Common Microbial Patho gens in Surgic al Prac tice

Motaz Qadan, BSc (Hons), MBChB, MRCS(Ed)a, William G. Cheadle, MDb,*

KEYWORDS  Bacteria  Fungi  Infection  Surgery  Post-operative

The process of inflammation as applied to surgical wounds was discussed by Hippocrates, who coined the term laudable pus as a sign of eventual wound healing, as opposed to erysipelas, a spreading inflammation that often meant the death of the patient. Although many scholars suspected microorganisms, it would take the development of the compound microscope to allow the microbiologists of the nineteenth century to describe the multitude of bacterial and fungal organisms and their relationship to infection. Pasteur developed the germ theory of disease by demonstrating that bacteria did not contaminate culture medium in curved flasks and Koch described the postulates by which infection from a particular microorganism would be defined. He was awarded the Nobel Prize in 1905 for his description of the Mycobacterium tuberculosis bacillus. The Hungarian obstetrician Ignaz Semmelweis, who practiced in Austria in the midnineteenth century, demanded that his residents and students wash their hands in sodium hypochlorite before touching patients and also had his obstetric instruments soaked in the same solution. This eventually ushered in the era of asepsis, and although his contemporaries failed to adopt these measures, the prevailing rate of postpartum endometritis, which had been extremely high, decreased markedly in his patients, to an estimated 5%.1 Lord Lister, a general surgeon who did mostly orthopedics, was the first to use an antiseptic agent, carbolic acid, in 1865, to reduce the risk of surgical site infection

Conflict of Interest Statement: W.G. Cheadle had full access to all the data and had final responsibility for the decision to submit the manuscript for publication. There were no personal relationships or financial conflicts to disclose. This article is an original contribution that has neither been published before nor is under consideration for publication elsewhere. Dr. Motaz Qadan holds the Joint Royal College of Surgeons of Edinburgh (RCSEd)/James and Emmeline Ferguson Research Fellowship. a Price Institute of Surgical Research, Department of Surgery, University of Louisville, Louisville, KY 40202, USA b Veterans Affairs Medical Center, Department of Surgery, University of Louisville, Louisville, KY 40202, USA * Corresponding author. Veterans Affairs Medical Center (151), 800 Zorn Avenue, Louisville, KY 40206. E-mail address: wg.cheadle@louisville.edu (W.G. Cheadle). Surg Clin N Am 89 (2009) 295310 doi:10.1016/j.suc.2008.09.002 0039-6109/08/$ see front matter. Published by Elsevier Inc. surgical.theclinics.com

296

Qadan & Cheadle

(SSI). This treatment revolutionized the treatment of open fractures in which the extremity was salvaged. These early measures have been refined to the modern aseptic and antiseptic techniques used today, and with appropriate use of prophylactic antibiotics, the overall SSI rate has been reduced to approximately 5%.2 The National Surgical Quality Improvement Program (NSQIP) identified that pneumonia, urinary tract infection (UTI), and sepsis respectively occurred in 3.6%, 3.5%, and 2.1% of surgical patients in the database.3 Since infection rates are not zero, significant improvements with additional knowledge of local wound conditions and the infecting microbes can still be made.
ANATOMIC CONSIDERATIONS OF BACTERIAL AND FUNGAL PATHOGENS

Apart from viruses and prions, which are beyond the scope of this report, all pathogenic organisms are made up of cells. Cells are distinct entities of cytoplasm that are bound by a cell membrane and consist of genetic (DNA) material. Bacterial cells are referred to as prokaryotes and all other cells are eukaryotes. Prokaryotes lack a distinct nuclear compartment, have DNA in the form of a single circular chromosome (additional bacterial DNA may be carried in plasmids), and are able to undergo simultaneous transcription and translation without mRNA. They also lack any membranebound organelles within their cellular boundaries. Interestingly, eukaryotic membrane-bound organelles, such as mitochondria, are thought to share common evolutionary pathways with entire prokaryotic cells, a fundamental hypothesis in the endosymbiosis theory. In fact, the term pro-karyote literally translates to before the nucleus and refers to the evolutionary origin of prokaryotic cells preceding more complex eukaryotes. Bacterial cell walls are complex and divide bacteria into two classes: gram-positive and gram-negative cells. Gram staining, developed by the Danish scientist Hans Christian Gram in 1884, tests the ability of bacteria to retain a violet stain after washing with iodine and alcohol, with purple indicating a positive Gram stain and pink indicating a negative one. In gram-positive bacteria, the outer wall is made of peptidoglycan, whereas gram-negative species have little peptidoglycan but possess an additional outer layer rich in polysaccharides. Bacterial cell wall layers provide complex protective defense shields against immune cells and antimicrobial agents. Potentially, they may stimulate certain pathogenic responses on degradation and systemic spread. Some prokaryotes possess flagella (tails), which permit motility, and fimbriae or pili, which aid in adhesion to various surfaces. Bacterial ribosomes (denoted 70S), although similar to eukaryotic ribosomes (80S), are the specific target of antimicrobial agents such as aminoglycosides. Fig. 1 provides a schematic representation of the generalized structure of a prokaryotic cell. Classification of prokaryotes is complex. Based on a mixture of size, shape, color, and immunohistochemical and biologic markers, bacteria are classified into genera (singular genus), which are further subdivided into species (capable of interbreeding). Examples include Escherichia coli and Staphylococcus aureus. Differences within a genus depend on immunologic and phenotypic properties, including the presence of flagella, the type of toxins produced, the ability to hemolyze blood, and so forth. Direct genomic studies are also employed today to accurately identify organisms based on genome size, ratio of bases within DNA, and the presence of certain DNA sequences. Fungi are eukaryotes that are very different from human and plant cells. They are multicellular multinucleate organisms that grow either in filaments (hyphae) to form a mycelium, or as mononuclear spherical organisms that replicate by budding and

Common Microbial Pathogens in Surgical Practice

297

Fig. 1. Structure of a prokaryotic cell. (Courtesy of T. Sheppard, BSc., London. Copyright 2005 Tim Sheppard. Available at www.blobs.org; used with permission.)

division (yeast). Although some may exist as commensals on human skin and hair, several are important human pathogens both superficially and deeper in tissues, where they invade and digest surrounding material by releasing digestive enzymes and absorb available nutrients for survival.
Gram-Positive Cocci Staphylococcus

Staphylococcus aureus is a catalase and coagulase-producing gram-positive organism that frequently occurs in human nasal passages, mucous membranes, or skin of carriers. It is traditionally identified by its characteristic golden yellow grapelike clumped colonies on culture (staphule Greek for grapes; aureus Latin for gold) (Fig. 2). This organism is arguably the most important pathogenic organism in evolving surgical infections, and thus, receives considerable attention below. S aureus constitutes the majority of skin and soft tissue infections encountered in the surgical population, accounting for up to 20% of SSI isolates but also 13% of all nosocomial infections (Table 1).4 This facultatively anaerobic organism was first reported in 1880 in Aberdeen, Scotland, by the surgeon Sir Alexander Ogston, in pus drained from infected abscesses. Since then, an estimated 500,000 patients a year

Fig. 2. Gram-positive cocci.

298

Qadan & Cheadle

Table 1 National Nosocomial Infections Surveillance top 10 most common isolates (percentage distribution) in surgical site infections and nosocomial infections Pathogen Staphylococcus aureus Escherichia coli Coagulase-negative Staphylococci Enterococcus spp Pseudomonas aeruginosa Enterobacter spp Candida albicans Klebsiella pneumoniae Gram-positive anaerobes Proteus mirabilis Surgical Site Infections (n 5 17,671) 20 8 14 12 8 7 3 3 1 3 All Sites (n 5 101,821) 13 12 11 10 9 6 5 5 4 3

Data from National Nosocomial Infections Surveillance (NNIS) report, data summary from October 1986April 1996, issued May 1996. A report from the National Nosocomial Infections Surveillance (NNIS) System. Am J Infect Control 1996;24(5):3808.4

are thought to contract S aureus in US hospitals.5 Superficial carriage is arguably commensal in nature and often nonpathogenic but deep-seated S aureus penetration is associated with significant morbidity and mortality and requires intensive therapy. In the nonsurgical population, it is the cause of pneumonia, endocarditis, disseminated bacteremia, toxic shock syndrome, and food poisoning among many other disease entities in adult and pediatric populations. S aureus is capable of producing several exotoxins, including enterotoxins and superantigens, which result in the organisms virulence.6 These include the following:  Alpha-toxin (hemolysin), which binds to susceptible cells such as monocytes and platelets and results in leakage of contents. When released systemically, septic shock ensues.  Beta-toxin, which classically binds, and is tested for, using sheep erythrocytes and is not usually encountered in human disease states.  Delta-toxin, which is produced by S aureus as well as other staphylococcal species but its function remains largely unknown.  Leucocidin, which is a hemolytic toxin (less so than alpha-toxin) that acts on polymorphonuclear leukocytes and helps S aureus evade phagocytosis. It is expressed in only 2% of S aureus isolates but is identified in over 90% of necrotizing lesions that contain S aureus.  ETA and ETB exfoliation toxin, which results in widespread epidermal loss and skin blistering in neonates via protease- and esterase-mediated degradation of important integrity-maintaining epidermal proteins.  Enterotoxins and toxic shock syndrome toxin (TSST), which possess superantigenic properties and may cause toxic shock syndrome. Enterotoxins, when ingested, result in the most common form of food poisoning. Activation of T cells and cytokine release account for the actions of these toxins. Mildly pathogenic products include:  Coagulase, which binds to prothrombin, and, in turn, converts fibrinogen to fibrin, thereby resulting in clot formation. It is thought to deter immune cells from arriving at the site of S aureus action.

Common Microbial Pathogens in Surgical Practice

299

 Staphylokinase, which degrades fibrin, much like streptokinase, and may aid in bacterial spreading.  Proteases, lipases, DNase and fatty-acid modifying enzyme (FAME), which degrade various components and may aid in S aureus spread within abscesses. Following the introduction of penicillin by Sir Alexander Fleming in 1943, antibacterial sensitivity of S aureus to penicillin has been gradually replaced by resistance. By the 1960s, resistance was thought to near 80%.7 Resistance to penicillin is mediated by penicillinase (beta-lactamase), an enzyme that degrades the beta-lactam ring of penicillin. The emergence of penicillinase-resistant penicillins such as methicillin in 1959 and flucloxacillin shortly after were a welcomed discovery, until less than 2 years later, when, in 1961, the first reported case of resistance to methicillin was observed! Following initial identification, methicillin-resistant S aureus (MRSA) has risen to endemic rates in US and UK hospitals, with a sharp rise in incidence occurring in the 1990s. Incidence rates published by the US Centers for Disease Control and Prevention (CDC) have demonstrated a greater than twofold increase from 127,000 reported cases to 278,000 between 1999 and 2005.8 Risk factors include previous antibiotic administration, prolonged hospitalization, and multiple patient comorbidities.9 Despite evasion of methicillin to bacterial penicillinase, the organism was able to acquire new-found resistance, encoded for in the mec operon coding region, which is part of the staphylococcal cassette chromosome mec (SCCmec) within bacterial plasmids. Resistance conferred via the mecA gene alters penicillin binding properties and thus also implies automatic resistance to penicillinase-sensitive antibiotics such as penicillin and cephalosporins. MRSA is now understood to consist of two exclusive subtypes: a nosocomial, or hospital-acquired, type (HA-MRSA) and a community-acquired type (CA-MRSA). Although originally defined according to source of origin, the apparently clear-cut distinction between these subtypes is more complex. Both types are equally resistant to traditional beta-lactam antibiotics although HA-MRSA appears to have a larger resistance profile, with sensitivity restricted to vancomycin, teicopleinin, or the newer oxazolidinones such as linezolid. HA-MRSA appears to affect patients in hospitals with open wounds, those who undergo invasive procedures, and ones with weakened immune systems. Transfer is predominantly staff- and instrument-related, awareness of which has resulted in the development of strict hand-washing and barrier-oriented infection control policies that are now in place. Although most MRSA infections remain health careassociated, a rising incidence of community-acquired infection is apparent. Community-acquired infection incidence rates in the United States in 2005 were estimated at 13.7% in a recently published large series.10 Consequently, community-acquired MRSA (CA-MRSA) is gaining increased attention among microbiologists and health care workers today. It was first noted in the early 1990s and was associated with a number of different skin and soft tissue syndromes (furuncles, impetigo, and cellulitis) in individuals who were previously healthy and had not been hospitalized within 1 year of infective episodes.1113 Originally thought to be similar in origin to its nosocomial counterpart, community-acquired strains have been shown to be genetically diverse with unique microbiologic properties, rendering them a separate entity.13 Areas of aggregation have included army bases, jails, and among inner-city children, where close individual contact and poor hygiene, and hence transmission, are most likely. The communityacquired strain is associated with virulence factors thought to promote transmissibility and likelihood of disease. CA-MRSA is specifically associated with carriage of

300

Qadan & Cheadle

SCCmec Type IV and panton-valentine leucocidin (PVL) virulence factor. In a study of patients from the San Francisco Bay Area, 70% of MRSA isolates from prison inmates and clinics specializing in soft and skin tissue infections were positive for PVL carriage.14 Of 671 isolates collected over a 5-year period, most could be traced back to only two clonal groups, both of which carried the SCCmec type IV resistance determinate and both more likely to be recovered from skin. This pattern indicated the likelihood of rapid clonal supplantation within community-based transmission, probably attributable to the aforementioned virulence factors. In another study of over 800 soldiers from Brook Army Medical Center, it was found that 3% (24) of soldiers were colonized with CA-MRSA, 9 of whom developed soft tissue infections in the 8- to 10-week observation that followed.15 PVL genes were detected in all nine cases. In contrast, of 28% who were colonized with the methicillin-sensitive S aureus (MSSA) strain, only 3% went on to develop soft tissue infections in the same observation period, highlighting very clearly the increased virulence potentially associated with carriage of the PVL gene in community evolving species. MRSA has recently been treated with newer antimicrobial agents such as clindamycin and linezolid. These new agents are available in the oral form, thereby avoiding complex administration issues associated with intravenous delivery. More serious invasive MRSA infection, which is typically hospital-acquired, requires intravenous vancomycin treatment, a glycopeptide that is associated with toxic side effects and poorly absorbed in the oral form. Alarmingly, a rising vancomycin minimum inhibitory concentration (MIC) in the hospital-acquired strain is well documented, confirming the emergence of vancomycin-intermediate-resistant S aureus (VISA) and vancomycinresistant S aureus (VRSA) species.11 The former was first identified in Japan in 1996 and the latter in the United States in 2002. These organisms have since affected specific populations, such as hemodialysis patients, but incidence rates are nevertheless rising.16 Preliminary reports of S aureus resistance to linezolid are available and pose serious future concern.17 Another frequently encountered bacterium in surgical infections is the skin commensal Staphylococcus epidermidis. This facultatively anaerobic, catalase-positive and coagulase-negative organism, along with Staphylococcus saprophyticus and Staphylococcus capitis, are collectively referred to as Staphylococcal albus, because of the formation of white spherical colonies on culture (albus Latin for white). Although less virulent than S aureus, S epidermidis is able to form a teichoic acid slime, derived from the staphylococcal cell wall, which results in the formation of a resilient biofilm that protects the bacterium against host and chemotherapeutic defense mechanisms, and thus, renders the organism more virulent.18,19 Furthermore, in a recent study by El-Azizi and colleagues,20 the authors were able to show that bacteria isolated from disrupted prosthetic biofilm were significantly less resistant to antimicrobial therapy than those in the biofilm itself. Classically, S epidermidis is isolated from infected surgical wounds, particularly sternal wounds, where it is the most common isolate.21,22 Other common operations where this organism is implicated include that that use prostheses, such as joint replacement and vascular graft procedures. It is commonly recovered from the site of infected indwelling catheters, where it is usually associated with the formation of bacterial biofilm.18,19 Little else is known about the pathogenesis of S epidermidis. Treatment is complex with resistance reported to both penicillin and methicillin. In 2003, approximately 90% of all coagulase-negative staphylococcal species were resistant to methicillin.23

Common Microbial Pathogens in Surgical Practice

301

Streptococcus

These gram-positive, facultatively anaerobic cocci play a significant role in surgical infections such as erysipelas and type II necrotizing fasciitis (streptococcal fasciitis), despite being commensal organisms of the mouth, throat, skin, and human intestine. Their name is derived from their twisted chain-like pattern of growth following cellular division (strepto Greek for twisted). An organized approach to classification of these organisms yields a better understanding of their various roles in disease (see Fig. 2). They are first divided into their ability to break down red blood cells in the laboratory, which yields three types: alpha-hemolytic, beta-hemolytic, and nonhemolytic. Alpha-hemolytic species cause partial breakdown of blood, which results in an impartially degraded green haem halo surrounding the streptococcal colony in blood agar. Within this group, there are two dominant species, Streptococcus viridans (viridans Latin for green) and Streptococcus pneumoniae, the causative organisms for endocarditis and pneumococcal pneumonia respectively. Their role in surgical disease is limited. Beta-hemolytic organisms cause complete hemolysis of red cells in agar, and, therefore, form a white area surrounding the colony. They are further divided into Lancefield Types A-T, named after the prominent work of the late American microbiologist, Rebecca Craighill Lancefield. Surgically relevant are Streptococcus pyogenes, a Lancefield group A organism, and Enterococcus (formerly Streptococcus group D reclassified in 1984).24 These organisms play a large pathogenic role in surgical microbial disease and are discussed below. Non-hemolytic streptococcal species, often referred to as gamma-hemolytic (a misnomer), rarely account for serious human disease. Enterococcal species, which cause a variable degree of hemolysis, must not be confused with nonhemolytic streptococci, an entirely different bacterial genus. Streptococcus pyogenes, also known as group A Streptococcus (GAS), was traditionally regarded as the main pathogen of complicated skin and soft tissue infection. Its presence in cellulitis, and more specifically, erysipelas, which primarily affects the upper dermis, is well documented. It has also been reported in infected abdominal wounds, bites, and complicated poly-microbial diabetic disease. Its most notable role, however, remains its etiologic role in type II necrotizing fasciitis, or streptococcal gangrene, where it is the dominant organism along with few other Streptococcal group B, C, and G species.25 The organisms ability to multiply and spread laterally in deep dermal tissue is often life-threatening. Early recognition and aggressive treatment is imperative in this disease. In a recently published series of 165 patients with necrotizing fasciitis, overall mortality was reported at 17% with 25% requiring amputation of the affected extremity in addition to surgical debridement.26 Central to pathogenic mechanisms is the production of extracellular toxins, of which two are hemolytic and three pyrogenic. There are various other nucleases, DNAses, and proteolytic enzymes that are also secreted. Hemolytic toxins include Streptolysin O and S, the former usually used as an antigenic serum marker of recent streptococcal infection. These degrade red blood cells as well as platelets and polymorphonuclear leukocytes. Pyrogenic toxins are classified from A to C and are responsible for the development of scarlet fever. Common sequelae of streptococcal exotoxins include streptococcal toxic shock syndrome (TSS), glomerulonephritis, and, less commonly today, acute rheumatic fever. Interestingly, streptokinase, an enzyme produced by the bacteria, is used as a cardiovascular thrombolytic agent following myocardial infarction (MI), more often than its staphylococcal counterpart.6,27

302

Qadan & Cheadle

Treatment is with penicillin and its various derivates. However, appreciation that this organism often coexists in polymicrobial disease indicates that additional broadspectrum coverage is frequently required. For example, type I necrotizing fasciitis often includes highly virulent clostridial anaerobes among other organisms. Enterococcal species include both Enterococcus faecalis and Enterococcus faecium, commensals in the adult gastrointestinal tract (90% and 5%, respectively).28 These partially hemolytic organisms frequently account for SSIs, particularly following clean-contaminated and contaminated surgery of the bowel. Enterococcal organisms have gained recent attention because of their intrinsic resistance to a variety of antimicrobial agents, including semisynthetic penicillinase-resistant penicillins, cephalosporins, trimethoprim-sulfamethoxazole, aminoglycosides, and clindamycin.29 These organisms are also capable of acquiring resistance to other agents including chloramphenicol, macrolides, tetracycline, and fluoroquinolones. Interestingly, enterococcal organisms were the first to exhibit resistance against vancomycin in 1986.30,31 The mechanism of resistance involves alteration of vancomycin-binding targets. Vancomycin binds to [d-alanine d-alanine] targets, which are either replaced with [d-lactate] or the entire synthesis of cell wall precursors with vancomycin-binding targets are inhibited. Several subtypes of vancomycin resistance are described and are denoted VanA to VanE.32 Since the emergence of vancomycin-resistant enterococcus (VRE), incidence has steadily increased in the United States (although not the United Kingdom) until, in 2004, the National Nosocomial Infections Surveillance (NNIS) reported that 30% of all ICU enterococcal infections were vancomycin resistant.23 Currently, almost 75% of E faecium and 5% of E faecalis are resistant to vancomycin, with the latter fortunately accounting for the vast majority of recovered isolates.33,34 Alarmingly, recent evidence shows this resistance could be transferred to other organisms, such as MRSA.35,36 Sensitive enterococcal organisms may be treated with ampicillin or vancomycin. Vancomycin-resistant E faecium is treated generally with linezolid, or can be treated with daptomycin or quinupristin/dalfopristin. For vancomycin-resistant E faecalis infections, ampicillin may be used if the organism is sensitive. Quinupristin/dalfopristin should not be used to treat E faecalis, since this organism is intrinsically resistant to this antibiotic.37,38
Gram-Positive Bacilli

These Gram-positive rod-shaped bacteria are obligate anaerobes that are capable of spore formation, and include Clostridium perfringens, Clostridium difficile, Clostridium tetani, and Clostridium botulinum (Kloster Greek for rods). The latter two are known for producing tetanus and botulinum toxins respectively but otherwise have a limited role in surgical disease. C perfringens causes the rare surgical disease known as gas gangrene, a rapidly spreading surgical emphysema mediated by the enterotoxin alpha-toxin. Its ability to form gaps between cells results in the characteristic formation of gas pockets below the dermis. Untreated, it results in life-threatening sequelae. It is most commonly encountered in type I polymicrobial cases of necrotizing fasciitis. Its presence has been shown to be an independent predictor of mortality and limb loss among affected cases in the recently published series described earlier.26 Although C perfringens is often implicated in monobacterial gas gangrene, it is not exclusively associated with this disease. Other clostridial species, such as C septicum, may also cause gas gangrene.

Common Microbial Pathogens in Surgical Practice

303

C difficile is frequently seen on surgical wards in patients on prolonged antibiotic therapy. This organism has recently gained attention in public health circles because of increasing incidence rates and severity of the symptomatic pathognomic disease, pseudomembranous colitis.39 Eradication of the normal colonic flora with previously administered antibiotics combined with C difficile ingestion may result in the formation of pseudomembranes. A severe hemorrhagic inflammation often ensues, resulting in a profound and rapidly transmissible diarrheal state in hospitalized patients.40 In the elderly, frail, and immunocompromised, sequelae may be life-threatening. Classically, abdominal radiographs fail to demonstrate evidence of obstruction. Risk factors for disease development include antimicrobial therapy and proton pump inhibitors (PPIs).4144 Symptoms are often compounded by narcotics prescribed for associated pain, which inhibit colonic peristalsis and may potentially cause toxic megacolon, a surgical emergency.45,46 Inflammation, mucosal secretion, and cell damage in the colon are mediated via the secretion of two toxins, known as toxin A and toxin B.47 It is unclear as to why certain individuals will develop symptomatic disease but production of these toxins is essential for disease to occur.39 Furthermore, recent strains associated with increased severity of disease, such as the North American pulsed-field gel electrophoresis type 1 (NAP 1), have been shown to produce up to 16 times more toxin A and 23 times more toxin B than standard less virulent strains of C difficile. NAP 1 also exhibits resistance to moxifloxacin and gatifloxacin, a phenomenon not encountered in previous C difficile strains.39 Effective treatment of clostridial species is with metronidazole, although, once again, special attention should be paid to individual circumstances; for example broad-spectrum antimicrobial coverage may be required for other organisms likely to coexist (type I necrotizing fasciitis) or discontinuing original culprit antimicrobial agents that may have permitted uncontrolled growth of the clostridial species (C difficile pseudomembranous colitis). Oral vancomycin is also effective in the treatment of symptomatic C difficile. Appropriate stool culture and sensitivities will guide the treating surgeon and careful liaison with hospital microbiologists is essential to ensure adequate isolation and disinfection protocols are followed.
Other Gram-Positive Species

There are several other Gram-positive bacilli such as Bacillus, Cornyebacterium, Lactobacilli, and Listeria, which may cause serious disease in humans but are less relevant to surgical readers. Additional details are not provided in this article.
Gram-Negative Cocci

The most notable gram-negative cocci are the Neisseria species, Neisseria meningitides and Neisseria gonorrhoeae, which commonly cause meningitis and gonorrhea respectively and do not feature in surgical disease. The discussion therefore moves on to the more relevant gram-negative bacilli, which are frequently encountered in surgical patients.
Gram-Negative Bacilli

Almost all surgically relevant gram-negative bacilli are aerobes, apart from Bacteroides fragilis, an anaerobe that frequently affects surgical patients. Generally speaking, gram-negative bacterial species tend to occur as intestinal commensals in humans, and, as such, infection related to these organisms usually follows abdominal bowel surgery, particularly colonic surgery, where there is breach of an abdominal viscus. Gram-negative bacteria account for a significant proportion of SSI isolates and all

304

Qadan & Cheadle

nosocomial infections. Enterobacter spp, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis account for 21% of all SSIs alone.4
Enterobacteriaceae

This is a large family of gram-negative bacterial rods, which, for classification purposes, are divided into lactose fermenters, and nonlactose fermenters (NLF). Lactose fermenters are able to ferment sugars to produce lactic acid, and include Enterobacter spp, E coli, K pneumoniae and Proteus spp, which are discussed in the following paragraphs. NLFs include Salmonella, Shigella, and Yersinia species and account for the nonsurgical, but, nevertheless, important disease entities such as typhoid (Salmonella typhii), bacillary dysentery (Shigella dysenteriaea), food poisoning (Salmonella entiridis), and historically, the Plague (Yersinia pestis). E coli is arguably is the most intensively studied bacterial organism since its discovery in 1885. Simple growth requirements and an easily manipulated genetic make-up have resulted in an important biotechnological role today, via the creation of recombinant DNA for the mass production of a variety of proteins. Without acquiring virulence factors, it is an unharmful colonic commensal that often protects bowel against overgrowth of pathogenic species. However, virulent strains of E coli account for several types of gastroenteritis and often result in food product recalls and considerable media attention. Easily transmissible through the fecal-oral route, contamination of food products with harmful strains occurs mostly through unhygienic food preparation and include enterotoxigenic, enteropathogenic, enteroinvasive, enterohemorrhagic (0157), and enteroaggregative strains, all of which cause profound diarrhea, with or without fever, and which may be life-threatening. Toxins produced by the various subtypes mediate many of the pathogenic gastroenteritic features. The enterohemorrhagic 0157 strain also causes hemolytic-uremic syndrome in children around 5% of the time, where spread of the 0157 Vera-toxin classically results in the triad of microangiopathic hemolytic anemia, acute renal failure, and thrombocytopenia. Following colonic surgery, E coli may result in SSI and/or peritonitis, where illness may be profound. Fortunately the organism remains very sensitive to gentamicin as well as other antimicrobial agents such as cephalosporins, carbapenems, aztreonam, ciprofloxacin, trimethoprim-sulfamethoxazole, and nitrofurantoin. E coli resistance to antimicrobial therapy is a growing problem since adaptive mutations in the genome were found to occur at an alarmingly faster rate than previously anticipated.48 Furthermore, as a common bacterium in polymicrobial biofilm, E coli carries multiresistant drug plasmids, which it is able to transfer to other neighboring species, such as S aureus, thereby acting as a reservoir of transferable resistance.49 Beta-lactam resistance is also on the rise and results in multidrug resistance to a large variety of penicillins and cephalosporins, rendering treatment more difficult.50 The extensive and empiric use of third generation cephalosporins in surgical intensive care units is etiologic to growing E coli antibiotic resistance. The concepts of beta-lactamase resistance and plasmid transference apply similarly to K pneumoniae and other Enterobacteriaceae species. Extended-spectrum beta-lactamase production by gram-negatives resulting in multidrug resistance has been shown to significantly increase mortality, length of hospitalization, and associated costs.16,51,52
Pseudomonads

Pseudomonas aeruginosa is a gram-negative rod generally associated with opportunistic infections and most commonly accounts for infections of the urinary tract, ventilator-associated pneumonias (VAP), and wound infections. It is thought to account

Common Microbial Pathogens in Surgical Practice

305

for up to 8% of SSIs.4 It plays a role in the formation of bacterial biofilm and is the most frequent colonizer of medical devices and catheters. Community-acquired disease is only rarely caused by P aeruginosa. As a commensal colonizer, superficial culture does not always provide grounds for treatment but blood-borne and deep-seated infections are indications for urgent intervention. This organism has recently gained microbiological attention because of emerging multidrug resistance, thought to occur via complex multistep genetic mutations, drug efflux mechanisms, and horizontal transfer within colonies. The 2004 NNIS report documented rising resistance rates of P aeruginosa to both quinolones and imipenem, although imipenem has remained widely effective in many units in the past decade.23,25 Aminoglycosides and third-generation cephalosporins also remain effective at this time.
Curved, Spiral, or Helical Organisms Campylobacter jejuni

Via the production of a cholera-like enterotoxin, Campylobacter jejuni is now recognized as the most common cause of food-borne gastroenteritis in the developed world, and results in epithelial cell damage in jejunal and ileal segments of affected  neuropathy patients. Postinfection, this organism will rarely result in the Guillain-Barre several weeks following gastroenteritic symptoms in affected individuals.
Helicobacter pylori

Helicobacter pylori is a classic helical organism that was only identified as late as 1982 by the Australian Nobel Prize winners Robin Warren and Barry Marshall. Their discovery paved the way for the production of highly effective drug therapy and simple cures, reducing surgical treatment of peptic ulcer disease to a relative rarity. H pylori is currently thought to infect half of the worlds population and is a recognized risk factor for gastric carcinogenesis.53 Through its ability to produce urease, this organism is able to evade the hostile acidic environment of the stomach where it most commonly resides and contributes to 90% of peptic ulcer disease. Mucinase production, evasion of the host IgG response, and the potential production of IL-10 to counteract T-lymphocyte cytokine production are all mechanisms that contribute to the organisms virulence.54 H pylori was originally classified as a Campylobacter organism, which was subsequently modified to a Campylobacter-like organism (CLO). It was reclassified again as a separate entity altogether. CLO tests may still ring familiar among surgeons who biopsy gastric mucosa in search of this organism. Peptic ulcer disease therapy was modified to include antibiotics with antacid treatments following successful isolation of the organism and classically includes two of amoxicillin, clarithromycin, tetracycline, or metronidazole with the newer and more potent PPIs.
Other Gram-Negative Species Acinetobacter spp

This strictly aerobic nonfermenting cocco-bacillus is a nosocomial organism that accounts for serious life-threatening infection in debilitated patients. Sources include hospital surfaces and medical devices because this bacterium is able to survive on wet and dry surfaces alike. Rising resistance among the species along with inherent resistance to antimicrobial agents including penicillin and, occasionally, aminoglycosides has provided cause for concern. Like Pseudomonas species, drug efflux and horizontal transfer of resistance play key roles in rising resistance rates. Last resort carbapenems, which were previously highly effective against this organism, are now

306

Qadan & Cheadle

susceptible to evolving resistance mechanisms as reported by the CDC. Recent promise has been shown using Polymyxin B in highly resistant species.55
Bacteroides fragilis

Bacteroides fragilis is a normal component of the human bowel flora, and the most common anaerobic species involved in intra-abdominal infections. B fragilis, an obligate anaerobe, has a polysaccharide capsule that retards phagocytosis and is thus able to evade innate host defense mechanisms.56 The capsular material is important in the organisms ability to form abscesses, even after the organism has been heat-killed, and is thought to account for its common etiologic role in the formation of appendicitic abscesses. This anaerobic organism is typically associated with other aerobic pathogens in a synergistic relationship, causing mixed infection but prolonging its survival in aerobic conditions. This requires special attention for therapy and in terms of awareness of transference of resistance. This organism is inherently resistant to many antibiotics including aminoglycosides and beta-lactams with recent acquired resistance reported for erythromycin, clindamycin and tetracycline. Current sensitivities include metronidazole, carbapenems, and penicillinase-resistant penicillins.
Fungi

Although these organisms are not typical surgical pathogens, they are seen in surgical patients who are debilitated as a result of comorbid disease, prolonged hospitalization, or extensive antibiotic treatment, where protective commensal flora are eliminated, allowing for pathogenic species of all types to freely differentiate and multiply. Even commensal fungi develop pathogenic properties during times of suboptimal host defense capabilities. Infection caused by fungal organisms is known as mycosis. Fungal mycoses are broadly divided into superficial and deep infections. Superficial infections include skin, hair, and subcutaneous tissue layers, such as nails and deeper skin planes. Spread usually occurs following direct contact. Deep infection involves internal organs and the bloodstream, where infection is normally restricted to opportunistic fungi affecting immunocompromised individuals. This type of infection is often life-threatening, particularly in debilitated individuals. In the context of surgical disease, fungal infection is best divided into C albicans related disease (candidiasis) and nonC albicans disease, since C albicans is the most frequently encountered fungal pathogen in surgical patients. NonC albicans fungi are rarely encountered in surgical patients and are summarized in Table 2. C albicans is a yeastlike fungus that is able to grow in filaments (hyphae and pseudohyphae), a factor that contributes to the organisms potential virulence. Surgical patients who receive potent antimicrobial or chemotherapeutic agents are most susceptible, as well as immunocompromised individuals with nonsurgical diseases such as leukemia and AIDS. Infection in surgical patients occurs in two ways:  It may occur at sites of normal commensal growth, where elimination of other protective commensals by antimicrobial agents provides an opportunity for unrestricted growth of the fungus. Sites include the mouth, skin, nails, vagina, and bowel.  Infection may also occur in areas of skin breach, where loss of integrity of the protective defense layer occurs. These areas frequently include blood-catheter sites, where the catheter then acts as a transport medium for the organism from the skin into the circulation. Life-threatening blood-borne candidiasis may ensue. Other areas of skin breach include surgical wounds, where C albicans is infrequently involved.

Common Microbial Pathogens in Surgical Practice

307

Table 2 Important fungal pathogens57 Superficial Infection Epidermophyton Microsporum Trichophyton Sporothrix Deep Infection Aspergillus Blastomyces Candida Coccidioides Cryptococcus Histoplasma Paracoccidioides Data from Mims C, Dockrell H, Goering R, et al. Medical microbiology. 3rd edition. Mosby; 2004.

Diagnosis may often be made by clinical examination; the appearance of oral candidiasis (thrush) for example is characteristic. However, cultures of blood, wounds, or catheters are usually required. Interpretation of such culture results is problematic, because, except in the case of fungemia, positive culture results may indicate only colonization rather than a true invasive candidal infection. Antifungal agents are used to treat C albicans infections. These are applied topically in the case of superficial infections, or administered intravenously in the case of deepseated organ infections or fungal septicemic states. Drug resistance has not been an issue when treating these relatively uncommon pathogens, probably because of the lack of empiric, oversubscribed, and unnecessary prescription of chemotherapy. An appreciation by the treating surgeon that serious fungal infections are likely to coexist with overwhelming bacterial sepsis, especially in the debilitated host, provides grounds for urgent bacterial culture and empiric therapy.
FUTURE IMPLICATIONS

Fundamental research into resistance mechanisms and the genome of the microbe will be required to lower the risk of surgical infections even further. However, an integral understanding of local conditions and the early innate immune response will also be required, as it is doubtful that microbe contamination can ever be eliminated. Definition of the host defense response for a particular individual, particularly those prone to repetitive infections, will eventually lead to targeted therapy augmentation before surgical treatment if infections are to be eliminated. The potential genetic mechanisms that cause only some individuals to spiral into full-fledged septic shock while others are able to fully recover following a microbial insult remain unclear. The heterogeneity of the innate immune cell performance remains poorly defined, but when further understood, will ultimately provide novel avenues for future immune therapy. University and private sector funding into research dedicated to the intensive study of bacterial genomics and the comprehensive understanding of mechanisms by which resistance is acquired will lead to the development of new and effective antimicrobial agents with previously unrecognized targets. The rapid rise of resistance and acquired adaptive mutations to last-resort chemotherapeutic agents warrants an urgent understanding of the issues at stake. A willingness to contribute through the adequate, accurate, timely, and nonprolonged prescribing of antibiotics is the first step to halting the rapid progression in microbial resistance and is the shared responsibility of all treating surgeons today.

308

Qadan & Cheadle

REFERENCES

1. Turina M, Cheadle WG. The management of established surgical site infections. Surg Infect (larchmt) 2006;7(S3):3341. 2. Polk HC Jr, Lopez-Mayor JF. Postoperative wound infection: a prospective study of determinant factors and prevention. Surgery 1969;66(1):97103. 3. Khuri SF, Daley J, Henderson W, et al. The National Veterans Administration Surgical Risk Study: risk adjustment for the comparative assessment of the quality of surgical care. J Am Coll Surg 1995;180(5):51931. 4. National Nosocomial Infections Surveillance (NNIS) report, data summary from October 1986April 1996, issued May 1996. A report from the National Nosocomial Infections Surveillance (NNIS) System. Am J Infect Control 1996;24(5):3808. 5. Bowersox J. Experimental staph vaccine broadly protective in animal studies. 1999. Available at: http://www3.niaid.nih.gov/news/newsreleases/1999/staph. htm. Accessed October 20, 2008. 6. Todar K. Todars online textbook of bacteriology. Online edition 2008. Available at: http://www.textbookofbacteriology.net/. Accessed October 20, 2008. 7. Chambers HF. The changing epidemiology of Staphylococcus aureus? Emerg Infect Dis 2001;7(2):17882. 8. Klein E, Smith DL, Laxminarayan R. Hospitalizations and deaths caused by methicillin-resistant Staphylococcus aureus, United States, 19992005. Emerg Infect Dis 2007;13(12):18406. 9. Crum NF, Lee RU, Thornton SA, et al. Fifteen-year study of the changing epidemiology of methicillin-resistant Staphylococcus aureus. Am J Med 2006; 119(11):94351. 10. Klevens RM, Morrison MA, Nadle J, et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 2007;298(15):176371. 11. Awad SS, Elhabash SI, Lee L, et al. Increasing incidence of methicillin-resistant Staphylococcus aureus skin and soft-tissue infections: reconsideration of empiric antimicrobial therapy. Am J Surg 2007;194(5):60610. 12. Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA 2003;290(22):297684. 13. Department of Health and Human Services, Centers for Disease Control and Prevention. Community-Associated MRSA Information for Clinicians. 2008. Available at: http://www.cdc.gov/ncidod/dhqp/ar_mrsa_ca_clinicians.html. Accessed October 20, 2008. 14. Diep BA, Sensabaugh GF, Somboona NS, et al. Widespread skin and soft-tissue infections due to two methicillin-resistant Staphylococcus aureus strains harboring the genes for Panton-Valentine leucocidin. J Clin Microbiol 2004;42(5):20804. 15. Ellis MW, Hospenthal DR, Dooley DP, et al. Natural history of community-acquired methicillin-resistant Staphylococcus aureus colonization and infection in soldiers. Clin Infect Dis 2004;39(7):9719. 16. Siegel JD, Rhinehart E, Jackson M, et al. The Healthcare Infection Control Practices Advisory Committee. Management of multidrug-resistant organisms in healthcare settings 2006. Available at: http://www.cdc.gov/ncidod/dhqp/pdf/ar/ mdroguideline2006.pdf. Accessed October 20, 2008. 17. Hentschke M, Saager B, Horstkotte MA, et al. Emergence of linezolid resistance in a methicillin resistant Staphylococcus aureus strain. Infection 2008;36(1):857. 18. Vadyvaloo V, Otto M. Molecular genetics of Staphylococcus epidermidis biofilms on indwelling medical devices. Int J Artif Organs 2005;28(11):106978.

Common Microbial Pathogens in Surgical Practice

309

19. von EC, Arciola CR, Montanaro L, et al. Emerging Staphylococcus species as new pathogens in implant infections. Int J Artif Organs 2006;29(4):3607. 20. El-Azizi M, Rao S, Kanchanapoom T, et al. In vitro activity of vancomycin, quinupristin/dalfopristin, and linezolid against intact and disrupted biofilms of staphylococci. Ann Clin Microbiol Antimicrob 2005;4:211. 21. Gardlund B, Bitkover CY, Vaage J. Postoperative mediastinitis in cardiac surgerymicrobiology and pathogenesis. Eur J Cardiothorac Surg 2002;21(5): 82530. 22. Tegnell A, Aren C, Ohman L. Coagulase-negative staphylococci and sternal infections after cardiac operation. Ann Thorac Surg 2000;69(4):11049. 23. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control 2004;32(8):47085. 24. Schleifer KH, Kilpper-Balz R, Kraus J, et al. Relatedness and classification of Streptococcus mutans and mutans-like streptococci. J Dent Res 1984;63(8): 104750. 25. Turina M, Cheadle WG. Clinical challenges and unmet needs in the management of complicated skin and skin structure, and soft tissue infections. Surg Infect (Larchmt) 2005;6(Suppl 2):2336. 26. Anaya DA, McMahon K, Nathens AB, et al. Predictors of mortality and limb loss in necrotizing soft tissue infections. Arch Surg 2005;140(2):1517. 27. Sharma S. Toxic shock syndrome. 2006. Available at: http://www.emedicine.com/ med/topic2292.htm. Accessed October 20, 2008. 28. Fischetti VA, Novick RP, Ferretti JJ, et al. Gram-positive pathogens. Washington, DC: ASM Press ; 2000. 29. Marothi YA, Agnihotri H, Dubey D. Enterococcal resistancean overview. Indian J Med Microbiol 2005;23(4):2149. 30. Leclercq R, Derlot E, Duval J, et al. Plasmid-mediated resistance to vancomycin and teicoplanin in Enterococcus faecium. N Engl J Med 1988;319(3):15761. 31. Uttley AH, Collins CH, Naidoo J, et al. Vancomycin-resistant enterococci. Lancet 1988;1(85756):578. 32. Murray BE. Vancomycin-resistant enterococcal infections. N Engl J Med 2000; 342(10):71021. 33. Karlowsky JA, Jones ME, Draghi DC, et al. Prevalence and antimicrobial susceptibilities of bacteria isolated from blood cultures of hospitalized patients in the United States in 2002. Ann Clin Microbiol Antimicrob 2004;3:715. 34. Franklin GA, Moore KB, Snyder JW, et al. Emergence of resistant microbes in critical care units is transient, despite an unrestricted formulary and multiple antibiotic trials. Surg Infect (Larchmt) 2002;3(2):13544. 35. Perichon B, Courvalin P. Heterologous expression of the enterococcal vanA operon in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2004;48(11):42815. 36. Whitener CJ, Park SY, Browne FA, et al. Vancomycin-resistant Staphylococcus aureus in the absence of vancomycin exposure. Clin Infect Dis 2004;38(8): 104955. 37. Rice LB. Antimicrobial resistance in gram-positive bacteria. Am J Infect Control 2006;34(5 Suppl 1):S119. 38. Tunger A, Aydemir S, Uluer S, et al. In vitro activity of linezolid and quinupristin/ dalfopristin against gram-positive cocci. Indian J Med Res 2004;120(6):54652. 39. Sunenshine RH, McDonald LC. Clostridium difficile-associated disease: new challenges from an established pathogen. Cleve Clin J Med 2006;73(2):18797.

310

Qadan & Cheadle

40. Barbut F, Petit JC. Epidemiology of Clostridium difficile-associated infections. Clin Microbiol Infect 2001;7(8):40510. 41. Bignardi GE. Risk factors for Clostridium difficile infection. J Hosp Infect 1998; 40(1):115. 42. Dial S, Alrasadi K, Manoukian C, et al. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ 2004;171(1):338. 43. Dial S, Delaney JA, Barkun AN, et al. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA 2005;294(23):298995. 44. Pepin J, Saheb N, Coulombe MA, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 2005;41(9):125460. 45. Cone JB, Wetzel W. Toxic megacolon secondary to pseudomembranous colitis. Dis Colon Rectum 1982;25(5):47882. 46. George WL, Rolfe RD, Finegold SM. Treatment and prevention of antimicrobial agent-induced colitis and diarrhae. Gastroenterology 1980;79(2):36672. 47. Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med 1994;330(4):25762. 48. Johnson JR, Kuskowski MA, Menard M, et al. Similarity between human and chicken Escherichia coli isolates in relation to ciprofloxacin resistance status. J Infect Dis 2006;194(1):718. 49. Salyers AA, Gupta A, Wang Y. Human intestinal bacteria as reservoirs for antibiotic resistance genes. Trends Microbiol 2004;12(9):4126. 50. Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev 2005;18(4):65786. 51. Cosgrove SE. The relationship between antimicrobial resistance and patient outcomes: mortality, length of hospital stay, and health care costs. Clin Infect Dis 2006;42(Suppl 2):S829. 52. Stone PW, Gupta A, Loughrey M, et al. Attributable costs and length of stay of an extended-spectrum beta-lactamase-producing Klebsiella pneumoniae outbreak in a neonatal intensive care unit. Infect Control Hosp Epidemiol 2003;24(8):6016. 53. Kwok A, Lam T, Katelaris P, et al. Helicobacter pylori eradication therapy: indications, efficacy and safety. Expert Opin Drug Saf 2008;7(3):27181. 54. Weir DM, Stewart J. Immunology. 8th edition. Edinburgh, UK: Churchill Livingstone; 1997. 55. Rahal JJ. Novel antibiotic combinations against infections with almost completely resistant Pseudomonas aeruginosa and Acinetobacter species. Clin Infect Dis 2006;43(Suppl 2):S959. 56. Onderdonk AB, Kasper DL, Cisneros RL, et al. The capsular polysaccharide of Bacteroides fragilis as a virulence factor: comparison of the pathogenic potential of encapsulated and unencapsulated strains. J Infect Dis 1977;136(1):829. 57. Mims C, Dockrell H, Goering R, et al. Medical microbiology. 3rd edition. Mosby; 2004.