram-
altered to fit the regional differences. Clean surgical negative rods, whereas contamination from the sinus
wounds, which have a low infection rate, usually and nose may include Haemophilus influenzae, dip-
involve no significant tissue trauma or inflammation, theroids, and peptostreptococci [4]. When the skin is
the incision is closed primarily, the wound is not involved, the presence of Staphylococcus aureus and
drained, and there is no communication with the oral epidermidis also must be considered.
cavity. Clean-contaminated surgical wounds are sim- Although the first consideration is that the anti-
ilar to clean wounds except that there is a greater risk of biotic selected is effective against the major contam-
infection because communication with the oral cavity inating organisms, it also must be nontoxic and
occurs. Contaminated wounds are fresh traumatic relatively nonallergenic, bactericidal, capable of
injuries that involve the oral cavity, whereas dirty achieving therapeutic tissue concentrations, and have
wounds are traumatic injuries with delayed treatment a long half-life so that redosing is generally not
that communicate with the oral cavity and contain required during the procedure. The antibiotic that
devitalized tissue or foreign bodies. currently still fulfills these requirements best is peni-
Clean surgical wounds do not require antibiotic cillin. When skin contaminants are a concern, how-
prophylaxis; however, it should be used in clean- ever, a first-generation cephalosporin, such as
contaminated wounds. Contaminated wounds usually cefazolin, can be used because of its effectiveness
can be managed with preoperative prophylactic anti- against most staphylococci.
biotics if there are no other significant risk factors.
Otherwise, patients with such wounds also should
receive postoperative prophylactic antibiotics. Patients Antibiotic administration
with dirty wounds, which are already infected, require
preoperative and postoperative therapeutic antibiotics. Although one selects the appropriate antibiotic for
The decision not to use antibiotics or to use only prophylaxis, its ultimate effectiveness in preventing
preoperative prophylactic antibiotics is always based infection still depends on proper administration. This
on the assumption that the patient does not have any decision varies according to whether one is dealing
significant medical risk factors that could affect the with normal patients, in whom there is only concern
body’s humoral and cellular defense mechanisms. about the initial bacterial contamination that can
These risk factors include poorly controlled diabetes, occur during the operation, or patients with other
end-state renal disease and uremia, severe alcoholism, significant risk factors that decrease the body’s
an immunocompromising disease (eg, leukemia, lym- defenses and retard healing, which makes them more
phoma, or an advanced malignant neoplasm), and the susceptible to recontamination during the healing
use of chemotherapeutic agents or other immunosup- period. In the first instance, the antibiotic must be
pressive drugs. In such patients, one is concerned not administered intravenously or intramuscularly within
only with preventing the initial contamination of the 30 minutes of the incision time at twice the thera-
wound but also with the possibility of recontamina- peutic dose [5]. For penicillin, the dose is 2 million
tion during the postoperative period. Therefore, post- U, and for cefazolin it is 1 g. This dose generally
operative prophylaxis is also indicated. provides adequate coverage for up to 4 hours. If the
procedure is prolonged, however, it is advisable to
administer additional doses every 4 hours until the
Antibiotic selection operation is completed. In patients who are medically
compromised or immunosuppressed, it may be advis-
Once it has been determined that prophylactic able to continue prophylactic oral antibiotics until
antibiotics are indicated in a particular patient, the biologic sealing of the wound has occurred. No data
second principle involves making the appropriate exist on how long this period should be or even if it
selection. The choice of antibiotic is determined prevents postoperative infections. In fact, one must be
largely by its effectiveness against the pathogens concerned about promoting the emergence of resist-
commonly encountered at the specific surgical site. ant strains and causing superinfections. In a wound
It need not be able to eradicate every potential that is healing by primary intention, the period should
D.M. Laskin / Oral Maxillofacial Surg Clin N Am 15 (2003) 155–160 157

probably be no longer than 48 hours postoperatively Impacted third molar surgery


and in a wound healing by secondary intention it
should be no longer than 3 to 5 days, at which time a Although many practitioners routinely prescribe
biologic seal should have occurred. antibiotics for patients who have impacted third
molars removed [7,8], they are generally prescribed
postoperatively. This practice does not accomplish
Adjunctive procedures the true purpose of using prophylactic antibiotics:
having a high tissue concentration present at the
Although the correct use of prophylactic anti- time of surgery when the wound is exposed to
biotics significantly reduces the incidence of post- bacterial contamination. It is not surprising that no
operative infections, their occurrence can be reduced convincing data show a significant reduction in
further by careful attention to proper surgical tech- postoperative infections after third molar removal
nique. Proper technique involves adequate cleansing when antibiotics are used in this manner [7,9]. The
of the surgical site, strict adherence to sterile tech- fact that such infections are relatively uncommon
nique, avoiding tissue trauma, and minimizing oper- also may be a contributing factor to such findings
ating time. In general, the risk of infection has been [10,11]. Most studies that report high postoperative
shown to increase with each hour of surgery. Shav- infection rates [12] include alveolar osteitis (dry
ing the skin in the surgical site with a razor the socket) and fascial space infections. In such stud-
evening before the operation also has been shown to ies, however, there is still not a significant reduc-
increase the infection rate, probably because of tion in either type of problem, whether the
bacterial proliferation in the areas of minor trauma antibiotics are given postoperatively or preopera-
produced by shaving [6]. When shaving is neces- tively [13 – 15].
sary, it should be done just before preparation of the Although isolated cases of severe fascial space
surgical site. infections after third molar removal have been
The use of drains also may contribute to post- reported [16], the incidence is too low to justify the
operative infections. When drains are necessary in routine use of prophylactic antibiotics. Such treat-
noninfected wounds, the closed-suction type is prefer- ment should be reserved only for patients with
able to open drains. They should not be placed through significant medical risk factors for infection [1,17].
the operative incision and should be removed as soon In these cases it should be given immediately before
as possible. Paying proper attention to these details surgery and for 3 to 5 days after surgery to provide an
during management of the surgical patient greatly adequate period of coverage.
improves the effectiveness of antibiotic prophylaxis.

Dental implants
Specific applications in oral and
maxillofacial surgery (Table 1) Few studies have been conducted on the effect of
antibiotics on the infection rate after implant place-
Exodontia and dentoalveolar surgery ment. Two studies in which no control group was
used [18,19] concluded that preoperative prophylactic
Although intraoral surgical wounds are contami- antibiotics were effective in preventing postoperative
nated by the oral flora, the ability of patients infections. In a subsequent, better controlled study
normally to tolerate this bacterial population and [20], however, no difference in postoperative infec-
the excellent blood supply to the oral tissues allow tions or implant failure was found between the
such wounds to be managed similarly to clean two groups.
wounds. It is unnecessary to use prophylactic anti- In a more recent, large, multicenter study, Dent et
biotics to prevent infection when performing most al [21] analyzed implant failures (which probably
types of exodontia and dentoalveolar surgery unless included some cases with infection) and found sig-
there are other contributing risk factors (Table 1). If nificantly fewer failures up to stage 2 surgery, when
the procedure involves the maxillary sinus or nasal high-dose preoperative antibiotics (penicillin in 69%
cavity, however, this can result in cross-contamina- of cases) were administered. These findings were
tion with new organisms, and prophylactic antibi- confirmed in a follow-up study at 36 months in the
otics should be used except when there is already same patient population (4.6% versus 10% failure)
infection in these areas. In the latter instance, thera- [22]. Thus, there seems to be a benefit in using
peutic antibiotics are indicated. prophylactic antibiotics in dental implant patients.
158 D.M. Laskin / Oral Maxillofacial Surg Clin N Am 15 (2003) 155–160

Table 1
Indications for prophylactic antibiotics
Procedure Antibiotic regimen Exceptionsa
Exodontic and dentoalveolar surgery None High risk for infection; communication
with sinus or oral cavity
Impacted third molar surgery None High risk for infection
Dental implants Preoperative Also postoperative prophylaxis when
high risk of infection
Orthognathic surgery (extraoral approach) None Preoperative when anticipate possible
oral contamination
Orthognathic surgery (intraoral approach) Preoperative and None
1-day postoperative
Mandibular fractures (no oral communication) None None
Mandibular fractures (oral communication) Preoperative and Use prophylactic antibiotics 3 – 5 days
12 hours postoperative postoperatively when treatment delayed
Facial bone fractures Preoperative None
Soft tissue trauma (oral injuries) None Preoperative when high risk for infection
Soft tissue trauma (clean extraoral lacerations) None Preoperative when high risk for infection
Soft tissue trauma (blunt trauma, gunshot wounds, Preoperative Postoperative prophylaxis for 3 – 5 days
bites, orocutaneous communication) when high risk for infection
Major head and neck surgery Preoperative Postoperative prophylaxis 3 – 5 days when
packs or drains used; lack of watertight
closure; high risk for infection
a
High risk for infection refers to such factors as poor nutritional status, complicating medical problems, presence of necrotic
tissue or foreign bodies, and decreased blood supply to the region.

Orthognathic surgery biotics is effective in reducing postoperative infec-


tions [28,29]. In most of these studies, however, the
Orthognathic surgery performed via an extraoral antibiotics were given not only preoperatively but
approach is considered a clean procedure and pro- also for a long period postoperatively. More recent
phylactic antibiotics should not be necessary unless investigations [28,30] have shown that prophylactic
communication with the mouth is anticipated [23]. antibiotics given preoperatively and for no longer
Intraoral procedures and procedures that involve the than 12 hours postoperatively are just as effective as
maxillary sinus and nasal passages are clean-contam- long-term use in preventing postoperative infections.
inated operations, and short-term prophylactic anti- These findings apply only to fractures that are treated
biotics have been shown to reduce the postoperative shortly after the injury has occurred. Fractures for
infection rate [24,25]. There seems to be no advan- which there is delayed treatment should be consid-
tage in prolonged postoperative antibiotic administra- ered dirty wounds, and such patients should receive
tion [25,26]. In one study in which a 5-day regimen therapeutic antibiotics postoperatively.
was shown to be better than a 1-day regimen [27], as
pointed out by Abubaker [24], the difference was Facial bone fractures
caused by the difference in the criteria used to
establish wound infection. Although it has been suggested that any mid-
facial fracture compounded into the mouth, nose,
Mandibular fractures or paranasal sinuses requires antibiotic coverage
[31,32], other studies [28,33] have shown that it
Patients with condylar process fractures treated may not be necessary. Because one of these studies
by either open or closed reduction require no pro- [33] was not well controlled and the other [28] had a
phylactic antibiotics. The same is true for fractures in relatively small number of cases, the issue remains
other non – tooth-bearing areas that are not in com- unresolved. Based on the fact that such compound
munication with the mouth, because these are all fractures communicate with a contaminated cavity,
clean wounds. In patients with compound man- they should be considered as clean-contaminated
dibular fractures, however, which are contaminated wounds and preoperative prophylactic antibiotics
wounds, studies have shown that the use of anti- should be used.
D.M. Laskin / Oral Maxillofacial Surg Clin N Am 15 (2003) 155–160 159

Soft tissue trauma administer appears to transcend therapeutic rationale


and provokes the use of antibiotics for purposes often
Patients with traumatic injuries that involve the obscure and irrelevant. It is only natural that great
oral mucosa, gingiva, or tongue do not require inventions and discoveries should gain wide acclaim
prophylactic antibiotics because such wounds, and enthusiastic endorsement and enjoy universal
although contaminated, generally heal without infec- acceptance far in excess of which they merit.’’
tion. Simple extraoral lacerations from relatively
clean objects that are closed within 4 hours also have
a low infection rate and do not require prophylactic References
antibiotics [34]. Extraoral soft tissue injuries, such as
those caused by blunt trauma, gunshot wounds, and [1] Miles AA, Miles EM, Burke J. The value and duration
bites and injuries that involve orocutaneous commu- of defense reaction of the skin to primary lodgment
nication, fall into either the category of clean-con- of bacteria. British Journal of Experimental Pathology
taminated or contaminated wounds, and the patient 1957;38:79 – 86.
should receive pretreatment antibiotic prophylaxis. [2] Burke JF. The effective period of preventive antibiotic
If the wounds are extremely dirty, the patient also action in experimental incisions and dermal lesions.
should receive postoperative therapeutic antibiotics. Surgery 1961;50:161 – 8.
[3] Altemeier WA, Burke JF, Pruitt Jr BA, et al. Manual on
control of infection in surgical patients. 2nd edition.
Major head and neck surgery
Philadelphia: JB Lippincott; 1984. p. 26 – 9.
[4] Gagliano NC, Leisure GS. Perioperative pharmacol-
Researchers generally agree that patients who ogy. In: Stone OJ, Bogdonoff DL, Leisure GS, et al,
undergo major surgical procedures in the head and editors. Perioperative care: anesthesia, medicine, and
neck region, such as oncologic and reconstructive surgery. St. Louis: Mosby; 1998. p. 486.
surgery, should receive preoperative prophylactic [5] Peterson LJ. Principles of antibiotic therapy. In: Topa-
antibiotics [31,35 – 39]. There is a question regarding zian RG, Goldberg MH, editors. Oral and maxillofacial
how long they should be used postoperatively. Sev- infections. 3rd edition. Philadelphia: WB Saunders;
eral studies [31,35,36,38,39] that have shown that 1994. p. 160 – 97.
there is no advantage in extending the prophylactic [6] Cameron JL. Current surgical therapy. 7th edition.
St. Louis: Mosby; 2001. p. 1281.
antibiotics beyond 1 day after surgery in such cases
[7] Capuzzi P, Montebugnoli L, Vaccaro MA. Extraction
unless there are packs or drains in the wound or it is of impacted third molars: a longitudinal, prospective
not possible to obtain a watertight closure and there is study. Oral Surg Oral Med Oral Pathol 1994;77:
prolonged leakage of saliva into the wound [40]. 341 – 3.
[8] Piecuch JF, Arzadon J, Lieblich SE. Prophylactic anti-
biotics for third molar surgery: a supportive opinion.
Summary J Oral Maxillofac Surg 1995;53:53 – 60.
[9] Chiapasco M, Cicco LD, Marrone G. Side effects and
Although prophylactic antibiotics do not prevent complications associated with third molar surgery. Oral
all postoperative infections, they can reduce the Surg Oral Med Oral Pathol 1993;76:312 – 20.
[10] Goldberg MA, Nemarich AN, Marco WP. Complica-
incidence significantly when administered correctly.
tions after mandibular third molar surgery: a statistical
However, they should be used only in patients in analysis of 500 consecutive procedures in private prac-
whom the surgical procedure or the medical condition tice. J Am Dent Assoc 1985;111:277 – 9.
puts them at a high risk of developing such infec- [11] Osborn TP, Frederickson G, Small IA, et al. A prospec-
tions. As a general rule, the anticipated risk should tive study of complications related to mandibular third
exceed 10% [41]. Use of antibiotics in low-risk cases molar surgery. J Oral Maxillofac Surg 1985;43:767 – 9.
in an attempt to prevent postoperative infections, [12] Mitchell DA. A controlled clinical trial of prophylactic
especially when used for prolonged periods, can tinidazole for chemoprophylaxis in third molar surgery.
result in adverse drug effects, superinfections, and Br Dent J 1986;160:284 – 6.
the emergence of resistant strains without providing [13] Curran JB, Kennett S, Young AR. An assessment of
the use of prophylactic antibiotics in third molar sur-
any significant benefits. As Furstenburg [42] stated so
gery. Int J Oral Surg 1974;3:1 – 6.
succinctly more than 50 years ago: ‘‘With the dis- [14] Happonen R-P, Backstrom A-C, Ylipaavalniemi P.
covery of penicillin, its allied agents, and their mass Prophylactic use of phenoxy-methylpenicillin and tini-
production, clinicians have employed them in differ- dazole in mandibular third molar surgery: a com-
ent forms and by various methods for almost every parative placebo controlled clinical trial. Br J Oral
illness in the category of medicine. The urge to Maxillofac Surg 1990;28:12 – 5.
160 D.M. Laskin / Oral Maxillofacial Surg Clin N Am 15 (2003) 155–160

[15] Thomas DW, Hill CM. An audit of antibiotic prescrib- [29] Zallen RD, Curry JT. A study of antibiotic usage in
ing in third molar surgery. Br J Oral Maxillofac Surg compound mandibular fractures. J Oral Surg 1975;33:
1997;35:126 – 8. 431 – 4.
[16] Indresano AT, Haug RH, Hoffman MJ. The third molar [30] Abubaker AO, Rollert MA. Postoperative antibiotic
as a cause of deep space infections. J Oral Maxillofac prophylaxis in mandibular fractures: a preliminary
Surg 1992;50:33 – 5. randomized, double-blind, and placebo-controlled clin-
[17] MacGregor AJ. Reduction in morbidity in the surgery ical study. J Oral Maxillofac Surg 2001;59:1415 – 9.
of the third molar removal. Dent Update 1990;17: [31] Eschelman LT, Schleuning AJ, Brummett RE. Prophy-
411 – 4. lactic antibiotics in otolaryngologic surgery: a double-
[18] Larsen P, McGlumphy E. Antibiotic prophylaxis for blind study. Transactions of American Academy Op-
placement of dental implants. J Oral Maxillofac Surg thalmology and Otolaryngology 1971;75:387 – 94.
1993;51:194. [32] Zallen RD, Black SL. Antibiotic therapy in oral and
[19] Peterson L, McGlumphy E, Halikas L. Long-term anti- maxillofacial surgery. J Oral Surg 1976;34:349 – 51.
biotic prophylaxis is not necessary for placement of [33] Paterson JA, Cordo Jr VA, Stratigas GT. An examina-
dental implants. J Oral Maxillofac Surg 1996;54:76. tion of antibiotic prophylaxis in oral and maxillofacial
[20] Gynther G, Kondell P, Moberg L, et al. Dental implant surgery. J Oral Maxillofac Surg 1970;28:753 – 9.
installation without antibiotic prophylaxis. Oral Surg [34] Dellinger ED. Antibiotic use. In: Trunkey DD, Lewis
Oral Med Oral Pathol Oral Radiol Endod 1998;85: Jr FR, editors. Current therapy of trauma. 3rd edition.
509 – 22. St. Louis: Mosby; 1991. p. 47.
[21] Dent CD, Olson JW, Farish SE, et al. Influence of [35] Conover M, Kaban LB, Mulliken JB. Antibiotic pro-
preoperative antibiotics on success of endosseous im- phylaxis for major maxillocraniofacial surgery. J Oral
plants up to and including Stage 2 surgery: a study Maxillofac Surg 1985;43:865 – 70.
of 2,641 implants. J Oral Maxillofac Surg 1997;55: [36] Fee Jr WE, Glenn M, Handen C, et al. One day versus
19 – 24. 2 days of prophylactic antibiotics in patients under-
[22] Laskin DM, Dent CD, Morris HF, et al. The influence going major head and neck surgery. Laryngoscope
of preoperative antibiotics on success of endosseous 1984;94:612 – 4.
implants at 36 months. Ann Periodontol 2000;5: [37] Johnson JT, Myers EN, Thearle PB, et al. Antibiotic
166 – 74. prophylaxis for contaminated head and neck surgery.
[23] Zallen RD, Strader RJ. The use of prophylactic anti- Laryngoscope 1984;94:46 – 51.
biotics in extraoral procedures for mandibular prog- [38] Johnson JT, Schuller DE, Silver E, et al. Antibiotic
nathism. J Oral Surg 1971;29:178 – 9. prophylaxis in high-risk head and neck surgery: one-
[24] Abubaker AO. Antibiotic prophylaxis in orthognathic day vs five-day therapy. Otolaryngol Head Neck Surg
surgery: a 1-day versus 5-day regimen [discussion]. 1986;95:554 – 7.
J Oral Maxillofac Surg 1999;57:230 – 2. [39] Mombelli G, Coppens I, Dor P, et al. Antibiotic pro-
[25] Ruggles JE, Hann JR. Antibiotic prophylaxis in intrao- phylaxis in surgery for head and neck cancer: com-
ral orthognathic surgery. J Oral Maxillofac Surg parative study of short and prolonged administration
1984;42:797 – 801. of carbenicillin. J Antimicrob Chemother 1987;7:
[26] Fridrich KL, Partnoy BE, Zeitler DL. Prospective anal- 667 – 71.
ysis of antibiotic prophylaxis for orthognathic surgery. [40] Shapiro M. Prophylaxis in otolaryngologic surgery
Int J Adult Orthod Orthognath Surg 1994;9:129 – 31. and neurosurgery: a critical review. Rev Infect Dis
[27] Bentley KC, Head TW, Aiello GA. Antibiotic prophy- 1991;13(Suppl 10):S858 – 68.
laxis in orthognathic surgery: a 1-day versus 5-day regi- [41] Burkett HG, Quick RG, Gott DT. Essential surgery:
men. J Oral Maxillofac Surg 1999;57:226 – 30. problems, diagnosis and management. 2nd edition. Ed-
[28] Chole RA, Yee J. Antibiotic prophylaxis for facial inburgh: Churchill-Livingstone; 1998. p. 70.
fractures: a prospective, randomized clinical trial. Arch [42] Furstenburg AC. Antibiotics in the treatment of disease
Otolaryngol Head Neck Surg 1987;113:1055 – 6. of the ear, nose, and throat. Ann Otol 1949;58:5 – 17.
Oral Maxillofacial Surg Clin N Am 15 (2003) 161 – 165

Index
Note: Page numbers of article titles are in boldface type.

A
Abscesses, retropharyngeal, versus cellulitis, imaging Bisphosphonates, for diffuse sclerosing osteomyelitis,
of, 47 of jaws, 76
Actinomycosis, cervicofacial. See Cervicofacial acti- Bite wounds, management of, 145 – 147
nomycosis.
Bone penetration, by antibiotics, 21
Acyclovir, for viral infections, due to laser-assisted
skin resurfacing, 155
AIDS. See also HIV infection; Immunocompro- C
mised patients.
Candidal infections, laser-assisted skin resurfacing
and oropharyngeal candidiasis, 93 – 94
and, 155
immune defects in, 107
oropharyngeal. See Oropharyngeal candidiasis.
Airway management, in head and neck
Cellulitis, versus retropharyngeal abscesses, imaging
infections, 107
of, 47
Alcoholism, immune defects in, 106
Cerebrospinal fluid penetration, by antibiotics, 21, 23
Aminoglycosides, for head and neck infections, 26
Cervicofacial actinomycosis, 51 – 58
Amoxicillin, for head and neck infections, 23 clinical features of, 55 – 56
Amphotericin B, for oropharyngeal candidiasis, diagnosis of, 56 – 57
97 – 99 histopathology of, 54 – 55
historical aspects of, 53
Antibiotics, for bite wounds, 146 – 147 management of, 57 – 58
for head and neck infections. See Head and medicolegal considerations in, 58
neck infections. microbiology of, 54
for infections due to laser-assisted skin resurfac- natural history of, 54
ing, 154, 156
for peri-implantitis, 135 Chemotherapy, and oropharyngeal candidiasis, 93
for post-traumatic soft tissue infections, Clotrimazole, for oropharyngeal candidiasis, 97, 98
143 – 144, 145
to prevent maxillofacial infections. See Maxillo- Computed tomography, of maxillofacial infections.
facial infections. See Maxillofacial infections.

Antiseptic agents, for oropharyngeal candidiasis, 97 Condyloma acuminatum, dental issues in, 86 – 87

Avelox, for head and neck infections, 33034 Corticosteroids, for recurrent aphthous stomatitis. See
Recurrent aphthous stomatitis.
Azoles, for oropharyngeal candidiasis, 97, 98
Cutaneous maxillofacial infections, microbiology of,
11 – 12

B Cytochrome P450 system, and antibiotic


Bacterial infections, laser-assisted skin resurfacing metabolism, 27
and, 152 – 154 Cytomegalovirus, dental issues in, 84 – 85

1042-3699/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.
PII: S1042-3699(02)00097-3
162 Index / Oral Maxillofacial Surg Clin N Am 15 (2003) 161–165

D G
Deep neck infections, recurrent, imaging of, 47 Gemifloxacin, for head and neck infections, 33034
Dental implant surgery, prophylactic antibiotics in, Guided bone regeneration, for peri-implantitis,
161 – 162 135 – 137
Dentoalveolar surgery, prophylactic antibiotics
in, 161 H
Denture wearers, oropharyngeal candidiasis in, 94, 95 Head and neck, necrotizing fasciitis of. See
Necrotizing fasciitis.
Diabetes mellitus, and oropharyngeal candidiasis, 93
Head and neck cancer, and oropharyngeal
immune defects in, 105 – 106
candidiasis, 93
Diffuse sclerosing osteomyelitis, of jaws, 69 – 78
Head and neck infections. See also
case report of, 77 – 78
Maxillofacial infections.
clinical features of, 72
antibiotics for, 17 – 38
differential diagnosis of, 71
fluoroquinolones, 33 – 34
etiology of, 71
for fungal infections, 36 – 37
histology of, 73
for odontogenic infections, 35 – 36
imaging of, 72 – 73
for osteomyelitis of jaw, 36
laboratory tests for, 73 – 74
for sinus infections, 36
management of, 75 – 77
ketolides, 34 – 35
microbiology of, 74 – 75
oxazolidinones, 34
pathogenesis of, 71
pristinamycins, 35
Disodium clodrenate, for diffuse sclerosing osteo- resistance to, mechanisms of, 18
myelitis, of jaws, 76 molecular biology of, 17
prevention of, 18 – 19
selection of, adverse reactions in, 26
allergy or intolerance in, 19 – 20
E antimicrobial spectrum in, 21
cost in, 27, 30, 33
Enterocolitis, periodontal surgery and, 127
drug interactions in, 26 – 27
Enteroviruses, dental issues in, 87 – 88 for usual pathogens, 19
in children, 26
Epstein-Barr viruses, dental issues in, 83 – 84
in immunocompromised patients, 20 – 21
Exodontia, prophylactic antibiotics in, 161 in pregnancy, 26
pharmacokinetics in, 23, 26
previous antibiotic therapy and, 21
tissue distribution in, 21, 23
prevention of, antibiotics in, 163
F
Facial bone fractures, antibiotics for, 162 – 163 Hepatitis C virus infections, dental issues in, 88
Fluconazole, for candidal infections, due to laser- Herpes simplex virus infections, dental issues in,
assisted skin resurfacing, 155 82 – 83
for oropharyngeal candidiasis, 97 laser-assisted skin resurfacing and, 154 – 155
maxillofacial, microbiology of, 12
Fluoroquinolones, for head and neck
infections, 33034 Herpesvirus infections, dental issues in, 82 – 83,
85 – 86
Fractures, facial bone, antibiotics for, 162 – 163
mandibular, antibiotics for, 162 HIV infection. See also AIDS;
Immunocompromised patients.
Frontal sinusitis, microbiology of, 10 – 11 and oropharyngeal candidiasis, 93
Fungal infections, laser-assisted skin resurfacing dental issues in, 81 – 82
and, 155 head and neck infections with, antibiotics for, 20
of head and neck, antibiotics for, 36 – 37 immune defects in, 106 – 107
Index / Oral Maxillofacial Surg Clin N Am 15 (2003) 161–165 163

Human papillomavirus, dental issues in, 86 – 87 Laser-assisted skin resurfacing, and infections,
147 – 153
Hyposalivation, and oropharyngeal candidiasis, 94
bacterial, 148 – 152
candidal, 152
fungal, 152
I prevention of, 151 – 152
Immunocompromised patients. See also AIDS; versus normal skin healing, 150
HIV infection. versus normal skin microbiology, 150
head and neck infections in, 103 – 110 viral, 152 – 153
AIDS patients, 107 Leukoplakia, dental issues in, 83 – 84
airway management in, 107 oropharyngeal candidiasis and, 95
alcoholic patients, 106
antibiotics for, 20 – 21, 107 – 108 Lichen planus, oral, dental issues in, 88
diabetic patients, 105 – 106 Linezolid, for head and neck infections, 34
HIV-positive patients, 106 – 107
versus normal immune system, 103 – 105
Impacted third molar surgery, prophylactic antibiotics
in, 161 M
Magnetic resonance imaging, of maxillofacial
Infections, head and neck. See Head and
infections. See Maxillofacial infections.
neck infections.
laser-assisted skin resurfacing and. See Mandibular fractures, antibiotics for, 162
Laser-assisted skin resurfacing.
Maxillary sinusitis, microbiology of, 9 – 10
maxillofacial. See Maxillofacial infections.
periodontal. See Periodontal infections. Maxillofacial infections. See also Head and
post-traumatic soft tissue. See Post-traumatic soft neck infections.
tissue infections. imaging of, 39 – 49
computed tomography in, interpretation of, 44
Infectious rhinitis, microbiology of, 10
necrotizing fasciitis, 48 – 49
Itraconazole, for oropharyngeal candidiasis, 97 retropharyngeal abscess versus cellulitis, 47
septic thrombophlebitis, 47 – 48
sialadenitis, 48
sinusitis, 49
J technique for, 41 – 43
Jaws, diffuse sclerosing osteomyelitis of. See Diffuse magnetic resonance imaging in, interpretation
sclerosing osteomyelitis. of, 44 – 45
osteomyelitis of, antibiotics for, 36 sinusitis, 49
technique for, 43 – 44
microbiology of, 1 – 15
K acute maxillary sinusitis, 9 – 10
chronic maxillary sinusitis, 10
Kaposi’s sarcoma, dental issues in, 96
cutaneous infections, 11 – 12
Ketek, for head and neck infections, 34 – 35 frontal and sphenoid sinusitis, 10 – 110
herpes simplex infections, 12
Ketoconazole, for oropharyngeal candidiasis, 97
infectious rhinitis, 10
Ketolides, for head and neck infections, 34 – 35 odontogenic infections, 4 – 7
Koebner phenomenon, in recurrent aphthous antibiotic-resistant, 7
stomatitis, 114 culture and antibiotic sensitivity in, 4
isolates per patient in, 4
patient characteristics in, 4
polymicrobial, 4 – 6
L trauma-related, 7 – 9
b-Lactam antibiotics, for head and neck infections, prevention of, antibiotics in, 155 – 160
19 – 20 adjunctive procedures with, 158
164 Index / Oral Maxillofacial Surg Clin N Am 15 (2003) 161–165

administration of, 157 – 158 Nontuberculous mycobacterial infections,


choice of, 157 maxillofacial, imaging of, 47
for dental implants, 158 – 159
Nystatin, for oropharyngeal candidiasis, 96 – 97
for exodontia and dentoalveolar
surgery, 158
for facial bone fractures, 159 – 160 O
for impacted third molar surgery, 158
Odontogenic infections, antibiotics for, 35 – 36
for major head and neck surgery, 160
imaging of, 45, 47
for mandibular fractures, 159
microbiology of. See Maxillofacial infections.
for orthognathic surgery, 159
for post-traumatic soft tissue Oral contraceptives, failure of, antibiotics and, 27
infections, 160
Oral mucosa, disruption of, and oropharyngeal can-
principles of, 156
didiasis, 94
risk of, 156 – 157
versus normal microflora, 2 – 3 Oropharyngeal candidiasis, 91 – 102
cutaneous, 2 – 3 clinical features of, 94 – 95
nasal and paranasal, 3 diagnosis of, 95
oral, 3 management of, 95 – 99
viral, 79 – 89 amphotericin B in, 97 – 99
cytomegalovirus, 84 – 85 antiseptic agents in, 97
enteroviruses, 87 – 88 choice of, 95 – 96
Epstein-Barr viruses, 83 – 84 combination therapy in, 99
hepatitis C virus, 88 nystatin in, 96 – 97
herpes simplex, 82 – 83 polyene antifungal agents in, 96 – 99
herpesvirus 8, 86 resistance to, 98
herpesviruses 6 and 7, 85 susceptibility testing in, 95
HIV infection, 81 – 82 risk factors for, 92 – 94
human papillomavirus, 86 – 87 local and oral, 94
Kaposi’s sarcoma virus, 86 microbial, 93
varicella-zoster virus, 85 systemic, 93 – 94
systemic, 95
Miconazole, for oropharyngeal candidiasis, 97
Orthognathic surgery, prophylactic antibiotics in, 162
Mononucleosis, dental issues in, 83 – 84
Osteomyelitis, diffuse sclerosing. See Diffuse
Moxifloxacin, for head and neck infections, 33034
sclerosing osteomyelitis.
Mycobacterial infections, maxillofacial, imaging of jaw, antibiotics for, 36
of, 47
Oxazolidinones, for head and neck infections, 34

N
Nasal sinus infections, microbiology of. See P
Maxillofacial infections. Paranasal sinus infections, microbiology of. See
Maxillofacial infections.
Necrotizing fasciitis, of head and neck, 59 – 67
classification of, 63 Penicillins, for cervicofacial actinomycosis, 57
clinical features of, 65 for head and neck infections, 19, 36
diagnosis of, 65 – 66 cerebrospinal fluid penetration by, 21, 23
historical aspects of, 61 – 63 pharmacokinetics of, 23
imaging of, 48 – 49 Peri-implantitis, 129 – 138
management of, 66 – 67
diagnosis of, 132 – 134
results of, 67 – 68
implant salvage in, 134 – 137
microbiology of, 63
antibiotics in, 135
pathogenesis of, 63 – 65
guided bone regeneration in, 135 – 137
NewTom imaging, of maxillofacial infections, 43 microbiology of, 129 – 130
Index / Oral Maxillofacial Surg Clin N Am 15 (2003) 161–165 165

retrograde, 132 Retropharyngeal abscesses, versus cellulitis, imaging


titanium implants and, 130 – 131 of, 47
hydroxyapatite-coated, 131 – 132 Rhinitis, infectious, microbiology of, 10
Periodontal infections, 123 – 128
diagnosis of, 124 – 125
in adults, 124 – 125
S
in children, 124 Salivary gland function, impaired, and oropharyngeal
management of, 125 – 128 candidiasis, 94
complications of, 127 Septic thrombophlebitis, maxillofacial, imaging of,
Plain films, of peri-implantitis, 133 47 – 48
Sialadenitis, imaging of, 48
Polyene antifungal agents, for oropharyngeal
candidiasis, 96 – 99 Sinusitis, antibiotics for, 36
Post-traumatic soft tissue infections, 139 – 146 imaging of, 49
microbiology of. See Maxillofacial infections.
antibiotics for, 143 – 144, 145, 163
bite wounds and, 145 – 147 Skin resurfacing, laser-assisted. See Laser-assisted
antibiotics for, 146 – 147 skin resurfacing.
débridement of, 143, 145 Soft tissue infections, post-traumatic. See
postoperative care for, 143 – 144 Post-traumatic soft tissue infections.
prevention of, 142 – 143
risk factors for, 142 Sphenoid sinusitis, microbiology of, 10 – 11
wound closure in, 143, 145 Squamous cell carcinoma, oral, dental issues in, 87
wounding mechanism in, 141 – 142 Synercid, for head and neck infections, 35
Pregnancy, head and neck infections in, antibiotics
for, 26
T
Pristinamycins, for head and neck infections, 35 Telithromycin, for head and neck infections, 34 – 35
Tetracycline, for peri-implantitis, 135

Q Thalidomide, for recurrent aphthous stomatitis, 120


Quinupristin/dalfopristin, for head and neck Third molar surgery, prophylactic antibiotics in, 161
infections, 35 Thrombophlebitis, septic, maxillofacial, imaging of,
47 – 48
Titanium implants, hydroxyapatite-coated, success
R and failure of, 131 – 132
Recurrent aphthous stomatitis, 111 – 122 success and failure of, 130 – 131
clinical features of, 114 – 116 Trauma, maxillofacial, and infections, 7 – 9
etiology of, 111
genetic factors in, 112 Tuberculous infections, maxillofacial, imaging of, 47
histopathology of, 116
immunologic factors in, 112 – 113
management of, 116 – 120 V
burst therapy in, 119 – 120 Varicella-zoster virus, dental issues in, 85
corticosteroid injections in, 119 Verruca vulgaris, dental issues in, 87
corticosteroid rinses in, 118 – 119
Verrucous leukoplakia, dental issues in, 87
corticosteroid syrup in, 119 – 120
objectives, principles, and caveats of, 117 Viral infections, laser-assisted skin resurfacing and,
thalidomide in, 120 154 – 155
topical corticosteroids in, 118 – 119
microbiology of, 113
nutritional factors in, 113 – 114 Z
pathogenesis of, 111 – 112 Zyvox, for head and neck infections, 34