Common MicrobialPathogens in SurgicalPractice

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 Hippo-crates, who coined the term laudable pus as a sign of eventual wound healing, asopposed to erysipelas, a spreading inflammation that often meant the death of thepatient. Although many scholars suspected microorganisms, it would take the develop-ment of the compound microscope to allow the microbiologists of the nineteenth centuryto describe the multitude of bacterial and fungal organisms and their relationship to in-fection. Pasteur developed the germ theory of disease by demonstrating that bacteriadid not contaminate culture medium in curved flasks and Koch described the postulatesby which infection from a particular microorganism would be defined. He was awardedthe Nobel Prize in 1905 for his description of the Mycobacterium tuberculosis bacillus.

The Hungarian obstetrician Ignaz Semmelweis, who practiced in Austria in the mid-nineteenth century, demanded that his residents and students wash their hands insodium hypochlorite before touching patients and also had his obstetric instrumentssoaked in the same solution. This eventually ushered in the era of asepsis, and al-though his contemporaries failed to adopt these measures, the prevailing rate of post-partum endometritis, which had been extremely high, decreased markedly in hispatients, to an estimated 5%.1

Lord Lister, a general surgeon who did mostly orthopedics, was the first to use anantiseptic 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 finalresponsibility for the decision to submit the manuscript for publication. There were nopersonal relationships or financial conflicts to disclose. This article is an original contributionthat 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 andEmmeline Ferguson Research Fellowship.a Price Institute of Surgical Research, Department of Surgery, University of Louisville, Louisville,KY 40202, USAb 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) 295–310doi:10.1016/j.suc.2008.09.002 surgical.theclinics.com0039-6109/08/$ – see front matter. Published by Elsevier Inc.

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(SSI). This treatment revolutionized the treatment of open fractures in which theextremity was salvaged. These early measures have been refined to the modern asep-tic and antiseptic techniques used today, and with appropriate use of prophylacticantibiotics, the overall SSI rate has been reduced to approximately 5%.2 The NationalSurgical Quality Improvement Program (NSQIP) identified that pneumonia, urinarytract infection (UTI), and sepsis respectively occurred in 3.6%, 3.5%, and 2.1% ofsurgical patients in the database.3 Since infection rates are not zero, significantimprovements with additional knowledge of local wound conditions and the infectingmicrobes 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 patho-genic organisms are made up of cells. Cells are distinct entities of cytoplasm thatare bound by a cell membrane and consist of genetic (DNA) material. Bacterial cellsare referred to as prokaryotes and all other cells are eukaryotes. Prokaryotes lacka 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 simul-taneous transcription and translation without mRNA. They also lack any membrane-bound organelles within their cellular boundaries. Interestingly, eukaryoticmembrane-bound organelles, such as mitochondria, are thought to share commonevolutionary pathways with entire prokaryotic cells, a fundamental hypothesis in theendosymbiosis theory. In fact, the term ‘‘pro-karyote’’ literally translates to ‘‘beforethe nucleus’’ and refers to the evolutionary origin of prokaryotic cells precedingmore complex eukaryotes.

Bacterial cell walls are complex and divide bacteria into two classes: gram-positiveand gram-negative cells. Gram staining, developed by the Danish scientist HansChristian Gram in 1884, tests the ability of bacteria to retain a violet stain after washingwith iodine and alcohol, with purple indicating a positive Gram stain and pink indicat-ing a negative one. In gram-positive bacteria, the outer wall is made of peptidoglycan,whereas gram-negative species have little peptidoglycan but possess an additionalouter layer rich in polysaccharides. Bacterial cell wall layers provide complex protec-tive defense shields against immune cells and antimicrobial agents. Potentially, theymay 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 antimicrobialagents such as aminoglycosides. Fig. 1 provides a schematic representation of thegeneralized 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 withina genus depend on immunologic and phenotypic properties, including the presenceof flagella, the type of toxins produced, the ability to hemolyze blood, and so forth.Direct genomic studies are also employed today to accurately identify organismsbased on genome size, ratio of bases within DNA, and the presence of certain DNAsequences.

Fungi are eukaryotes that are very different from human and plant cells. They aremulticellular multinucleate organisms that grow either in filaments (hyphae) to forma mycelium, or as mononuclear spherical organisms that replicate by budding and

Fig. 1. Structure of a prokaryotic cell. (Courtesy of T. Sheppard, BSc., London. Copyright ª2005 Tim Sheppard. Available at www.blobs.org; used with permission.)

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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 enzymesand absorb available nutrients for survival.

Gram-Positive Cocci

StaphylococcusStaphylococcus aureus is a catalase and coagulase-producing gram-positive organ-ism that frequently occurs in human nasal passages, mucous membranes, or skin ofcarriers. It is traditionally identified by its characteristic golden yellow grapelikeclumped colonies on culture (staphule – Greek for grapes; aureus – Latin for gold)(Fig. 2). This organism is arguably the most important pathogenic organism in evolvingsurgical infections, and thus, receives considerable attention below.

S aureus constitutes the majority of skin and soft tissue infections encountered inthe surgical population, accounting for up to 20% of SSI isolates but also 13% of allnosocomial infections (Table 1).4 This facultatively anaerobic organism was first re-ported in 1880 in Aberdeen, Scotland, by the surgeon Sir Alexander Ogston, in pusdrained from infected abscesses. Since then, an estimated 500,000 patients a year

Fig. 2. Gram-positive cocci.

Table 1National Nosocomial Infections Surveillance top10 most common isolates (percentage distribution)in surgical site infections and nosocomial infections

Pathogen Surgical Site Infections (n 5 17,671) All Sites (n 5 101,821)Staphylococcus aureus 20 13

Escherichia coli 8 12

Coagulase-negative Staphylococci 14 11

Enterococcus spp 12 10

Pseudomonas aeruginosa 8 9

Enterobacter spp 7 6

Candida albicans 3 5

Klebsiella pneumoniae 3 5

Gram-positive anaerobes 1 4

Proteus mirabilis 3 3

Data from National Nosocomial Infections Surveillance (NNIS) report, data summary from October1986–April 1996, issued May 1996. A report from the National Nosocomial Infections Surveillance(NNIS) System. Am J Infect Control 1996;24(5):380–8.4

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are thought to contract S aureus in US hospitals.5 Superficial carriage is arguably com-mensal in nature and often nonpathogenic but deep-seated S aureus penetration isassociated with significant morbidity and mortality and requires intensive therapy. Inthe nonsurgical population, it is the cause of pneumonia, endocarditis, disseminatedbacteremia, toxic shock syndrome, and food poisoning among many other diseaseentities in adult and pediatric populations.

S aureus is capable of producing several exotoxins, including enterotoxins andsuperantigens, which result in the organism’s virulence.6 These include the following:

� Alpha-toxin (hemolysin), which binds to susceptible cells such as monocytes andplatelets and results in leakage of contents. When released systemically, septicshock 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 spe-

cies but its function remains largely unknown.� Leucocidin, which is a hemolytic toxin (less so than alpha-toxin) that acts on poly-

morphonuclear leukocytes and helps S aureus evade phagocytosis. It is ex-pressed in only 2% of S aureus isolates but is identified in over 90% ofnecrotizing 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 ofimportant integrity-maintaining epidermal proteins.� Enterotoxins and toxic shock syndrome toxin (TSST), which possess superanti-

genic properties and may cause toxic shock syndrome. Enterotoxins, when in-gested, result in the most common form of food poisoning. Activation of T cellsand 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 arriv-ing at the site of S aureus action.

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� Staphylokinase, which degrades fibrin, much like streptokinase, and may aid inbacterial spreading.� Proteases, lipases, DNase and fatty-acid modifying enzyme (FAME), which de-

grade various components and may aid in S aureus spread within abscesses.

Following the introduction of penicillin by Sir Alexander Fleming in 1943, antibac-terial 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 me-diated by penicillinase (beta-lactamase), an enzyme that degrades the beta-lactamring of penicillin. The emergence of penicillinase-resistant penicillins such as methi-cillin in 1959 and flucloxacillin shortly after were a welcomed discovery, until lessthan 2 years later, when, in 1961, the first reported case of resistance to methicillinwas observed!

Following initial identification, methicillin-resistant S aureus (MRSA) has risen to en-demic rates in US and UK hospitals, with a sharp rise in incidence occurring in the1990s. Incidence rates published by the US Centers for Disease Control and Preven-tion (CDC) have demonstrated a greater than twofold increase from 127,000 reportedcases to 278,000 between 1999 and 2005.8 Risk factors include previous antibioticadministration, prolonged hospitalization, and multiple patient comorbidities.9

Despite evasion of methicillin to bacterial penicillinase, the organism was able to ac-quire new-found resistance, encoded for in the mec operon coding region, which ispart of the staphylococcal cassette chromosome mec (SCCmec) within bacterial plas-mids. Resistance conferred via the mecA gene alters penicillin binding properties andthus also implies automatic resistance to penicillinase-sensitive antibiotics such aspenicillin and cephalosporins.

MRSA is now understood to consist of two exclusive subtypes: a nosocomial, orhospital-acquired, type (HA-MRSA) and a community-acquired type (CA-MRSA).Although originally defined according to source of origin, the apparently clear-cutdistinction between these subtypes is more complex. Both types are equally resistantto traditional beta-lactam antibiotics although HA-MRSA appears to have a largerresistance profile, with sensitivity restricted to vancomycin, teicopleinin, or the neweroxazolidinones such as linezolid. HA-MRSA appears to affect patients in hospitalswith open wounds, those who undergo invasive procedures, and ones with weakenedimmune systems. Transfer is predominantly staff- and instrument-related, awarenessof which has resulted in the development of strict hand-washing and barrier-orientedinfection control policies that are now in place.

Although most MRSA infections remain health care–associated, a rising incidenceof community-acquired infection is apparent. Community-acquired infection inci-dence rates in the United States in 2005 were estimated at 13.7% in a recentlypublished large series.10 Consequently, community-acquired MRSA (CA-MRSA) isgaining increased attention among microbiologists and health care workers today. Itwas first noted in the early 1990s and was associated with a number of differentskin and soft tissue syndromes (furuncles, impetigo, and cellulitis) in individuals whowere previously healthy and had not been hospitalized within 1 year of infectiveepisodes.11–13 Originally thought to be similar in origin to its nosocomial counterpart,community-acquired strains have been shown to be genetically diverse with uniquemicrobiologic properties, rendering them a separate entity.13 Areas of aggregationhave included army bases, jails, and among inner-city children, where close individualcontact and poor hygiene, and hence transmission, are most likely. The community-acquired strain is associated with virulence factors thought to promote transmissibilityand likelihood of disease. CA-MRSA is specifically associated with carriage of

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SCCmec Type IV and panton-valentine leucocidin (PVL) virulence factor. In a study ofpatients from the San Francisco Bay Area, 70% of MRSA isolates from prison inmatesand clinics specializing in soft and skin tissue infections were positive for PVL car-riage.14 Of 671 isolates collected over a 5-year period, most could be traced backto only two clonal groups, both of which carried the SCCmec type IV resistance deter-minate and both more likely to be recovered from skin. This pattern indicated the likeli-hood of rapid clonal supplantation within community-based transmission, probablyattributable to the aforementioned virulence factors. In another study of over 800 sol-diers from Brook Army Medical Center, it was found that 3% (24) of soldiers were col-onized with CA-MRSA, 9 of whom developed soft tissue infections in the 8- to10-week observation that followed.15 PVL genes were detected in all nine cases. Incontrast, 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 observationperiod, highlighting very clearly the increased virulence potentially associated withcarriage of the PVL gene in community evolving species.

MRSA has recently been treated with newer antimicrobial agents such as clindamy-cin and linezolid. These new agents are available in the oral form, thereby avoidingcomplex administration issues associated with intravenous delivery. More seriousinvasive MRSA infection, which is typically hospital-acquired, requires intravenousvancomycin treatment, a glycopeptide that is associated with toxic side effects andpoorly absorbed in the oral form. Alarmingly, a rising vancomycin minimum inhibitoryconcentration (MIC) in the hospital-acquired strain is well documented, confirming theemergence of vancomycin-intermediate-resistant S aureus (VISA) and vancomycin-resistant S aureus (VRSA) species.11 The former was first identified in Japan in 1996and the latter in the United States in 2002. These organisms have since affected spe-cific populations, such as hemodialysis patients, but incidence rates are neverthelessrising.16 Preliminary reports of S aureus resistance to linezolid are available and poseserious future concern.17

Another frequently encountered bacterium in surgical infections is the skin com-mensal Staphylococcus epidermidis. This facultatively anaerobic, catalase-positiveand coagulase-negative organism, along with Staphylococcus saprophyticus andStaphylococcus capitis, are collectively referred to as Staphylococcal albus, becauseof 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 acidslime, derived from the staphylococcal cell wall, which results in the formation of a re-silient biofilm that protects the bacterium against host and chemotherapeutic defensemechanisms, and thus, renders the organism more virulent.18,19 Furthermore, in a re-cent study by El-Azizi and colleagues,20 the authors were able to show that bacteriaisolated from disrupted prosthetic biofilm were significantly less resistant to antimicro-bial therapy than those in the biofilm itself.

Classically, S epidermidis is isolated from infected surgical wounds, particularlysternal wounds, where it is the most common isolate.21,22 Other common operationswhere this organism is implicated include that that use prostheses, such as joint re-placement and vascular graft procedures. It is commonly recovered from the site ofinfected indwelling catheters, where it is usually associated with the formation of bac-terial biofilm.18,19

Little else is known about the pathogenesis of S epidermidis. Treatment is com-plex with resistance reported to both penicillin and methicillin. In 2003, approxi-mately 90% of all coagulase-negative staphylococcal species were resistant tomethicillin.23

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StreptococcusThese gram-positive, facultatively anaerobic cocci play a significant role in surgicalinfections 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 cellulardivision (strepto – Greek for twisted).

An organized approach to classification of these organisms yields a better under-standing of their various roles in disease (see Fig. 2). They are first divided into theirability 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 im-partially degraded green haem halo surrounding the streptococcal colony in bloodagar. Within this group, there are two dominant species, Streptococcus viridans (viri-dans – Latin for green) and Streptococcus pneumoniae, the causative organisms forendocarditis and pneumococcal pneumonia respectively. Their role in surgical dis-ease 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 Lan-cefield Types A-T, named after the prominent work of the late American microbiolo-gist, Rebecca Craighill Lancefield. Surgically relevant are Streptococcus pyogenes,a Lancefield group A organism, and Enterococcus (formerly Streptococcus groupD – reclassified in 1984).24 These organisms play a large pathogenic role in surgicalmicrobial disease and are discussed below.

Non-hemolytic streptococcal species, often referred to as gamma-hemolytic (a mis-nomer), rarely account for serious human disease. Enterococcal species, which causea 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 tradi-tionally regarded as the main pathogen of complicated skin and soft tissue infection.Its presence in cellulitis, and more specifically, erysipelas, which primarily affects the up-per dermis, is well documented. It has also been reported in infected abdominalwounds, bites, and complicated poly-microbial diabetic disease. Its most notablerole, however, remains its etiologic role in type II necrotizing fasciitis, or streptococcalgangrene, where it is the dominant organism along with few other Streptococcal groupB, C, and G species.25 The organism’s ability to multiply and spread laterally in deepdermal tissue is often life-threatening. Early recognition and aggressive treatment is im-perative in this disease. In a recently published series of 165 patients with necrotizingfasciitis, overall mortality was reported at 17% with 25% requiring amputation of the af-fected extremity in addition to surgical debridement.26

Central to pathogenic mechanisms is the production of extracellular toxins, of whichtwo are hemolytic and three pyrogenic. There are various other nucleases, DNAses,and proteolytic enzymes that are also secreted. Hemolytic toxins include StreptolysinO and S, the former usually used as an antigenic serum marker of recent streptococcalinfection. These degrade red blood cells as well as platelets and polymorphonuclearleukocytes. Pyrogenic toxins are classified from A to C and are responsible for the de-velopment of scarlet fever. Common sequelae of streptococcal exotoxins includestreptococcal toxic shock syndrome (TSS), glomerulonephritis, and, less commonlytoday, acute rheumatic fever. Interestingly, streptokinase, an enzyme produced bythe bacteria, is used as a cardiovascular thrombolytic agent following myocardial in-farction (MI), more often than its staphylococcal counterpart.6,27

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Treatment is with penicillin and its various derivates. However, appreciation that thisorganism often coexists in polymicrobial disease indicates that additional broad-spectrum coverage is frequently required. For example, type I necrotizing fasciitisoften 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 par-tially hemolytic organisms frequently account for SSIs, particularly following clean-con-taminated and contaminated surgery of the bowel. Enterococcal organisms havegained recent attention because of their intrinsic resistance to a variety of antimicrobialagents, including semisynthetic penicillinase-resistant penicillins, cephalosporins, tri-methoprim-sulfamethoxazole, aminoglycosides, and clindamycin.29 These organismsare also capable of acquiring resistance to other agents including chloramphenicol,macrolides, tetracycline, and fluoroquinolones.

Interestingly, enterococcal organisms were the first to exhibit resistance againstvancomycin in 1986.30,31 The mechanism of resistance involves alteration of vanco-mycin-binding targets. Vancomycin binds to [d-alanine – d-alanine] targets, whichare either replaced with [d-lactate] or the entire synthesis of cell wall precursorswith vancomycin-binding targets are inhibited. Several subtypes of vancomycin resis-tance are described and are denoted VanA to VanE.32

Since the emergence of vancomycin-resistant enterococcus (VRE), incidence hassteadily increased in the United States (although not the United Kingdom) until, in2004, the National Nosocomial Infections Surveillance (NNIS) reported that 30% ofall 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 fortu-nately accounting for the vast majority of recovered isolates.33,34 Alarmingly, recentevidence shows this resistance could be transferred to other organisms, such asMRSA.35,36

Sensitive enterococcal organisms may be treated with ampicillin or vancomycin.Vancomycin-resistant E faecium is treated generally with linezolid, or can be treatedwith daptomycin or quinupristin/dalfopristin. For vancomycin-resistant E faecalisinfections, ampicillin may be used if the organism is sensitive. Quinupristin/dalfopristinshould not be used to treat E faecalis, since this organism is intrinsically resistant tothis antibiotic.37,38

Gram-Positive Bacilli

These Gram-positive rod-shaped bacteria are obligate anaerobes that are capable ofspore formation, and include Clostridium perfringens, Clostridium difficile, Clostridiumtetani, and Clostridium botulinum (Kloster – Greek for rods). The latter two are knownfor producing tetanus and botulinum toxins respectively but otherwise have a limitedrole in surgical disease.

C perfringens causes the rare surgical disease known as gas gangrene, a rapidlyspreading surgical emphysema mediated by the enterotoxin alpha-toxin. Its abilityto form gaps between cells results in the characteristic formation of gas pockets belowthe dermis. Untreated, it results in life-threatening sequelae. It is most commonlyencountered in type I polymicrobial cases of necrotizing fasciitis. Its presence hasbeen shown to be an independent predictor of mortality and limb loss among affectedcases in the recently published series described earlier.26 Although C perfringens isoften implicated in monobacterial gas gangrene, it is not exclusively associated withthis disease. Other clostridial species, such as C septicum, may also cause gasgangrene.

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C difficile is frequently seen on surgical wards in patients on prolonged antibiotictherapy. This organism has recently gained attention in public health circles becauseof increasing incidence rates and severity of the symptomatic pathognomic disease,pseudomembranous colitis.39 Eradication of the normal colonic flora with previouslyadministered antibiotics combined with C difficile ingestion may result in the formationof pseudomembranes. A severe hemorrhagic inflammation often ensues, resulting ina profound and rapidly transmissible diarrheal state in hospitalized patients.40 In theelderly, frail, and immunocompromised, sequelae may be life-threatening. Classically,abdominal radiographs fail to demonstrate evidence of obstruction. Risk factors fordisease development include antimicrobial therapy and proton pump inhibitors(PPIs).41–44 Symptoms are often compounded by narcotics prescribed for associatedpain, which inhibit colonic peristalsis and may potentially cause toxic megacolon,a surgical emergency.45,46 Inflammation, mucosal secretion, and cell damage in thecolon 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 butproduction of these toxins is essential for disease to occur.39 Furthermore, recentstrains associated with increased severity of disease, such as the North Americanpulsed-field gel electrophoresis type 1 (NAP 1), have been shown to produce up to16 times more toxin A and 23 times more toxin B than standard less virulent strainsof C difficile. NAP 1 also exhibits resistance to moxifloxacin and gatifloxacin, a phe-nomenon not encountered in previous C difficile strains.39

Effective treatment of clostridial species is with metronidazole, although, onceagain, special attention should be paid to individual circumstances; for examplebroad-spectrum antimicrobial coverage may be required for other organisms likelyto coexist (type I necrotizing fasciitis) or discontinuing original culprit antimicrobialagents that may have permitted uncontrolled growth of the clostridial species (C dif-ficile pseudomembranous colitis). Oral vancomycin is also effective in the treatment ofsymptomatic C difficile. Appropriate stool culture and sensitivities will guide the treat-ing surgeon and careful liaison with hospital microbiologists is essential to ensureadequate 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 lessrelevant 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 meningit-ides and Neisseria gonorrhoeae, which commonly cause meningitis and gonorrhearespectively and do not feature in surgical disease. The discussion therefore moveson to the more relevant gram-negative bacilli, which are frequently encountered in sur-gical patients.

Gram-Negative Bacilli

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

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

EnterobacteriaceaeThis is a large family of gram-negative bacterial rods, which, for classification pur-poses, are divided into lactose fermenters, and nonlactose fermenters (NLF). Lactosefermenters are able to ferment sugars to produce lactic acid, and include Enterobacterspp, E coli, K pneumoniae and Proteus spp, which are discussed in the followingparagraphs. NLFs include Salmonella, Shigella, and Yersinia species and accountfor the nonsurgical, but, nevertheless, important disease entities such as typhoid (Sal-monella typhii), bacillary dysentery (Shigella dysenteriaea), food poisoning (Salmonellaentiridis), and historically, the Plague (Yersinia pestis).

E coli is arguably is the most intensively studied bacterial organism since its discov-ery in 1885. Simple growth requirements and an easily manipulated genetic make-uphave resulted in an important biotechnological role today, via the creation of recombi-nant DNA for the mass production of a variety of proteins. Without acquiring virulencefactors, it is an unharmful colonic commensal that often protects bowel againstovergrowth of pathogenic species. However, virulent strains of E coli account for sev-eral types of gastroenteritis and often result in food product recalls and considerablemedia attention. Easily transmissible through the fecal-oral route, contamination offood products with harmful strains occurs mostly through unhygienic food preparationand include enterotoxigenic, enteropathogenic, enteroinvasive, enterohemorrhagic(0157), and enteroaggregative strains, all of which cause profound diarrhea, with orwithout fever, and which may be life-threatening. Toxins produced by the various sub-types mediate many of the pathogenic gastroenteritic features. The enterohemorrha-gic 0157 strain also causes hemolytic-uremic syndrome in children around 5% of thetime, where spread of the 0157 ‘‘Vera-toxin’’ classically results in the triad of microan-giopathic hemolytic anemia, acute renal failure, and thrombocytopenia.

Following colonic surgery, E coli may result in SSI and/or peritonitis, where illnessmay be profound. Fortunately the organism remains very sensitive to gentamicin aswell as other antimicrobial agents such as cephalosporins, carbapenems, aztreonam,ciprofloxacin, trimethoprim-sulfamethoxazole, and nitrofurantoin. E coli resistance toantimicrobial therapy is a growing problem since adaptive mutations in the genomewere found to occur at an alarmingly faster rate than previously anticipated.48 Further-more, as a common bacterium in polymicrobial biofilm, E coli carries multiresistantdrug plasmids, which it is able to transfer to other neighboring species, such asS aureus, thereby acting as a reservoir of transferable resistance.49

Beta-lactam resistance is also on the rise and results in multidrug resistance toa large variety of penicillins and cephalosporins, rendering treatment more difficult.50

The extensive and empiric use of third generation cephalosporins in surgical intensivecare units is etiologic to growing E coli antibiotic resistance. The concepts ofbeta-lactamase resistance and plasmid transference apply similarly to K pneumoniaeand other Enterobacteriaceae species.

Extended-spectrum beta-lactamase production by gram-negatives resulting inmultidrug resistance has been shown to significantly increase mortality, length ofhospitalization, and associated costs.16,51,52

PseudomonadsPseudomonas aeruginosa is a gram-negative rod generally associated with opportu-nistic infections and most commonly accounts for infections of the urinary tract, ven-tilator-associated pneumonias (VAP), and wound infections. It is thought to account

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for up to 8% of SSIs.4 It plays a role in the formation of bacterial biofilm and is the mostfrequent colonizer of medical devices and catheters. Community-acquired disease isonly rarely caused by P aeruginosa.

As a commensal colonizer, superficial culture does not always provide grounds fortreatment but blood-borne and deep-seated infections are indications for urgent inter-vention. This organism has recently gained microbiological attention because ofemerging multidrug resistance, thought to occur via complex multistep genetic muta-tions, drug efflux mechanisms, and horizontal transfer within colonies. The 2004 NNISreport documented rising resistance rates of P aeruginosa to both quinolones and imi-penem, although imipenem has remained widely effective in many units in the past de-cade.23,25 Aminoglycosides and third-generation cephalosporins also remain effectiveat this time.

Curved, Spiral, or Helical Organisms

Campylobacter jejuniVia the production of a cholera-like enterotoxin, Campylobacter jejuni is now recog-nized as the most common cause of food-borne gastroenteritis in the developedworld, and results in epithelial cell damage in jejunal and ileal segments of affectedpatients. Postinfection, this organism will rarely result in the Guillain-Barr�e neuropathyseveral weeks following gastroenteritic symptoms in affected individuals.

Helicobacter pyloriHelicobacter pylori is a classic helical organism that was only identified as late as 1982by the Australian Nobel Prize winners Robin Warren and Barry Marshall. Their discov-ery 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 cur-rently thought to infect half of the world’s population and is a recognized risk factor forgastric carcinogenesis.53 Through its ability to produce urease, this organism is able toevade the hostile acidic environment of the stomach where it most commonly residesand contributes to 90% of peptic ulcer disease. Mucinase production, evasion of thehost IgG response, and the potential production of IL-10 to counteract T-lymphocytecytokine production are all mechanisms that contribute to the organism’s virulence.54

H pylori was originally classified as a Campylobacter organism, which was subse-quently modified to a Campylobacter-like organism (CLO). It was reclassified againas a separate entity altogether. ‘‘CLO tests’’ may still ring familiar among surgeonswho biopsy gastric mucosa in search of this organism. Peptic ulcer disease therapywas modified to include antibiotics with antacid treatments following successfulisolation 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 sppThis strictly aerobic nonfermenting cocco-bacillus is a nosocomial organism thataccounts for serious life-threatening infection in debilitated patients. Sources includehospital surfaces and medical devices because this bacterium is able to survive onwet and dry surfaces alike. Rising resistance among the species along with inherentresistance to antimicrobial agents including penicillin and, occasionally, aminoglyco-sides has provided cause for concern. Like Pseudomonas species, drug efflux andhorizontal transfer of resistance play key roles in rising resistance rates. Last resortcarbapenems, which were previously highly effective against this organism, are now

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

Bacteroides fragilisBacteroides fragilis is a normal component of the human bowel flora, and the mostcommon anaerobic species involved in intra-abdominal infections. B fragilis, an ob-ligate anaerobe, has a polysaccharide capsule that retards phagocytosis and isthus able to evade innate host defense mechanisms.56 The capsular material is im-portant in the organism’s ability to form abscesses, even after the organism hasbeen heat-killed, and is thought to account for its common etiologic role in the for-mation of appendicitic abscesses. This anaerobic organism is typically associatedwith other aerobic pathogens in a synergistic relationship, causing mixed infectionbut prolonging its survival in aerobic conditions. This requires special attention fortherapy and in terms of awareness of transference of resistance. This organism isinherently resistant to many antibiotics including aminoglycosides and beta-lac-tams with recent acquired resistance reported for erythromycin, clindamycin andtetracycline. Current sensitivities include metronidazole, carbapenems, and penicil-linase-resistant penicillins.

Fungi

Although these organisms are not typical surgical pathogens, they are seen in surgicalpatients who are debilitated as a result of comorbid disease, prolonged hospitaliza-tion, or extensive antibiotic treatment, where protective commensal flora are elimi-nated, allowing for pathogenic species of all types to freely differentiate andmultiply. Even commensal fungi develop pathogenic properties during times of subop-timal host defense capabilities. Infection caused by fungal organisms is known asmycosis.

Fungal mycoses are broadly divided into superficial and deep infections. Superficialinfections include skin, hair, and subcutaneous tissue layers, such as nails and deeperskin planes. Spread usually occurs following direct contact. Deep infection involvesinternal organs and the bloodstream, where infection is normally restricted to oppor-tunistic fungi affecting immunocompromised individuals. This type of infection is oftenlife-threatening, particularly in debilitated individuals.

In the context of surgical disease, fungal infection is best divided into C albicans–related disease (candidiasis) and non–C albicans disease, since C albicans is themost frequently encountered fungal pathogen in surgical patients. Non–C albicansfungi 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 pseu-dohyphae), a factor that contributes to the organism’s potential virulence. Surgical pa-tients who receive potent antimicrobial or chemotherapeutic agents are mostsusceptible, as well as immunocompromised individuals with nonsurgical diseasessuch 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 pro-tective commensals by antimicrobial agents provides an opportunity for unre-strictedgrowthof the fungus. Sites include themouth, skin, nails, vagina,andbowel.� Infection may also occur in areas of skin breach, where loss of integrity of the protec-

tivedefense layer occurs.These areas frequently includeblood-catheter sites,wherethe catheter then acts as a transport medium for the organism from the skin into thecirculation. Life-threatening blood-borne candidiasis may ensue. Other areas of skinbreach include surgical wounds, where C albicans is infrequently involved.

Table 2Important fungal pathogens57

Superficial Infection Deep InfectionEpidermophyton Aspergillus

Microsporum Blastomyces

Trichophyton Candida

Sporothrix Coccidioides

Cryptococcus

Histoplasma

Paracoccidioides

Data from Mims C, Dockrell H, Goering R, et al. Medical microbiology. 3rd edition. Mosby; 2004.

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Diagnosis may often be made by clinical examination; the appearance of oralcandidiasis (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 onlycolonization rather than a true invasive candidal infection.

Antifungal agents are used to treat C albicans infections. These are applied topicallyin the case of superficial infections, or administered intravenously in the case of deep-seated organ infections or fungal septicemic states. Drug resistance has not been anissue when treating these relatively uncommon pathogens, probably because of thelack of empiric, oversubscribed, and unnecessary prescription of chemotherapy. Anappreciation by the treating surgeon that serious fungal infections are likely to coexistwith overwhelming bacterial sepsis, especially in the debilitated host, providesgrounds for urgent bacterial culture and empiric therapy.

FUTURE IMPLICATIONS

Fundamental research into resistance mechanisms and the genome of the microbewill be required to lower the risk of surgical infections even further. However, an inte-gral understanding of local conditions and the early innate immune response will alsobe required, as it is doubtful that microbe contamination can ever be eliminated. Def-inition of the host defense response for a particular individual, particularly those proneto repetitive infections, will eventually lead to targeted therapy augmentation beforesurgical treatment if infections are to be eliminated. The potential genetic mechanismsthat cause only some individuals to spiral into full-fledged septic shock while othersare able to fully recover following a microbial insult remain unclear. The heterogeneityof the innate immune cell performance remains poorly defined, but when furtherunderstood, will ultimately provide novel avenues for future immune therapy.

University and private sector funding into research dedicated to the intensive studyof bacterial genomics and the comprehensive understanding of mechanisms by whichresistance is acquired will lead to the development of new and effective antimicrobialagents with previously unrecognized targets. The rapid rise of resistance and acquiredadaptive mutations to last-resort chemotherapeutic agents warrants an urgent under-standing of the issues at stake. A willingness to contribute through the adequate,accurate, timely, and nonprolonged prescribing of antibiotics is the first step to haltingthe rapid progression in microbial resistance and is the shared responsibility of alltreating surgeons today.

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