ANTIBIOTICS FOR THE ACUTE ABDOMEN

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ABDOMINAL EMERGENCIES

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ANTIBIOTICS FOR THE ACUTE ABDOMEN Mitchell S. Farber, MD, and Jerome H. Abrams, MD

The surgical diagnosis of the acute abdomen depends on the host response to irritation of the peritoneal cavity. Such irritation may occur from a variety of causes. Common pathologies include bowel obstruction, inflammation, perforation of a hollow viscus, trauma, and ischemia. The injury to the peritoneal structures can produce acid or alkaline secretions, pus, or spillage of enteric contents with resulting peritoneal inflammation. Although antibiotics may be important, they play a role secondary to prompt surgical intervention to correct the underlying surgical disease. Immediate surgical intervention to achieve source control and peritoneal toilet is the most important part of treatment for preventing serious intra-abdominal infection after peritoneal contamination.'O, 85, lo2 Antibiotic use is limited to prophylaxis against deep wound infection or to treatment of established infection of the peritoneal cav47 itY.27* The following discussion considers the pathogenesis of bacterial secondary peritonitis, selection of antimicrobials, special considerations for enterococci and fungi, prophylaxis, appropriate dosing, duration of antibiotic treatment, and the secondary role of antibiotic therapy compared with proper surgical management. The discussion is limited to adult patients with nonobstetrical and nongynecologic pathology. BACTERIAL SECONDARY PERITONITIS

The source of bacterial contamination associated with secondary peritonitis is the endogenous gut flora. Frequently, the source is a From the Department of Surgery, the University of Minnesota Medical School, Minneapolis, Minnesota

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perforated hollow viscus. Alternatively, the source of contamination may be the biliary tract or the genitourinary system following acute disease or a traumatic insult. Although these fluids should normally be sterile, they may contain bacteria that originate from the bowel flora.Is The normal gradient of increasing bacterial concentrations from the stomach to the rectum may not be present in certain disease states. The acid environment of the stomach maintains a very low concentration of bacteria, but the use of histamine antagonists or proton pump inhibitors, as well as severe gastric outlet obstruction, can markedly increase the bacterial concentration.6* 67 Similarly, long-standing obstruction of the small intestine can permit overgrowth of enteric bacteria in the more proximal portions of the jejunum. Perforations of these viscera or purposeful surgical openings into these structures can result in the spillage of significant concentrations of bacteria. In the colon, the bacterial concentration has been reported to exceed 10l2bacteria per gram of f e ~ e s . ~ ~ , ~ Although facultative aerobes such as Escherichia coli are present in large numbers, more than 99% of the colonic flora are anaerobic species such as Bacteroides, Fusobacterium, Clostridium, and anaerobic cocci.67Detailed microbiology of the colon demonstrates about 500 different microbial species.18,67 When spillage of such an array of organisms occurs, only a small subset of species survives. Most series indicate that an average of two to three species of aerobic bacteria and up to nine species of anaerobic bacteria survive.6The selection process is not a random event because certain bacterial species consistently tend to emerge as the dominant pathogens.18,67, 84 These pathogens typically consist of gramnegative facultative aerobic rods such as E. coli and other coliforms, as well as anaerobes such as Bacteroides fyasilis, if the most distal portions of the gut have been violated. The robustness of these organisms is likely a consequence of experimentally demonstrated synergy. Immediately after any uncontrolled colonic spillage, the subsequent septic response is caused by the gram-negative coliforms with their release of e n d ~ t o x i n If . ~ ~the host survives this initial insult and if local host defenses are intact, localized abscess formation is likely to occur. Synergy results from the polysaccharide capsule of the anaerobic species and their release of short-chain volatile fatty acids, two mechanisms that make clearing these bacteria via phagocytosis difficult. The result is the formation of a walled-off abscess.6 SELECTING APPROPRIATE ANTIMICROBIALS

Several experimental studies and early clinical experiences have documented the importance of providing an antibiotic regimen that adequately covers both the facultative aerobic gram-negative organisms and anaerobic species.66Many antibiotic agents and combinations of antibiotic drugs are available for use in preventing or treating intraabdominal infections. Published antibiotic trials may be found to support the use of any given drug or antibiotic combination. Nonetheless, a

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large number of these studies identify no difference between antibiotic regimens for treating intra-abdominal infection. Unfortunately, there are several flaws in the design of these Because the primary management of bacterial secondary peritonitis is surgical, the effectiveness of source control and removal of peritoneal contamination is probably the most critical influence on patient outcome.84,93 To use comparative trials of antibiotics to detect small differences in efficacy, these studies would need to include large patient sample sizes and homogeneous causes for serious intra-abdominal infection.@,93 Instead, these studies typically choose small cohorts of patients and exclude the most serious intra-abdominal infections, such as postoperative ~ e r i t o n i t i s . ~ ~ Some studies have also been criticized for underdosing the "standard" arm of the study, as demonstrated by the delayed therapeutic peak 66 In view of similar efficacy, the least toxic levels of aminoglyc~sides.~~, regimen is generally chosen. A recent Surgical Infection Society Policy StatementI2regarding antiinfective agents for intra-abdominal infection has been very helpful for selecting suitable antibiotic regimens. The antibiotic selection for patients with mild to moderate infection that results from community-acquired organisms is distinguished from a list of antibiotics intended for the treatment of serious abdominal infections or infections that are likely to be due to bacteria resistant to antimicrobials, such as hospital-acquired bacteria. Incorporated within these recommendations is the recognition that certain agents offering broad-spectrum monotherapy are at least equivalent to the historical standard of dual-agent therapy with an aminoglycoside and an anti-anaerobic drug6,64, 84 Since the publication of this policy statement, additional data on existing and novel antibiotics have become available that suggest the need for minor modifications to the list of recommended antibiotic regimens (Table 1). The distinct groupings of these antibiotics are related to differences in their spectrum of activity, even though each regimen is designed to cover aerobic as well as anaerobic bacteria. The groupings reflect the pharmacodynamic properties describing how these antibiotics penetrate the bacterial cell wall, bind to penicillin-binding proteins (PBP), maintain a postantibiotic effect (PAE), and either resist degradation by p-lacta-

Table 1. ANTIMICROBIAL REGIMENS FOR BACTERIAL SECONDARY PERITONITISlZ. 6 6 . 7 4 . 8 4 104 Mild to Moderate Infection (Community-Acquired Bacteria)

Severe Infection (Hospital-Acquired or Resistant Bacteria)

Cefoxitin Cefotetan Cefmetazole Ampicillin-sulbactam Ticarcillin-clavulanate Aztreonam + clindamycin

Cefepime anti-anaerobe Piperacillin-tazobactam Imipenem-cilastatin or meropenem Aminoglycoside anti-anaerobe Third-generation cephalosporin or aztreonam + anti-anaerobe

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mases or neutralize these bacterial products. Some of these properties also determine the mean bactericidal concentration (MBC) and mean inhibitory concentration (MIC) of the antibiotic. The MBC is the antibiotic concentration determined in vitro that kills a standard inoculum of The MIC refers to the antibiotic concentrabacteria over 16 to 24 tion that inhibits the growth phase of bacteria. All p-lactam antibiotics, including the various cephalosporins, monobactams, and carbapenems, rely on their ability to penetrate the bacterial cell wall and bind to various classes of PBP.2nThese enzymes within the bacterial cell membrane are involved in the synthesis of bacterial cell wall peptidoglycan during cell division. Binding of PBP by p-lactam agents results in a defective cell wall that is then lysed by bacterial autolysins with resulting cell death.2nTherefore, p-lactam antibiotics are considered bactericidal. Although some bacteria achieve resistance by altering their PBPs, the major challenge of antibiotic resistance has been the ability of bacteria to produce p-lactamases that hydrolyze the p-lactam ring and render the antibiotic agent ineffective.2nf3-Lactamase antimicrobial resistance is complicated. The genetic code for these enzymes is often carried on plasmids and other readily exchangeable genetic material. The production of p-lactamases by members of staphylococci, Enterobacteriaceae, and other gram-negative organisms, as well as anaerobes, has been the principal determinant of antibiotic selection. To an increasing degree, this problem exists for infections occurring with community-acquired bacteria. The second-generation cephalosporins known as cephamycins (cefoxitin and cefotetan) are particularly useful as single agents for both prophylaxis and treatment because they have activity against some plactamase-producing staphylococci, multiple gram-negative bacteria, and many anaerobes.2oThese agents can be easily administered preoperatively to ensure adequate tissue levels prior to incision. For treatment, the third-generation cephalosporins offer the advantage of enhanced activity against gram-negative organisms. In particular, ceftazidime has excellent activity against Pseudomonas aeruginosa.20 Most cephalosporins have hepatic metabolism and renal excretion, but some agents are eliminated in the bile. These agents, such as cefoperazone, are more frequently associated with bowel flora changes with resultant loss of vitamin K formation and diarrhea.49,93 The cephalosporins with a methylthiotetrazole side group (i.e., moxalactam, cefamandole, cefotetan, and cefoperazone) have been associated with bleeding.15,2o Cefepime represents a fourth-generation cephalosporin. Its activity against gram-negative bacilli exceeds that of most third-generation cephalosporins, and it has gram-positive coverage that is at least equivalent to that of cefotaxime.'O8The unique structure of cefepime results in the lowest affinity for p-lactamase enzymes of all of the currently available cephalosporins. The molecule is highly resistant to hydrolysis by these bacterial enzymes.lo8 Cefepime is comparable to ceftazidime in its activity against P. aeruginosa, and the drug is also very effective against species of Enterobacter. Many strains of non-aeruginosa Pseudomonas are resistant. Other resistant organisms include Stenotropkomonas (formerly Xantkomonas) rnalto-

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philia, Enterococcus, and B. fragilis. The use of cephalosporins has been linked to the overgrowth of enterococci and the induction of plactamases.", 83 Compared with other cephalosporins, cefepime has been found to be a weaker inducer of p-lactamases.Io8Given the risk of inducing p-lactamases, antibiotic selection should probably avoid antibiotic regimens consisting of two P-lactams.20The combination of p-lactamase inhibitors with extended-spectrum penicillins provides another effective ~egimen.4~ Although originally omitted from the list of suggested agents, the combination of ampicillin and sulbactam does appear to be reasonable therapy for mild to moderate infections.84,Io1 Previous concern for resistance of E. coli to ampicillin-sulbactam reflected an aberration in laboratory assay.I2 The new combination of piperacillintazobactam is even more active against aerobic and anaerobic gramnegative bacilli that produce P-la~tarnase.~~ Tazobactam has activity against Class 11-V p-lactamases, and it appears to inhibit the Class I plactamases of Acinetobacter, Citrobacter, and Proteus species. The piperacillin-tazobactam combination has compared favorably with imipenemcilastatin for treating serious abdominal infection^.^^ Among the available p-lactam antibiotics, carbapenems have the widest spectrum of antimicrobial activity. The first carbapenem developed for clinical use is imipenem. This drug is not bound extensively to serum proteins and is readily hydrolyzed by a renal dipeptidase enzyme located on the proximal renal tubular cells. Cilastatin inhibits this renal enzyme and prolongs the half-life of imipenem.20In addition to its excellent spectrum of activity, imipenem-cilastatin has a long PAE.20Of importance, Enterococcus faecium, group JK corynebacteria, S. maltophilia, Pseudomonas cepacia, and Flavobacterium species are resistant. There have also been reports of resistance by P. aeruginosa with extensive use of imipenem. In patients with renal impairment, clearance is reduced and seizures have occ~rred.'~ Meropenem is a new carbapenem that does not require the addition of cilastatin and has a lower seizure p0tentia1.I~ For all of these p-lactam-derived drugs, an increased risk of an allergic reaction exists in patients known to be allergic to penicillin. In contrast, the monobactam aztreonam is relatively safe to administer to such patients allergic to penicillin or cephalosporins. The spectrum of activity for aztreonam is limited to aerobic and facultative gram-negative bacilli. Because of its lack of gram-positive or anaerobic coverage, aztreonam should be combined with clindamycin for the treatment of abdominal infections. Most commonly used for its coverage of anaerobic species, clindamycin is also active against aerobic gram-positive bacteria, including many strains of staphylococci. Clindamycin exerts bacteriostatic activity by binding to bacterial ribosomes and inhibiting protein synthesis.I5 Reports of resistance by gram-negative anaerobes such as B. fvagilis have appeared, but such in vitro activity may not be clinically important.6 Another anti-anaerobic agent is metronidazole. Its spectrum of activity includes almost all anaerobic gram-negative bacilli.2Resistance of these organisms to metronidazole is unusual. In contrast, metronidazole has

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less activity against Clos tridiurn species and anaerobic gram-positive cocci, whereas microaerophilic streptococci, Actinornyces, and Propionibacteriurn species are generally resistanL6Metronidazole exerts bactericidal activity by inhibiting nucleic acid ~ynthesis.'~ The drug is equally effective via oral and parenteral routes and is the preferred initial treatment for CIostridium difficile colitis even in neutropenic patients. The use of metronidazole or clindamycin, combined with an aminoglycoside for treatment of abdominal infections, has been a mainstay of therapy. Aminoglycosides bind irreversibly to the bacterial ribosomal subunit 30s to inhibit bacterial protein synthesis with consequent bacterial cell death.20These agents demonstrate concentration-dependent bactericidal activity.15,2y To ensure therapeutic peak and nontoxic trough levels, serum concentrations should be monitored.12 These drugs are highly effective against most gram-negative organisms that produce plactamases and are resistant to p-lactams. Resistance to aminoglycosides does occur via a plasmid-encoded enzyme that modifies the aminoglycoside molecule. Resistance is least to amikacin because it is a poor substrate for most of the inactivating bacterial enzyme^.'^ Today, aminoglycosides are indicated primarily for serious gramnegative infe~tions.4~ Aminoglycoside uptake is facilitated in the presence of inhibitors of bacterial cell wall synthesis, and this finding may account for the synergy observed when an aminoglycoside is used in combination with other 6-lactam antipseudomonal drugs15 (i.e., ticarcillin-clavulanate, piperacillin k tazobactam, imipenem-cilastatin, ceftazidime, and cefepime). Other examples of synergy include the combination of p-lactams and aminoglycosides to treat enterococcal and staphylococcal infections. The incidence of nephrotoxicity seems to be variable in different studies, with Stone et a195reporting a rate of 6.3% but Zaske et allo9reporting a rate less than 1%.The incidence of nephrotoxicity is increased in the settings of hypotension, prolonged therapy, pre-existing renal insufficiency, advanced age, associated liver disease, and coadministration of other nephrotoxic drugs.66The nephrotoxicity is reversible, but the vestibular-auditory deficits sometimes encountered can be permanent. For the patient with renal insufficiency, alternatives to an aminoglycoside for the specific coverage of gram-negative organisms include monobactam and third-generation cephalosporins." Another potential alternative, the fluoroquinolones, has not been subjected to the rigorous testing of many of the other antibiotics for treating abdominal infectiona4Although some of these agents have activity against grampositive organisms, fluoroquinolones have been most effective against the Enterobacteriaceae and other gram-negative bacteria, including P. aeruginosa. Fluoroquinolones may be useful to treat abdominal infection in patients with renal insufficiency and significant allergy to p-lactam agentss4 Because their spectrum of activity is similar to that of aztreonam, they should be combined with clindamycin. Another potential role for the fluoroquinolonesmay be gut decontamination with norfloxacin in critically ill ventilator-dependent patients and in neutropenic patients.90 Independent of the antibiotic regimen that is selected, dosages and

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dosing intervals should be adjusted to achieve therapeutic levels and to avoid toxic effects. When available, sensitivities of isolated organisms to the chosen antibiotic regimen can confirm the appropriateness of antibiotic selection. IDENTIFYING AND MANAGING PROBLEMATIC ORGANISMS

Some authorities in the field of serious abdominal infection have discouraged obtaining intraoperative cultures during the initial laparotomy for bacterial peritonitis. They cite experimental and clinical studies that demonstrate that the most important aspect of antibiotic coverage is that gram-negative facultative aerobic organisms and anaerobic species are adequately covered. They argue that with feculent peritonitis a reproducible spectrum of bacteria is isolated. In addition, they point out that the results of intraoperative culture specimens are rarely examined postoperatively and are infrequently used to make modifications to the antibiotic regimen.50Furthermore, it has been customary not to provide specific antimicrobial coverage for Enterococcus species or Candida when these organisms are isolated from the peritoneal cavity during the initial laparotomy.6,66, 67 Mosdell et a P found that inappropriate initial antibiotic coverage was highly associated with persistent infection, and their results suggested that modification of the antibiotic regimen postoperatively after culture results were available did not alter outcome. In an accompanying editorial commentary, however, Dunn32argued that most (almost two thirds) of the modifications to the initial antibiotic regimen remained inadequate. Routine intraoperative cultures of peritoneal fluid are probably not cost effective for most cases of limited peritoneal contamination and when the patient with minimal premorbid conditions is treated promptly. These patients usually resolve their peritonitis with appropriate antibiotic coverage. Obtaining intraoperative cultures may be most useful for the patients who have multiple premorbid medical problems, present for treatment after a significant delay, are acutely physiologically debilitated, are receiving immunosuppressive medications, or have altered gut flora because of recent hospitalization or treatment with antibiotics.66,Io3 This population of patients typically manifests suppressed local host immune defenses and is at high risk for persistent peritonitis. In these cases, the culture results should be used to modify antimicrobial coverage. The identification of resistant organisms may indicate the need for more aggressive surgical management and intensive supportive care.83 As recently pointed out by de Vera and Simm0ns,2~the increasing frequency of isolating Enterococcus species from the peritoneal cavity reflects the changing face of surgical infections. Among these species, Enferococcus faecalis accounts for approximately 90% of the clinical isolates.6 Most clinical studies suggest that patients with normal host defenses are resistant to enterococcal infections? With impaired local host

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defenses, prolonged administration of antibiotics, and increasing resistance to antimicrobial agents, enterococci emerge as nosocomial opportunists. Because enterococcal septicemia arising from an intra-abdominal focus is accompanied by mortality rates in excess of 50'?'0,2~ the compromised host with enterococcal overgrowth should have adequate antibiotic ~overage.~ de Vera and Simmonsz4suggest performing postoperative surveillance cultures to ensure proper antibiotic coverage. Selection of appropriate antibiotics for established enterococcal infections is problematic. Resistance to p-lactam agents (i.e., penicillins and cephalosporins) is mediated by both the presence of altered penicillin-binding proteins, which cause decreased affinity for p-lactams, and the production of p-lactamases. These organisms have been killed by the synergistic combination of high-dose penicillin and an aminoglycoside.z4 With increased production of low-affinity penicillin-binding proteins, however, this synergy is lost. Also, the En terococcus has acquired a plasmid that enables it to produce an aminoglycoside-modifying en~ y r n e Most . ~ ~ enterococcal infections resistant to aminoglycosides are still sensitive to the glycopeptide vancomycin. Single-agent therapy with this cell wall-active agent achieves only bacteriostatic Of grave concern today is the emergence of vancomycin-resistant enterococcal (VRE) infection^.^^ The gene VanA, responsible for much of this resistance, is carried on a transposon, a mobile genetic element, transferable by conjugation with other bacteria.z4Risk factors for outbreaks of VRE in intensive care units include the liberal use of vancomycin and thirdgeneration cephalo~porins.~~~ 24 About 90% of the VRE isolates have been E. faecium (VREF),which are often resistant to p-lactam and aminoglycoside agents.z4Although certain investigational antibiotics have demonstrated some effectiveness against VREF, at this time data from the National Nosocomial Infections Surveillance System show a higher mortality rate in patients with vancomycin-resistant isolates than with vancomycin-susceptible strains. Of even greater concern is the demonstration that the VanA gene can be transferred to staphylococcal and streptococcal species. Vancomycin-resistant Streptococcus hemolyticus and strains of methicillin resistant staphylococcus aureus (MRSA)that exhibit impaired clinical responses to vancomycin have already been deIn addition to Enterococcus species, the loss of endogenous flora secondary to prolonged antibiotic use permits the establishment of superinfection by resistant strains of P. aeruginosa, Enterobacter, and Staphylococcus epidermidis. The presence of these organisms typically serves as a marker of persistent diffuse peritonitis that is difficult to eradicate.= This entity has been labeled tertiary peritonitis because it follows a failed attempt at treating secondary peritonitis. When isolated from the peritoneum of patients with impaired host defenses, these organisms should be covered with appropriate antibiotics in an attempt to control the infection and prevent seeding of other sites secondary to bacteremia.84 Fungi represent another organism associated with the development species account for the vast majority of of tertiary ~ e r i t o n i t i sCandida .~~

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these infections, but species of Tordopsis and Aspevgillus are also identified. Candida is normally considered a commensal organism found within the endogenous gut flora, but Candida possesses several virulence factors capable of leading to invasive infection. Usually, Candida growth is limited by the heavy population of commensal gut bacteria that compete for mucosal binding sites and nutrients. The transition from an endogenous commensal to an opportunistic pathogen with invasive characteristics is the result of an altered balance in host-fungus interaction. Other defenses that limit the proliferation of Candidn include gastric acid, which reduces the number of Candida organisms presented to the small bowel, and the peristaltic action of the intestines. The virulence factors of Candida include the liberation of adhesion molecules that facilitate colonization of epithelial surfaces and then disrupt the epithelial boundary with ingrowth of h ~ p h a eThe . ~ ~density of Candida locally appears to be an important factor in its potential for invasive behavior and systemic spread.46Thus, yeast are known to translocate through even normal gut m u c o ~ a Indwelling .~~ vascular catheters provide another common route for systemic dissemination. Candida can become firmly adherent to such foreign bodies and can also incorporate themselves into the organized thrombus that may reside at the catheter tip. If Candida does penetrate the epithelial barrier or migrate through the vascular space, under normal circumstances, the invading organism is rapidly cleared by neutrophils that perform phagocytosis and oxygenmediated intracellular lysis. Beyond local host defenses, specific cellmediated mechanisms that depend upon activated macrophages and T lymphocytes are effective in clearing the yeast. Several factors can impair this defense system. During hyperglycemia with glucose concentrations in excess of 180 mg/dL, Candida species are capable of liberating cell surface proteins that interfere with normal opsonization and phagocytos ~ s Other . ~ ~ immune barriers are impaired by the administration of corticosteroids, immunosuppressive medications, and antimetabolites. The prolonged use of potent broad-spectrum antibiotics permits the overgrowth of Candida. The resulting increased density of Candida organisms within the gut fosters invasive behavior. Despite mortality rates in excess of 50% for disseminated systemic fungal infections, a diagnosis of disseminated infection is difficult.38,42, 46, 92 Because of efficient hematogenous clearing mechanisms, approximately half of patients with disseminated disease do not have positive blood cultures, and half with positive blood cultures do not have disseminated disease.4hThe presence of fungi in repeated blood cultures increases the reliability of an invasive fungal infection. Burchard et all3 described criteria for diagnosing disseminated fungal infection, including a presumptive diagnosis on the basis of at least three colonized sites. Recently, Cornwell et alZ1demonstrated that positive fungal cultures from only two or more nonhematogenous sites had an associated mortality similar to that attributable to disseminated fungal infection. Nassoura et aP5 found that even candiduria in critically ill patients with Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) I1 scores greater than 12 served

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as an indicator of disseminated Candida infection. Another potentially useful marker of disseminated candidiasis is endophthalmitis, which .~~ occurs in up to 37% of patients with systemic fungal i n f e ~ t i o n Most authorities on intra-abdominal infection agree that unless the patient is immunocompromised, small colony counts of Candida isolated from peritoneal cultures obtained at an initial laparotomy for a perforated viscus do not warrant therapy.I2 The presence of a pure culture of Candida, of increasing colony counts with sequential peritoneal culture or other evidence for systemic fungal infection as indicated above, indicates that immediate treatment is needed.6 Among surgical patients, the efficacy of amphotericin B therapy appears to depend on the timeliness of therapy and total dose. In a study reported by Marsh et a1,58patient survival from major candidal infections was associated with receiving a dose of at least 200 mg of amphotericin B. More commonly, total doses of amphotericin B in excess of 1 g are necessary to eradicate serious peritoneal infections. Concern for renal toxicity limits dosing to 0.3 to 0.5 m g / k g / d a ~ In . ~established ~ renal insufficiency, alternate-day dosing is commonly used. High doses of fluconazole, a triazole derivative, may be effective for systemic candidiasis and possibly intra-abdominal candidal infections.54, In choosing antifungal therapy, the clinician should recognize that Candida kreusi and Torulopsis glabrata are resistant to fluconazole, and Candida tropicalis has been observed to be especially virulent. For these organisms, treatment with amphotericin B is appropriate. For other candidal species, treatment with fluconazole or combinations of amphotericin B in a total dose greater than 200 mg followed by fluconazole may be a c ~ e p t a b l eThe . ~ ~ use of empiric therapy with antifungal agents has generally been effective in treating suspected fungal infections in neutropenic leukemic but it is uncertain if surgical patients would experience the same benefit. The data presented by Cornwell et alZ1and Nassoura et aF5indicate a role for therapy with fluconazole when critically ill patients are found to have bladder colonization, especially if one other site of colonization is also identified. PROPHYLAXISVERSUSTREATMENT

In his landmark article of 1961, Burke14demonstrated that antibiotics can prevent infection only when they are administered prior to the infectious chal1enge.lo6When normally sterile tissues are exposed to bacterial contamination, the host defense mechanisms cannot react fast enough to effectively defend against the sudden bacterial invasion. If antibiotics are present at inhibitory concentrations in the tissues before bacterial contamination, then bacterial proliferation is arrested. In the absence of such therapeutic antibiotic levels, bacteria start multiplying 91, Io6 Inflamed, necrotic, and may reach levels that foster tissue in~asion.~, or significantly traumatized tissues may develop an established infection at significantly lower bacterial counts than surrounding normal tissues.lx,“Ih The peritoneal cavity has several lines of defense that attempt to prevent such established infections, but these defenses are

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overwhelmed at very high bacterial concentrations. The serous fluid in the peritoneal cavity is normally less than 100 mL, but this fluid is distributed throughout the peritoneal cavity by the driving force of the contracting diaphragm.84The peritoneum overlying the muscular portion of the diaphragm is interrupted by a large number of intercellular gaps called stomas. These stomas communicate directly with the lymphatic ducts that drain via the mediastinal lymph nodes into the thoracic duct and thus eventually into the systemic circulation to encounter the reticuloendothelial system.6,84 Components of complement reside in the peritoneal fluid and are activated during contact with peritoneal bacteria. C3a and C5a stimulate chemotaxis of neutrophils and promote the degranulation of basophils and mast cells. The resultant increase in vascular permeability leads to a marked influx of fluid containing phagocytic cells, fibrin, opsins, and inflammatory mediators. Resident macrophages and recruited macrophages and neutrophils phagocytose the bacteria.30The omentum localizes infection by adhering to sites of inflammation or perforation. Similar to the diaphragmatic stomas, the omentum is capable of absorbing foreign particles and bacteria.45 The peritoneal cavity contains tertiary lymphoid tissue that is capable of recruiting lymphocytes during peritoniti~.~~ Utilizing these nonspecific and specific immune mechanisms, the peritoneal cavity attempts either to rapidly clear bacterial contamination or effectively localize and wall it off. The administration of preoperative antibiotics is aimed at preventing infection at sites that have not encountered the bacterial challenge.47Prophylaxis is particularly aimed at protecting the normally sterile tissues of the surgical wound. Although some authors have described the use of antibiotics to ”prevent” infection in areas of “contamination,” infections cannot be prevented after the bacterial ~hallenge.~ Instead, ~ , ~ ~ a, ~judgment ~ must be made by the surgeon about the probability for an established infection after mechanically clearing gross contamination. In addition to the presence of purulent exudate, the probability of established infection is increased by delays in clinical presentation or treatment, by shock, by the presence of residual debris, and by the presence of other possible adjuvants of bacterial infection (e.g., blood, b a r i ~ m ) . In ~ ~the , ~absence ~ , ~ ~of established infection, studies that have compared an isolated preoperative dose96(or 12 to 24 hours of perioperative antibiotics) have had outcomes similar to ”prophylactic” antibiotic courses lasting 5 days.28,34 Most authorities now agree that a single preoperative dose of antibiotics constitutes sufficient prophylaxis.86One exception may be the need to continue prophylaxis through the time that packs are left in the abdomen for hemostasis.62These recommendations are modified by the surgeon’s judgment regarding the probability of established infection. For example, a colonic perforation secondary to penetrating trauma would have different implications than a free colonic perforation that occurs after several days of progressive inflammation of untreated diverticulitis. In the former case, if there is no delay in presentation or treatment, then only a preoperative dose of antibiotic(s) is necessary. In the latter case, the likelihood that an estab-

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lished infection has occurred in the area of previously inflamed tissue seems very high7%and, after a preoperative dose, the patient should receive a postoperative therapeutic course of antibiotics. The restricted duration of antibiotics intended for prophylaxis 44 Bergquist would have a substantial impact on health care and Murphey7 reported that half of all antibiotics were prescribed for prophylactic purposes. Of greater importance would be the resultant preservation of a patient’s microbial ecology.52Inappropriate antibiotic prophylaxis has been associated with the development of pseudomembranous enterocolitis with the organism C. dificile. This organism is carried by 3% of healthy adults and 11%of hospitalized patients without inflammatory bowel disease or recent antibiotic the rap^.^ During hospitalization, patients can be infected by this organism from patient-topatient contact, hospital personnel-to-patient contact, and environmental fomites-to-patient c ~ n t a c tSuch . ~ transmission is markedly increased after an index case of C. dzficile-associated diarrhea. Antibiotic therapy eliminates endogenous commensal intestinal flora and permits selective proliferation of C. dificile and production of its cytotoxin. Ever since the 1974 publication of Tedesco et a1,98 which described the association between the use of clindamycin phosphate and C. dificile enterocolitis, clinicians have recognized that this entity rarely occurs without prior antibiotic therapy.53C. dificile colitis has now been related to all classes of antibiotics except vancomycin and the aminoglycosides.lOO In a retrospective study, Block et a19 found that the perioperative use of cefoxitin was linked to the development of C. dificile-associated diarrhea. The properties of broad-spectrum coverage (especially anaerobes) combined with bile excretion were thought to increase the risk for this superinfection. In general, however, Kreisel et a153found that the prolonged use of prophylactic antibiotics increased the risk of developing toxin-positive C. dificile infection. PHARMACOKINETICS AND APPROPRIATE DOSING OF ANTIBIOTICS A simplistic but useful pharmacokinetic model to describe the distribution of antibiotics has been the open two-compartment model (Fig. 1).20, Io5 In this model, the body consists of a central (vascular) and peripheral (tissue) compartment. As shown, the central compartment is filled directly by intravenous injection. During the initial phase of distribution, called the a-phase, the antibiotic reaches its peak concentration in serum and then distributes from the central compartment to the peripheral compartment. Toward the end of the a-phase, the tissue concentration of the peripheral compartment achieves a concentration higher than that of the central compartment as a consequence of active elimination of the drug from the central compartment via renal and hepatic routes. This concentration gradient results in rediffusion of the drug from the peripheral compartment to the central compartment. As elimination from the central compartment continues, the result is a

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Hours after IV Administration Figure 1. Serum and tissue concentrations of an antibiotic with a half-life of 60 min and breakpoint of 8 mg/L after IV bolus injection. The tissue concentration of an antibiotic will be above the breakpoint from 30 min to 6 h following the beginning of the injection. ( f r o m Condon RE, Wittman DH: The use of antibiotics in general surgery. Curr Probl Surg 28:807-907, 1991; with permission.)

parallel decrease in the antibiotic concentration in both compartments, referred to as the P-phase. With knowledge of an antibiotic's MIC for the spectrum of bacteria encountered, one can predict when the antibiotic needs to be redosed to maintain tissue concentrations above the MIC. The half-life of the antibiotic is expressed as a function of the elimination P-phase. For an antibiotic with a half-life of 1 hour, the tissue concentrations remain above the MIC (or breakpoint) from 30 minutes to as long as 6 hours after IV injection.20This finding accounts for the rationalization of dosing the preoperative antibiotic 30 minutes prior to incision and the need to redose the prophylactic antibiotic intraoperatively if the procedure exceeds 4 to 6 hours. Recently, concern that critically ill patients may be receiving subtherapeutic doses of antibiotics has been voiced.20,33, 36 Fear of nephrotoxicity more frequently leads to underdosing of aminoglycosides. In several comparative antibiotic trials, delays of several days in achieving appropriate peak aminoglycoside levels to exceed the MIC of infecting bacteria were observed.66The severely ill postoperative patient retains a significant amount of interstitial and other third-space fluid losses. These patients demonstrate a marked increase in the patient's volume of distrib ~ t i o n .36, ~ ~ , In addition, the hyperdynamic physiologic response of these patients may result in an increasing glomerular filtration rate that accelerates the elimination of these drugs.61Following the manufacturer's initial dosing recommendations quickly results in subtherapeutic dosing. Because of these findings, aminoglycoside serum concentrations should be carefully monitored not only to avoid toxicity, but also to ensure target

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peak drug levels. Most drugs, such as p-lactams and anti-anaerobic agents, are not monitored for serum concentrations. Their pharmacokinetics are subject to the same increases in the volume of distribution, and these agents are cleared more rapidly as a result of greater renal perfusion or hypermetabolic hepatic responses. When expected clinical responses are not achieved, attention should be paid to increasing the dose or changing the dosing interval of these agents. The neutropenic patient lacks effective local host defense mechanisms. These patients should receive doses high enough to achieve antibiotic levels above the MBC and not just the MIC.I5 As pointed out by prolonged subtherapeutic concentrations of antibiotics can be a potential mechanism to foster antimicrobial resistance. If the patient develops the sequela of organ dysfunction, dosing should be adjusted to prevent toxicity. Other aspects of pharmacokinetics and pharmacodynamics are altered in these critically ill patients. The amount of protein binding, ongoing fluid losses from drains or open wounds, and blood loss may alter the clearance of a n t i b ~ d i e sA . ~recent ~ study examined the effect of significant intraoperative blood loss on serum concentrations of cefazolin. The findings supported the recommendation to provide additional doses of cefazolin when the blood loss exceeds 1500 mL.97By analogy, loss of antibiotic by blood loss would necessitate additional doses when other prophylactic antibiotics are alternatively being used. DURATION OF ANTIBIOTIC TREATMENT

Another important problem in the use of therapeutic antibiotics for bacterial secondary peritonitis is deciding an appropriate duration of therapy. In the guidelines of Surgical Infection Society policy statement,’* antibiotic treatment for generalized peritonitis or localized abdominal abscess is recommended for 5 to 7 days. Lennard et a155advised against such fixed treatment courses. For example, significant risk for recurrent infection is present if the patient continues to have fever or leukocytosis. This finding was modified further by Stone et al.94Their group found that the risk of recurrent infection was negligible if the patient’s antibiotics were discontinued when the patient had no fever, had normal WBC count, and demonstrated a differential blood smear that showed less than 73% granulocytes and less than 3% immature granulocytes. In practice, many surgeons define a fixed interval of treatment (i.e., 7 to 10 days) or decide on terminating antibiotics when and if the patient becomes afebrile without leukocytosis. Recently, Holzheimer et a14*made a strong plea for shortening the course of therapeutic antibiotics treating an established intraperitoneal infection. Examining data from their study on staged abdominal repair (STAR), they found that two or three planned reoperations supplemented with a short course of systemic antibiotics were sufficient to effectively sterilize the peritoneum in cases of severe peritonitis. Thus, the bacterial burden that caused infection should be eradicated after just

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a short course of appropriate antibiotics. These findings are tempered by the observation that with increasing severity of infection, the failure 72 Several authors have found rate of eradicating the infection increases.71, that the APACHE I1 score is inversely correlated with the clearance of infection.', 87 Severe infection can cause such a profound physiologic insult that the resultant systemic inflammatory response disrupts the critical, delicate coordination of the local and systemic immune defenses. The length of antibiotic treatment has little favorable influence on the outcome of these critically ill patients.lo7Schein et a189agree that the risk of recurrent infection is extremely low when antibiotics are discontinued at the time the patient has no fever and no leukocytosis. Schein et als7 stress that continuing antibiotics on the basis of persistent fever or leukocytosis does not abort the development of infective complications. In fact, the cellular and humoral arms of the immune response may be adversely affected by the excessive use of antibiotics at therapeutic 27 Furthermore, growing evidence supports the fact that concentrations.20, the prolonged use of potent antibiotics to treat intra-abdominal infection leads to a profound impact on the patient's microbial ecology (especially the elimination of commensal anaerobic bacteriaso,81) that fosters the development of tertiary peritonitis.lo7 Wittmann and Scheinlo7emphasize that the duration of treatment with antibiotics for bacterial peritonitis should be tailored to the intraoperative findings and immunocompetence of the patient.86If the patient had a resectable source of infection, such as a gangrenous appendix or gallbladder, or strangulated bowel without perforation, then the patient should receive a short course (i.e., 24 hours) of antibiotics. These entities are usually surrounded by inflammation of the adjacent structures and represent a low-grade peritoneal infection. If an established intraperitoneal infection is detected by the presence of purulent exudate or strongly suspected by other factors, then an antibiotic course between 48 hours and 5 dayslo7should be selected based on the assessed severity. Suspicion for infection can be based on known risk factors,s7 such as any severe premorbid clinical conditions (i.e., heart failure, pulmonary disease, cirrhosis, metastatic cancer), states of decreased immunocompetence (i.e., steroids, malnutrition), duration of hypotension, delay in presentation or surgical intervention, magnitude of feculent contamination, residual adjuvants of infection (i.e., blood, fibrinous exudate, barium), and an extensive degree of tissue trauma or inflammation.22, 69 For clinical situations in which the source of infection can be neither completely resected nor debrided, for example, infected pancreatic necrosis, or, occasionally, when prolonged peritoneal toilet is necessary with planned re-explorations, a prolonged course of antibiotics should be a n t i ~ i p a t e dWhen . ~ ~ severe acute pancreatitis is complicated by necrosis early in its course, the areas of necrosis are often diffuse with necrotic islands of tissue intermixed with viable pancreas. Several weeks may elapse before these areas demarcate, coalesce, and liquefy into drainable collection^.^^ The early administration of imipenem-~ilastatin~~, 73 or cefuroximes2 may prevent the development of infective complications in

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severe acute pancreatitis. If percutaneous sampling or operative findings confirm the presence of infected pancreatic necrosis, then antibiotics may need to be administered for several weeks until the necrotic tissue has been replaced by granulation ti~sue.3~ Well-defined pancreatic abscesses that occur later in the natural history of severe acute pancreatitis should be drained, and short concurrent courses of antibiotics should be Differences in the duration of antibiotics for these two entities reflect the differences in time required for tissue repair. With excellent penetration into pancreatic tissue and its appropriate spectrum of activity, imipenem-cilastatin appears to be a good choice for therapy, but the antibiotic regimen must ensure activity against all isolated species. If the anticipated duration of antibiotics for any of these entities is completed and the patient's clinical course is unexpectedly marked by persistent fever, leukocytosis, or other findings consistent with sepsis, blindly continuing the present antibiotic regimen or changing antibiotic agents may be of little benefit to the patient.12The clinician should begin an exhaustive search for extra-abdominal and especially intraperitoneal sources of infection. Diagnostic tests should include multiple cultures, including cultures of all invasive lines, as well as imaging studies of the abdomen and pelvis with ultrasonography or CT. Although ultrasonography is frequently hampered by bowel gas, this test can be performed at the bedside and pelvic images may detect loculated fluid collections.6,41 Although considered to be quite sensitive for detecting postoperative abdominal abscesses, CT may fail to recognize organizing collections during the early postoperative period. Computed tomography may also miss interloop abscesses and pelvic abscesses with inadequate bowel contrast.6,41 When these imaging studies detect well-defined fluid collections, the fluid should be sampled for evidence of microorganisms, amylase, or other inflammatory stimuli. If the fluid collection is accessible to a percutaneous approach, then ultrasound- or CT-guided aspiration and drainage should be ~ n d e r t a k e nPercutaneous .~~ drainage should lead to a rapid clinical improvement, or consideration should be given to more thorough surgical drainage.36Prophylactic antibiotics should be administered for the percutaneous drain placement because the drain traverses normally sterile tissue. With a mature abscess cavity, only a brief course of therapeutic antibiotics typically should be necessary." If the failure of percutaneous drainage leads to surgical exploration, then operative findings should dictate the need for a longer therapeutic course of antibiotics. Occasionally, relaparotomy may be indicated if the clinical suspicion for an intraperitoneal source is strong despite negative investigative studies. ANTIBIOTICS CANNOT REPLACE PROPER SURGICAL MANAGEMENT

The outcome of bacterial secondary peritonitis is determined by early surgical intervention to achieve source control and peritoneal toilet. For patients with little physiologic reserve or with immunoincompe-

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tence, this first laparotomy may be the best chance the patient has to survive the bacterial challenge. Nonviable tissue and sources of contamination must be resected, debrided, or controlled. In heavily contaminated fields, definitive repairs such as suture lines or anastomoses may be of high risk.99Under such circumstances, where the development of intra-abdominal infection is likely, proximal fecal diversion may be preferable. The peritoneum should then be cleaned of bacterial contamiNo evidence suggests that the nation via irrigation or mechani~ally.~~ use of antibiotics in the irrigant provides any additional benefit to the systemic prophylactic antibiotics.l*,6o At laparotomy, the surgeon must must make a judgment about the presence of established infection. If infection is mild to moderate, then the patient requires a short course of 89 If the infection is obviously therapeutic antibiotics po~toperatively.~~, severe, the patient requires a longer course of postoperative antibioti c ~ .But ~ ~ the, surgeon ~ ~ must also decide on the need to perform several laparotomies or maintain an open peritoneal cavity to achieve adequate peritoneal toilet.70Without adequate peritoneal toilet, the bacterial concentration remains too high for resolution of the infection by the host's immune defenses, even with antibiotic tissue concentrations above the MBC or MIC.71,78,107 Another goal of peritoneal toilet is to remove sites, such as fibrinous clot, where bacteria may be sequestered from antibiotic penetration.'O With the reduction of bacterial counts, granulation tissue signals that further efforts toward peritoneal toilet are unnecessary. Intraperitoneal drains should be used to drain a well-defined abscess cavity or to divert bile, pancreatic juice, or urine collections that may become secondarily infected. Drains should also be used in areas that act as a source of continuing contamination but cannot be completely debrided, such as infected pancreatic necrosis.85In contrast, drains that are arbitrarily placed onto infected beds of peritoneum may perpetuate infection by acting as a foreign body that develops a bacterial b i ~ f i l m All .~~ these measures must be performed with the primary goal of rapidly achieving control of the intraperitoneal infection. With the high incidence of infection after primary closure of a heavily contaminated wound, such wounds should be left open.3,lo,36 If the surgical wound edges are not too distant, subsequent wound closure options include delayed primary closure and closure by secondary intention. In addition to surgical intervention and antibiotics, the third pillar of care for these patients is intensive physiologic and metabolic support.% Detailed attention must be given to such issues as resuscitation, maintenance of acid-base balance and electrolytes, and nutrition. The intensity of nursing care, the need for invasive hemodynamic monitoring, and the need for rigorous physiologic support require patients with severe intra-abdominal infection to be in an intensive care unit. EFFECT OF SYSTEMIC RESPONSE ON PATIENT OUTCOME

The goal of achieving very early control of the intra-abdominal infection is to avoid the sequelae of sepsis and multiple organ failure

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syndrome (MOFS).s5Most studies of severe intra-abdominal infection report a mortality of approximately 3Oy0.'~The development of MOFS is associated with mortality rates in excess of 50°/0."j Despite an approach of early aggressive treatment, many of these patients still progress toward MOFS, and appropriate searches for continuing sources of infection yield only sterile culture^.^^,^^^ In this population of patients, two other factors appear to be critical. One factor may be iatrogenic and correctable, but the other is beyond our control at this time. The prolonged use of potent broad-spectrum antibiotics eliminates the host defense of colonization resistancesoand leads to the overgrowth in the gut of low-virulence organisms such as Enterococcus, S. epidermidis, and Candida, as well as highly resistant nosocomial organisms such as Pseudomonas and Enterobucter.lo2 Superinfection of the peritoneum by these organisms, by an unproven mechanism, serves as a marker of tertiary peritoniti~.~~, '07 Although impaired host defenses account for the development of tertiary peritonitis, the peritoneal superinfection provides a continuing source of systemic inflammation with the generation of cytokines that disable the host's physiologic systems and immune 77 Even if antibiotics are no longer needed to control bacterial concentrations at sites of previous infection, their continued administration leads to destruction of residual gram-negative rods in the gut and other locations. The liberation of the lipopolysaccharide has the potential to augment response of previously stimulated macrophagesz6,27, 51, 63 The resulting persistent release of cytokines may have detrimental effects on the host. Thus, proper utilization of antibiotics may decrease the incidence of tertiary peritonitis and the magnitude of the systemic inflammatory response syndrome. A reasonable guideline is to limit the use of antibiotics to the treatment of microbiologically proven infection and understand that the goal of treatment is only to assist the host's immune system by reducing bacterial counts at the site of i n f e ~ t i o nUnfortunately, .~~ even proper antibiotic usage may not eliminate life-threatening consequences. One patient may manifest a relatively minor systemic response to a source of infection, whereas another patient with a comparable insult may develop a rapid and profound manifestation of sepsis. Recent findings suggest that the genetic control of the release of cytokines, such as tumor necrosis factor-a, may dictate the magnitude of the host's re~ponse.'~ Conceivably, some patients do not immediately turn off the inflammatory mediators upon control of the infection. They may continue to manifest a fever or leukocytosis for some time after the eradication of infection." Continuing antibiotics in these patients is probably more harmful than beneficial. Such patients warrant an exhaustive search for sources of infection that would prevent the resolution of inflammation. In the absence of such findings, antibiotics should be discontinued. For some patients the magnitude of the inflammatory response progresses to MOFS, independent of the surgical, antimicrobial, and critical care provided to these s5 patients.59,

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SUMMARY

Antibiotics are only an adjunct to proper surgical therapy for the treatment of the acute abdomen associated with bacterial secondary peritonitis. Upon presentation, all patients require a preoperative dose of antibiotics for prophylaxis against infection of remaining sterile tissues. Patients found intraoperatively to have an established peritoneal infection benefit from an immediate postoperative course of therapeutic antibiotics. A regimen that adequately covers facultative and aerobic gram-negative bacilli and anaerobic organisms is essential. The duration of therapeutic antibiotics is probably best decided on an individual patient The goal of antibiotics is to reduce the concentration of bacteria invading tissues. The pathogens of bacterial peritonitis are influenced by such factors as the patient’s pre-existing chronic diseases, state of acute physiologic debilitation, immunocompetence, recent antibiotic use, recent hospitalization, and neutralization of gastric acidity. Intraoperative peritoneal cultures are most useful in patients suspected of having impaired local host defenses. In these patients, all identified organisms, such as Enterococcus or Cundida, may be potential pathogens. The common practice of administering empiric and prolonged courses of broad-spectrum antibiotics in patients who manifest persistent signs of inflammation may be more harmful than beneficial. These patients warrant an exhaustive search for extra-abdominal and intraperitoneal sources of new infection. Otherwise, such use of antibiotics may continue to promote the selection of bacteria that are highly resistant to conventional antibiotics and permit the overgrowth of organisms commonly seen with tertiary peritonitis. The best chance of resolving bacterial peritonitis is through early, aggressive surgical management complemented by short courses of potent antibiotics and appropriate physiologic support. Through these efforts, the clinician tries to help the systemic inflammatory response to benefit the host and not become unregulated, result in MOFS, and produce a high mortality. References 1. Andaker LH, Hojer H, Kihlstrom E: Stratified duration of prophylactic antimicrobial treatment in emergency abdominal surgery. Acta Chir Scand 153:185-192, 1987 2. Aprahamian C, Schein M, Wittmann DH: Cefotaxime and metronidazole in severe intra-abdominal infection. Diagn Microbiol Infect Dis 22:183-188, 1995 3. Badia JM, De LaTorre R, Farre M, et al: Inadequate levels of metronidazole in subcutaneous fat after standard prophylaxis. Br J Surg 82479482, 1995 4. Barie PS: Emerging problems in gram-positive infections in the postoperative patient. Surg Gynecol Obstet 177(Suppl):55-64, 1993 5. Barie PS, Christou NV, Dellinger EP, et al: Pathogenicity of the enterococcus in surgical infections. Ann Surg 212:155-159, 1990 6. Bartlett TG: Intra-abdominal sepsis. Med Clin North Am 79:599-617, 1995 7. Bergquist EJ, Murphey SA: Prophylactic antibiotics for surgery. Med Clin North Am 71:357-368. 1987 8. Bergstein JM: The role of shock. Eur J Surg 576(Suppl):16-18, 1996

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9. Block BS, Mercer LJ, Ismail MA, et a1 Clostridiurn dificile associated diarrhea follows perioperative prophylaxis with cefoxitin. Am J Obstet Gynecol 153:835-838, 1985 10. Bohnen JMA: Operative management of intra-abdominal infections. Infect Dis Clin North Am 6:511-523, 1992 11. Bohnen JMA Postoperative peritonitis. Eur J Surg 576(Suppl):50-52, 1996 12. Bohnen JMA, Solomkin JS, Dellinger EP, et al: Guidelines for clinical care: Antiinfective agents for intra-abdominal infection: A Surgical Infection Society Policy Statement. Arch Surg 12783-89, 1992 13. Burchard KW, Minor LB, Slotman GJ, et al: Fungal sepsis in surgical patients. Arch Surg 118:217-221, 1983 14. Burke JA: The effective period of preventive antibiotic action in experimental incisions and dermal lesions. Surgery 50:161-168, 1961 15. Bush LM, Levison ME: Antibiotic selection and pharmacokinetics in the critically ill. Crit Care Clin 4299-324, 1988 16. Butler JA, Huang J, Wilson SE: Repeated laparotomy for postoperative intra-abdominal sepsis. Arch Surg 122:702-706, 1987 17. Christou NV: Host defense mechanisms of surgical patients: Friend or foe? Arch Surg 131:1136-1140, 1996 18. Condon RE: Microbiology of intra-abdominal infection and contamination. Eur J Surg 576(S~ppl) :9-12, 1996 19. Condon RE, Walker AP, Sirinek KR, et a1 Meropenem versus tobramycin plus clindamycin for treatment of intra-abdominal infections: Results of a prospective, randomized, double-blind clinical trial. Clin Infect Dis 21:544-550, 1995 20. Condon RE, Wittmann D H The use of antibiotics in general surgery. Curr Probl Surg 28:807-907, 1991 21. Cornwell EE, Belzberg H, O f h e TV, et al: The pattern of fungal infections in critically ill surgical patients. Am Surg 61:847-850, 1995 22. Culver DH, Horan TC, Gaynes RP, et al: Surgical wound infection rates by wound class, operative procedure, and patient risk index. Am J Med 91:152S-l57S, 1991 23. Davis JM, Huycke MM, Wells CL, et al: Surgical Infection Society position on vancomycin-resistant enterococcus. Arch Surg 131:1061-1068, 1996 24. de Vera ME, Simmons RL: Antibiotic-resistant enterococci and the changing face of surgical infections. Arch Surg 131:338-342, 1996 25. Dean DA, Rurchard KW: Fungal infection in surgical patients. Am J Surg 171:374382. 1996 26. Deitch EA, Dazhong X, Franko L, et al: Evidence favoring the role of the gut as a cytokine-generating-organ in rats subjected to hemorrhag; shock. Shock 1:741-146, 1994 27 Dellinger El? Undesired effects of antibiotics and future studies. Eur J Surg 576(S~ppl):29-32,1996 28. Dellinger EP, Wertz MJ, Lennard ES, et al: Efficacy of short-course antibiotic prophylaxis after penetrating intestinal injury. Arch Surg 121:23-30, 1986 29. DiPiro JT, Edmiston CE, Bohnen JMA: Pharmacodynamics of antimicrobial therapy in surgery. Am J Surg 171:615422, 1996 30. Dries DJ, Jurkovich GJ, Maier RV, et al: Effect of interferon gamma on infectionrelated death in patients with severe injuries. Arch Surg 129:1031-1041, 1994 31. Dunagan WC, Woodward RS, Medoff G, et a1 Antimicrobial misuse in patients with positive blood cultures. Am J Med 87253-259, 1989 32. Dunn DL: Antibiotic treatment for surgical peritonitis [editorial]. Ann Surg 214:550, 1991 33. Ericsson CD, Fischer RP, Rowlands BJ, et al: Prophylactic antibiotics in trauma: The hazards of underdosing. J Trauma 29:1356-1361, 1989 34. Fabian TC, Croce MA, Payne LW, et al: Duration of antibiotic therapy for penetrating abdominal trauma: A prospective trial. Surgery 12788-795, 1992 35. Fabian TC, Hess MM, Croce MA, et al: Superiority of aztreonam/clindamycin compared with gentamicin/clindamycin in patients with penetrating abdominal trauma. Am J Surg 167:291-296, 1994

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36. Feliciano DV, Spjut-Patrinely V: Pre, intra, and postoperative antibiotics. Surg Clin North Am 70:689-701, 1990 37. Foitzik T, Castillo CF, Ferraro MJ, et al: Pathogenesis and prevention of early pancreatic infection in experimental acute necrotizing pancreatitis. Ann Surg 222:179-185, 1995 38. Fraser VJ, Jones M, Dunkel J, et al: Candidemia in a tertiary care hospital: Epidemiology, risk factors and predictors of mortality. Clin Infect Dis 15:414421, 1992 39. Frileux P, Parc Y Pancreatic infections. Eur J Surg 576(Suppl):53-55, 1996 40. Fry DE: The importance of antibiotic pharmacokinetics in critical illness. Am J Surg 172(Suppl 6A):20%25S, 1996 41. Gerzof SG, Oates ME: Imaging techniques for infections in the surgical patient. Surg Clin North Am 68:147-165, 1988 42. Giamarellou H, Antoniadou A: Epidemiology, diagnosis, and therapy of fungal infections in surgery. Infect Control Hosp Epidemiol 17558-564, 1996 43. Gorbach S L Intra-abdominal infections: State of the art clinical article. Clin Infect Dis 17961-967, 1993 44. Hadjiminas D, Cheadle W, Spain D, et a1 Antibiotic overkill of trauma victims. Am J Surg 168:288-290, 1994 45. Heel KA, Hall JC: Peritoneal defences and peritoneum-associated lymphoid tissue. Br J Surg 83:1031-1036,1996 46. Henderson VJ, Hirvela E R Emerging and reemerging microbial threats. Arch Surg 131:330-337, 1996 47. Hirshberg A, Mattox KL: Penetrating abdominal trauma. Eur J Surg 576(Suppl):5658, 1996 48. Holzheimer RG, Schein M, Wittmann DH: Inflammatory mediators in plasma and peritoneal exudate of patients undergoing staged abdominal repair (STAR) for severe peritonitis. Arch Surg 13O:lOOO-1006, 1995 49. Hooker KD, DiPiro J T Effect of antimicrobial therapy on bowel flora. Clin Pharmacol 7878-888, 1988 50. Hopkins JA, Lee JCH, Wilson SE: Susceptibility of intra-abdominal isolates at operation: A predictor of postoperative infection. Am Surg 59:791-796, 1993 51. Hurley JC: Antibiotic-induced release of endotoxin: A reappraisal. Clin Infect Dis 15:840-854, 1992 52. Jarvis WR Preventing the emergence of multidrug-resistant microorganisms through antimicrobial use controls: The complexity of the problem. Infect Control Hosp Epidemiol 17:490495, 1996 53. Kreisel D, Save1 TG, Silver AL, et al: Surgical antibiotic prophylaxis and Clostridium difficile toxin positivity. Arch Surg 130:989-993, 1995 54. Kujath P, Lerch K, Kcendorfer P, et a1 Comparative study of the efficacy of fluconazole versus amphotericin B/flucytosine in surgical patients with systemic mycoses. Infection 21:376-382, 1993 55. Lennard ES, Dellinger EP, Wertz MJ, et al: Implications of leukocytosis and fever at conclusion of antibiotic therapy for intra-abdominal sepsis. Ann Surg 195:19-24, 1982 56. Levison MA: Percutaneous versus open operative drainage of intra-abdominal abscesses. Infect Dis Clin North Am 6:525-544, 1992 57. Livingston DH, Shumate CR, Polk HC, et al: More is better-antibiotic management after hemorrhagic shock. Ann Surg 208:451459, 1988 58. Marsh PK, Tally FP, Kellum J, et al: Candida infections in surgical patients. Ann Surg 198:4247, 1983 59. Marshall JC, Sweeney D Microbial infection and the septic response in critical illness: Sepsis, not infection, determines outcome. Arch Surg 125:17-23, 1990 60. Martin C, Viviand X, Poti6 F: Local antibiotic prophylaxis in surgery. Infect Control Hosp Epidemiol 17539-544, 1996 61. McKindley DS, Fabian TC, Boucher BA, et al: Antibiotic pharmacokinetics following fluid resuscitation from traumatic shock. Arch Surg 130:1321-1329, 1995 62. Melcher GA, Ruedi TP: Blunt abdominal trauma. Eur J Surg 576(Suppl):5940, 1996 63. Mock CN, Jurkovich GJ, Dries DJ, et al: Clinical significance of antibiotic endotoxinreleasing properties in trauma patients. Arch Surg 130:1234-1241, 1995

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64. Mosdell DM, Morris DM, Voltura A, et al: Antibiotic treatment for surgical peritonitis. AM Surg 214:543-549, 1991 65. Nassoura Z, Ivatury RR, Simon RJ, et al: Candiduria as an early marker of disseminated infection in critically ill surgical patients: The role of fluconazole therapy. J Trauma 35:290-295, 1993 66. Nathens AB, Rotstein O D Antimicrobial therapy for intra-abdominal infection. Am J Surg 172(suppl 6A):1%6S, 1996 67. Nathens AB, Rotstein OD: Therapeutic options in peritonitis. Surg Clin North Am 74:677491, 1994 68. Nichols RL, Holmes JWC: Prophylaxis in bowel surgery. Curr Clin Topics Infect Dis 15:76-96, 1995 69. Nichols RL, Smith J W Risk of infection, infecting flora and treatment considerations in penetrating abdominal trauma. Surg Gynecol Obstet 177(Suppl):50-54, 1993 70. Nichols RL, Smith JW: Wound and intra-abdominal infections: Microbiological considerations and approaches to treatment. Clin Infect Dis 16(Suppl4):S266-S272, 1993 71. Nystrom P: Transition from contamination to infection: Implications to colonic surgery. Eur J Surg 576(Suppl):42-46,1996 72. Pacelli F, Doglietto GB, Alfieri S, et al: Prognosis in intra-abdominal infections, multivariate analysis on 604 patients. Arch Surg 131:641-645, 1996 73. Pederzoli P, Bassi C, Vesentini S, et al: A randomized multicenter clinical trial of antibiotic prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem. Surg Gynecol Obstet 176:480-483, 1993 74. Polk HC, Fink MP, Laverdiere M, et al: Prospective randomized study of piperacillin/ tazobactam therapy of surgically treated intra-abdominal infection. Am Surg 59:598605, 1993 75. Pollock AV: At what point is infection cured but inflammation persists? Eur J Surg 576(S~ppl):13-15,1996 76. Rangel-Frausto MS, Pittet D, Costigan M, et al: The natural history of systemic inflammatory response syndrome (SIRS). JAMA 273:117-123, 1995 77. Reemst PHM, Goor HV, Goris JA: SIRS, MODS and tertiary peritonitis. Eur J Surg 576(Suppl):47-49,1996 78. Robson MC: Wound infection: A failure of wound healing caused by an imbalance of bacteria. Surg Clin North Am 77637-650, 1997 79. Rowlands RJ, Ericsson CD, Fischer RP: Penetrating abdominal trauma: The use of operative findings to determine length of antibiotic therapy. J Trauma 27250-255, 1987 80. Saadia R, Lipman J: Antibiotics and the gut. Eur J Surg 576(Suppl):3941, 1996 81. Saadia R, Schein M, MacFarlane C, et al: The gut barrier function and the surgeon. Br J Surg 77487-492, 1990 82. Sainio V, Kemppainen E, Puolakkainen P, et al: Early antibiotic treatment in acute necrotising pancreatitis. Lancet 346:663467, 1995 83. Sanderson PJ: Antimicrobial prophylaxis in surgery: Microbiologicalfactors. J Antimicrob Chemother 31(Suppl B):1-9, 1993 84. Sawyer MD, Dunn DL: Antimicrobial therapy of intra-abdominal sepsis. Infect Dis Clin North Am 6:545-570, 1992 85. Schein M: Management of severe intra-abdominal infection. Surg AMU 2447-68,1992 86. Schein M, Wittmann D H Editorial: Antibiotics in abdominal surgery: The less the better. Eur J Surg 159:451-453, 1993 87. Schein M, Assalia A, Bachus H: Minimal antibiotic therapy after emergency abdominal surgery: A prospective study. Br J Surg 81:989-991, 1994 88. Schein M, Wittmann DH, Holzheimer R, et al: Hypothesis: Compartmentalization of cytokines in intra-abdominal infection. Surgery 119:694-700, 1996 89. Schein M, Wittmann DH, Lorenz W: Forum statement: A plea for selective and controlled postoperative antibiotic administration. Eur J Surg 576(Suppl):66-69, 1996 90. Selective Decontamination of the Digestive Tract Trialist’s Collaborative Group: Metaanalysis of randomized controlled trials in selective decontamination of the digestive tract. Br Med J 307525-532, 1993

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