Hai Proceedings of Hai Summit Clin Infect Dis.-2008-Kollef-s55-99

SUPPLEMENT ARTICLE
Health CareAssociated Infection (HAI): A Critical

Appraisal of the Emerging ThreatProceedings of
the HAI Summit
Marin H. Kollef,1,2 Lena M. Napolitano,3 Joseph S. Solomkin,4 Richard G. Wunderink,5 In-Gyu Bae,7
Vance G. Fowler,7 Robert A. Balk,6 Dennis L. Stevens,8 James J. Rahal,9,10 Andrew F. Shorr,11,12 Peter K. Linden,13
and Scott T. Micek1,2
1
Washington University School of Medicine and 2Barnes-Jewish Hospital, St. Louis, Missouri; 3University of Michigan Health Center, Ann Arbor;
University of Cincinnati College of Medicine, Cincinnati, Ohio; 5Feinberg School of Medicine, Northwestern University, and 6Rush University
Medical Center and Rush Medical College, Chicago, Illinois; 7Duke University Medical Center, Durham, North Carolina; 8Veterans Affairs Medical
Center, Boise, Idaho; 9New York Hospital Queens, Flushing, and 10Weill Medical College of Cornell University, New York, New York; 11Washington
Hospital Center and 12Georgetown University, Washington, DC; and 13University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
4
The classification of bacterial infections is in a state of

flux. Most of the prior classification schemes have segregated these infections according to the site of infection (e.g., lung, urinary tract, soft tissue and skin, and
intra-abdominal) and the location of the patient at the
time the infection developed. The latter has historically
been divided into community-acquired and nosocomial
(hospital-acquired) infections [1, 2]. Unfortunately,
this simple classification scheme is no longer adequate,
because of changing patient demographics and risk
profiles for infection with potentially antibiotic-resistant bacteria, which historically have been encountered
primarily in the hospital setting.
Patients with serious infections (e.g., pneumonia,
bacteremia, and septic shock) should be given treatment initially with antibiotics active against the bacterial pathogens causing the infection (i.e., appropriate
antibiotic therapy). Additionally, appropriate antibiotic
Reprints or correspondence: Dr. Marin H. Kollef, Div. of Pulmonary and Critical

Care Medicine, Washington University School of Medicine, 660 S. Euclid Ave.,
Campus Box 8052, St. Louis, MO 63110 (mkollef@im.wustl.edu).
Clinical Infectious Diseases 2008; 47:S5599
2008 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2008/4707S2-0002$15.00
DOI: 10.1086/590937
therapy should be administered in a timely manner to

optimize the likelihood of a clinical response. The support for these recommendations comes from investigations demonstrating that patients initially given treatment with antibiotic regimens that are not active against
the causative bacterial species (i.e., inappropriate antibiotic therapy) have a greater risk for in-hospital mortality than do patients receiving appropriate therapy [3
5]. Classification schemes should assist clinicians in
identifying patients at risk for antibiotic-resistant infections, thereby requiring initial treatment with broadspectrum antimicrobials. The recognition of potentially
antibiotic-resistant infections occurring outside the
hospital setting has resulted in the formulation of the
new category, termed health careassociated infections (HAIs). Implicit in the definition of HAIs is that
patients will require initial therapy with more broadspectrum antibiotics, compared with patients with
community-acquired infections.
HAIs have been defined using various criteria (table
1). Friedman et al. [6] evaluated patients admitted to
the hospital with bloodstream infections (BSIs) and
showed that individuals with HAI risk factors were statistically more likely than were patients with community-acquired infections to be infected with antiHAI Summit Critical Appraisal CID 2008:47 (Suppl 2) S55
Downloaded from http://cid.oxfordjournals.org/ by guest on March 24, 2012
During the Health CareAssociated Pneumonia Summit conducted in June 2007, it was found that there is a
need for educational efforts in several areas of health careassociated infections (HAI) that extend beyond
pneumonia. This supplement to Clinical Infectious Diseases represents the proceedings of the HAI Summit,
a diverse panel of clinical investigators whose goal was to assess the quality of evidence regarding issues
surrounding HAI and to discuss potential implications for its diagnosis and treatment in the future.
Table 1. Risk factors used to define health careassociated

infections.
Infection type [source] and criteria
NOTE. Adapted from [6], from [7], and from [8]. BSI, bloodstream infection;
HCAP, health careassociated pneumonia; VAP, ventilator-associated pneumonia.
biotic-resistant bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and antibiotic-resistant enterococci. In
an accompanying overview, the importance of the classification
of HAIs was emphasized in terms of identifying a group of
patients who would potentially benefit from initial treatment with
broad-spectrum antibiotics [9]. Similarly, Kollef et al. [7] examined 4543 patients with microbiologically confirmed pneumonia from a multicenter administrative database. They separated patients into 4 categories: community-acquired pneumonia
(CAP), health careassociated pneumonia (HCAP), hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia
(VAP). Patients with HCAP had underlying comorbidities and
bacterial pathogens similar to those of patients with HAP and
S56 CID 2008:47 (Suppl 2) Kollef et al.
Bacteremia [6]
Health careassociated BSI was defined by a positive culture result for a blood specimen obtained from a patient at the
time of hospital admission or within 48 h after admission
if the patient fulfilled any of the following criteria:
1. Received intravenous therapy at home; received wound
care or specialized nursing care through a health care
agency, family, or friends; or had self-administered intravenous medical therapy in the 30 days before the BSI. Patients whose only home therapy was oxygen use were
excluded.
2. Attended a hospital or hemodialysis clinic or received intravenous chemotherapy in the 30 days before the BSI
3. Was hospitalized in an acute care hospital for 2 days in
the 90 days before the BSI
4. Resided in a nursing home or long-term-care facility
Pneumonia [7]
HCAP was defined as a diagnosis of pneumonia in patients with
a first positive bacterial respiratory culture finding within
2 days of admission and any of the following:
1. Admission source indicates a transfer from another health
care facility
2. Receiving long-term hemodialysis
3. Prior hospitalization within 30 days for those whose condition does not meet VAP definition
Pneumonia [8]
HCAP was defined as a diagnosis of pneumonia in patients admitted to the hospital who met at least 1 of the following
criteria:
1. Admission from a nursing home, rehabilitation hospital, or
other long-termnursing care facility
2. Previous hospitalization within the immediately preceding
12 months
3. Receiving outpatient hemodialysis, peritoneal dialysis, or infusion therapy necessitating regular visits to a hospitalbased clinic
4. Having an immunocompromised state
VAP. The most common bacterial pathogen isolated in patients

with HCAP was MRSA. The in-hospital mortality rate among
patients with HCAP was similar to that observed among patients
with HAP (19.8% vs. 18.1%; P .005), both being almost twice
the mortality rate observed among patients with CAP (10%;
P ! .001 for both comparisons) [7].
The American Thoracic Society (ATS) and Infectious Diseases
Society of America (IDSA) guidelines for HCAP, HAP, and VAP
have summarized potential risk factors for HAIs (table 1) [1, 2].
These are the first published guidelines to recognize the category
of HCAP in terms of recommending initial broad-spectrum antimicrobial treatment because of the high prevalence of antibiotic-resistant bacteria as the causative agents of infection. Further
support for this recommendation comes from a large singlecenter study evaluating patients with microbiologically confirmed
pneumonia admitted to an urban teaching hospital [8]. Among
the 639 patients with microbiologically confirmed pneumonia
evaluated in that study, HCAP made up 67.4% of the pneumonia
cases, and CAP accounted for 32.6%. Patients with HCAP were
statistically more likely to be infected with MRSA, Pseudomonas
aeruginosa, and other nonfermenting gram-negative rods, compared with patients with CAP. Patients with HCAP were also
significantly more likely to have received inappropriate initial
antimicrobial therapy (28.3% vs. 13.0%; P ! .001) and had
greater in-hospital mortality (24.6% vs. 9.1%; P ! .001), compared with patients with CAP.
The importance of correctly classifying patients with HAI risk
profiles is demonstrated by 2 recent studies. Schramm et al. [5]
evaluated patients with MRSA sterile-site infections and showed
that patients with a positive sterile-site culture specimen obtained
during the first 48 h of hospitalization were significantly less
likely to have received empirical treatment for MRSA. This occurred despite the fact that most patients had readily identifiable
risk factors for HAI, which suggests that the treating clinicians
did not recognize either the presence of these risk factors or the
associated therapeutic implications. In a prospective before-after
study using a protocol and standardized order set for the management of septic shock in the emergency department, a statistically significant reduction (from 48.3% to 30%; P p .04) in
28-day mortality was associated with the prescription of broadspectrum antibiotics to patients with risk factors for HAI [10].
These studies suggest that many patients evaluated during the
early periods of their hospitalization may benefit from having
their infection identified as an HAI, so that more-appropriate
initial antibiotic therapy can be prescribed.
During the HCAP Summit conducted in June 2007, it was
found that there is a need for educational efforts in several
areas of HAI that extend beyond pneumonia. This supplement
to Clinical Infectious Diseases represents the proceedings of a
diverse panel of clinical investigators whose goal was to assess
the quality of evidence in support of the clinical classification
Table 2. Health CareAssociated Infection (HAI) Summit clinical practice statements.

Workshop 1: Treatment by Sites of Infection (statements 15)
1. Patients at risk for health careassociated complicated skin
and soft tissue infections are more likely to have both resistant gram-negative and gram-positive pathogens. (L.M.N.)
2. Patients with health careassociated intra-abdominal infections should receive dual empiric therapy for resistant gramnegative and gram-positive pathogens. (J.S.S.)
3. Early aggressive, appropriate empiric treatment and de-escalation for HCAP reduces mortality and minimizes resistance.
(R.G.W.)
4. Health careassociated BSIs require empiric coverage for
MDR gram-negative bacteria and MRSA, as well as coverage
for fungal pathogens in patients with specific risk factors.
(V.G.F.)
5. Initial appropriate antimicrobial therapy and source control are
the most important determinants of outcome in severe sepsis
and septic shock. (R.A.B.)
NOTE. BSI, bloodstream infection; HCAP, health careassociated pneumonia; MDR, multidrug resistant; MRSA, methicillin-resistant Staphylococcus
aureus.
Table 3. Workshop and Health CareAssociated Infection Summit panel voting schemes.
Category
I
of HAI as a distinct entity and the need for specific therapeutic

interventions for HAI. Ten clinical practice statements were
drafted by the chair (M.H.K.) and the 2 workshop leaders
(L.M.N. and D.L.S.) and were subsequently evaluated by an
11-member panel with expertise in infectious diseases, surgery,
critical care, pharmacology, and outcomes research (table 2).
Before the summit was convened, each participant was assigned
a statement and was instructed to systematically review and
summarize the evidence supporting or refuting that statement.
In the first phase of the live meeting, the simultaneously
conducted workshops Treatment by Sites of Infection and
Treatment by Organism included a leader and 4 or 5 content
experts and served as a forum for each individual to present
the evidence for his or her assigned statement. When the data
were presented, primary attention was given to the study methodology, the number of patients enrolled, and the outcome
events. After the presentation of data for each statement, workshop members discussed the evidence, graded the strength of
the evidence, and assigned the statement a consensus numeric
grade through a voting process (table 3).
In the second phase of the live meeting, all summit panelists
II
III
Nature of evidence
Evidence obtained from at least 1 well-designed,
randomized, controlled trial
Evidence obtained from well-designed cohort or
case-control studies
IV
Evidence obtained from case series, case reports,

or flawed clinical trials
Opinions of respected authorities based on clinical experience, descriptive studies, or reports
of expert committees
Insufficient evidence to form an opinion

Level of workshop support for statement
A
B
C
There is good evidence to support the statement

There is fair evidence to support the statement
There is poor evidence to support the statement,
but recommendations may be made on other
grounds
There is fair evidence to reject the statement
There is good evidence to reject the statement
1
2
Accept recommendation completely

Accept recommendation with some reservations
3
4
5
Accept recommendation with major reservations

Reject recommendation with reservations
Reject recommendation completely
Individual level of support
HAI Summit Critical Appraisal CID 2008:47 (Suppl 2) S57
Workshop 2: Treatment by Organism (statements 610)

6. Vancomycin is obsolete for treating MRSA infections. (D.L.S.)
7. Serious HAIs due to suspected gram-negative bacteria should
be treated empirically with dual coverage that includes an
aminoglycoside. (J.J.R.)
8. Patients with serious HAIs who have risk factors for fungal
infections require early empiric antifungal therapy to reduce
mortality. (A.F.S.)
9. All infections in immunocompromised patients should be considered HAIs until proven otherwise. (P.K.L.)
10. Adjunctive therapy should be utilized to prevent and treat
serious HAIs. (S.T.M.)
reconvened as a single group, reviewed the workshop summaries, and discussed each statement further. After each discussion, all participants voted on their individual levels of support, using the grading scheme shown in table 3. In addition
to defining the level of evidence available for each statement,
the panel members also outlined additional data required to
further refine the statements for future clinical uses.
Before the summit meeting, clinical perspectives of practicing physicians were measured via a Web-based survey. Email polling was done to ascertain their level of support for
the same 10 statements. The e-mail invitation to participate
in the electronic survey was sent to 3300 members of the
IDSA (all active e-mail addresses). Of the IDSA members
surveyed, 744 (23%) responded. The purpose of the electronic
surveys was to provide information that would allow for the
comparison of data-driven responses from the content experts at the summit with those from clinicians practicing in
the field. The summit participants and the surveyed physicians
used the same voting scheme for Individual Level of Support to grade the 10 statements (table 3).
This exercise was performed to determine the prevailing current opinions regarding HAIs and areas where additional research and knowledge is required. In this era of increasing
antimicrobial resistance, clinical decision making regarding the
management of suspected bacterial infections has become increasingly complex. Given factors such as the aging of our
population, the increasing use of immunomodulating therapies,
and the practice of caring for patients with more-complicated
cases outside of the hospital setting, it is very likely that the
prevalence of HAIs will increase. Research to better define this
category of infection and its management appears to be very
relevant.
STATEMENT 1: PATIENTS AT RISK FOR HEALTH
CAREASSOCIATED COMPLICATED SKIN AND
SOFT-TISSUE INFECTIONS ARE MORE LIKELY
TO HAVE BOTH RESISTANT GRAM-NEGATIVE
AND GRAM-POSITIVE PATHOGENS
Rationale and Definition of Statement
A PubMed database search to identify studies related to the

clinical and microbiological features of health careassociated
cSSTIs was completed on 4 September 2007. The search term
skin infections yielded a total of 78,866 articles. The search
term complicated skin and skin structure infection (cSSSI)
yielded 244 articles, and the search term complicated skin and
soft tissue infection (cSSTI) yielded 100 articles. The search
terms health care associated, healthcare associated, and
healthcare-associated yielded 51,504, 38,460, and 288 articles,
respectively. Combining the search terms health care associated, healthcare associated, and healthcare-associated with
infection, using the AND function, produced 5154, 3759,
and 250 articles, respectively. Combining the search terms
health care associated, healthcare associated, and healthcare-associated with skin infections, using the AND function, produced 138, 109, and 5 articles, respectively. After limiting these articles to the English language, a total of 147 articles
were reviewed, and 2 articles were deemed relevant to the
statement.
Evidence
Prevalence of health careassociated cSSTI. No studies were

identified as specifically focusing on the prevalence of health
careassociated cSSTI. One study specifically addressed the issue of overall prevalence of HAIs in general and included a
cohort of patients with skin infections. This study involved a
cross-sectional population survey of patients, aged 19 years,
admitted to 25 acute-care hospitals participating in the Canadian Nosocomial Infection Surveillance Program, to determine the prevalence of HAIs. A 1-day HAI point-prevalence
survey was conducted in February 2002. Adult patients who
had been admitted at least 48 h before the day of the survey
were identified, and the primary outcome was the presence of
an HAI, which was identified as an infection not present at
admission and with onset at least 72 h after admission. Some
would consider these nosocomial infections. The study was
limited to the following infections: pneumonia, urinary-tract
infection, BSI, surgical-site infection, and Clostridium difficile
infection. Centers for Disease Control and Prevention (CDC)
definitions were used for all HAIs. A total of 5750 adults were
surveyed, 2086 (36%) of whom were receiving at least 1 systemic antimicrobial agent; 601 patients had 667 HAIs, giving
a prevalence of 10.5% for infection and 11.6% for HAI. The
only skin infection reported was surgical-site infection, which
was identified in 146 patients (2.5%). In the multivariate logistic
regression model for HAI, the following characteristics were all
independently associated with HAI: extended hospital stays of
17 days before the day of the survey, having a central venous
Presently, there is no standard definition for health careassociated complicated skin and soft-tissue infection (cSSTI). The
terminology of HAIs was first devised as a new classification
scheme for BSIs to distinguish patients with community-acquired, health careassociated, and nosocomial infections [6].
Skin and soft-tissue infections (SSTIs) have traditionally been
categorized as either uncomplicated or complicated infections,
by use of the US Food and Drug Administration (FDA) criteria
[11]. Uncomplicated skin infections include simple abscesses,
impetiginous lesions, furuncles, and cellulitis. Complicated skin
infections include deeper soft-tissue infections or those requiring significant surgical intervention, such as infected ulcers,
burns, and major abscesses or a significant underlying disease
state that complicates the response to treatment. Superficial
infections or abscesses in an anatomical site, such as the rectal
area, where the risk of anaerobic or gram-negative pathogen
involvement is higher, should be considered complicated
infections.
The microbiology of uncomplicated and complicated skin
infections is not the same. In uncomplicated skin infections,
S. aureus and Streptococcus pyogenes are the 2 most commonly
seen pathogens. Among complicated skin infections, the possible pathogens are numerous, may be monomicrobial or polymicrobial, and are dependent on the clinical situation, the
location of the infection, and the medical history of the individual patient.
Because no standard definition for health careassociated
cSSTI is available, we will review data regarding HAIs in general
and the changing epidemiology of cSSTIs. This section aims to
assess the strength of evidence supporting the assertion that
patients at risk for health careassociated cSSTI are more likely
to be infected with both resistant gram-negative and grampositive pathogens.
Methods
(typical of community-associated MRSA). Among predictor variables independently associated with MRSA infection, the strongest was presence of furunculosis (OR, 28.6). In this urban population, MRSA was the leading pathogen in SSTIs [16].
The CDC and 3 sites participating in the Emerging Infections
Program began a specialized, prospective MRSA surveillance
project in 2001 using the Active Bacterial Core Surveillance
program, a population-based surveillance component of the
Emerging Infections Program Network designed to study the
epidemiologic features of invasive bacterial disease and to track
drug resistance in the United States. The MRSA Active Bacterial
Core Surveillance project monitored all MRSA isolates from all
body sites from patients in select hospitals in Baltimore, Atlanta,
and Minnesota. From 2001 through 2002, 1647 cases of community-acquired MRSA infections were reported, and 77% involved skin and soft tissue. Overall, 23% of patients were hospitalized for the MRSA infection. This study concluded that
community-associated MRSA skin infections were now a common problem [17].
A prospective multicenter study confirmed this finding.
Adult patients with acute, purulent SSTIs presenting to 11 university-affiliated emergency departments during the month of
August 2004 were enrolled to determine the causative bacterial
isolates. S. aureus was isolated from 320 (76%) of 422 patients
with SSTIs. The prevalence of MRSA was 59% overall, and USA
300 isolates accounted for 97% of MRSA isolates; SCC mec
type IV and the Panton-Valentine leukocidin toxin gene were
detected in 98% of MRSA isolates, consistent with communityassociated MRSA infection. Methicillin-susceptible S. aureus
(MSSA) was identified in only 17% of patients with SSTIs. In
this study, MRSA was the most common identifiable cause of
SSTIs among patients presenting to emergency departments in
11 US cities [18].
None of these studies specifically differentiate between the
epidemiologic characteristics of community-associated (i.e.,
with no established risk factors) versus health careassociated
(i.e., with health careassociated risk factors) SSTIs. They do,
however, address the issue of differences in the microbiological
characteristics between the community-associated and health
careassociated MRSA isolates (table 4) [19].
An active, prospective, laboratory surveillance study conducted at a 1000-bed urban hospital and its affiliated outpatient
clinics in Atlanta, Georgia, identified S. aureus that was recovered from SSTIs in 384 persons and 389 episodes of infection,
with MRSA accounting for 72% (279 of 389 episodes). Among
all S. aureus isolates, 63% (244 of 389 isolates) were community-acquired MRSA. Among MRSA isolates, 87% (244 of 279
isolates) were community-acquired MRSA, and 99% were USA
300 clones. Factors independently associated with communityacquired MRSA infection were black race (prevalence ratio,
catheter, having an indwelling urinary catheter, or having an

endotracheal tube with or without mechanical ventilation [12].
Epidemiology and microbiology of health careassociated
cSSTI. No studies were identified that specifically focused on
the microbiology of health careassociated cSSTI. However,
multiple studies reported the microbiology of SSTIs in hospitalized patients and patients presenting to the emergency
department.
The SENTRY Antimicrobial Surveillance Program, established in 1997 by the Jones Group/JMI laboratories and funded
by SmithKline Beecham, is designed to monitor antimicrobial
resistance among various pathogens around the globe [13]. The
SENTRY program recently reported data regarding causative
isolates from SSTIs from 3 continents during a 7-year period
(19982004) [14]. Each year, participating medical centers sent
50 consecutive pathogens from hospitalized patients that were
determined to be significant causes of pyogenic wound infections. The isolates were from an SSTI or surgical-site infection
and were either community acquired or nosocomial in origin.
The predominant pathogens included S. aureus (ranked first
in all geographic regions), P. aeruginosa, Escherichia coli, and
Enterococcus species. On the global scale, S. aureus was the most
frequently occurring pathogen from an SSTI, with MRSA being
the greatest resistance concern. Considerable variation in the
MRSA rate was noted between countries and continents, with
the overall rate highest in North America (35.9%), followed by
Latin America (29.4%) and Europe (22.8%). It was noted that
the rate of MRSA in North America increased from 26.2% of
isolates in 1998 to 47.4% of isolates in 2004. Gram-negative
isolates as causes of SSTIs were common, and, among nonEnterobacteriaceae gram-negative bacilli, P. aeruginosa had the
highest occurrence in SSTIs in all geographic regions.
Community-associated MRSA has increased markedly to become the greatest problem facing treatment of SSTIs in the
outpatient setting. A comparison of community-associated and
health careassociated MRSA infections was performed as a
prospective cohort study of patients with MRSA infection identified at 12 Minnesota laboratory facilities from 1 January
through 31 December 2000. Of 1100 MRSA infections, 131
(12%) were community associated, and 937 (85%) were health
care associated. SSTIs were more common among communityassociated cases (75%) than among health careassociated cases
(37%) (OR, 4.25; 95% CI, 2.975.90) [15].
A prospective, observational study examined patients with
SSTIs presenting to the emergency department in an urban public
hospital in Oakland, California. Among the 137 patients enrolled,
MRSA was present in 51% of infection-site cultures. Of 119 S.
aureus isolates (from infection site and nares), 89 (75%) were
MRSA, and almost all (99%) of the MRSA isolates possessed the
staphylococcal cassette chromosome (SCC) mec type IV allele
Table 4. Comparison of community-associated and health careassociated methicillin-resistant

Staphylococcus aureus (MRSA).
Characteristic
Community-associated MRSA
Health careassociated MRSA
Chloramphenicol
Clindamycin
Usually susceptible
Usually susceptible
Frequently resistant
Frequently resistant
Erythromycin
Fluoroquinolone
Usually resistant
Geographic variability
Usually resistant
Usually resistant
TMP-SMZ
SCC mec type
Usually susceptible
IV
Usually susceptible
II
Lineage
Toxin producing
USA 300, USA 400

More
USA 100, USA 200

Fewer
Common
Less frequent
Rare
More frequent
Susceptibility, drug
Panton-Valentine leukocidin producing

Health care exposure
NOTE. SCC, staphylococcal chromosome cassette; TMP-SMZ, trimethoprim-sulfamethoxazole. Adapted from [19].
common. Gram-negative isolates (only E. coli) were uncommon

and were isolated in only 59 patients [23].
Two large, multinational, double-blind, randomized, phase 3
clinical studies (ATLAS 1 and ATLAS 2) enrolled 1867 patients
with cSSTI, 719 of whom were infected with MRSA, and determined that televancin was not inferior to vancomycin. S. aureus
was the primary pathogen isolated in these studies, as it was in
the 2 prior phase 2 trials (FAST 1 and FAST 2) [2426].
A multicenter, global, randomized, double-blind trial compared ceftobiprole with vancomycin for patients (n p 784)
with cSSTI and confirmed the noninferiority of ceftobiprole,
and S. aureus was the primary causative isolate [27]. A second
cSSTI trial also included patients with diabetic foot infections,
and gram-negative pathogens were more common. Gram-positive pathogens were isolated from 79% of patients and MRSA
was the most common pathogen (42.4%). Gram-negative pathogens were isolated from 29% of patients, and E. coli (11.0%)
and Pseudomonas isolates (6.6%) were the most common [28].
All these studies confirm that the most common causative
pathogens in cSSTIs are aerobic gram-positive cocci, with S.
aureus and MRSA as the leading isolates.
Epidemiology and microbiology of surgical-site infections.
Surgical-site infections are also included in the cSSTI category.
In a report from the National Nosocomial Infections Surveillance System from 19862003, an analysis of 1410,000 bacterial
isolates associated with hospital-acquired infections (BSIs,
pneumonia, surgical-site infection, and urinary-tract infection)
in intensive care units (ICUs) were reported. For surgical-site
infections, the percentage of bacterial isolates that were gram
negative decreased during the study period (from 56.5% in
1986 to 33.8% in 2003). By the mid-1990s, gram-positive bacterial pathogens were more commonly reported as causative
isolates in surgical-site infections, with S. aureus as the leading
pathogen [9]. MRSA has emerged as the most common isolate
1.53; 95% CI, 1.162.02), female sex (prevalence ratio, 1.16;

95% CI, 1.021.32), and hospitalization within the previous 12
months (prevalence ratio, 0.80; 95% CI, 0.660.97). Inadequate
initial antibiotic therapy was statistically significantly more
common among those with community-acquired MRSA (65%)
than among those with MSSA (1%) SSTI. This study concluded
that the community-acquired MRSA USA 300 clone was the
predominant cause of community-onset S. aureus SSTIs, and
therefore empirical use of agents active against communityacquired MRSA is warranted for patients presenting with serious SSTIs. The study setting was a 1000-bed, urban hospital
and its affiliated outpatient clinics in Atlanta, Georgia [20].
Epidemiology and microbiology of cSSTI. Because no published data are available for health careassociated cSSTIs, we
reviewed recent studies that served as FDA registration trials
for antimicrobials used to treat cSSTI. In 2 randomized international trials involving 1092 patients with cSSTI, daptomycin
was compared with conventional antibiotics (penicillinase-resistant penicillin or vancomycin). S. aureus was the leading
causative pathogen, isolated in 70% of patients; MRSA accounted for only 10% of the S. aureus isolates. Streptococci
and enterococci were also common causative pathogens [21].
In another phase 3 cSSTI study, patients (n p 854) were
randomized to receive dalbavancin or linezolid. Baseline cultures yielded at least 1 gram-positive pathogen for 550 patients
(64%; the microbiological intent-to-treat population). Of these,
90% presented with a single gram-positive pathogen. S. aureus
was predominant (89% of all patients). Of the S. aureus isolates,
278 (57%) of 492 were MRSA. Overall, 51% of patients presented with cSSTI that involved MRSA [22].
Two phase 3, double-blind studies randomized hospitalized
adults with cSSTI to receive tigecycline or vancomycin-aztreonam (n p 1116). S. aureus, with a majority of isolates being
MSSA, was the leading pathogen, and streptococci were also
Figure 1. Voting comparison for statement 1 (Patients at risk for health careassociated complicated skin and soft tissue infections are more
likely to have both resistant gram-negative and gram-positive pathogens). IDSA refers to the members of the Infectious Diseases Society of America
who responded to a Web-based survey; Summit refers to the Health CareAssociated Infection Summit panel.
Grading of Evidence
On the basis of a review of the studies cited above, the workshop

members agreed that there was substantial evidence available
to reject this statement. In evaluating the nature of the evidence,
20% voted category I, 60% voted category II, and 20% voted
category III (table 3).
Level of Support
When voting on the individual level of support for this statement,

0% of the summit participants voted to accept the statement
completely, 18% voted to accept the statement with some reservations, 9% voted to accept the statement with major reservations, 45% voted to reject the statement with reservations, and
27% voted to reject the statement completely. In comparison, of
the 744 IDSA members who participated in the online survey,
32% voted to accept the statement completely, 42% voted to
accept the statement with some reservations, 11% voted to accept
the statement with major reservations, 12% voted to reject the
statement with reservations, and 3% voted to reject the statement
completely (figure 1).
Discussion
Presently, there is no true category or definition of health care

associated cSSTI, and no studies were identified in the published
literature. The traditional categories of SSTI include uncomplicated versus complicated (initially proposed by the FDA for the
conduct of clinical trials for SSTIs) and community acquired or
community onset versus hospital acquired or nosocomial.
The leading causative pathogen of SSTIs in both community
and hospitalized patients is MRSA. This has been confirmed
with an in-depth review of the recent registration trials for
cSSTIs that discusses the microbiology of new antimicrobials
(daptomycin, dalbavancin, telavancin, tigecycline, and ceftobiprole). S. aureus was the leading pathogen in all studies, with
rising rates of MRSA. The SENTRY Antimicrobial Surveillance
Program has documented that the rate of MRSA in SSTIs in
causing surgical-site infections in most institutions [29]. MRSA

surgical-site infections are associated with significantly increased mortality (OR, 3.4; P p .003 ), length of hospital stay,
and costs, compared with MSSA surgical-site infections [30].
Community-associated MRSA strains are increasingly recovered from hospital settings, and a recent retrospective review
of surgical-site infection in 20042005 in Alabama determined
that 57% of MRSA strains from surgical-site infections were of
the USA 300 genotype, confirming that community-associated
MRSA was a prominent cause of surgical-site infection at that
institution [31].
Epidemiology and microbiology of diabetic foot infection.
The bacteriology of diabetic foot infections was assessed in a
recent study of 371 patients (infected ulcer and cellulitis were
the most common types of infection). Overall, one-half of all
patients had only gram-positive cocci isolated (355 isolates).
Of these, S. aureus, coagulase-negative staphylococci, streptococci, and enterococci were the most common isolates. Gramnegative bacteria, predominantly Pseudomonas and Enterobacteriaceae species, were isolated in 105 patients, and 32% had
mixed infections with both gram-positive and gram-negative
pathogens [32]. In the SIDESTEP study (of ertapenem vs. piperacillin/tazobactam for treatment of diabetic foot infection;
n p 586), infections were polymicrobial in 47% of evaluable
patients, and 9% had both gram-positive and gram-negative
aerobic organisms isolated by culture. The most commonly
isolated pathogens were gram-positive aerobic cocci (257 isolates), with S. aureus as the leading isolate, followed by gramnegative aerobic bacilli isolates (102 isolates), with Enterobacteriaceae species as the leading isolates [33].
The IDSA guidelines for diagnosis and treatment of diabetic
foot infection state, Aerobic gram-positive cocci (especially S.
aureus) are the predominant pathogens in diabetic foot infections. Patients who have chronic wounds or who have recently
received antibiotic therapy may also be infected with gramnegative rods, and those with foot ischemia or gangrene may
have obligate anaerobic pathogens [34, p. 885].
additional cSSTI categories in which resistant gram-positive and

gram-negative pathogens would be likely. These include perineal infections, necrotizing soft-tissue polymicrobial infections,
pressure ulcer and decubitus infections, and surgical-site infections related to abdominal and genitourinary surgical
procedures.
Future Directions
Future directions discussed by the summit members include

the need to evaluate whether a category of health careassociated cSSTIs is appropriate at this time. The use of HAI categories in bacteremia and pneumonia are thought to be important for improving the recognition of those patients who
may be infected with MDR pathogens and therefore warrant
more broad-spectrum empirical antimicrobial therapy. There
is minimal evidence to suggest that the addition of health care
associated cSSTIs would have significant implications for the
selection of empirical antimicrobial therapy for these patients
with skin infections. Other potential classification schemes
could be considered for cSSTIs, such as monomicrobial versus
polymicrobial, necrotizing versus nonnecrotizing, and pyogenic
versus nonpyogenic. Additional detailed studies of SSTIs are
warranted to further delineate changes in the microbial etiology
of cSSTIs, to optimize treatment strategies and also to evaluate
risk factors for recurrence.
STATEMENT 2: PATIENTS WITH HEALTH CARE
ASSOCIATED INTRA-ABDOMINAL INFECTIONS
SHOULD RECEIVE DUAL EMPIRIC THERAPY
FOR RESISTANT GRAM-NEGATIVE AND GRAMPOSITIVE PATHOGENS
Complicated intra-abdominal infections (cIAIs) are defined as

infections that extend beyond the hollow viscus of origin into
the peritoneal space and are associated with either abcess for-
Table 5. Definitions used for epidemiologic classification of invasive methicillin-resistant

Staphylococcus aureus (MRSA) infections.
Classification
Definition
Health care associated

Community onset
Hospital onset
Community associated
Cases with at least 1 of the following health care risk factors: (1)
presence of an invasive device at time of admission; (2) history
of MRSA infection or colonization; (3) history of surgery, hospitalization, dialysis, or residence in a long-term-care facility in previous 12 months preceding culture date
Cases with positive culture result from a normally sterile site obtained 148 h after hospital admission. These cases might also
have 1 of the community-onset risk factors.
Cases with no documented community-onset health care risk factor
NOTE. Reprinted from JAMA 2007; 298:176371 [39]. Copyright 2007, American Medical Association.
All rights reserved.
North America increased substantially, from 26.2% of isolates

in 1998 to 47.4% of isolates in 2004. Community-associated
MRSA is the primary pathogen in patients without health care
associated risk factors. S. aureus is also the leading pathogen
in surgical-site infections, with rising rates of MRSA.
Given the high prevalence of MRSA cSSTI at present, is it
important to standardize the classification of these invasive
MRSA infections? Several methods are used to classify MRSA
as health care associated or community associated, including
(1) genotypic testing, based on the results of PFGE or other
molecular techniques; (2) phenotypic testing, based on antimicrobial susceptibility testing; and (3) epidemiologic analysis,
based on the time from hospital admission to a positive culture
result. Definitions of community-associated MRSA often use
time-based criteria in which the recovery of MRSA isolates
within 48 or 72 h after hospital admission is considered indicative of community-associated MRSA. However, time-based
criteria do not consider patients with MRSA infection after
recent health care exposure. Furthermore, community-associated MRSA has emerged as a health careassociated and nosocomial pathogen [3538]. Community-associated MRSA
strains differ from hospital-acquired MRSA strains in that they
are generally susceptible to most antibiotics, whereas nosocomial strains are generally multidrug resistant (MDR). However,
these data are not available to the prescribing clinician when
empirical antibiotics are selected.
The recent epidemiologic reports of invasive MRSA infections (n p 8987) in the United States, which were associated
with 1598 in-hospital deaths, classified cases into mutually exclusive groups (health care associated vs. community associated), first on the basis of health care risk factors. HAIs, in
turn, were classified as either community onset or hospital onset
(table 5) [39].
In contrast, in diabetic foot infections, gram-negative pathogens and polymicrobial infections are more common than are
surgical-site infections and cSSTIs. There are, however, some
whether an expanded classification system that includes health

careassociated cIAI is needed and would benefit a potential
new subgroup of patients.
Methods
A PubMed database search was conducted on 4 September 2007

to identify relevant reports involving the treatment and microbiological features of health careassociated IAIs. The search
term intra-abdominal infections yielded a total of 2347 articles. The search terms health care associated, healthcareassociated, and healthcare associated yielded 51,504, 38,460,
and 288 articles, respectively. When these terms were combined
with intra-abdominal infections, using the AND function,
22 articles were found. After the results were limited to the
English language, 0 articles were found to be relevant to the
statement.
In a second PubMed database search, the search term postoperative peritonitis OR secondary peritonitis yielded 9237
articles. This term was combined with microbiology, using
the AND function, yielding 168 articles; with the search term
drug resistance, yielding 198 articles; and with the search term
appropriate therapy, yielding 220 articles. After results were
limited to humans and the English language, 5 articles were
found to be relevant to the statement. The IDSA and the Surgical Infection Society guidelines for the treatment of cIAIs were
also reviewed.
Evidence
No studies specifically related to health careassociated intraabdominal infections were identified. The 2 issues of empirical
antibiotic therapy and dual empirical therapy for treatment of
infection with resistant gram-positive and gram-negative pathogens will be addressed separately.
Empirical antimicrobial therapy for cIAI. The first portion
of the statement recommends that patients with health care
associated IAI should receive empirical antimicrobial therapy.
A retrospective case study by Krobot et al. [43] assessed the
effect of inappropriate initial empirical antibiotic therapy in
425 patients with community-acquired secondary peritonitis.
E. coli was the most commonly isolated pathogen. A total of
54 patients (13%) received inappropriate initial therapy. Clinical success, predefined as resolution of infection with initial
or step-down therapy after primary surgery, was achieved for
322 patients (75.7%). However, patients were more likely to
have clinical success if the initial antibiotic therapy was appropriate than if it was inappropriate (75.7% vs. 53.4%). Patients
who had clinical success had a mean length of stay of 13.9
days, compared with 19.8 days for those who had clinical failure. Furthermore, multinomial analyses (with adjustment for
patient age, sex, and comorbidities) revealed that inappropriate
mation or peritonitis [40]. Intra-abdominal infections pose serious challenges to the treating physicians, and mortality rates
approach 60% [41]. Rapid diagnosis, appropriate intervention,
and timely and efficacious anti-infective therapy are of critical
importance and have been shown to lead to improved patient
outcomes.
The traditional binary classification scheme for cIAIs has
consisted of nosocomial and community-acquired infections.
At present, there is no defined category for health careassociated cIAI, unlike the distinction that has been made recently
with BSI and pneumonia. Many of the data regarding epidemiology and antimicrobial treatment of cIAI are derived from
antimicrobial trials, and most patients who entered into those
trials had community-acquired infections, such as perforated
or complicated appendicitis, and have not been severely ill.
It is estimated that 80% of all intra-abdominal infections
(IAIs) are acquired in a community setting [42]. In community-acquired infections, the location of the gastrointestinal perforation defines the infecting flora: infections that
occur beyond the proximal small bowel are caused by facultative and aerobic gram-negative organisms; infections that
occur past the proximal ileum can be caused by a variety of
anaerobic microorganisms.
The IDSA guidelines for cIAI used the term health care
associated infections to describe nosocomial infections, including cIAIs acquired postoperatively. HAIs were specifically
defined as infections that are most commonly acquired as
complications of previous elective or emergent intra-abdominal
operations and are caused by nosocomial isolates particular to
the site of the operation and to the specific hospital and unit
[40, p. 997].
In the context of the HAI Summits reference to other infections, the term HAI was used to describe infections in individuals who regularly interact with the health care environment. It has been suggested that HAIs represent a unique
population of patients. These patients are thought to be infected
not only with a different spectrum of pathogens but also with
potentially more-resistant flora.
The term HAI was first used to characterize a spectrum of
BSIs [6]. Similarly, patients with cIAI with these same risk
factors for HAI may have ample opportunity to acquire resistant bacteria. It is undetermined at present whether an expanded classification scheme, to include health careassociated
cIAI, may be necessary for patients with IAIs. There is currently
no standard category or definition for HAIs in the broader
category of IAIs.
This review focuses on the available literature that characterizes the microbiology of cIAIs (both community acquired
and nosocomial), the importance of appropriate initial empirical therapy, and the incidence of MDR organisms. By assessment of the strength of this evidence, it is possible to ascertain
IDSAs treatment recommendations for nosocomial cIAI suggest multidrug regimens guided by knowledge of nosocomial
flora and susceptibility patterns.
Several studies have documented that infections involving
resistant organisms, particularly those likely to be acquired in
the health care setting, are associated with an increased risk of
treatment failure, morbidity, and mortality [4952]. Prolonged
preoperative length of stay and prolonged (12 days) preoperative antimicrobial therapy are significant predictors of antimicrobial failure leading to recurrent infection, which suggests
that organisms resistant to the empirical antimicrobial regimen
may be responsible for infection. Patients with these risk factors
should be given treatment for nosocomial infection.
Montravers et al. [52] evaluated the incidence of resistant
bacterial strains among patients with postoperative peritonitis,
as well as the efficacy of empirical antimicrobial therapy. In
this study, 100 resistant pathogens were isolated from 70 patients who underwent repeated operation for generalized postoperative peritonitis. Candida species and both gram-negative
and gram-positive anaerobic bacteria were isolated (table 7)
[52]. The relative frequencies of different pathogens cultured
in this patient population differed from those typically found
in patients with community-acquired peritonitis. Furthermore, the authors determined that 54% of the patients who
received inadequate initial empirical therapy for these resistant
pathogens had poorer outcomes, compared with patients who
received adequate therapy (P ! .05).
Roehrborn et al. [53] examined the microbiology of postoperative peritonitis in a prospective case study involving 67 patients. The most common isolates from patients with postoperative peritonitis were E. coli and Enterococcus, Enterobacter,
Bacteroides, and Klebsiella species. In addition, patients with postoperative peritonitis were significantly more likely than were patients with community-acquired infections to have the following
isolates: enterococci (23 vs. 6), Enterobacter species (13 vs. 4), S.
aureus (7 vs. 1), and coagulase-negative staphylococci (7 vs. 1).
Patients with community-acquired infections were significantly
more likely to have streptococci and E. coli isolated.
The Study for Monitoring Antimicrobial Resistance Trends,
begun in 2002 and developed by the Merck research program,
is designed to monitor resistance patterns among aerobic and
facultative gram-negative bacilli isolated worldwide from intraabdominal bacterial clinical isolates collected from multiple
centers (including both teaching and community hospitals)
[54]. Data from the 2004 report [55] were used in the evaluation
of 6156 unique aerobic and facultatively anaerobic gram-negative bacilli isolated from IAIs. Enterobacteriaceae composed
86% of the total isolates, with E. coli (48%), Klebsiella species
(16%), and Enterobacter species (9%) comprising the majority
of isolates. Quinolone susceptibility rates for E. coli were significantly reduced (60%70% susceptible), with the lowest rates
antimicrobial therapy was associated with the need for secondline antibiotic therapy and repeated operation.
A more recent multicenter study of 425 patients with community-acquired IAI in Spain examined the consequences of
inappropriate initial empirical parenteral antibiotic therapy
[44]. Initial empirical therapy was classified as appropriate if
all isolates were susceptible to at least 1 of the antibiotics administered. A total of 387 patients (92%) received appropriate
initial empirical therapy. Patients receiving inappropriate therapy were less likely to have clinical success (79% vs. 26%;
P ! .001), more likely to require additional antibiotic therapy
(40% vs. 7%; P ! .01), and more likely to be rehospitalized
within 30 days after discharge (18% vs. 3%; P ! .01). Multivariate analyses also showed that inappropriate therapy was
associated with an almost 16% increase in length of stay and
a 26% increase in the number of days of antibiotic therapy.
Inappropriate initial antibiotic therapy was associated with a
significantly higher proportion of unsuccessful patient outcomes, including death, repeated operation, rehospitalization,
additional antibiotic therapy, and increased length of stay. Other
studies have confirmed similar findings [4547]. These data
clearly confirm that patients with IAI should receive appropriate
empirical antimicrobial therapy.
Dual empirical antimicrobial therapy for cIAI with resistant gram-positive and gram-negative pathogens. The second portion of the statement recommends that dual empirical
therapy for resistant gram-positive and gram-negative pathogens should be used for patients with health careassociated
cIAI.
The IDSA guidelines for cIAI separate the recommendations
regarding selection of anti-infective agents into 2 categories
mild-to-moderate and high-severity infectionsand these
may occur in both patients with community-acquired and patients with nosocomial infections [40]. Similarly, the Surgical
Infection Society guidelines for cIAI separate the recommendations into lower-risk patient and higher-risk patient [48].
In general, for less severely ill patients with community-acquired infections, antimicrobial agents with a narrow spectrum
of activity are adequate.
The IDSA recommends that community-acquired infections
may be managed with a variety of single- and multiple-agent
therapeutic regimens that are based, in part, on in vitro activities. The IDSA advises that no particular antimicrobial regimen
has consistently been demonstrated to be superior or inferior
(table 6).
For higher-risk patients or for those with high-severity IAIs,
broader-spectrum empirical antimicrobial therapy is recommended to cover potential MDR pathogens. Nosocomial IAIs
are typically caused by a more-resistant flora, which may include P. aeruginosa, Acinetobacter species, Enterobacter species,
Proteus species, MRSA, enterococci, and Candida species. The
Cefuroxime plus metronidazole

Ciprofloxacin plus metronidazole
Aztreonam plus clindamycin
Third/fourth-generation
cephalosporinc plus an
antianaerobe
Aminoglycosided plus an
antianaerobe
SIS

Aztreonam plus metronidazole
Aztreonam plus clindamycin
c
cephalosporinc plus metronidazole
cephalosporin plus an
antianaerobe
Aminoglycosided plus an
antianaerobee
Cefuroxime or cefazolin plus

metronidazole
Fluoroquinoloneb plus metronidazole
IDSA
Combination regimen
Because increasing resistance of Escherichia coli to ampicillin and to ampicillin/sulbactam has been reported, local susceptibility profiles should be reviewed before use.
Ciprofloxacin, levofloxacin, moxifloxacin, or gatifloxacin.
Cefepime, cefotaxime, ceftazidime, ceftizoxime, or ceftriaxone.
Amikacin, gentamicin, netilmicin, or tobramycin.
Clindamycin or metronidazole.
NOTE. Adapted from [40] and from [48].
Piperacillin/tazobactam
Imipenem/cilastatin
Meropenem
High risk (categorized as high-sePiperacillin/tazobactam

verity infections by the IDSA and Imipenem/cilastatin
higher-risk patients by the SIS) Meropenem
SIS
Ampicillin/sulbactam
Ticarcillin/clavulanic acid
Ertapenem
Cefotetan
Cefoxitin
Piperacillin/tazobactam
Imipenem/cilastatin
Meropenem
IDSA
Low risk (categorized as mild-toAmpicillin/sulbactam

moderate infections by the IDSA Ticarcillin/clavulanic acid
and lower-risk patients by the
Ertapenem
SIS)
Classification
Single agent
Table 6. Therapeutic regimens for complicated intra-abdominal infections, according to guidelines from the Infectious Diseases Society of America (IDSA) and the Surgical Infection
Society (SIS).
Table 7. Organisms reported in a study of postoperative peritonitis by Montravers et al. [52].
Organism
No. of
isolates
Gram negative
Escherichia coli
Proteus/Morganella species
Pseudomonas species
Klebsiella species
53
25
21
14
Enterobacter cloacae
Acinetobacter/Citrobacter/Serratia species
10
10
Gram positive
Methicillin-resistant Staphylococcus species
Enterococcus faecalis
24
19
19
Bacteroides species
13
Candida species
23
NOTE. Adapted from [52], with permission from the University of Chicago
Press. Some patients had 11 isolate.
in the Asia/Pacific region and Latin America. Extended-spectrum b-lactamases (ESBLs) were detected phenotypically in
10% of E. coli, 17% of Klebsiella species, and 22% of Enterobacter species worldwide, representing an increase from the 2
previous years.
In this large surveillance program, an additional analysis of
7002 E. coli isolates documented that increasing resistance rates
have been seen in both community-acquired and hospital-acquired E. coli infections [56]. Ampicillin-sulbactam was the least
active agent (45.1%67.6% of isolates were susceptible). Quinolones (ciprofloxacin and levofloxacin) also demonstrated low
activity (69%75% susceptible). E. coli isolated !48 h after
hospital admission (presumed to be community acquired) were
more often susceptible to the agents tested than were E. coli
isolated 148 h after hospitalization (presumed to be hospital
acquired). There were small differences in susceptibility rates
between community-acquired and hospital-acquired E. coli for
the carbapenems and amikacin, but there were more sizable
differences for other agents, including ampicillin-sulbactam
(60.3% vs. 48.4%), ciprofloxacin (83.7% vs. 71.6%), and levofloxacin (83.8% vs. 73.5%). Antimicrobial resistance among
gram-negative bacteria isolated from IAIs, both community
acquired and nosocomial, is emerging as a more significant
problem worldwide.
Although resistance rates are of growing concern, there are
rare studies that examine the consequences of resistance and
adequate empirical treatment for outcomes. A retrospective cohort study by Peralta et al. [57] analyzed patients with E. coli
bacteremia to identify associations between antibiotic resistance,
adequacy of empirical therapy, and mortality. Of the 663 patients
included in the study, those with MDR E. coli bacteremia had a
Grading of Evidence

members agreed that there was substantial evidence to accept
the statement. In evaluating the nature of the evidence, 40%
voted category II, 20% voted category III, and 40% voted category IV (table 3).
Level of Support
When voting on the support for this statement, 0% of the

summit participants voted to accept the statement completely,
27% voted to accept the statement with some reservations, 64%
voted to accept the statement with major reservations, 9% voted
to reject the statement with reservations, and 0% voted to reject
the statement completely. In comparison, of the 744 IDSA
members who participated in the online survey, 30% voted to
accept the statement completely, 38% voted to accept the state-
Enterococcus faecium
Anaerobe
significantly lower frequency of correct empirical treatment than

did patients with non-MDR E. coli bacteremia (relative risk [RR],
0.53; 95% CI, 0.480.67), coupled with a considerably higher
mortality rate (RR, 3.31; 95% CI, 1.726.36).
A prospective observational study by Seguin et al. [58] reported factors associated with MDR bacteria in secondary peritonitis. Forty-four cases of community-acquired peritonitis and
49 cases of nosocomial peritonitis (35 postoperative cases) were
reported. In univariate analysis, the risk of acquiring an MDR
organism was significantly associated with a higher Acute Physiology and Chronic Health Evaluation (APACHE) II score. In
addition, preoperative length of hospital stay, previous antimicrobial therapy, and the duration and modification of postoperative antimicrobial therapy were significantly associated
with the presence of MDR bacteria. Multivariate analysis confirmed that patients with a preoperative length of hospital stay
of 5 days had a higher risk for developing an MDR IAI,
especially if antibiotics had been used previously. The authors
concluded that knowledge of these 2 risk factors for acquiring
MDR bacteria (preoperative length of stay and prior use of
antibiotics) enables the use of expanded-spectrum empirical
antimicrobial therapy for these specific high-risk patients.
No studies were identified that specifically focused on the
epidemiology and/or incidence of MDR organisms of health
careassociated IAIs. Additional discussion regarding the potential definition of health careassociated IAIs and patients
who would be included in such a category suggested that it
could include patients with cIAIs such as peritoneal dialysiscatheter infections, patients with spontaneous bacterial peritonitis with multiple prior episodes, and patients in nursing
homes or long-term-care facilities who develop cIAIs including
appendicitis, cholecystitis, and diverticulitis. There is no consensus as to whether this category of health careassociated
cIAI should be created.
ment with some reservations, 11% voted to accept the statement with major reservations, 18% voted to reject the statement
with reservations, and 3% voted to reject the statement completely (figure 2).
spectrum therapy is associated with its own problems, caution

should be exercised. Future studies will need to be conducted
to examine whether health careassociated cIAI should be delineated as a separate category of IAIs before specific recommendations can be made.
Discussion
Future Directions
Traditional categorization of IAIs has segregated them as nosocomial or community-acquired infections. In recent years,
epidemiologic studies have identified that pathogens associated
with cIAI demonstrate rising levels of drug resistance in both
groups. It has also been shown that inadequate initial empirical
therapy is associated with a significantly higher rate of failures
and death. On the basis of studies of patients with postoperative
peritonitis, it is reasonable to suggest that select patients may
benefit from broad-spectrum empirical therapy. For patients
with peritonitis, several attempts have been made to identify
clinical features that increase the risk of adverse outcomes. For
these patients, the IDSA suggests that antimicrobial regimens
with expanded spectra may be warranted. Finally, given the
different spectrum of pathogens and the varying levels of resistance seen in patients with peritonitis, an effort should be
made to identify other patient types and specific risk factors
for IAIs due to resistant pathogens. Because unnecessary broad-
STATEMENT 3: EARLY AGGRESSIVE,

APPROPRIATE EMPIRIC TREATMENT
AND DE-ESCALATION FOR HCAP REDUCES
MORTALITY AND MINIMIZES RESISTANCE
A designation of health careassociated infection was first

used for cases of bacteremia in which patients who acquired
bacteremia as outpatients were found to have pathogens usually
associated with hospital-acquired infections [6]. Of significance,
the term referred only to patients who were hospitalized with
an infection, not to those who remained in their nonhospital
setting. The term health care associated seemed to apply to
a variety of infections, including pneumonia, with a similar
propensity to be caused by typically nosocomial pathogen. The
concept of HCAP was therefore readily embraced. For this
reason, HCAP was included in the latest statement on HAP
from the ATS and IDSA [1] and was essentially excluded from
discussion in the recent IDSA-ATS consensus guidelines on the
management of CAP [2].
Because several principals of treatment have been thought
to be important for outcomes among patients with HAP and
VAP, logic would suggest that these principals are applicable to
HCAP as well. These principals include: (1) early initiation of
empirical antibiotic treatment; (2) use of broad-spectrum, empirical, antibiotic therapy to avoid inappropriate therapy; and
(3) narrowing or de-escalation of empirical antibiotic therapy
on the basis of results of respiratory-tract cultures [1]. The
purported benefits of such an approach were to decrease the
mortality associated with inappropriate initial antibiotics while,
at the same time, lessening the emergence of antibiotic-resistant
Figure 2. Voting comparison for statement 2 (Patients with health careassociated intra-abdominal infections should receive dual empiric therapy
for resistant gram-negative and gram-positive pathogens). IDSA refers to the members of the Infectious Diseases Society of America who responded
to a Web-based survey; Summit refers to the Health CareAssociated Infection Summit panel.
In summary, a review of the literature produced very limited

retrospective studies in general support of the statement. However, in practice, patients suspected of having risk factors for
a health careassociated infection typically receive empirical
therapy for MDR gram-positive and gram-negative organisms.
On the basis of the presented studies of patients with secondary
peritonitis, it is reasonable to assume that certain patient subgroups were infected with a different spectrum of bacteria, as
well as with MDR bacteria. The current studies of patients with
secondary peritonitis document that appropriate empirical antibiotic coverage as well as coverage for MDR organisms lead
to improved outcomes.
pathogens. Although it may be logical to assume that these

principals and expected results apply to HCAP, this section aims
to assess the strength of evidence supporting this assertion.
Methods
Evidence
No randomized, controlled trials of treatment specific to hospitalized patients with HCAP were found. No concurrent cohort studies of antibiotic treatment in general for hospitalized
patients with HCAP were found. Only 1 randomized, controlled
trial involving nursing home patients that specifically addressed
treatment in the nursing home was available [59].
No category I evidence for any aspect of the statement.
Because the entity of HCAP has been defined only recently,
studies of either CAP or HAP may have bearing on the statement; therefore, this evidence will also be reviewed. Furthermore, because the statement is multifaceted, each statement
component will be discussed separately.
Appropriate empirical therapy. Only 1 study specifically
addressed the issue of appropriate empirical therapy for HCAP
[59]. This was a preintervention and postintervention study of
the management of nursing homeacquired pneumonia with
either oral or parenteral antibiotic therapy. The actual intervention was a guideline for the indication for parenteral antibiotics in a randomized study of 10 skilled-nursing facilities
involving either a multidisciplinary or a physician-only training
program. After the intervention, use of parenteral antibiotics,
when indicated by guidelines, increased significantly (P ! .02)
without differences by randomization. No overall mortality
benefit was seen. Emergence of resistance was not addressed.
Because 35%40% of patients ultimately required hospitalization, the results have some pertinence to the issue of HCAP.
The issue of appropriate antibiotic therapy for HCAP reS68 CID 2008:47 (Suppl 2) Kollef et al.
A PubMed search was performed on 1 October 2007. With the

search limited to the English language, the term health care
associated OR healthcare associated OR health care-associated
OR healthcare-associated gave a total of 33,408 articles. This
result combined with the term pneumonia resulted in a total
of 333 articles. This result combined with the term treatment
yielded 309 articles. The abstracts were reviewed for pertinence,
and additional related articles were also screened. The text
word antibiotic was also combined with the 333 health care
associated/pneumonia articles, resulting in 87 common articles.
Abstracts of all these articles were examined, as were the related
articles for each. One apposite article was found.
As a consequence of the overlap of HCAP with other pneumonia terms, additional searches were performed. Combination of the terms nursing home AND pneumonia AND treatment resulted in 262 English language articles and 1 relevant
article.
volves around the microbial etiology of HCAP, specifically

whether broad-spectrum antibiotic therapy is needed to empirically cover MDR pathogens, such as P. aeruginosa, MRSA,
and ESBL-producing Enterobacteriaceae. Surprisingly, only 3
epidemiologic studies address this issue specifically. Two retrospective US studies focused on culture-positive cases; the first
study examined a large administrative database [7], and the
second analyzed a single large tertiary care referral hospital [8].
Both studies demonstrated that HCAP was more common than
CAP, with a high frequency (20%25%) of each of the MDR
pathogens listed above. Conversely, another study involving a
Spanish, multicenter, prospective, observational cohort of patients admitted with pneumonia found that only 17.3% of cases
could be classified as HCAP and that the incidences of cases
of pneumonia caused by gram-negative organisms (other than
Legionella species and Hemophilus influenzae, typical CAP pathogens) and S. aureus were both !5% [60]. However, 32% of
patients with HCAP in this study did not receive a microbiological diagnosis, and an additional 20% received a diagnosis
of aspiration pneumonia, which left a positive microbiological
diagnosis for !50%.
Several explanations for these major differences in etiology
of HCAP exist. By far the most important is the inclusion of
HCAP cases without a microbiological diagnosis. Others include differences in criteria (all immunocompromised patients
included vs. only severely immunocompromised patients included; previous hospitalization in the past 12 months vs. the
past 3 months), different types of hospitals (major referral centers vs. smaller local hospitals), and study design (retrospective
vs. prospective).
Even if MDR pathogens occur at high frequency, the use of
broad-spectrum therapy is still of unclear benefit with regard
to mortality. Two studies, both using the before-after intervention format, specifically addressed this issue. Ibrahim et al. [61]
found that the use of a 3-drug, broad-spectrum protocol for
late-onset VAP was able to decrease the percentage of patients
administered inappropriate initial empirical antibiotic therapy
to 5.8%, as opposed to 52% before protocol introduction. Mortality was unaffected, although the incidence of recurrent VAP
and subsequent infection with MDR pathogens decreased. The
second study [62], which used a similar type of empirical protocol, also demonstrated that the use of inappropriate initial
antibiotic therapy was decreased significantly, and broaderspectrum therapy resulted in decreased mortality at 14 days
after treatment (27% vs. 8%; P p .03 ). However, the statistically
significant reduction in mortality was not maintained for 30day or in-hospital mortality.
An additional article from the CAP literature on cases of
pneumonia caused by gram-negative pathogens from a prospective CAP database was pertinent and thus was reviewed
[63]. Most patients with CAP caused by gram-negative path-
hour delay in initiation of antibiotic therapy was associated

with a 7.6% increase in mortality [4]. In this study, 37% of
patients had pneumonia.
Early de-escalation of empirical therapy. De-escalation has
a variety of definitions. The most accepted definition is a decrease in the number of different antibiotics being used for
treatment; however, de-escalation may also include switching
to a narrower-spectrum agent, shortening the duration of therapy, or even ceasing the administration of antibiotics altogether
when culture results are negative.
Both before-after antibiotic treatment protocols included decreasing the number of empirical antibiotics (once culture results were known), as well as the duration of use [61, 62].
Although neither protocol was associated with a mortality benefit, the use of very-broad-spectrum antibiotics and de-escalation was associated with a decrease in the subsequent occurrence of colonization or infection with MDR pathogens [61,
62, 71]. Some evidence of antibiotic pressure was seen in the
study by Soo Hoo et al. [62], in which 6 of the 7 imipenemresistant isolates occurred in patients given the more aggressive
empirical regimen (which included imipenem). Two additional
randomized trials are significant. Singh et al. [71] demonstrated
that, among patients with HAP or VAP who have a persistently
low clinical pulmonary infection score, the discontinuation of
antibiotic therapy after 3 days was associated with a decrease
in the percentage of pathogens that were MDR (14% vs. 38%;
P p .017) and a trend toward mortality differences. Chastre et
al. [72] demonstrated that patients with VAP randomized to
receive 8 days of therapy had lower rates of emergence of MDR
pathogens than did those who received 15 days of therapy
(42.1% vs. 62%; P p .04). A randomized, controlled trial of
diagnostic methods also demonstrated that, when fewer antibiotics were used, the 14-day mortality (16.2% vs. 25.8%;
P p .022) and severity-adjusted 28-day mortality were decreased, although no differences in the emergence of MDR
pathogens was demonstrated (61.3% vs. 59.8%; P 1 .2) [73].
In summary, early de-escalation of therapy has an unclear
association with decreased mortality. The strongest support
comes from avoiding or discontinuing antibiotic therapy completely, rather than narrowing the spectrum or decreasing the
number of antibiotics. Conversely, any type of de-escalation is
associated with a decrease in the emergence of MDR pathogens.
The major benefit appears to occur with a decrease in the overall
duration of therapy, rather than de-escalation per se.
Grading of Evidence
On the basis of a review of the studies cited above, 83% of the

members of this workshop agreed that the nature of the evidence available to support this statement was category II for
the statement in general, with the remainder grading the evidence as category III (table 3).
ogens had risk factors that would likely qualify them for HCAP
status. Provision of appropriate initial therapy was not associated with a significant improvement in mortality (32% vs.
13%; P p .27).
In summary, despite being intuitively logical and supported
by multiple retrospective studies, no prospective study of VAP,
nursing homeacquired pneumonia, HCAP, or CAP has demonstrated a mortality benefit from broader-spectrum protocolized antibiotic regimens, despite efforts made to consistently
decrease rates of inappropriate therapy to low levels. Thus, the
support for a mortality benefit of aggressive broad-spectrum
therapy for HCAP cannot even be extrapolated from studies
of other types of pneumonia.
Aggressive empirical therapy. The use of the broad-spectrum multiple-drug regimens discussed above can be considered
aggressive empirical therapy. However, the only published study
specifically addressing HCAP is a retrospective review of vancomycin dosing for patients with HAP and HCAP [64]. The
authors compared dosing that was adjusted to achieve a serum
trough level of 115 mg/mL, as recommended by the ATS-IDSA
guidelines because of poor outcomes with standard dosing. The
group that achieved trough levels greater than this threshold did
not have a mortality benefit and had more adverse effects [65].
Early empirical therapy. The timing of appropriate antibiotic therapy has received significant attention. No study of HCAP
has specifically examined the timing of antibiotic therapy. However, 2 large retrospective reviews of Medicare patients suggested
a survival advantage when there was earlier provision of antibiotics [66, 67]. Many of these patients were likely to have HCAP.
Although significant differences in mortality among patients receiving antibiotics in the first 48 h were documented, the trend
toward increased mortality was heterogeneous, with some of the
highest mortality rates found among those who received antibiotics in the first 2 h after presentation to the emergency department. More importantly, prospective studies of CAP guideline implementation have demonstrated that mortality is
unchanged despite significant increases in the proportion of
patients receiving antibiotics within 4 or 8 h [68].
The only prospective trial involving VAP did not show a
difference in mortality if antibiotics were started empirically
when VAP was suspected, compared with when the culture
results were returned [69]. However, the study was limited to
trauma patients for whom an attributable mortality due to VAP
was unclear and VAP was less likely to have been caused by
MDR pathogens. Duration of ventilation was increased for patients randomized to receive culture-directed treatment. Retrospective data from a medical ICU population suggest that a
delay of 24 h in initiating therapy is associated with excess
mortality [70].
The strongest evidence in favor of early antibiotic therapy is
from a retrospective review of septic shock, in which every 1-
Level of Support

workshop members voted to accept the statement with some
reservations, and 45% voted to accept the statement with major
reservations. In comparison, of the 744 IDSA members who
participated in the online survey, 56% voted to accept the statement completely, 36% voted to accept the statement with some
reservations, 5% voted to accept the statement with major reservations, 2% voted to reject the statement with reservations,
and 1% voted to reject the statement completely (figure 3).
Discussion
Future Directions
No prospective, randomized trial comparing appropriate versus

inappropriate initial antibiotic therapy for HCAP has been performed. Therefore, the only information regarding the benefit
of early appropriate initial therapy will have to come from
studies of alternative empirical regimens, such as those for VAP.
Given the wide discrepancy in the frequencies of MDR pathogens in HCAP cases in recent studies, this type of study is
clearly needed.
STATEMENT 4: HEALTH CAREASSOCIATED
BSIs REQUIRE EMPIRIC COVERAGE FOR MDR
GRAM-NEGATIVE BACTERIA AND MRSA,
AS WELL AS COVERAGE FOR FUNGAL
PATHOGENS IN PATIENTS
WITH SPECIFIC RISK FACTORS
BSI is a common and potentially lethal complication of health

care contact. A significant minority of hospitalized patients
develop a BSI. Among these patients, mortality rates are high.
This high mortality may be caused in part by the emergence
of antimicrobial resistance in pathogens associated with the
health care system. Such antimicrobial resistance increases the
possibility of inadequate empirical antimicrobial therapy, which
can delay the time until effective antimicrobial therapy is
administered.
The entity of health careassociated BSI was first defined by
Friedman et al. [6] as involving a positive culture result from
a blood specimen that was obtained from a patient within 48
h after admission if the patient received intravenous therapy,
wound care, or specialized nursing care or did any of the following: received self-administered intravenous medical therapy
in the 30 days before the BSI; attended a hospital or hemo-
Figure 3. Voting comparison for statement 3 (Early aggressive, appropriate empiric treatment and de-escalation for HCAP reduces mortality and
minimizes resistance). IDSA refers to the members of the Infectious Diseases Society of America who responded to a Web-based survey; Summit
refers to the Health CareAssociated Infection Summit panel. HCAP, health careassociated pneumonia.
The difference between the voting of the workshop participants

and that of the IDSA members is striking. The most likely
explanation is an overestimation of the literature support for
the concept of HCAP. Only 3 studies have specifically addressed
HCAP [7, 8, 60]. Most of the other information is extrapolated
from either HAP/VAP or CAP literature.
The second major issue is the over-reliance on retrospective
studies, which is particularly true for data on inappropriate
initial empirical therapy, for which multiple retrospective studies consistently show excess mortality among patients receiving
inappropriate initial empirical therapy [1]. The prospective trials of broad-spectrum empirical therapy with de-escalation do
not demonstrate that providing appropriate initial antibiotics
is sufficient to improve mortality [61, 62]. One explanation for
this seemingly paradoxical finding between retrospective and
prospective trials is that antibiotics for MDR pathogens may
frequently be ineffective, despite being appropriate [1].
Another explanation may be that the patients host response
is unable to cure the pneumonia despite antibiotic therapy.
Here, the difference between CAP and HAP, especially VAP, is
likely to be great. Many VAP cases occur during a period of
relative immunoparalysis after initial ICU admission for a critical illness [74]. In contrast, most CAP cases are characterized
by a proinflammatory state. Although the pathogens associated
with HCAP may resemble HAP and/or VAP, it is unclear

whether the physiologic response will vary in the same way.
dialysis clinic or received chemotherapy in the 30 days before

the BSI; was hospitalized in an acute care hospital for 2 days
in the 90 days before the BSI; or resided in a nursing home or
long-term-care facility. A key finding of this study was that the
prevalence of antimicrobial-resistant pathogens among patients
with non-nosocomial health careassociated BSI (i.e., BSI that
did not originate in the hospital setting) resembled that among
patients with nosocomial BSI. Thus, for the purposes of the
present article, HAIs are defined as both nosocomial and nonnosocomial HAIs.
Methods
Evidence
Health careassociated status is a risk factor for ineffective antibiotic therapy of BSI. One study specifically focused on the
impact of health careassociated status on the likelihood of ineffective therapy for patients with BSI [75]. In this prospective,
multicenter, cohort study of 466 adults with BSI, only 132 (28%)
had community-acquired BSI. The most common pathogens in
BSI were E. coli (14.2%) and MRSA (13.1%). Although the microbiological characteristics of nosocomial and non-nosocomial
health careassociated BSIs were similar, microbiological characteristics of both groups differed significantly from those of
community-associated BSI. In multivariable logistic regression
analysis, both health careassociated (OR, 3.1; 95% CI, 1.66.1)
and nosocomial (OR, 4.3; 95% CI, 2.28.3) status were independently associated with ineffective initial antibiotic therapy.
Specific causes of BSI, including MRSA (OR, 1.7; 95% CI, 1.0
2.8) and Enterococcus species (OR, 2.3; 95% CI, 1.34.1), were
also associated with ineffective initial therapy.
Assessment of association between appropriate antibiotic
therapy and mortality in patients with bacteremia. Studies
of the association between inappropriate therapy and mortality
A PubMed search related to health careassociated BSI was

completed on 28 September 2007. The search terms health
care associated, health care-associated, healthcare associated, and healthcare associated OR health care-associated OR
health care associated OR healthcare-associated gave a total
of 54,638 articles. The search terms blood stream infection,
bloodstream infection, bacteremia, bloodstream infection,
and blood stream infection, combined using the OR function, yielded a total of 27,839 articles. The search term ineffective therapy OR ineffective antibiotic therapy OR delayed
antibiotic treatment OR delayed receipt of effective antimicrobial therapy OR inadequate antimicrobial treatment OR delay
in effective therapy yielded a total of 24,230 articles. Combining the bloodstream infection search with the ineffective therapy search, using the AND function, resulted in
a total of 232 articles. All these articles were reviewed; 13 were
relevant to the statement.
among patients with bacteremia have yielded conflicting results.

One recent article [76] systematically reviewed the published
literature evaluating the association between inappropriate antibiotic therapy and mortality among patients with bacteremia.
The authors found that 51 studies meeting their inclusion criteria exhibited significant heterogeneity in design, definition,
measurement of variables, and statistics. Thirty-four studies
(67%) measured the severity of illness, but only 6 (12%) specified when it was assessed. Only 8 studies (16%) defined inappropriate antibiotic therapy as that which was inactive in
vitro against the isolated organism and was not consistent with
current clinical practice recommendations and also distinguished between empirical and definitive treatment. McGregor
et al. [76] identified key methodological recommendations to
improve the validity and generalizability of future studies, including a robust, consistent definition of inappropriate therapy based on in vitro susceptibility data; separate consideration
of empirical and definitive therapy; and appropriate statistical
adjustment for the baseline severity of illness of the patient.
Association between patient outcome and antibiotic therapy
for BSI caused by MDR gram-negative pathogens. A recent
meta-analysis of 16 peer-reviewed studies examined associations between ESBL production in Enterobacteriaceae species
causing bacteremia, time to effective antibiotic therapy, and
patient mortality [77]. Meta-analysis of crude RR demonstrated
a significantly increased incidence of delay in effective therapy
(pooled RR, 5.56; 95% CI, 2.9410.51; P ! .001) and significantly increased mortality (pooled RR, 1.85; 95% CI, 1.392.47;
P ! .001) in bacteremia caused by ESBL-producing bacteria.
The meta-analysis was unable to evaluate adjusted mortality,
because only 1 of the 16 included studies reported these data.
A total of 7 additional reports were published after the enrollment period for the meta-analysis [7884]. All were retrospective, and all but 1 was a single-center study [80]. Most
[1, 5, 7, 10,78, 81, 82, 84] but not all [79, 83] of the 7 additional
studies found an association between delayed effective therapy
for BSI caused by MDR gram-negative pathogens and mortality.
Consistent with the report by McGregor et al. [76], significant
heterogeneity existed among the 7 studies in patient population,
definitions of delayed antibiotic therapy, follow-up period, and
statistical methodology. Moreover, establishing the risks of attributable mortality remains difficult.
Using classification and regression tree (CART) analysis,
Lodise et al. [81] evaluated the relationship between delayed
appropriate antibiotic therapy and risk of 30-day mortality in
100 patients with nosocomial P. aeruginosa bacteremia. Delayed
antibiotic therapy was defined using CART analysis as receipt
of effective antibiotic therapy 152 h after the culture result was
obtained. Mortality was significantly higher among patients
with delayed appropriate antibiotic therapy than among patients whose therapy was not delayed (44% vs. 19%; P p
for patients receiving inappropriate initial antimicrobial treatment than for patients receiving appropriate initial treatment
(30.7% vs. 17.8%; P p .018). Multiple logistic regression analysis identified inappropriate initial antimicrobial treatment
(AOR, 2.04; 95% CI, 1.422.92; P p .048) as an independent
predictor of in-hospital mortality. An appropriate initial antimicrobial regimen was administered more often to patients
receiving empirical combination antimicrobial treatment for
gram-negative bacteria than to those receiving empirical monotherapy (79.4% vs. 65.5%; P p .011).
Two studies found no increased risk with delayed effective
therapy for BSI caused by MDR gram-negative pathogens. Osih
et al. [83] assessed the effect of appropriate empirical therapy
on in-hospital mortality and length of stay among 167 patients
with P. aeruginosa BSI. Adequate empirical antibiotic therapy
was defined on the basis of in vitro susceptibility testing from
8 h before the first positive blood culture to the time the susceptibility results were known. After adjustment for age, severity
of illness, and time at risk, appropriate empirical antibiotic
therapy was not significantly associated with mortality (OR,
0.96; 95% CI, 0.312.9; P p .58). Deal et al. [79] sought to
identify predictors of in-hospital mortality among 124 patients
with bacteremia caused by Enterobacter or Citrobacter species
from 1998 through 2004. Appropriate empirical antibiotic therapy was administered to three-quarters of the patients and was
similar among survivors and nonsurvivors (74% vs. 81%;
P p .51). An important limitation to this investigation was
sample size.
Association between patient outcome and antibiotic therapy
for MRSA bacteremia. Two meta-analyses involving 16000
staphylococcemic patients have shown that the mortality rate
among patients with MRSA bacteremia was significantly greater
than that among patients with MSSA bacteremia [85, 86]. Using
data from 13900 patients from 30 studies, Cosgrove et al. [85]
showed that mortality was significantly higher among patients
with MRSA bacteremia than among patients with MSSA bacteremia (36% vs. 23%; RR, 1.42; 95% CI, 1.251.63; P ! .001).
Whitby et al. [86] reviewed 9 studies of nosocomial S. aureus
bacteremia published in 19902000. In this analysis, the RR of
death also was significantly higher among patients with MRSA
bacteremia (29% vs.12%; RR, 2.12; 95% CI, 1.762.57; P !
.001).
Several investigations have sought to quantify the impact of
delayed effective therapy on outcomes for patients with MRSA
bacteremia [8790]. Results have varied, with 2 studies finding
no difference in mortality, and 2 studies finding higher mortality
rates among patients with MRSA bacteremia receiving delayed
antibiotic therapy. Roghmann et al. [90] retrospectively evaluated
132 episodes in 128 patients with MRSA bacteremia to estimate
the impact of delayed initiation of vancomycin on clinical outcomes. Patients with MRSA bacteremia were significantly less
.008). Appropriate antibiotic therapy delayed 152 h was independently associated with resistance to 13 antibiotic classes
(adjusted OR [AOR], 4.6; 95% CI, 1.911.2; P p .001), chronic
obstructive pulmonary disease (AOR, 5.4; 95% CI, 1.519.7;
P p .01), and 30-day mortality (OR, 4.1; 95% CI, 1.213.9;
P p .03) among patients with P. aeruginosa BSI.
Tumbarello et al. [84] sought to identify the impact of inadequate initial antibiotic therapy (defined as initiation of treatment with active antimicrobial agents 172 h after collection of
the first positive blood culture specimen) on 21-day mortality
in 186 hospitalized patients with BSI caused by ESBL-producing
organisms. Patients receiving inadequate treatment had a 3-fold
increase in mortality, compared with the group receiving adequate treatment (59.5% vs. 18.5%; 95% CI, 1.763.22; P ! .001).
In multivariate analysis, the significant predictors of mortality
were inadequate initial antimicrobial therapy (OR, 6.28; 95% CI,
3.1812.42; P ! .001) and unidentified primary infection site
(OR, 2.69; 95% CI, 1.385.27; P p .004). The antibiotic regimens
most frequently classified as inadequate were based on oxyimino
cephalosporin or fluoroquinolone therapy.
Using a multicenter, nested, case-control study, Hyle et al.
[80] evaluated the association of inadequate initial antimicrobial therapy with mortality in 187 patients with BSI caused by
ESBL-producing organisms. Initial antimicrobial therapy was
defined as inadequate when there was 148 h between the time
a culture specimen was obtained and the initiation of therapy
with an agent to which the infecting organism was susceptible.
Infection with MDR ESBL-producing E. coli or Klebsiella species
(AOR, 14.58; 95% CI, 1.91111.36) and health careacquired
infection with ESBL-producing E. coli or Klebsiella species
(AOR, 4.32; 95% CI, 1.4912.54) were independent risk factors
for inadequate initial antimicrobial therapy, and inadequate
initial antimicrobial therapy was an independent risk factor for
mortality among patients with nonurinary infection with ESBLproducing E. coli or Klebsiella species (AOR, 10.04; 95% CI,
1.9052.96).
Anderson et al. [78] used multivariable logistic regression to
identify predictors of all-cause in-hospital mortality among 60
patients with bacteremia due to ceftazidime-resistant Klebsiella
pneumoniae. Only 72% of patients received effective therapy
within 5 days after the diagnosis of BSI. Delay in the initiation
of effective therapy for 172 h after diagnosis of BSI was an
independent predictor of mortality (OR, 3.32; 95% CI, 1.07
10.3; P p .04).
Micek et al. [82] evaluated 305 patients with P. aeruginosa
BSI to determine whether the administration of appropriate
initial antimicrobial treatment was associated with a better clinical outcome and to examine the relationship between the empirical administration of combination antimicrobial therapy for
gram-negative pathogens and appropriate treatment for P. aeruginosa BSI [82]. In-hospital mortality was statistically greater
P p .0138). In the second study, Morrell et al. [92] evaluated

157 candidemic hospitalized patients to identify the influence
of delayed empirical antifungal treatment on clinical outcome.
By multivariable analysis, administration of antifungal treatment 112 h after the first positive blood culture specimen was
drawn (AOR, 2.09; 95% CI, 1.532.84; P p .018) was independently associated with in-hospital mortality. Of note, only
5.7% of patients received antifungal therapy within 12 h after
the initial positive result of blood culture. Investigators in both
of these studies concluded that delay in initiation of fluconazole
therapy for hospitalized patients with candidemia had a significant impact on mortality. Delayed treatment of Candida BSI
could be minimized by the development of more-rapid diagnostic techniques for the identification of Candida BSI or
through increased use of empirical antifungal treatment for
selected patients at risk for fungemia.
Grading of Evidence

members considered the nature of the evidence supporting this
statement to be category II (67% of votes) or category III (33%
of votes) (table 3).
Level of Support

73% voted to accept the statement with some reservations, and
18% voted to accept the statement with major reservations. In
comparison, of the 744 IDSA members who participated in the
online survey, 25% voted to accept the statement completely,
voted to accept the statement with major reservations, 17%
voted to reject the statement with reservations, and 4% voted
to reject the statement completely (figure 4).
Discussion
This statement is critically important, given the growing problems of sepsis, bacteremia [93], and antimicrobial resistance
[94]. The majority of the studies reviewed for this statement
support the assertion that delayed appropriate antibiotic therapy is associated with higher mortality among patients with
BSIs. Although none of the studies were able to accurately
establish causal relationships between delayed appropriate antimicrobial therapy and increased mortality and most suffered
in one way or another from methodologic limitations [76],
their conclusions are generally consistent with current treatment guidelines for other HAIs [1] and with previous reports
evaluating the impact of such treatment delays for patients with
sepsis [3]. As evidenced by the results of the IDSA membership
poll related to this statement, the important influence of time
likely to receive effective antibiotic therapy during the first 48 h

of hospitalization (45% vs. 98%; P ! .01) than were patients with
MSSA bacteremia. However, this ineffective empirical therapy
was not significantly associated with an increased mortality risk
(RR, 0.82; 95% CI, 0.361.88) and did not change significantly
when adjusted for age, occurrence of sepsis, or nosocomial infection. Kim et al. [88] evaluated 238 retrospectively identified
patients with MRSA bacteremia who received vancomycin or
ineffective therapy. Using a propensity-matching case-control design to adjust for confounding introduced by the clinicians
choice of antibiotic, these investigators compared the outcomes
for patients with MRSA bacteremia who received inappropriate
empirical therapy with those of control patients with a similar
score but who received vancomycin. In the matched case-control
analysis of 50 propensity scorematched pairs with MRSA bacteremia, inappropriate empirical antibiotic therapy was not associated with a statistically significant difference in mortality (OR,
1.15; 95% CI, 0.512.64).
By contrast, 2 investigations found higher mortality among
patients receiving delayed effective therapy for S. aureus bacteremia. Using CART analysis, Lodise et al. [89] evaluated the
impact of delayed effective therapy on 167 retrospectively identified patients with nosocomial S. aureus bacteremia. The breakpoint between delayed and early therapy by use of CART analysis was 44.75 h. In a multivariate analysis, delayed treatment
was found to be an independent predictor of infection-related
mortality (OR, 3.8; 95% CI, 1.311.0; P p .01) and was associated with longer hospital stay when compared with early
treatment (20.2 vs. 14.3 days; P p .05). The authors concluded
that delay of therapy has deleterious effects on clinical outcomes
and underscores the importance of early appropriate therapy.
Similar conclusions were reached by Khatib et al. [87], who
found that, in a cohort of 342 retrospectively identified patients
with S. aureus bacteremia, the time to effective antibiotic therapy was longer for MRSA-infected patients than for MSSAinfected patients (25.5 vs. 9.6 h; P ! .0005) and all-cause mortality was higher among patients receiving inappropriate
therapy than among those receiving appropriate therapy (35.0%
vs. 20.9%; P p .02).
Association between patient outcome and antimicrobial
therapy for fungal BSI in patients with specific risk factors.
Two studies evaluated the risk of delayed effective therapy in
fungemic patients. Garey et al. [91] evaluated the relationship
between treatment delay and mortality in 230 retrospectively
identified patients with Candida BSI. Although the mortality
was the lowest among patients who began therapy on day 0
(15%), day 1 (24%), day 2 (37%), or day 3 or later (41%)
(P p .0009 for trend), only 40% of patients received antifungal
therapy within the first day. By multivariate modeling, increased
time (per day) to administration of fluconazole was independently associated with mortality (AOR, 1.5; 95% CI, 1.092.09;
Figure 4. Voting comparison for statement 4 (Health careassociated BSIs require empiric coverage for MDR gram-negative bacteria and MRSA,
as well as coverage for fungal pathogens in patients with specific risk factors). IDSA refers to the members of the Infectious Diseases Society of
America who responded to a Web-based survey; Summit refers to the Health CareAssociated Infection Summit panel. BSI, bloodstream infection;
MDR, multidrug resistant; MRSA, methicillin-resistant Staphylococcus aureus.
to fungal organisms increased by 207% [93]. Given the increasing importance of fungemia and the suggestion that early
empirical antifungal therapy may reduce mortality among patients with this infection, further studies are clearly needed to
help determine which patients, if any, should receive empirical
antifungal treatment.
Future Directions
Future directions discussed by the summit members reflected

many of the limitations indicated by McGregor et al. [76].
Appropriately designed epidemiologic studies with rigorous attention to important design details are required, including a
consistent definition of inappropriate therapy based on in
vitro susceptibility data, separate consideration of empirical and
definitive therapy, and appropriate statistical adjustment for the
baseline severity of illness of the patient. The need for morerapid diagnostic tests was emphasized. Finally, until such bedside diagnostic technologies are available, additional studies to
identify patients at risk for colonization or infection with MDR
pathogensespecially the fungiare required to best balance
the dual needs for judicious and effective empirical antimicrobial therapy for patients with BSIs.
STATEMENT 5: INITIAL APPROPRIATE
ANTIMICROBIAL THERAPY AND SOURCE
CONTROL ARE THE MOST IMPORTANT
DETERMINANTS OF OUTCOME IN SEVERE
SEPSIS AND SEPTIC SHOCK
Severe sepsis and septic shock are commonly encountered consequences of severe infection, both community acquired and
hospital acquired [97]. Sepsis and its adverse sequelae, shock
and organ dysfunction, are currently the 10th leading cause of
death in the United States and one of the most common causes
of death in the noncoronary ICU [97, 98]. Martin et al. [93]
found that the incidence of sepsis in the United States has
to administration of effective antimicrobial therapy on the clinical outcome also makes intuitive sense to many clinicians.
The primary rate-limiting steps to effective antimicrobial
therapy for health careassociated BSI remain diagnostics and
susceptibility testing. Even when guided by local antimicrobial
susceptibility, empirical therapy often becomes little more than
an educated guess. Until diagnostic strategies emerge to provide
real-time, point-of-care information on the identification and
susceptibility of a bloodstream pathogen, clinicians will be
forced to make important decisions about initial antibiotic selection without the luxury of definitive data. In this light, observations from these studies are important.
Among patients with BSI caused by gram-negative pathogens, early effective therapy was usually associated with reduced
mortality, and the likelihood of accomplishing early effective
therapy was higher when combination empirical antimicrobial
therapy was employed. Obviously, clinicians should consider
both the risks and benefits of adding a second antibioticoften
an aminoglycosideto an empirical regimen to treat gramnegative pathogens in individual patients. However, the predominance of MRSA as a cause of health careassociated bacteremia, the availability of an FDA-approved agent for the
treatment of S. aureus bacteremia and right-sided endocarditis
(e.g., daptomycin), and the prospects of several anti-MRSA
agents in late stages of clinical development emphasize the need
for appropriately designed clinical studies to better address this
important issue. Significant controversy remains over the role
of vancomycin for treatment of MRSA bacteremiawhether
empirical or targeted [95, 96].
Finally, the emerging importance of fungi as a cause of BSI
and sepsis is a potentially important change to consider in the
management of BSI. For example, in an evaluation of the hospital discharge records of 110 million cases of sepsis in the
United States over 22 years, there was an annualized increase
in the incidence of sepsis of 8.7%, from 164,000 cases (82.7
per 100,000 population) to nearly 660,000 cases (240.4 per
100,000 population). During this time, the rate of sepsis due
ministration). Studies that are amenable to prospective, randomized clinical trials involve the use of single versus multiple
antibiotic agents and the effects on outcome parameters.
The adequacy of source control is also a difficult topic to
evaluate with the published literature [104]. Few studies have
commented on the adequacy of drainage or debridement. The
adequacy of source control is evaluated primarily by retrospective review of the clinical course or by a post hoc adjudication committee. As in investigations evaluating the effectiveness of antibiotic therapy, ethical concerns preclude a study
of adequate versus inadequate source control. Therefore, to
answer both of these important questions, we must turn our
attention to an analysis of the limited available literature, with
emphasis on clinical trials that have evaluated or commented
on the adequacy of either antibiotic therapy or source control,
as it relates to outcome for patients with sepsis.
Methods
A PubMed search to identify studies related to appropriate

antibiotic use and source control in sepsis outcome was performed on 14 September 2007. The search was limited to 1996
through September 2007, and all searches were restricted to the
English language, adult humans, and full-text articles. The text
words adequate antibiotics yielded 18,240 articles, sepsis/
septic shock yielded 14,423 articles, and survival/mortality
yielded 93,638 articles. When the search for adequate antibiotics was combined with that for sepsis/septic shock, the
result was 1209 articles. The combination of the search for
adequate antibiotics and the search for survival/mortality
yielded 7744 articles. When the search was limited to adequate
antibiotics AND sepsis/septic shock AND survival/mortality,
the result was 680 articles. A review of the titles and abstracts
of the 680 articles resulted in 16 articles that were relevant to
the statement. In addition, an evidence-based review from the
Surviving Sepsis Campaign on the topics of adequate antimicrobial therapy and adequate source control was examined
along with the references from these articles [100, 104].
Evidence
To evaluate evidence concerning appropriate antibiotic therapy

for severe sepsis and septic shock, we must first acknowledge
that no clinician would intentionally give a patient ineffective
antibiotic therapy. It is convention to classify appropriate or
effective antibiotic therapy on the basis of the culture and susceptibility results; however, not all patients with sepsis will have
positive culture results. Most large clinical trials report that
approximately one-third of patients have positive blood culture
results and approximately one-quarter of patients will have no
positive culture result of any type [105]. It is also disappointing
to find that several large epidemiologic studies and clinical trials
involving patients with sepsis do not give any data concerning
dramatically increased over a 22-year period (19792000), from

82.7 cases per 100,000 population to 240.4 cases per 100,000
population, for an annualized increase of 8.7%. The incidence
of severe sepsis is predicted to continue to rise in the next 2
decades [99].
To prevent the progression to organ dysfunction and other
adverse sequelae of severe sepsis and septic shock, it is important to identify the patient with sepsis as early as possible and
to institute effective therapy [97, 98, 100]. Representatives from
11 societies proposed a consensus guideline for severe sepsis
and septic shock management [101], and they recommended
the following actions: the early administration of effective antibiotics, source control when appropriate, provision of early
goal-directed fluid resuscitation and vasopressor support when
required, maintenance of adequate oxygenation and ventilation
as necessary, use of physiologic steroid-replacement therapy for
vasopressor-dependent patients with relative adrenal insufficiency, antithrombotic therapy when warranted and not contraindicated, and prevention of the various complications of
critical illness [101]. The Surviving Sepsis Campaign recently
published an update to these recommendations [102] that advises institution of early, effective antibiotic therapy; evaluation
of the need for source control; early, goal-directed fluid resuscitation with either crystalloid or colloid norepinephrine or
dopamine as needed to maintain a mean arterial blood pressure
65 mm Hg; dobutamine for patients with myocardial depression; packed RBCs to treat hemoglobin levels of !7.0 g/dL;
use of lung-protective ventilatory support strategies when
needed; weaning from ventilatory support by protocol and
spontaneous breathing trials; prevention of complications of
critical illness (insulin to maintain blood sugar levels at !150
mg/dL); deep vein thrombosis prophylaxis; stress ulcer prophylaxis; and use of sedation protocols [102].
The use of early, effective antibiotic therapy and source control, when indicated, has been considered the cornerstone of
sepsis therapy. Conventional wisdom would suggest that appropriate (effective) antibiotic therapy is essential for an improved outcome. This hypothesis will never be clinically tested
because it would be considered unethical to deprive a patient
of timely or effective antibiotic treatment.
Most of our current evidence in support of early, effective
antibiotic therapy is based on retrospective outcome analysis
comparing early, effective antibiotic therapy with initially ineffective antibiotic agents. Because the definition of sepsis has
varied over time and, in the older literature, often required the
presence of bacteremia and hypotension, it is difficult to make
comparisons with some of the current data [103]. However, it
is still apparent that, regardless of the definition, mortality rates
improve with timely use of effective, appropriate antibiotic
therapy. Other important aspects of antibiotic effectiveness relate to the timing of antibiotic therapy (early vs. delayed ad-
initially, after results of cultures were obtained, and after the

susceptibility results were available; this study noted an increase
of up to 3.18 in the RR for death, when effective therapy was
compared with ineffective therapy at all time points [112].
The investigation of innovative therapies to improve the outcome of severe sepsis and septic shock seems a perfect opportunity to evaluate the relationship between effective antibiotic
therapy and outcome. Unfortunately, this important variable
is often not assessed as part of a trial. Typically, the evaluation
of effective antibiotic and/or source control therapy involves
the use of a post hoc adjudication committee to evaluate the
culture and susceptibility results in relation to the antimicrobial
agents administered. A multicenter, prospective, randomized,
double-blind, controlled trial of high-dose intravenous immunoglobulin (IVIG), in addition to antibiotic therapy, given
to patients with sepsis undergoing surgery, found that overall
mortality increased from 20.4% with effective antibiotic therapy
to 87.5% with ineffective therapy [113].
In the PROWESS trial, drotrecogin alfa (activated) significantly reduced mortality among patients with severe sepsis, but
148 patients (8.8%) in the intention-to-treat population (patients given drotrecogin alfa [activated], n p 74; patients given
placebo, n p 74) received inadequate antibiotic therapy [114].
In a subsequent analysis, it was noted that the observed mortality rates for patients given drotrecogin alfa (activated) and
patients given placebo who did not receive adequate antibiotic
therapy (29.7% and 43.2%, respectively) were higher the observed mortality rates for those who received adequate antiinfective therapy (24.2% and 29.6%, respectively) [115]. The
provision of adequate antimicrobial treatment, when evaluated,
has been quite variable, with reported values ranging from 75%
[116] to 88% [117].
The timing of antibiotic administration has also been found
to be an extremely important factor in outcome. A retrospective
cohort study of 2731 patients with hypotension and sepsis
found that mortality increased 7.6% for each 1-hour delay in
antibiotic administration after the onset of hypotension [4].
When antibiotics were administered within 30 min after the
onset of hypotension, the survival rate was 82.7%, but it fell
to 42% when the antibiotics were delayed 6 h after the onset
of hypotension. To improve the timely administration of antibiotics and other diagnostic and therapeutic aspects of sepsis
management, clinicians have incorporated recommended therapies into bundles of care [118]. Nguyen et al. [118] conducted
a 2-year, prospective, observational cohort study of 330 patients
who presented to the emergency department with severe sepsis
or septic shock, and they found a significant reduction (from
20.8% to 39.5%; P ! .01) in mortality when bundles were used
and, specifically, when antibiotics were administered within 4
h after presentation (OR, 0.38; 95% CI, 0.180.80; P p .03).
Adequacy of source control is evaluated even less frequently
the administration of effective antibiotic therapy or the adequacy of source control [106, 107]. Other important questions
(related to the use of culture and susceptibility results) surround
the ability of in vitro culture results to reflect in vivo effects of
antibiotics, as well as the debate about the thresholds differentiating a true pathogen from a colonizing organism. A retrospective review of 612 patients with bacteremia caused by
gram-negative bacteria demonstrated a significant reduction in
mortality when appropriate antibiotic therapy was administered
[108]. Fish [109] reviewed mortality differences between patients receiving appropriate antimicrobial therapy and patients
receiving inappropriate antimicrobial therapy in 11 studies and
demonstrated an association between a significant reduction in
mortality and appropriate antibiotic treatment.
Furthermore, in the Surviving Sepsis Campaign, the 11 societies used a modified Delphi method to define the role of
effective antimicrobial therapy in the management of severe sepsis and septic shock [100]. The consensus committee concluded
that prompt institution of effective antimicrobial therapy is one
of the most important predictors of outcome; unfortunately,
most of the evidence in support of their recommendations reflects category III, IV, or V evidence (table 3). Using the same
modified Delphi method to assess source control in the management of severe sepsis and septic shock, the same group concluded that source control represents a key component for successful sepsis management and should be used when indicated
[104]. Source control includes drainage of infected fluids, debridement of infected soft tissues, and removal of infected devices
or foreign bodies. Source control should correct anatomic derangements resulting in ongoing contamination and restore function [104].
In Spain, Garnacho-Montero et al. [110] conducted a prospective cohort study of 406 critically ill patients with sepsis in
a tertiary care hospital, to determine the impact of effective,
empirical antibiotic therapy on early, 28-day, and 60-day mortality. The administration of inadequate antibiotic therapy was
associated with an RR of 1.55 (95% CI, 1.202.02) for increased
mortality, compared with effective antibiotic therapy. An observational, prospective cohort study of 3413 patients with BSI
also demonstrated an increased mortality RR (1.6; 95% CI,
1.31.9) associated with the administration of inadequate antibiotic therapy [111]. Ineffective antibiotic therapy was found
to increase all-cause mortality (52.1% vs. 23.5%; RR, 2.22; 95%
CI, 1.792.76; P ! .001) and infection-related mortality (42%
vs. 17.7%; RR, 2.37; 95% CI, 1.833.08; P ! .001) in 2000 consecutive ICU patients included in a prospective, observational,
cohort study [3]. In this study, the use of ineffective antibiotics
was greater in the setting of nosocomial infection with or without prior antibiotic therapy. A prospective study of 707 patients
with bacteremia and/or fungemia evaluated the impact of effective versus ineffective antimicrobial therapy administered
Grading of Evidence
On the basis of a review of the 12 studies cited above, 67% of

the workshop members agreed that the nature of the evidence
available to support this statement was category II, whereas
17% voted category III, and 17% voted category V (table 3).
Level of Support

voted to accept the statement with major reservations, and 0%
voted to reject the statement. In comparison, of the 744 IDSA
accept the statement completely, 35% voted to accept the statement with some reservations, 10% voted to accept the statement with major reservations, 5% voted to reject the statement
Discussion
Consideration of the statement concerning the importance of

effective antibiotics and source control in outcomes for patients
with severe sepsis and septic shock caused the vast majority
(180%) of the summit participants to support the statement
either completely or with some reservations. This conclusion
was reached by the participants despite the lack of multicenter,
prospective, randomized, placebo-controlled, double-blind
clinical trials substantiating the importance of effective antibiotic therapy in outcomes for patients with severe sepsis and
septic shock. Despite this lack of evidence, most clinicians believe that administration of early, effective antimicrobial therapy
and source control, when indicated, are among the key components of management of severe sepsis and septic shock. Other
key components of effective sepsis management include fluid
resuscitation, restoration and maintenance of hemodynamic
function, support of oxygenation and ventilation as necessary,
and prevention of the complications of critical illness [97, 98,
101, 102]. Ethical considerations and common sense prohibit
conducting clinical trials to establish the key role for effective
antibiotics and source control in the management of severe
sepsis. It is also impossible to establish the relative value of one
key component compared with another. The various components of effective sepsis management may be viewed as links
in a chain, and the chain is only as strong as its weakest link.
Therefore, without provision of all necessary aspects of sepsis
management, the outcome will be less than optimal.
Unfortunately, technology has not progressed to the point
where the clinician can rapidly diagnose the microbial cause
of the infection leading to sepsis or determine the susceptibility
of the organism at an early point in time and thus enable
provision of effective antibiotics at the time of diagnosis. Even
the diagnosis of sepsis is often not confirmed until the results
of cultures are available for review. This process typically takes
hours to days, and, to date, is not available during the golden
hour of initial management when the best outcome can be
expected [4]. The use of markers for sepsis (e.g., procalcitonin
levels, soluble triggering receptors expressed on myeloid cells,
and peptide nucleic acid fluorescence in situ hybridization) and
other techniques for early diagnosis may improve the diagnosis
of sepsis, but we still lack an early indicator of organism susceptibility to various antibiotics [120122]. For now, clinicians
have directed their attention to the implementation of sepsis
bundles, to ensure the early administration of effective sepsis
therapy, including antibiotics, to achieve the best possible outcomes for patients [118].
Future Directions
Although not necessarily the major determinant of outcome in

severe sepsis and septic shock, early, effective antibiotic therapy
and source control, when indicated, are among the key components necessary for optimal outcome. Future efforts will
likely focus on uses of advanced diagnostic techniques to identify specific bacterial and fungal pathogens, such as fluorescence
in situ hybridization and PCR. These tests will help facilitate
early diagnosis of sepsis and will direct more-appropriate early
therapy. In addition, the efficacy of antibiotic treatment should
be more definitively investigated in terms of the MIC of the
microbe and the blood level and, potentially, the mechanism
of action of the antibiotic. Relying only on the categories susceptible or resistant may not adequately define appropriate antibiotic treatment. This has particular relevance to antibiotics such as vancomycin and aminoglycosides. This strategy
than is antimicrobial therapy. Among patients requiring surgery

for source control in a multicenter, prospective, randomized,
double-blind, placebo-controlled trial of platelet-activating factor acetylhydrolase for treatment of severe sepsis and septic
shock, adequate source control occurred in 190% of both treatment groups [117]. In contrast, in the PROWESS trial of drotrecogin alfa (activated) for severe sepsis, the initial sourcecontrol procedure was judged to be adequate in only 90 (50.8%)
of 177 patients receiving drotrecogin alfa (activated) and 86
(47.3%) of 182 patients receiving placebo. Initial source control
was inadequate for 38 (21.5%) of 177 patients receiving drotrecogin alfa (activated) and 51 (28.0%) of 182 patients receiving placebo and was indeterminate for 49 (27.7%) and 45
(24.7%), respectively. In patients with adequate or inadequate
source control, no reduction in mortality was noted for drotrecogin alfa (activated). In patients with indeterminate source
control, drotecogin alfa (activated) was associated with a reduction in mortality (37.0% vs. 56.6%; OR, 0.65; 95% CI, 0.43
1.00; absolute risk reduction, 19.6%) [119].
Figure 5. Voting comparison for statement 5 (Initial appropriate antimicrobial therapy and source control are the most important determinants of
outcome in severe sepsis and septic shock). IDSA refers to the members of the Infectious Diseases Society of America who responded to a Webbased survey; Summit refers to the Health CareAssociated Infection Summit panel.
STATEMENT 6: VANCOMYCIN IS OBSOLETE

FOR TREATING MRSA INFECTIONS
combining the elements failure (162 articles), Staphylococcus

aureus (74 articles), and MRSA (30 articles). Excluding case
reports yielded 10 articles. Finally, 3 abstracts on in vitro susceptibility were added from abstracts from the annual meetings
of the IDSA and the Interscience Conference on Antimicrobial
Agents and Chemotherapy.
Vancomycin has been the workhorse antimicrobial for the treatment of MRSA infections for 140 years. In the past decade,
the prevalence of hospital-associated MRSA infections has
reached 64% in most US hospitals [123]. In addition, there has
been a virtual explosion of community-onset MRSA infections
among young, healthy individuals in a wide variety of situations, including high school, college, and professional football
teams; prisons; and so forth. Although vancomycin was prescribed sporadically and infrequently 2030 years ago, its use
has increased exponentially over the past decade. As a consequence, there is increasing evidence that vancomycin is not
currently as effective as it once was; this evidence results from
frank treatment failures as well as growing concern related to
the emergence of various types of vancomycin resistance. The
current epidemics of hospital-associated MRSA and community-onset MRSA infections have developed rapidly, and there
are no concrete guidelines addressing the current problems
associated with treatment of MRSA infections. The purpose of
the current investigation is to examine the mounting evidence
regarding treatment failures and reduced in vitro activity of
vancomycin against MRSA.
Methods
A PubMed database search to identify studies related to vancomycin was concluded on 26 September 2007. The search term
vancomycin yielded 13,064 articles. Vancomycin limited to
the English language resulted in 11,528 articles and, when combined with last ten years, yielded 4181 articles. When these
elements were combined with human, 3166 articles were
found. Further narrowing of the field was accomplished by
Evidence
Changes in the susceptibility of MRSA to vancomycin.

There have been 3 studies performed in the United States that
evaluated the in vitro susceptibility of MRSA strains to vancomycin over time, with the objective of identifying trends in
the susceptibility of MRSA to vancomycin. In the first study,
the MIC90 values for vancomycin among MRSA strains were
compared in vitro at M. D. Anderson Hospital across a 20year period; 25 strains from 1985 and 28 strains from 2004
were examined. This study demonstrated that the MIC90 increased from 0.2 mg/mL to 2.0 mg/mL during this nearly 20year time span [124]. The second study compared the in vitro
susceptibility of blood isolates of MRSA in 2002 with that of
blood isolates of MRSA in 2005 at the New England Medical
Center (Boston, MA) and demonstrated a dramatic increase in
the MICs for vancomycin (figure 6) [125]. The third study was
an in vitro investigation of MICs for vancomycin among 945
strains of S. aureus from 2000 and 1418 strains of S. aureus
from 2004. In 2000, 79.9% of strains had vancomycin MICs
of 0.5 mg/mL, and 19.9% (P ! .01) had vancomycin MICs of
1.0 mg/mL. In contrast, in 2004, 28.8% had vancomycin MICs
of 0.5 mg/mL, whereas 70.4% (P ! .01) had vancomycin MICs
of 1.0 mg/mL [126]. According to this study, a marked increase
in vancomycin MICs was apparent for MRSA isolates in Los
Angeles from 2000 through 2004.
Clinical failure of vancomycin in patients with bacteremia
caused by MRSA strains with MICs of 4 mg/mL. An observational series of 14 case reports of clinical failures of vancomycin for treatment of bacteremia caused by MRSA strains
with MICs of vancomycin 4 mg/mL were compiled [127]. These
not only will result in better sepsis outcome but also will assist
with antibiotic stewardship and potentially minimize the development of bacterial resistance.
Figure 6. In vitro comparison of vancomycin MICs at the New England

Medical Center (Boston, MA), in 2002 and 2005. Adapted from [125].
Figure 7. Clinical failures of vancomycin treatment for vancomycinsusceptible Staphylococcus aureus: the role of MICs. Data are from [134].
failures were the primary evidence compelling the Clinical and

Laboratory Standards Institute to lower the vancomycin-susceptible MRSA MIC breakpoint to 2 mg/mL.
Vancomycin-resistant MRSA. Absolute resistance of
MRSA strains has been described [128]. These strains are called
vancomycin-resistant MRSA and have been defined as strains
with MIC of 116 mg/mL for vancomycin. Thus far, 7 vancomycin-resistant MRSA strains have been described in Japan and
the United States [129].
Vancomycin-intermediate MRSA (VISA) and heteroresistant VISA (hVISA). The first descriptions of emergence of
vancomycin-intermediate strains of MRSA [130] or glycopeptide-intermediate S. aureus [131] were from Japan, and these
are defined as having MICs of 48 mg/mL [130]. Soon thereafter, clinical failures of vancomycin for patients with MRSA
bacteremia caused by vancomycin-intermediate strains were reported. In a retrospective study in Australia, 76% of 25 patients
with MRSA bacteremia who were given treatment with vancomycin experienced failed therapy, as defined as persistence
of bacteremia for 17 days. Interestingly, these MRSA strains
were relatively susceptible to vancomycin, with MICs of 24
mg/mL [132]. Although these strains were defined as being VISA
strains, they contained populations of microbes that were resistant to vancomycin. Because of the heterogenous population
of MRSA, these strains are called hVISA. In the laboratory,
demonstration of heteroresistance requires a large inoculum of
107 MRSA organims per mL because 1 in 100,000 bacteria is,
in fact, resistant to vancomycin. It likely has clinical relevance
for cases in which the load of MRSA is high, as one might
expect in a large abscess, necrotizing fasciitis, consolidative
pneumonia, bacteremia, and endocarditis. Because most clinical
laboratories are standardized to use inocula of 105 MRSA organisms for susceptibility testing, newer methods must be developed to alert clinicians of this phenomenon.
Failure of vancomycin in bacteremia caused by hVISA.
A retrospective study of isolates from all patients with MRSA
bacteremia (n p 53) in a hospital in Australia evaluated a 12-
month period (July 2001June 2002), with the objective of

identifying the prevalence of hVISA and the outcomes for these
patients given treatment with vancomycin [133]. No VISA isolates were recovered; however, 5 (9.4%) of 53 MRSA isolates
were heteroresistant to vancomycin. Patients infected with
hVISA were more likely to have high bacterial loads (P p
.001), compared with patients infected with vancomycin-susceptible MRSA, and patients with hVISA infections were more
likely to experience a failure of vancomycin treatment (P !
.001), compared with patients infected with vancomycin-susceptible MRSA [133].
Failure rate of vancomycin treatment as a function of rising
MICs in patients with infection caused by vancomycin-susceptible MRSA. A total of 122 S. aureus isolates, 63 of which
were MRSA with vancomycin MICs of 0.52.0 mg/mL, from
87 patients given treatment with vancomycin were analyzed.
Of the 87 patients, 45 had no clinical or bacteriological response
to vancomycin. Among the 36 clinically evaluable patients infected with S. aureus strains that had the accessory gene
regulator (agr) group II polymorphism, 31 had an infection
that failed to respond to vancomycin, whereas only 5 had an
infection that responded successfully to vancomycin. There was
a significant association between vancomycin treatment failure
(45 of 63) and MIC increase (P p .004) (figure 7) [134].
Failure of vancomycin as a function of the rapidity of bacterial killing. This investigation analyzed isolates (n p 30)
from patients with bacteremia in 24 US hospitals, with the objective of correlating clinical failure with in vitro vancomycin
susceptibility and bactericidal activity. For MRSA isolates with
vancomycin MICs 0.5 mg/mL, vancomycin was 55.6% successful in the treatment of bacteremia, whereas vancomycin was
only 9.5% (P p .02) effective in cases in which MRSA MICs for
vancomycin were 12 mg/mL. In addition, the failure rate for
vancomycin was 100% if !4.71 log of bacteria were killed in 72
h (n p 9); 77% if 4.716.26 log of bacteria were killed in 72 h
(n p 13); and 50% if 16.27 log of bacteria were killed in a 24-
or alternative therapy should be considered for invasive infections caused by these strains.
Will higher trough levels of vancomycin be associated with
a higher incidence of renal toxicity? In a prospective review
of patients with HAP, 43 patients were followed up for changes
in creatinine clearance (n p 43 ). Overall, there was a 25% decrease in creatinine clearance among all patients receiving vancomycin. There was a 30% decrease in creatinine clearance
among patients with a low trough level (515 mg/mL), compared with a 60% decrease in creatinine clearance among patients with high trough levels of 115 mg/mL (P p .006) [65].
Grading of Evidence
Of the workshop participants, 83% voted that the evidence to

support the statement was category III, and 17% voted that it
was category II (table 3).
Level of Support
Interestingly, 36% of the summit participants voted to accept

the statement with some reservations, 36% voted to accept the
statement with major reservations, 18% voted to reject the
statement with reservations, and 9% voted to reject the statement completely. In comparison, of the 744 IDSA members
who participated in the online survey, 1% accepted the statement completely, 9% accepted the statement with some reservations, 7% accepted the statement with major reservations,
38% rejected the statement with reservations, and 45% rejected
the statement completely (figure 8).
Discussion
This statement is of key importance, given the emerging data

regarding reduced susceptibility of MRSA to vancomycin and
the increasing reports of failure of vancomycin in the treatment
of clinical infections. Recognition of this problem is not yet
widespread, as evidenced by the IDSA memberships diverse
responses to this statement that vancomycin is obsolete in the
treatment of MRSA infections. Summit participants responses
were diverse yet more accepting of the statement.
The quality of the evidence supporting emerging resistance
to vancomycin and so-called MIC creep is not robust, largely
because it reflects regional differences and is not yet on a national scale. Still, these small studies are compelling because
the studies were done in several different geographical regions
by independent investigators. There may be some bias, since
many of the sites are large hospitals in densely populated
regions of the United States where vancomycin use may be
greater. In addition, some studies are retrospective and start
with patients who experienced failure of vancomycin treatment.
Not surprisingly, some of the isolates from these cases have
reduced susceptibility to vancomycin. Still, all studies presented
here support the contention that strains of MRSA are emerging
h period (n p 8). The differences between treatment groups were

statistically significant (P p .05) [135].
Vancomycin tolerance among MRSA isolates. Another
cause of failure of antimicrobial treatment is the phenomenon
of bacterial tolerance, which is defined as a minimum bactericidal concentration (MBC)/MIC ratio of 32 or an MBC of
16. Of 207 evaluated strains of S. aureus, 102 were MRSA;
14.7% of wild-type MRSA demonstrated tolerance, whereas
69.3% of hVISA and 100% of VISA isolates demonstrated tolerance. Thus, even large doses of vancomycin may not reach
bactericidal blood and tissue levels sufficient to kill tolerant
strains of MRSA [136].
Does increasing the dose of vancomycin to achieve serum
trough levels of 115 mg/mL increase efficacy, or does it increase
nephrotoxicity? The rationale for this study was a perceived
increase in vancomycin treatment failures for infections caused
by vancomycin-susceptible MRSA strains with high MICs and
the general practice to recommend a higher vancomycin target
trough level of 1520 mg/mL, in an effort to increase efficacy.
However, there are no data regarding potentially increased renal
toxicity associated with these higher doses.
In a prospective cohort study of patients with MRSA infections (n p 95), investigators sought to correlate the distribution of vancomycin MICs and treatment outcomes with trough
levels at least 4 times the MIC. There was no nephrotoxicity
when trough levels were !15 mg/mL. However, 11 (12%) of 63
patients developed nephrotoxicity with trough levels 15 mg/
mL. Multivariate analysis implicated concomitant nephrotoxins, such as aminoglycosides and amphotericin B. In the hightrough-level group, only 2% (in the absence of nephrotoxins)
developed nephrotoxicity [137]. Of the 95 patients in the study,
51 (54%) were infected with high-MIC strains and had pneumonia (77%) and/or bacteremia. An initial response rate of
74% was achieved when the target trough level was attained,
irrespective of MIC. However, despite achieving the target
trough level, the group infected with high-MIC strains had
fewer end-of-treatment responses (24 [62%] of 39 vs. 34 [85%]
of 40; P p .02) and higher infection-related mortality (11
[24%] of 51 vs. 4 [10%] of 44; P p .16), compared with the
group infected with low-MIC strains. Infection with a highMIC strain (P p .03) and high APACHE II score (P p .009)
were independent predictors of poor response in multivariate
analysis. Nephrotoxicity occurred only in the high-trough-level
group (11 [12%] of 63); this was significantly predicted by
concomitant therapy with other nephrotoxic agents.
A high prevalence of clinical MRSA strains with elevated
vancomycin MICs (2 mg/mL) requires aggressive empirical vancomycin dosing to achieve a trough level of 115 mg/mL. The
rationale for this recommendation is obvious, yet there is little
clinical experience with high vancomycin dosages, and toxicity
becomes an important issue, as discussed below. Combination
over time with reduced susceptibility to vancomycin and that

this phenomenon is associated with or causes treatment failures.
Thus, although the quality and size of these studies are not
robust, it is clear that vancomycin susceptibility among MRSA
isolates is changing rapidly, and these preliminary studies are
providing early warning of larger problems to come. It is also
true that very large doses of vancomycin may be necessary to
achieve an area under the concentration-time curve/MIC ratio
for MRSA infections caused by strains with vancomycin MICs
of 12 mg/mL [138].
Future Directions
STATEMENT 7: SERIOUS HAIs DUE TO

SUSPECTED GRAM-NEGATIVE BACTERIA
SHOULD BE TREATED EMPIRICALLY WITH
DUAL COVERAGE THAT INCLUDES AN
AMINOGLYCOSIDE
The terminology of HAIs is rapidly permeating the classification

of various infection types. Classification schemes for both BSIs
and pneumonia have already been adopted. These classifications identify specific patients at risk, as well as treatment recommendations. HAIs can describe a wide variety of infection
types; therefore, it is important to focus recommendations on
the basis of patient-specific circumstances. The evaluation of
this statement was insupportable in its entirety; therefore, the
review of the literature centered on the use of dual empirical
coverage as well as the use of an aminoglycoside in combination
therapy. The use of dual empirical coverage is well supported
in the literature; however, the selection of an aminoglycoside
is problematic because it is not necessarily appropriate in all
clinical situations. There are 5 inherent issues that will be addressed in the evaluation of this statement: the role of adequate
empirical therapy for serious HAI in the determination of outcome [139], the potential value of combination antimicrobial
Methods
A PubMed literature search was conducted on 4 September

2007 to identify studies related to dual empirical coverage of
infections with gram-negative pathogens. The search term
cross infection/drug therapy or cross infection therapy was
combined using the AND function with antibiotic therapy
and gram-negative. Results were limited to the English language and studies published within the past 5 years. The search
yielded 204 articles, 2 of which were relevant to the statement.
A second PubMed search was conducted using the search terms
gram-negative bacterial infections/drug therapy and cross
infection, combined using the AND function. This search
yielded 200 articles, 10 of which were relevant to the statement.
Twelve additional articles were also reviewed from previous
searches.
Evidence
The role of adequate empirical therapy for serious HAI in the

determination of outcome. The outcome of serious HAI is
improved by selection of adequate empirical antibiotic therapy,
as defined by susceptibility of the infecting organism(s) to the
agent(s) selected. Several retrospective and prospective clinical
studies since the mid-1990s have provided statistical evidence
of the positive effect of adequate empirical antibiotic therapy
on clinical outcome. These studies have also concluded that
adjustment of therapy when susceptibility data become available does not reverse the unfavorable effect of inadequate empirical therapy.
In 1997, Luna et al. [139] described a prospective cohort
study of 132 patients with VAP to determine the impact on
outcome of a change in antibiotic therapy based on the results
of culture of specimens collected by early bronchoalveolar lavage (BAL). Among patients from whom a pathogen was recovered by BAL, mortality was 91% after inadequate initial
therapy and 38% after adequate initial therapy (P ! .001). When
therapy was changed according to BAL culture results, mortality
was comparable to that among patients who continued to receive inadequate therapy. Kollef and Ward [140] reported the
results of a similar study in 1998 to determine the influence
of mini-BAL cultures on subsequent changes in antibiotic therapy and outcomes in 130 patients with suspected VAP. Mortality
among patients for whom therapy was either begun or changed
Future directions discussed by the summit members clearly

involve additional studies. Prospective studies that evaluate the
in vitro susceptibility of MRSA strains to vancomycin on regional and national scales are sorely needed. New assays to
detect heteroresistance among clinical isolates of MRSA need
to be developed and correlated with clinical outcomes. Finally,
prospective studies that evaluate clinical responses of MRSA
infections, in terms of susceptibility issues and vancomycin
trough levels, should be done immediately. Until then, if vancomycin is to be used, these data mandate increased knowledge
of the MICs and vancomycin trough levels, to ensure that patients are given appropriate treatment. Specifically, clinical laboratories need to provide clinicians with the actual vancomycin
MIC of the MRSA strain, because clinical failure increases proportionally to the MIC, even among susceptible strains.
therapy in the determination of outcome [140], the potential

efficacy of aminoglycosides as a component of combination
antimicrobial therapy for serious HAI [3], the potential efficacy
of quinolones as a component of combination therapy for serious HAI [141], and the influence of antibiotic-resistance surveillance on selection of therapeutic agents [46]. Each of these
issues will be discussed with respect to evidence in favor of or
against acceptance of the statement.
Figure 8. Voting comparison for statement 6 (Vancomycin is obsolete for treating MRSA infections). IDSA refers to the members of the Infectious
Diseases Society of America who responded to a Web-based survey; Summit refers to the Health CareAssociated Infection Summit panel. MRSA,
methicillin-resistant Staphylococcus aureus.
quate empirical combination therapy. In addition, adequate

definitive combination therapy given when susceptibility results
became available did not improve survival, compared with adequate definitive monotherapy. These results support the benefit of adequate empirical monotherapy or combination therapy, compared with delayed definitive therapy for bacteremia
due to P. aeruginosa. Adequate combination empirical therapy
was also more effective than adequate empirical monotherapy.
Neutropenic patients accounted for 30% (34 of 115 patients)
of the study population.
A prospective, observational study of 230 patients with Klebsiella bacteremia showed no difference (20% vs. 18%; P 1 .05)
in 14-day mortality between those given monotherapy and
those given combination therapy (b-lactam plus aminoglycoside) [143]. However, for the subgroup of patients who experienced hypotension (systolic blood pressure, 90 mm Hg)
within 72 h before or on the day of the positive blood culture,
those who received combination therapy experienced significantly lower mortality (24%) than did those who received
monotherapy (50%).
A meta-analysis published in 2004 reviewed 17 studies that
compared combination therapy and monotherapy for bacteremia caused by gram-negative organisms [144]. The authors
found no mortality benefit with combination therapy. However,
analysis of only P. aeruginosa bacteremia showed a significant
mortality benefit (OR, 0.50; 95% CI, 0.300.79).
In the above-mentioned studies, most of the effective combination therapies used b-lactam and aminoglycoside agents to
which common isolates were susceptible. In the more recent
era of MDR gram-negative bacilli, use of novel empirical antibiotic combinations may be dictated by advanced local resistance patterns. In certain areas of New York City and Morocco,
effective empirical combination therapy requires use of a polymyxin alone or in combination with other agents, according
to special in vitro susceptibility tests [145147].
The potential efficacy of aminoglycosides as a component
of combination antimicrobial therapy for serious HAIs.
at the time of BAL culture results was 60.8%, compared with

33.3% among patients requiring no change in initial antibiotic
therapy (P ! .001). Thus, a delay in initiation of adequate therapy was associated with greater mortality.
A prospective cohort study by Kollef et al. [3] was subsequently reported in 1999; the report described 655 critically ill
infected patients admitted to the ICU. The overall mortality
was 15.6%. Mortality among patients receiving inadequate initial antimicrobial treatment was 52.1%, compared with 12.2%
among patients who received adequate initial treatment (P !
.001). The effects of inappropriate initial antimicrobial therapy
on outcomes for 286 patients with bacteremia due to antibioticresistant organisms were reported by Kang et al. in 2005 [141].
In a study of patients with a high-risk source of bacteremia,
inappropriate initial antibiotic therapy was independently associated with increased mortality (mortality among those given
appropriate therapy, 27.4%; mortality among those given inappropriate therapy, 38.4%; P p .049) (OR, 3.64; 95% CI,
1.1311.72; P p .030). Fraser et al. [46] reported similar results
in a study published in 2006 involving 920 patients with microbiologically documented infections. Thirty-day all-cause
mortality was 20.1% among those who received inappropriate
initial empirical antibiotic therapy and was 11.8% among those
who received appropriate therapy (P p .001 ). In a study of
patients with bacteremia published in 2007 by Tumbarello et
al. [84], 186 patients infected with ESBL-producing organisms
had 21-day mortality of 59% after inadequate initial antimicrobial therapy, compared with 18.5% among those who received adequate initial therapy (P ! .001).
The potential value of combination antimicrobial therapy
in the determination of outcome. The potential benefit of
combination antibiotic therapy, compared with effective singledrug therapy, remains ill defined. However, in a retrospective
study of 115 patients with P. aeruginosa bacteremia, Chamot
et al. [142] found that adequate empirical combination therapy
yielded lower 30-day mortality than did adequate empirical
monotherapy, inadequate empirical monotherapy, or inade-
that these patients had received appropriate therapy. Currently,

there is no real clinical data supporting a synergistic effect of
dual coverage for P. aeruginosa or any other gram-negative
bacilli. The same is true for resistance. The main rationale for
dual coverage of gram-negative bacilli is to increase the likelihood of the administration of appropriate therapy. On another
note, in 2007, Livermore and Pearson [157] analyzed the utility
of international, national, and local resistance surveys. They
concisely summarized the essence of their findings in the title
Antibiotic resistance: location, location, location, emphasizing that for patient management, good local data are essential
[157, p. 7]. They highlighted the complexity of issues and large
variances in resistance rates according to country, patient characteristics, and unit of care (i.e., nursing home vs. ICU). The
authors concluded that, although these surveys help to illustrate
trends, local susceptibility data are essential to good clinical
management.
Grading of Evidence

workshop members voted that the evidence to support the
statement was category II, 50% voted that it was category III,
and 17% voted that it was category V (table 3).
Level of Support
Overall, 27% of the workshop members voted to accept the

statement with some reservations, 64% voted to accept the
statement with major reservations, and 9% voted to reject the
statement with reservations. None of the summit members
voted to accept or reject the statement completely. In comparison, of the 744 IDSA members who participated in the
online survey, 30% voted to accept the statement completely,
voted to accept the statement with major reservations, 18%
voted to reject the statement with reservations, and 3% voted
to reject the statement completely (figure 9).
Discussion and Future Directions
In conclusion, this statement can be supported by evidence that

microbiologically adequate empirical treatment of serious HAIs
due to gram-negative bacteria provides optimal clinical outcome. Evidence also supports the use of dual therapy to provide
broad empirical coverage, as well as improved mortality for
patients with bacteremia caused by P. aeruginosa. National surveillance data from the United States provide evidence that
aminoglycosides retain greater susceptibility than do quinolones as potential second agents in combination therapy. However, in selected and expanding geographic areas, antimicrobial
resistance has progressed to include all aminoglycosides and
quinolones, as well as all b-lactams. This phenomenon precludes the use of a definitive general statement that includes a
The potential efficacy of aminoglycosides as a component of

combination antibacterial therapy is illustrated by the studies
described above. Guidelines for the management of HAP, VAP,
and HCAP in adults were published jointly by the ATS and the
IDSA in 2005 [1]. Suggested antibiotic combinations included
either an aminoglycoside or quinolone, chosen on the basis of
local susceptibility data. Early evidence that aminoglycoside
therapy for serious pneumonia caused by gram-negative pathogens is relatively ineffective because of poor tissue penetration
is contradicted by more-recent pharmacokinetic/pharmacodynamic studies indicating that optimal aminoglycoside therapy is achieved by once-daily administration, not divided daily
doses [148].
The potential efficacy of quinolones as a component of combination therapy for serious HAIs. The potential efficacy of
quinolones as a component of adequate empirical combination
therapy depends on the intensity of local use and likely the
degree of resistance among invading gram-negative pathogens.
A surveillance study published by Neuhauser et al. [149] examined fluoroquinolone resistance in 19942000. They found
that overall susceptibility to ciprofloxacin decreased from 86%
in 1994 to 76% in 2000 and was significantly associated with
increased use of fluoroquinolones. Other studies published during the past decade have documented the rising use of fluoroquinolones in various areas of the United States and its association with increasing resistance among gram-negative
bacilli [149151].
The influence of antibiotic resistance surveillance on selection of therapeutic agents. Increasing antibiotic resistance
among gram-negative bacilli in the United States and internationally has been well documented in the past few decades.
Its local incidence should influence the selection of empirical
therapy for serious infections with gram-negative bacilli. National surveillance studies in the United States have indicated
a greater degree of quinolone resistance than aminoglycoside
resistance among P. aeruginosa and Acinetobacter isolates, particularly from ICUs [152154]. Routine colonization surveillance in an ICU has demonstrated that knowledge of colonization status before infection is associated with higher rates of
appropriate therapy for patients with bacteremia caused by antibiotic-resistant gram-negative bacilli [155]. A retrospective cohort study notes the clinical implications of resistance and the
value of accurate susceptibility information. In that study, Tam
et al. [156] examined 34 bacteremia episodes involving P. aeruginosa isolates with reduced susceptibility to piperacillin-tazobactam, which was given empirically for 7 episodes. Thirtyday mortality was found to be 85.7% in the group receiving
piperacillin-tazobactam, compared with 22.2% in the group
receiving other antipseudomonal agents (P p .004 ). Tam et al.
[156] observed an increase in mortality among patients infected
with an isolate that had increased resistance, despite the fact
Figure 9. Voting comparison for statement 7 (Serious HAIs due to suspected gram-negative bacteria should be treated empirically with dual
coverage that includes an aminoglycoside). IDSA refers to the members of the Infectious Diseases Society of America who responded to a Webbased survey; Summit refers to the Health CareAssociated Infection (HAI) Summit panel.
single agent or class of agents as appropriate therapy in all

locations.
Traditionally, patients presenting to the hospital with suspected

BSI or severe sepsis have been considered at risk for infections
with selected pathogens, including MSSA, Streptococcus pneumoniae, and gram-negative organisms such as E. coli. Recognition that risk factors for infection with antibiotic-resistant
pathogens include factors beyond the hospital setting has led
to the evolution of the concept of HAIs. Briefly, this concept
explained in detail elsewhere in this supplementattempts to
capture the fact that many patients regularly interact with the
health care system and are routinely exposed to extensive antimicrobial therapy outside the hospital. As such, they may
become infected with a broad range of pathogens, including
organisms traditionally classified as community associated
illness or with bacteria previously thought to arise only in hospitalized persons who develop nosocomial syndromes.
One class of nonbacterial organisms has recently emerged as
an important pathogen causing nosocomial BSIs [158, 159].
Yeast represents an increasingly common cause of serious hospital-acquired BSI. More specifically, Candida species are the
third or fourth most common cause of hospital-acquired BSIs,
depending on the epidemiologic literature reviewed [158, 159].
This observation begs the question as to whether this finding
applies to patients with health careassociated BSI. In other
words, does yeast now cause BSI in persons presenting to the
emergency department with a syndrome that resembles BSI or
severe sepsis? To validate the proposed statement, it is necessary
to explore 3 specific issues: What is the prevalence of Candida
as a cause of BSI in patients presenting to the emergency deS84 CID 2008:47 (Suppl 2) Kollef et al.
Methods
A literature search of the PubMed database was conducted on

4 September 2007. The search was not limited to the English
language. The purpose of the search was to identify articles
addressing the epidemiology of candidemia, the distribution of
the specific species of Candida that may cause BSI, the prevalence of candidemia among patients presenting to the emergency department, and treatment strategies for candidemia.
Specific search terms used included Candida, candidemia,
fungus, fungemia, bloodstream infection, and sepsis.
The term candidemia OR fungemia resulted in the identification of 2689 articles. Although searching for the terms
healthcare associated and healthcare-associated resulted in
150,000 potential articles, the combination of either of these
phrases with candidemia OR fungemia OR BSI yielded only
12 publications. To expand the potential number of studies to
be reviewed, the search strategy was subsequently modified to
incorporate these phrases: inappropriate therapy, risk factors, and presumptive therapy. These selections were pooled
in a Boolean fashion with the original search terms attempting
to capture BSI infection with yeast. Despite broadening the
search, only 4 additional articles potentially relevant to the
statement were located.
The paucity of published literature suggests that the concept
of health careassociated candidemia has not been well studied.
This may reflect that either the concept is relatively new or this
condition is not of clinical concern. In either case, the limited
number of studies necessarily precludes definitive and strongly
worded conclusions about the statement and suggests that readers of this literature must be cautious as they explore this area.
Additionally, the small number of analyses automatically must
make one skeptical as to the generalizability of the observations
described in reports of these studies.
STATEMENT 8: PATIENTS WITH SERIOUS HAIs

WHO HAVE RISK FACTORS FOR FUNGAL
INFECTIONS REQUIRE EARLY EMPIRIC
ANTIFUNGAL THERAPY TO REDUCE
MORTALITY
partment? Does failure to treat candidemia result in adverse

outcomes for patients? Do patients with such candidal BSI have
risk factors for HAI?
Evidence
Epidemiology of health careassociated candidemia. Two reports either directly or indirectly explored this question [160,
161]. In general, these studies suggest that health careassociated candidemia exists as a distinct entity. In a large surveillance project focused on patients with candidemia presenting
to the emergency department, Sofair et al. [161] prospectively
evaluated all cases of candidal BSI in several hospitals in various
regions of the United States. This project was sponsored by the
CDC and represented a specific effort to grapple with the notion
of community-onset candidemia. These investigators had clear
criteria for defining a BSI caused by Candida as community
onset in origin. Of 1143 cases of candidemia evaluated, the
authors determined that 356 (31%) were community-onset infections [161].
More importantly, these investigators determined the prevalence of select risk factors for candidemia in persons with
community-onset disease. A review of the distribution of these
risk factors reveals that the vast majority of these communityonset cases of candidemia did, in fact, represent HAIs. For
example, 1 in 5 subjects had underlying malignancy, and more
than a quarter of the 365 persons were receiving immunosuppressive therapy [161]. More strikingly, approximately half of
patients with community-onset infection had central venous
catheters in place. With respect to the distribution of specific
species causing candidemia, patients with community-onset infection were less likely than were persons with traditional nosocomial infection to have Candida albicans implicated. Additionally, 25% of community-onset infections were due to
Candida glabrataa rate no different from the one seen in the
traditional nosocomial candidemia cases.
Exploring the question of health careassociated candidemia
from a different perspective, Shorr et al. [160] reviewed a large
administrative database to determine the general prevalence of
health careassociated BSIs. They defined health careassociated BSI as a BSI case diagnosed within 2 days after infection
that had any of the following conditions: the patient was admitted from a nursing home, had been hospitalized in the past
30 days, was being given treatment with immunosuppressive
therapy, had active malignancy, or was receiving chronic hemodialysis. Among nearly 7000 blood-cultureconfirmed cases
of BSI, health careassociated processes accounted for nearly
55% [160]. Nearly 2% of health careassociated BSIs were due
to yeast [160]. This rate of fungal BSI was lower than the rate
of fungemia noted in nosocomial BSI. However, since the rate
was not zero, it indicated that the proposed definition for health
careassociated fungemia does capture a unique population of
patients. Conversely, these data underscore the relative infrequency of this condition, given the huge number of BSI cases
seen annually in emergency departments in the United States.
Implications of failure to treat candidemia. Over the past
5 years, multiple analyses have documented that failure to

promptly treat serious infections increases a patients probability of death [70, 79, 82, 162]. This finding has been confirmed
for multiple disease states, from VAP to severe sepsis and septic
shock [70, 79, 82, 162]. The relationship between mortality and
either a delay in initial antibiotic therapy or the administration
of inadequate therapy also applies if one focuses on specific
pathogens (e.g., MRSA), rather than on clinical syndromes [5].
The definitions used for inadequate therapy generally categorize
this as the administration of an anti-infective agent to which
the culprit pathogen is resistant in vitro.
For candidemia, only 2 reports attempted to address the
relationship between inadequate or delayed antifungal therapy
and survival [91, 92]. A potential explanation for the existence
of so few reports dealing with this topic is the fact that in vitro
susceptibilities for antifungal agents are not well described and
that controversy exists regarding what represents in vitro
resistance.
In a retrospective analysis, Morrell et al. [92] reviewed 157
cases of candidemia. Their aims were to determine predictors
of outcome in this disease and to describe the relationship
between survival and both delays in antifungal therapy and
inadequate antifungal treatment. Two analyses were conducted;
the primary analysis included all antifungals, and a secondary
analysis evaluated patients infected with C. albicans, Candida
parapsilosis, or Candida tropicalis generally susceptible to fluconazole. The results were not stratified by organism type. Approximately half of the patients were infected with a nonC.
albicans species, and nearly 1 in 5 cases was attributed to either
Candida krusei or C. glabrata [92]. They defined delayed therapy as administration of an antifungal agent 112 h after the
patients initial blood culture specimen was drawn. Inadequate
therapy represented use of fluconazole for infections due to C.
krusei. Specific MIC90 breakpoints were not determined. Overall
mortality approached 30%, which is similar to the death rate
for candidemia described in other reports [92]. For example,
in the analysis by Sofair et al. [161] noted above, the death rate
for candidemia exceeded 25%.
Of the 157 patients, only 5 received timely and adequate
antifungal therapy. Strikingly, the death rate among patients
given adequate treatment within 12 h after the blood culture
specimens were drawn was only 10% [92]. Among persons
given antifungal therapy beyond this 12-h window, the mortality rate increased to 33% (P p .169) [92]. More importantly,
when stratifying the time to therapy into the periods of 1224
h, 2448 h, and 148 h after blood culture specimens were
drawn, these authors saw no difference in mortality. In multivariate analysis, a delay in antifungal treatment independently
doubled a patients risk of death.
Confirming these observations, Garey et al. [91] reviewed
230 cases of candidemia at 4 different centers. The crude mor-
the purposes of determining who might be at greater risk for

health careassociated fungemia, their score may not be applicable, because it incorporates the findings from surveillance
cultures.
Addressing colonization in particular, Pairroux et al. [164]
explored a role for the colonization index in determining the
potential for candidemia. Again, admittedly, this strategy will
not be helpful in the emergency department. However, for
completeness, readers should familiarize themselves with this
paradigm. These researchers completed a before-after study relying on the colonization index. They computed the colonization index as the number of sites on a patient that tested
positive for Candida divided by the total number of sites
swabbed. Swabbing was done biweekly. If the colonization index was 10.4, these patients were given preemptive therapy
with fluconazole. With this technique and strategy, they were
able to significantly reduce rates of proven ICU-acquired candidemia (from 2.2% to 0%; P ! .001) [164].
There were no specific reports investigating risk stratification
in health careassociated or community-onset fungemia. This
is perhaps not surprising, given the overall limited literature
on this topic.
Grading of Evidence

members agreed that the nature of the evidence available to
support this statement was category II (table 3).
Level of Support

voted to accept the statement with major reservations, and 9%
voted to reject the statement with reservations. None rejected
the statement completely. In comparison, of the 744 IDSA
accept the statement completely, 44% voted to accept the statement with some reservations, 17% voted to accept the statement with major reservations, 10% voted to reject the statement
Discussion
This statement should be viewed as complementary to the others in this supplement, addressing both particular pathogens
and specific HAI syndromes. For the concept of HAI to prove
meaningful, it must be internally consistent. Thus, if one limited the health careassociated stratification to bacterial pathogens only, the entire notion might prove both difficult to apply
and unhelpful. Therefore, recognition that, even for fungal BSI,
the health careassociated concept is unique reinforces the sup-
tality rate in this cohort was 30%. Of note, all subjects were
given treatment with fluconazole. These authors determined
that persons given fluconazole on the day the culture specimen
was obtained faced a mortality risk of 15%. They also observed
a stepwise increase in probability of death as time progressed
(P p .0009). Specifically, persons given treatment on the day
after the culture specimen was drawn had a mortality rate of
25%, whereas those who were finally given fluconazole 3 days
after the culture specimen was drawn had a 40% unadjusted
chance for in-hospital death [91]. In their logistic regression,
delay in therapy heightened the potential for death by 50%
(AOR, 1.50; 95% CI, 1.092.09) [91]. This relationship persisted even after exclusion of persons for whom fluconazole
may have been inadequate on the basis of a definition similar
to the one employed by Morrell et al. [92].
Is risk stratification possible? Numerous reports detail potential risk factors for fungemia [158, 159]. These range from
patient variables, such as a history of recent abdominal surgery
and underlying malignancy, to process of care issues, including
presence of a central venous catheter or receipt of parenteral
nutrition [158, 159]. Unfortunately, efforts to develop a specific
risk score that identifies persons with fungemia as the likely
cause of their syndrome have been fraught with limitations.
Often 2 approaches are employedone relying on the presence
of certain risk factors, and the other using surveillance for
Candida colonization. Use of risk scores tends to compromise
specificity for the sake of sensitivity. In other words, although
a proposed score may identify a cohort of persons more likely
to have candidemia, the rate of candidemia remains sufficiently
low, and it can be presumed that clinicians would need to give
treatment to many patients without candidal infection to ensure
that they were capturing cases of candidemia. Alternatively,
surveillance-based strategies are necessarily cumbersome and
are unlikely to be of value for treatment of health careassociated candidemia, because the patient is, by definition, presenting to the emergency department and has not been in the
hospital long enough to have had surveillance cultures
performed.
A report by Leon et al. [163] represents a recent attempt to
refine the risk-score paradigm. In a multicenter trial in Spain,
these investigators studied 1669 persons who stayed in the ICU
for at least 7 days. The overall rate of candidemia was 6%
[163]. Specific variables associated with subsequent ICU-onset
candidemia included recent surgery, underlying severe sepsis,
use of parenteral nutrition, and known Candida colonization
[163]. Researchers developed a complex point-scoring tool
based on logistic regression, which employed good screening
characteristics for candidemia. Based on the plot of the receiver
operating curve, their score had an area under the curve of
0.85 [163]. However, this score has not been independently
validated in other settings or in other studies. Furthermore, for
that the vast majority of patients are not given prompt treatment, it appears there is ample room for improvement.
Future Directions
Figure 10. Voting comparison for statement 8 (Patients with serious

HAIs who have risk factors for fungal infections require early empiric
antifungal therapy to reduce mortality). IDSA refers to the members
of the Infectious Diseases Society of America who responded to a Webbased survey; Summit refers to the Health CareAssociated Infection
(HAI) Summit panel.
STATEMENT 9: ALL INFECTIONS IN

IMMUNOCOMPROMISED PATIENTS SHOULD
BE CONSIDERED HAIs UNTIL PROVEN
OTHERWISE
Infection due to a diverse spectrum of pathogens is the most

common and well-recognized complication in patients with
compromised immunologic host defenses as well as a native
disease and/or iatrogenic interventions. The microbial etiology
for such infections may vary across different specific immune
defects, severity and duration, and other modifiers, including
the patients prior and present geographic location, prior exposure to anti-infectives for prophylaxis or treatment, and exogenous exposures (e.g., transfused blood products or donor
organs). The orthodox view pertaining to the origin of infections in immunocompromised hosts recognizes that the inciting organism(s) may originate from (1) the patients native
endogenous flora or dormant organisms, which become reactivated with failed immune defenses; (2) endogenous flora,
which has been modified principally by exposure to anti-infective agents or the animate and inanimate nosocomial environment; (3) exogenous reservoirs; and (4) as-yet-unknown
sources. Among organ transplant recipients, the donor organ
represents another reservoir for pathogen transmission. Although much of the important clinical management of immunocompromised patients occurs within the hospital unit or
the critical care setting, some of the management has shifted
to the parahospital or outpatient health care facilities. Prominent examples include outpatient chemotherapy for oncologic
disease, management of HIV-associated illness, and long-term
acute care facilities that receive organ transplant recipients for
ventilator dependence or rehabilitation. HAIs within this expanded sphere might have a greater impact on the immunocompromised host than on immunocompetent patients and
also may be caused by a different spectrum of pathogens. With
port for the need to adopt HAIs as distinct syndromes. Although there is certainly overlap between community-acquired,
health careassociated, and nosocomial processes, the evidence
consistently underscores the need to break our traditional dichotomous classification scheme into 3 distinct components.
Unfortunately, there are only 2 analyses that specifically address the epidemiology of health careassociated candidal BSIs
[160, 161]. These studies, however, were internally valid and
well conducted. Thus, clinicians should at least recognize the
potential for candidemia to be a cause of BSI in patients presenting to the emergency department. This statement is not
meant to imply that physicians should prescribe antifungal
treatment either routinely or reflexively. Instead, local epidemiologic information must be gathered to facilitate the development of local protocols to determine whether Candida species are an issue of concern. Readers should also note that there
are no data suggesting that health careassociated candidemia
does not exist. In other words, there are no studies that specifically disprove this assertion.
For risk stratification, one must rely on clinical judgment.
No reliable tool exists to help determine which patients face
an elevated potential for candidemia. Given the pathophysiology of the process, it appears that immunosuppression or
presence of a central venous catheter is necessary, but neither
is a sufficient condition for this disease. Perhaps, therefore, in
giving treatment to persons presenting with a syndrome consistent with severe sepsis but not showing evidence of pulmonary infection (or other evident infection), clinicians should
consider more formally candidal BSI in the differential diagnosis, particularly if multiple risk factors, including those noted
above, are present. However, this recommendation represents
opinion more than fact but does acknowledge that failure to
promptly and adequately treat fungal BSI leads to substantial
excess mortality. Conversely, one cannot hope to begin antifungal therapy promptly if one presupposes that yeast can never
be a cause of health careassociated BSI. Given that it seems
Certainly, more broadly designed prospective epidemiologic research is required. Such projects must include a range of institutions, rather than a focus exclusively on academic centers.
With such information, geographic variations may become apparent. More importantly, these surveillance studies can simultaneously collect information that allows for the development and validation of risk-stratification tools. Finally, other
diagnostic measures are needed. Since cultures for Candida may
take several days to grow, clinicians require more-rapid diagnostic interventions to determine whether to continue or stop
presumptive antifungal treatment.
respect to MDR bacteria, the duration of antecedent colonization and the incidence of progression to infection are 2 parameters that may have a greater impact on immunocompromised patients. This section focuses on whether there is
evidence in the literature confirming that the health care environment is the exclusive source of all infections in the immunocompromised host.
Methods
Evidence
Is the health care environment the exclusive source for all

infections in immunocompromised patients? Not all infections in immunocompromised patients are the result of health
care exposures; some patients become colonized and infected
with pathogenic organisms as a result of their weakened immune status. Kotton et al. [165] mentioned numerous reports
of transmission of zoonosis to humans during and after solidorgan and hematopoietic stem cell transplantation. The maS88 CID 2008:47 (Suppl 2) Kollef et al.
A literature search of the PubMed database was performed on

15 September 2007, and results were narrowed to the English
language and human subjects. The purpose of the search was
to identify published articles on the epidemiology of infection
among immunocompromised hosts and, specifically, to determine whether the inciting pathogens were acquired in a community, health care, or hospital setting. The initial search terms
and combinations included immunocompromise AND
healthcare-associated infection, which yielded 656 articles;
immunocompromise AND infection AND epidemiology,
which yielded 1971 articles; and immunocompromise AND
community-acquired infection, which yielded 127 articles.
Only articles that included major immunocompromised host
categories (bone marrow or solid organ transplant recipients
and patients with cancer, neutropenia, granulocytopenia, or
AIDS) were selected for further review. After examinination of
all articles for these criteria, a total of 12 articles were deemed
relevant to the statement.
A second PubMed search for specific MDR pathogens of
interest (S. aureus, Enterococcus, P. aeruginosa, Candida, and
Aspergillus) was combined with immunocompromised and
was limited to the English language only. The search terms
immunocompromise AND antimicrobial resistance yielded
225 articles, methicillin-resistant Staphylococcus aureus
yielded 110 articles, immunocompromise AND Enterococcus
yielded 84 articles, immunocompromise AND Candida
yielded 970 articles, and immunocompromise AND Aspergillus yielded 904 articles. Since prolonged colonization with such
organisms may represent a more sensitive end point when the
presence of health care acquisition is discerned, all the organism-specific searches were also combined with the term
colonization.
jority of zoonoses cases are acquired after transplantation. Certain occupations (e.g., veterinarian, farmer, and forestry
worker), pet ownership, hobbies (e.g., hunting), and travel also
increase the risk of acquisition [166]. Lamaris et al. [167] also
reported the incidence of Scedosoprium infections among 21
patients with cancer in 19892006. The authors concluded that
these infections were associated with typical immunologic defects, such as hematologic cancer, neutropenia, lymphopenia,
and systemic steroid use. Although an increase in the incidence
was seen in the last 5 years of the study, there was no evidence
of nosocomial transmission.
Does immunocompromise contribute independently to the
alteration of the epidemiology of HAI? Several articles investigated whether there are significant differences in the etiology of infection between immunocompromised and nonimmunocompromised hosts. A study by Shorr et al. [160] of
a 2-year database of BSIs, which were subsequently classified
as community-acquired, health careacquired, or hospital-acquired infection, demonstrated only minimal differences in the
etiology between immunocompromised patients (n p 2140)
and immunocompetent patients (n p 4557 ). When all acquisition categories were analyzed, no significant differences in the
incidence of any gram-positive pathogen were observed.
Among gram-negative organisms, the incidences of Pseudomonas species (4.0% vs. 2.3%; P p .001 ) and Klebsiella species
(8.2% vs. 5.1%; P ! .001) were significantly higher among immunocompromised patients than among nonimmunocompromised patients [160].
A study by Dimiopoulos et al. [168] compared the characteristics of candidemia between immunocompromised (n p
9) and immunocompetent (n p 15) patients. The mean time
from hospitalization to diagnosis of candidemia was 9 days
(range, 511 days). With respect to risk factors, no important
differences were observed between the 2 cohorts [168].
Immunosuppression was not found to be a significant risk
factor for all MDR bacterial infections in the ICU in a retrospective, matched, case-control study of 256 medical/surgical
ICU patients [169]. With the notable exception of MRSA, which
was significantly more frequent in the immunosuppressed cohort (25 of 44 vs. 10 of 26; P p .01), there was no independent
association between immunosuppression and ICU-acquired
MDR organisms.
Does immunocompromise contribute to a higher incidence
of MDR colonization and thus act as a precursor to HAI?
Several studies have examined the incidence of MDR colonization among immunocompromised patients. In a prospective
observational study of 2347 admissions in 14 French ICUs,
nasal and cutaneous swab screening was performed to determine the variables associated with MRSA carriage at the time
of ICU admission [170]. Immunosuppression was not associated with an increased risk of MRSA carriage. Furuno et al.
amples found in the search included Legionella species, Mycobacterium tuberculosis, Aspergillus species and other mycelial
organisms, influenzae viruses, varicella-zoster virus, and respiratory syncytial virus [167, 176178]. Pneumocystis, on occasion, can be acquired as a nosocomial pathogen. Organisms
that appear to be acquired exclusively in the community setting
include Listeria monocytogenes, Nocardia species, Cryptococcus
neoformans, endemic mycoses, Pneumocystis jiroveci, Toxoplasma gondii, Strongyloides stercoralis, and other parasites, as
well as pathogens causing zoonotic infections [165].
Grading of Evidence

workshop members voted that the evidence to support the
statement was category II, 20% voted category III, and 60%
voted category V (table 3).
Level of Support
Overall, 0% of the summit participants voted to accept the statement completely, 0% voted to accept the statement with some
reservations, 27% voted to accept the statement with major reservations, 45% voted to reject the statement with reservations,
and 27% voted to reject the statement completely. In comparison,
of the 744 IDSA members who participated in the online survey,
11% voted to accept the statement completely, 28% voted to
accept the statement with some reservations, 15% voted to accept
the statement with major reservations, 27% voted to reject the
statement with reservations, and 19% voted to reject the statement completely (figure 11).
Discussion
Although the epidemiology of infection among immunocompromised patients has been studied intensively and reported
for decades, there are few, if any, studies that pinpoint the
precise time and location when the pathogen is acquired (other
than rare and well-documented epidemic outbreaks). Thus,
many of the diverse organisms that can cause infection in the
immunocompromised host are presumptively classified as community associated, hospital associated, or health care associated,
on the basis of the known ecology (i.e., natural reservoirs and
vectors), biology (i.e., incubation period and latency), and epidemiology (i.e., presence of geographic or temporal clusters
supported by molecular typing methods that match the organism patient-to-patient or between a patient and an environmental source) of the pathogen in question.
The paucity of precise investigations in this area necessitated
a somewhat oblique approach to the literature search. Not surprisingly, the search effort produced a very low level of evidence
in support of the statement that all infections should be considered health careassociated among immunocompromised
patients. It is reasonable to assume that (1) immunocomproHAI Summit Critical Appraisal CID 2008:47 (Suppl 2) S89
[171] confirmed that risk factors other than immunosuppression identified patients colonized with antibiotic-resistant bacteria. They found that previous hospital admission occurring
within 1 year before the time of current hospitalization was
independently associated with a high risk of carriage of antibiotic-resistant bacteria. Nseir et al. [169] conducted a retrospective case-control study to determine the relationship between immunosuppression and ICU-acquired MDR bacteria
(MRSA, ESBL-producing organisms, and MDR P. aeruginosa,
Acinetobacter baumannii, and Stenotrophonmonas maltophilia).
In univariate analysis, immunosuppressed patients had a higher
incidence of colonization with these organisms than did immunocompetent patients (22 per 1000 patient-days vs. 12 per
1000 patient-days; P p .004); however, in multivariate analysis,
antibiotic treatment administered before or during the ICU stay
remained a significant factor. A 6-year study by Reddy et al.
[172] examined the results of rectal swab screening for ESBLproducing gram-negative bacilli in 17,872 patients hospitalized
in high-risk units. Notably, the medical ICU service had the
highest incidence of colonization with ESBL-producing organisms during the study period, whereas the hematology/oncology
and solid-organ transplant units experienced significantly lower
incidences.
Does immunocompromise contribute to a prolongation of
MDR colonization and thus act as a precursor to HAI?
There is limited evidence examining the duration of MDR colonization in immunocompromised patients. Most of the available evidence focuses on duration of colonization with vancomycin-resistant enterococci (VRE). The reports that have
demonstrated a prolonged duration of VRE gastrointestinal colonization have studied immunocompromised patients, such as
abdominal solid-organ recipients and oncologic patients with
or without neutropenia [173175]. One study by Montecalvo
et al. [173] determined that 86 oncologic patients with VRE
colonization were identified. Colonization was persistent for 17
weeks in the majority of patients. Of 34 colonized patients
discharged from and then readmitted to the hospital after a
mean of 2.5 weeks, 22 (61%) were still colonized with VRE.
PFGE further demonstrated that VRE colonization with the
same strain could persist for at least 1 year. In a similar patient
population, Roghmann et al. [175] found a 44% rate of persistent VRE colonization. Patel et al. [174] reported the results
of serial rectal surveillance cultures from 52 liver and kidney
transplant recipients during both inpatient and outpatient periods and followed up for a median of 306 days. Persistent VRE
colonization was present in 150% of the initial cohort.
Are there infections in immunocompromised hosts that arise
from distinct community reservoirs or from shared reservoirs
between the community and the health care setting? There
is ample evidence that the same pathogen can originate from
both community and health care settings. Representative ex-
Figure 11. Voting comparison for statement 9 (All infections in immunocompromised patients should be considered HAIs until proven otherwise).
IDSA refers to the members of the Infectious Diseases Society of America who responded to a Web-based survey; Summit refers to the Health
CareAssociated Infection (HAI) Summit panel.
Future Directions
The idealized study prototype, which would allow a clear and

scientific conclusion as to whether a pathogen was health care
associated or nonhealth care associated among immunocompromised patients, requires sequential testing with a highly sensitive and specific assay for the presence of the pathogen of
interest performed throughout periods of health care exposure
and nonhealth care exposure. The rapid development and
deployment of gene-based and other molecular diagnostic
methods as investigative tools to detect the presence of resistance could be valuable in answering this intriguing question.
STATEMENT 10: ADJUNCTIVE THERAPY
SHOULD BE UTILIZED TO PREVENT AND
TREAT SERIOUS HAIs
Serious infections are a leading cause of death in hospitalized

patients, with a mortality rate of up to 60% among patients
manifesting septic shock [180]. Adjunctive therapies targeted

to control the immunologic, inflammatory, and procoagulant
response elicited by infection have been researched and prescribed for decades. In this section, we specifically review the
level of evidence supporting tight glycemic control, avoidance
of RBC transfusion, IVIG, and drotrecogin alfa (activated) as
adjunctive therapies for the treatment of HAIs, with emphasis
on the critically ill population.
Methods
A PubMed database search was conducted to identify relevant

reports involving each adjunctive therapy. The search strategy
was limited to humans, the English language, clinical trials,
randomized controlled trials, and meta-analyses. Text terms for
each adjunctive therapythat is, IVIG, IGIV, intravenous
immune globulin, and intravenous immunoglobulinwere
combined using the OR function and then were combined
using the AND function with search terms describing HAI,
including bacteremia, bloodstream infection, pneumonia, nosocomial infection, and infection. The search
yielded 88 articles for tight glycemic control, 29 articles for
red blood cell transfusion avoidance, 87 articles for IVIG,
and 88 articles for drotrecogin alfa (activated). Bibliographies
of selected articles were also reviewed to identify relevant
reports.
Evidence
Tight glycemic control. Hyperglycemia is a common occurrence in patients in the critical care setting, regardless of history
of diabetes mellitus. The etiology of hyperglycemia is multifactorial and may adversely affect immune function, such that
an inflammatory state is promoted and granulocyte adherence,
chemotaxis, phagocytosis, and intracellular killing are negatively altered [181]. Control of hyperglycemia in the acute care
setting has been associated with prevention of sternal wound
infection and survival in patients undergoing cardiac surgery
procedures [182, 183].
mised patients are exposed more intensively to the health care

setting after or between hospitalizations than are immunocompetent patients and (2) residual effects of health care exposure
could lead to health care acquisition of a finite number of
pathogens and infections attributable to those pathogens. However, with regard to MDR bacteria, the available literature fails
to show an independent association of immunocompromised
states with either colonization or infection with such pathogens.
Instead, such observations were mediated by more-dominant
mechanisms, such as antimicrobial exposure, intensity, and duration of health care exposures, in which immunocompromise was a surrogate marker. Although colonization-to-infection ratios may be quite high (particularly for low-virulence
pathogens, such as VRE), it was important to direct part of
the search effort to a colonization end point because modification of the patients endogenous microbial reservoirs is a
well-recognized antecedent condition to an overt infection
[179].
scrutinized in all critically ill patients, this form of therapy may

be correlated with major nosocomial complications, most notably infection.
The strongest evidence linking PRBC transfusion and nosocomial infection comes from large observational trials and,
therefore, should not be interpreted as absolute proof of hypothesis. Nonetheless, the accumulated data consistently point
to a direct relationship between transfusion and infectious complications. The CRIT triala prospective, observational study
of transfusion practices in the United States conducted over a
10-month period in 2000 and 2001evaluated 4892 patients
in 284 distinct ICUs [193]. Within this population, 3502 patients were free of BSI at baseline, as well as 48 h after enrollment, and were secondarily evaluated for the development
of BSI [194]. Of the patients, 49% received transfusion and
3.3% developed a BSI during the 30-day evaluation. Patients
who were found to develop BSI were significantly more likely
to receive PRBC transfusion (76.1% vs. 48.7%; P ! .001) and
to have a greater number of units transfused (4.0 4.6 U vs.
2.3 4.3 U; P ! .001), compared with patients without this
infectious complication. In multivariable analysis, transfusion
was found to significantly increase the likelihood of BSI (AOR,
2.23; 95% CI, 1.433.52; P ! .001), and the probability increased
as the number of PRBC units transfused increased. Using the
same CRIT study population, a subgroup of 1518 patients who
required mechanical ventilation for at least 48 h were evaluated
for the development of VAP [195]. Overall, 52.7% of patients
receiving mechanical ventilation received transfusion, and
22.6% received a diagnosis of VAP. Similar to findings of the
aforementioned BSI analysis, patients with VAP were significantly more likely to receive transfusion (58.2% vs. 51.4%;
P p .03), and transfusion was an independent predictor of VAP
development in the multivariable analysis (AOR, 1.89; 95% CI,
1.332.68; P p .0004). A single-center, prospective, observational cohort of 2085 mixed medical/surgical ICU patients
found that patients who received transfusion (n p 428 ) had a
significantly higher incidence of nosocomial infection (14.3%
vs. 5.8%; P ! .001), longer length of ICU stay (8.2 11.7 days
vs. 3.3 5.1 days; P ! .001), longer length of hospital stay
(18.3 18.7 days vs. 9.9 9.5 days; P ! .001), and higher inhospital mortality rate (10.2% vs. 21.8%; P ! .001), compared
with patients who did not receive transfusion [196].
Drotrecogin alfa (activated). The use of drotrecogin alfa
(activated), the recombinant form of human activated protein
C, as an adjunctive therapy for infections manifesting as severe
sepsis and septic shock has been widely studied. The question
of which patient subgroup is most likely to benefit from the
therapy and, at the same time, be protected from drug toxicity,
most notably bleeding, remains largely unresolved. Collectively,
4 large industry-sponsored trials form the basis for bedside
decision-making regarding the use of drotrecogin alfa (actiHAI Summit Critical Appraisal CID 2008:47 (Suppl 2) S91
Limited data are available on controlling glucose levels and

outcomes in critically ill patients with HAI. Compelling data
on critically ill patients with or without infection were reported
in a prospective, randomized, controlled trial that considered
whether intensive insulin therapy (defined by targeted blood
glucose levels of 80110 mg/dL) reduced ICU mortality among
1548 surgical ICU patients [184]. Compared with patients who
received conventional treatment (targeted blood glucose levels,
180200 mg/dL), patients randomized to receive intensive insulin therapy had significantly decreased rates of ICU mortality
(8.0% vs. 4.6%; P ! .04) and in-hospital mortality (10.9% vs.
7.2%; P p .01). The greatest reduction in mortality appeared
to be limited to patients who required 5 days of ICU care
and may have been linked to infection prevention, as indicated
by a marked reduction in deaths due to multiple organ failure
secondary to sepsis and in rates of septicemia. Not surprisingly,
hypoglycemia occurred in 39 patients in the intensive-treatment
group and in 6 patients in the conventional-treatment group.
A follow-up trial involving 1200 adult medical ICU patients
conducted by the same group of investigators using identical
methodology revealed similar findings [184, 185]. Although the
intention-to-treat in-hospital mortality was not statistically different between groups, the subgroup of patients requiring 3
days of ICU care and randomized to receive intensive insulin
therapy had significantly increased hospital survival, compared
with patients in the conventional arm (57% vs. 47%; P p
.009). The occurrence of hypoglycemia, defined as a blood
glucose level !40 mg/dL, was alarmingly high in the group
receiving intensive insulin therapy (25.1% vs. 3.9%; P ! .001).
A retrospective evaluation of the effects of tight glycemic control on critically ill patients with sepsis at the time of admission
found no difference in the in-hospital or ICU mortality among
all patients; however, a survival advantage was observed among
patients requiring 3 days of ICU care plus intensive insulin
therapy (OR, 2.9; 95% CI, 1.84.6; P ! .001) [186]. Further
evaluation of the impact of hypoglycemia in the subgroup of
patients with sepsis at ICU admission found it to be independently associated with in-hospital mortality (AOR, 2.8; 95%
CI, 1.84.2; P ! .001). This finding has been confirmed in a
separate evaluation [187].
Avoidance of RBC transfusions. Transfusion of packed
RBCs (PRBCs) is a common intervention for critically ill patients. For patients with severe sepsis, PRBC transfusion has
become part of a widely adopted resuscitation algorithm used
in many hospitals and endorsed by the Surviving Sepsis Campaign guidelines [10, 188191]. The basis of this recommendation and its subsequent implementation at the local level
stems from significantly improved survival in the landmark trial
of early goal-directed therapy [192]. However, whether transfusion therapy is a key ingredient of improved outcomes for
patients with severe sepsis remains uncertain, and, when closely
enriched immunoglobulin compared with placebo for neutropenic patients with sepsis caused by gram-negative organisms
(n p 211) found no difference in mortality at 28 days (26.2%
vs. 28.2%; P p .93) [208]. Additionally, it appears that polyclonal IVIG is of limited benefit relative to placebo in targeting
specific populations, including patients with streptococcal toxic
shock syndrome and intra-abdominal sepsis [113, 209].
Grading of Evidence
On the basis of a review of the literature cited above, workshop

members voted that the nature of evidence for the statement
ranged from category I to category IV (table 3).
Level of Support
Overall, 9% of the summit participants voted to accept the statement with some reservations, 73% voted to accept the statement
with major reservations, and 18% voted to reject the statement
with reservations. In comparison, of IDSA members who completed the online survey, 18% voted to accept the statement
completely, 40% voted to accept the statement with some reservations, 23% voted to accept the statement with major reservations, 18% voted to reject the statement with reservations,
and 0% voted to reject the statement completely (figure 12).
Discussion and Future Directions
This role of adjunctive therapies for the treatment of HAI remains unclear, as demonstrated by the summit participants and
IDSA membership. Summit participants did concede that there
is evidence that tight glycemic control reduces ICU mortality
and that the incidence of bacteremia, VAP, and mortality is
related to RBC transfusions. However, there is inadequate evidence for and controversy regarding the use of activated protein
C and IVIG as adjunctive therapies for the treatment of HAI.
The lack of consensus can be traced to the heterogeneous nature
of infections and patient populations. Therefore, translation of
the results of the cumulative literature for bedside care remains
a patient-by-patient decision. The practice of tight glycemic
control, avoidance of PRBC transfusion, and use of drotrecogin
alfa (activated) or IVIG for patients with HAI will become more
universal only with more succinctly defined clinical targets,
standardized preparations, and, perhaps, disease-state biomarkers identifying patients who would most likely benefit
from adjunctive therapies.
CONCLUSIONS
HAIs should be viewed as distinct infections that identify individuals with an increased risk of infection with MDR pathogens. The current level of evidence is such that this idea appears to be best supported for HCAP and health careassociated
BSIs. Other infections, including intra-abdominal, skin, urinary-tract, CNS, and pediatric infections, have not been as well
vated) for adults [114, 197199]. In each trial, 75% of patients

presented from the community, and among 50% of these patients, the lung was the site of infection. The FDA-approved
labeling for drotrecogin alfa (activated) is derived from the
initial landmark trial, PROWESS [114]. In this trial of 1690
patients with severe sepsis or septic shock, a 6.1% absolute risk
reduction in mortality was observed that favored drotrecogin
alfa (activated) over placebo; however, the benefit appeared to
be limited to the patient subgroup that had a higher severity
of illness, as indicated by an APACHE II score of 25 [200,
201]. Additional subgroup analysis of this trial revealed that
patients with severe CAP given treatment with drotrecogin alfa
(activated) were also statistically more likely to survive [202].
The lack of efficacy for patients with a low severity of illness,
as indicated by an APACHE II score of !25 or by single-organ
dysfunction, was confirmed in a follow-up trial that was halted
because of therapeutic futility found by an interim analysis
[197].
Two initial, randomized, placebo-controlled trials demonstrated consistent bleeding rates. In contrast, an open-label trial
of 2375 patients who received drotrecogin alfa (activated) revealed higher rates of serious bleeding during the 96-h infusion
period and the 28 days after drug initiation in a noncontrolled
setting [199]. These results, coupled with a higher number of
CNS bleeding events observed with administration of drotrecogin alfa (activated), compared with placebo, during the infusion (27 events vs. 3 events) and after 28 days (60 events vs.
6 events) in the accumulation of the 4 largest trials to date,
indicate that the serious bleeding risk posed by drotrecogin alfa
(activated) requires careful consideration before prescribing,
particularly for patients with severe thrombocytopenia or meningitis [203].
IVIG. IVIG in polyclonal form has been extensively studied
as an adjuvant therapy for severe infections. The complete
mechanism of action is unknown, but the fundamental pharmacology of IVIG is activity against bacterial products, including endotoxin, other superantigens, and host cytokines. Recently, 3 meta-analyses have been published on the use of
polyclonal IVIG for critically ill adult patients with sepsis, severe
sepsis, or septic shock [204206]. Despite the heterogeneous
patient populations, as well as variable dosing, duration, and
product composition, each evaluation found IVIG to be associated with a significant survival benefit. However, when only
high-quality trials (randomized, double-blind, placebo-controlled trials) are considered in the meta-analysis, the association with improved survival does not exist [205, 206]. This
finding is consistent with recently published high-quality trials.
The Score-Based Immunoglobulin Therapy of Sepsis study
found no difference in 28-day mortality between patients given
a 2-day course of intravenous IgG and patients given placebo
(39.3% vs. 37.3%; P p .67) [207]. Likewise, a trial of IgMA-
Figure 12. Voting comparison for statement 10 (Adjunctive therapy should be utilized to prevent and treat serious HAIs). IDSA refers to the
members of the Infectious Diseases Society of America who responded to a Web-based survey; Summit refers to the Health CareAssociated
Infection (HAI) Summit panel.
these infections, it is apparent that additional studies are needed

to define the criteria for and definition of HAI. For other infections, including skin and intra-abdominal infections, investigations evaluating patients at risk for HAI are needed. One
assumption made by the HAI Summit members is that the
criteria for HAI are similar for all the infections examined.
However, this may not be correct, and there is room for debate
regarding which patient subsets should be included. For example, the presence of a device such as a joint prosthesis could
be an unexplored criterion for health careassociated BSI, but
this might not be the case for HCAP. Clearly, there is overlap
among all these infections in terms of distinguishing HAI from
community-acquired infection. Nevertheless, additional studies
are needed to validate these statements.
In the Treatment by Organism workshop, these complex
concerns translated into discrepant opinions regarding the optimal approach to the administration of empirical therapy to
patients at risk for HAI. Again, the theme of antimicrobial deescalation emerged as a unifying concept, regardless of infection.
However, the specific agents employed for initial antimicrobial
treatment of HAI could vary, depending on the site of infection.
Additionally, the need to provide specific coverage for distinct
pathogens (MRSA and Candida species) in patients at risk for
HAI also led to much discussion and debate. These discussions
focused on the need to balance empirically covered MDR pathogens through the use of broad-spectrum therapy while minimizing the generation of more resistance through unnecessary
antibiotic use. An example is the need to provide double coverage
for suspected HAI caused by gram-negative bacteria. Adding an
aminoglycoside to a b-lactam or carbapenem is likely to increase
overall coverage, compared with the addition of a fluoroquinolone. However, unnecessary use of dual coverage could also
promote more antimicrobial resistance.
At the summits conclusion, participants identified several
areas of research that merit priority to refine our care of patients
with HCAP. Large-scale, multicenter, observational cohort
studies with rigorous microbiological data are needed to better
studied, and definitive statements regarding HAI for these categories await the findings of future studies. However, it appears
prudent to identify patients at risk for infection with MDR
pathogens or any other type of infection, to increase the likelihood of administration of appropriate empirical antimicrobial
therapy.
Initial treatment with an appropriate antimicrobial regimen
is associated with reduced risk of death and morecost-effective
medical care during hospitalization. To provide appropriate
empirical therapy, clinicians must actively identify risk factors
for colonization or infection with MDR pathogens in the patients for whom they provide treatment. Classification of the
patient as at risk for HAI is a surrogate marker for increased
risk of colonization and infection with MDR bacteria. At the
same time, clinicians must develop and implement strategies
in their hospitals to ensure that unnecessary antimicrobial usage
is avoided, to minimize the emergence of antibiotic resistance.
The de-escalation strategy is one that attempts to accomplish
this dual goal by providing for the administration of broadspectrum empirical antimicrobial therapy to patients at risk for
MDR infection while modifying the empirical antimicrobial
regimens on the basis of microbiological, antimicrobial-susceptibility, and clinical-response data. De-escalation also implies that the shortest antimicrobial regimen deemed appropriate for a patients infection and clinical response should be
employed. This strategy is intended to improve short-term outcomes for individual patients and long-term outcomes for the
general population.
The goal of the HAI Summit was to critically appraise existing literature, to assess the relative strengths and limitations
of our current knowledge in this area. A recurring theme, regardless of which statement was being discussed, was the paucity of specific data concerning HAIs and the frequent extrapolation of data from studies of nosocomial infections. The
Treatment by Sites of Infection workshop showed that only
HCAP and health careassociated BSI have been directly evaluated as separate distinct clinical entities. However, even for
define the precise subsets of patients at risk for infection with

MDR pathogens, as well as to better delineate risk factors for
specific pathogens. Similar studies are needed regarding the
implications of severity of illness for outcomes. In addition, a
clear need exists for specific studies on antibiotic therapy deescalation, specifically according to pathogen species, and the
optimal duration of therapy. Investigators should be actively
encouraged to pursue these lines of investigation in the future.
9.
10.
11.
Acknowledgments
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Supplement sponsorship. This article was published as part of a supplement entitled Health CareAssociated Infection (HAI): A Critical Appraisal of the Emerging ThreatProceedings of the HAI Summit, sponsored
by Medical Education Resources and Consensus Medical Communications
and supported by an unrestricted educational grant from Ortho-McNeil, Inc.,
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Potential conflicts of interest. M.H.K. has received grants/research
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SUPPLEMENT ARTICLE

Health CareAssociated Infection (HAI): A Critical

The classification of bacterial infections is in a state of

Reprints or correspondence: Dr. Marin H. Kollef, Div. of Pulmonary and Critical

therapy should be administered in a timely manner to

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Table 1. Risk factors used to define health careassociated

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VAP. The most common bacterial pathogen isolated in patients

Table 2. Health CareAssociated Infection (HAI) Summit clinical practice statements.

of HAI as a distinct entity and the need for specific therapeutic

Evidence obtained from case series, case reports,

Insufficient evidence to form an opinion

There is good evidence to support the statement

There is good evidence to reject the statement

Accept recommendation completely

Accept recommendation with major reservations

Individual level of support

HAI Summit Critical Appraisal CID 2008:47 (Suppl 2) S57

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Workshop 2: Treatment by Organism (statements 610)

S58 CID 2008:47 (Suppl 2) Kollef et al.

A PubMed database search to identify studies related to the

Prevalence of health careassociated cSSTI. No studies were

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HAI Summit Critical Appraisal CID 2008:47 (Suppl 2) S59

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catheter, having an indwelling urinary catheter, or having an

Table 4. Comparison of community-associated and health careassociated methicillin-resistant

Health careassociated MRSA

USA 300, USA 400

USA 100, USA 200

Panton-Valentine leukocidin producing

S60 CID 2008:47 (Suppl 2) Kollef et al.

common. Gram-negative isolates (only E. coli) were uncommon

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1.53; 95% CI, 1.162.02), female sex (prevalence ratio, 1.16;

On the basis of a review of the studies cited above, the workshop

When voting on the individual level of support for this statement,

Presently, there is no true category or definition of health care

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causing surgical-site infections in most institutions [29]. MRSA

additional cSSTI categories in which resistant gram-positive and

Future directions discussed by the summit members include

Complicated intra-abdominal infections (cIAIs) are defined as

Table 5. Definitions used for epidemiologic classification of invasive methicillin-resistant

Health care associated

S62 CID 2008:47 (Suppl 2) Kollef et al.

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North America increased substantially, from 26.2% of isolates

whether an expanded classification system that includes health

A PubMed database search was conducted on 4 September 2007

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S64 CID 2008:47 (Suppl 2) Kollef et al.

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Cefuroxime plus metronidazole

Ciprofloxacin plus metronidazole

Cefuroxime or cefazolin plus

NOTE. Adapted from [40] and from [48].

High risk (categorized as high-sePiperacillin/tazobactam

Low risk (categorized as mild-toAmpicillin/sulbactam

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Table 7. Organisms reported in a study of postoperative peritonitis by Montravers et al. [52].

On the basis of a review of the studies cited above, the workshop