Guidelines for the Selection of Anti-infective Agents for Complicated Intra-abdominal Infections

These guidelines, from the Infectious Diseases Society of America (IDSA), the Surgical Infection Society, the American Society for Microbiology, and the Society of Infectious Disease Pharmacists, contain evidence-based recommendations for selection of antimicrobial therapy for adult patients with complicated intra-abdominal infections. Complicated intra-abdominal infections extend beyond the hollow viscus of origin into the peritoneal space and are associated either with abscess formation or with peritonitis. These guidelines also address timing of initiation of antibiotic therapy, when and what to culture, modification of therapy based on culture results, and duration of therapy. Infecting flora. The anticipated infecting flora in these infections and, therefore, the agent(s) selected are determined by whether the infection is community acquired or health care associated. Health care–associated intra-abdominal infections are most commonly acquired as complications of previous elective or emergent intra-abdominal operations and are caused by nosocomial isolates particular to the site of the operation and to the specific hospital and unit. For community-acquired infections, the location of the gastrointestinal perforation (stomach, duodenum, jejunum, ileum, appendix, or colon) defines the infecting flora. Established infection beyond the proximal small bowel is caused by facultative and aerobic gram-negative organisms; infections beyond the proximal ileum also can be caused by a variety of anaerobic microorganisms. Microbiologic evaluation. Given the activity of common regimens against the anaerobic organisms identified in community-acquired infections, microbiologic workup for specimens from such infections should be limited to identification and susceptibility testing of facultative and aerobic gram-negative bacilli. Susceptibility profiles for Bacteroides fragilis group isolates demonstrate substantial resistance to clindamycin, cefotetan, cefoxitin, and quinolones, and these agents should not be used alone empirically in contexts in which B. fragilis is likely to be encountered. Recommended regimens. These infections may be managed with a variety of single- and multiple-agent regimens. The antimicrobials and combinations of antimicrobials listed in table 1 are considered appropriate for the treatment of community-acquired intra-abdominal infections. No regimen has been consistently demonstrated to be superior or inferior. Although many of the listed regimens have been studied in prospective clinical trials, many such studies have serious design flaws. Recommendations are, therefore, based in part on in vitro activities. Recommended agents for treatment of community-acquired complicated intra-abdominal infections. Community-acquired infections. For patients with community-acquired infections of mild-to-moderate severity, agents that have a narrower spectrum of activity and that are not commonly used for nosocomial infections, such as ampicillin/sulbactam, cefazolin or cefuroxime plus metronidazole, ticarcillin/clavulanate, ertapenem, and quinolones plus metronidazole, are preferable to agents that have broader coverage against gram-negative organisms and/or greater risk of toxicity. Cost is an important factor in the selection of a specific regimen. Patients with more-severe infections, as defined by accepted physiologic scoring systems, or patients deemed to have immunosuppression resulting either from medical therapy or from acute or chronic disease, might benefit from regimens with a broader spectrum of activity against facultative and aerobic gram-negative organisms. Recommended regimens include meropenem, imipenem/cilastatin, third- or fourth-generation cephalosporins (cefotaxime, ceftriaxone, ceftizoxime, ceftazidime, and cefepime) plus metronidazole, ciprofloxacin plus metronidazole, and piperacillin/tazobactam. Health care–associated infections. Postoperative (nosocomial) infections are caused by more-resistant flora, which may include Pseudomonas aeruginosa, Enterobacter species, Proteus species, methicillin-resistant Staphylococcus aureus, enterococci, and Candida species. For these infections, complex multidrug regimens are recommended, because adequate empirical therapy appears to be important in reducing mortality. Local nosocomial resistance patterns should dictate empirical treatment, and treatment should be altered on the basis of the results of a thorough microbiologic workup of infected fluid. These infections remain an important area for clinical research. Multiple implementation strategies should be used to maximize adherence to these recommendations. These include obtaining feedback from microbiologists, nurses, pharmacists, and physicians before local publication of selected regimens; use of lectures and publications; small-group interactive sessions; and computer-assisted care. Compliance may be monitored through pharmacy-based drug utilization reviews and through review of microbiology records. Complicated intra-abdominal infections are problems in clinical practice and consume substantial hospital resources. These resources include emergency department services, imaging services, operating room time, laboratory services, antibiotic therapy, and in-hospital care of variable intensity. Outcomes are heavily influenced by the rapidity of diagnosis and appropriate intervention and by the timeliness and efficacy of anti-infective therapy. A wide range of individual antimicrobial agents and combinations of agents is available for use in complicated intra-abdominal infections. There are convincing data that absent or inadequate empirical and definitive antibiotic therapy results in both increased failure rates and increased mortality [1–5]. Conversely, unnecessary or needlessly broad therapy is associated with its own problems. Cost remains an important issue in antimicrobial agent selection. Various patient- and agent-specific toxicities may occur, including superinfection and organ toxicity. Acquisition of intrinsically drug-resistant organisms and selective pressure for resistance within the unit, hospital, or community is of increasing concern [6, 7]. Development of these guidelines. These evidence-based guidelines were developed by an expert panel using the IDSA Guidelines Development process and have been endorsed by the IDSA, the Surgical Infection Society, the American Society for Microbiology, and the Society of Infectious Disease Pharmacists [8]. In addition, these guidelines conform with prevention strategies recommended in the Centers for Disease Control and Prevention's Campaign to Prevent Antimicrobial Resistance in Healthcare Settings (available at http://www.cdc.gov/drugresistance/healthcare/default.htm). The expert panel developed a clinical framework for managing intra-abdominal infections and reviewed studies on the site of origin of the intra-abdominal infections, their microbiology, the laboratory approach to infections, and the selection and duration of antibiotic therapy. The Therapeutic Agents Committee of the Surgical Infection Society recently completed an extensive review of published articles on the use of antimicrobials [9] that was used to develop the Surgical Infection Society Guidelines on Antimicrobial Therapy for Intra-abdominal Infections [10]. That work served as the initial review of clinical trials of antibiotic agents for the present guideline. Purpose of these guidelines. These guidelines are intended to define the types of infections that require antimicrobial therapy; categorize these infections and the microorganisms likely to be involved in each type of infection; and describe appropriate specimen processing, the use of specific antimicrobial agents or combination regimens appropriate for treatment, and the timing and duration of such therapy. The impact of therapy on the occurrence of antibiotic resistance is considered. Scope of these guidelines. Complicated intra-abdominal infections are defined as infections that extend beyond the hollow viscus of origin into the peritoneal space and that are associated either with abscess formation or peritonitis. These infections require either operative or percutaneous intervention to resolve. The current guidelines will not address intraparenchymal abscesses of the liver or spleen, infections arising in the genitourinary system, or infections of the retroperitoneum, with the exception of pancreatic infections. These guidelines are not intended to address infections occurring in children <18 years of age or primary peritonitis. Target audience. The target audience for these guidelines is the physician and pharmacy practitioners who are responsible for antibiotic selection for antimicrobial therapy and the laboratory personnel who are responsible for the processing of specimens obtained at intervention for intra-abdominal infections. Identification of relevant clinical trials. The bases for these guidelines are published articles on the use of antimicrobials to treat intra-abdominal infections published between 1990 and 2003. The 1990 cutoff was selected because relevant literature up to 1990 was the subject of a previous guideline [11]. The MEDLINE database was searched using multiple strategies, in which the names of specific antimicrobials or more general descriptors (such as “cephalosporins”) were paired with words and phrases indicating an intra-abdominal infection (such as “peritonitis” and “appendicitis”). This search included studies that were in the MEDLINE database as of 1 February 2003. The Cochrane Database was also searched for other prospective trials, although none were identified. Scientific review. Using this methodology, the published studies used to create recommendations were categorized according to study design and quality; then, the recommendations developed from these studies were graded according to the strength of evidence behind them. For particular recommendations and statements, the strength of the supporting evidence and quality of the data are rated by use of an IDSA–United States Public Health Service grading system (table 2) [8]. Infectious Diseases Society of America–United States Public Health Service grading system for rating recommendations in clinical guidelines. Bowel injuries due to penetrating, blunt, or iatrogenic trauma that are repaired within 12 h and intraoperative contamination of the operative field by enteric contents under other circumstances should be treated with antibiotics for ⩽24 h (A-1). For acute perforations of the stomach, duodenum, and proximal jejunum in the absence of antacid therapy or malignancy, therapy is also considered to be prophylactic (B-2) [12, 13]. Similarly, acute appendicitis without evidence of gangrene, perforation, abscess, or peritonitis requires only prophylactic administration of inexpensive regimens active against facultative and obligate anaerobes (A-1). Acute cholecystitis is often an inflammatory but noninfectious disease. If infection is suspected on the basis of clinical and radiographic findings, urgent intervention may be indicated, and antimicrobial therapy should provide coverage against Enterobacteriaceae (B-2) [14]. Activity against enterococci is not required, because their pathogenicity in biliary tract infections has not been demonstrated. Coverage against anaerobes is warranted in treatment of patients with previous bile duct–bowel anastomosis (C-3). Infections occurring during the course of acute necrotizing pancreatitis are due to microbial flora similar to that found in infections resulting from colonic perforations [15]. Antibiotic choices appropriate for other types of intra-abdominal infection are considered appropriate for the empirical treatment of infected necrotizing pancreatitis. The administration of prophylactic antibiotics to patients with severe necrotizing pancreatitis before the diagnosis of infection is a common but unproved practice [16]. If a patient with diagnosed infection has previously been treated with an antibiotic, that patient should be treated as if he or she had a health care–associated infection (B-3). Established infection is defined primarily by the history of the illness and by the findings at the time of operative or percutaneous intervention. Evidence of established infection includes the presence of a systemic and local inflammatory response, the latter as indicated by the presence of a purulent exudate and inflamed tissue. Once the diagnosis of intra-abdominal infection is suspected, it is appropriate to begin antimicrobial therapy before an exact diagnosis is established and before results of appropriate cultures are available. The goals of antibiotic therapy for intra-abdominal infection are to eliminate infecting microorganisms, to decrease the likelihood of recurrence, and to shorten the time to resolution of signs and symptoms of infection. Infecting microorganisms heavily contaminate surgical wounds, and it is important that effective antimicrobial therapy be begun before any intervention, so that subsequent surgical-site infection can be prevented. Antibiotics should be administered after fluid resuscitation has been initiated, so that adequate visceral perfusion can be restored and better drug distribution is possible. Particularly in the case of aminoglycosides, nephrotoxicity is exacerbated by impaired renal perfusion [17]. Infections derived from the stomach, duodenum, biliary system, and proximal small bowel can be caused by gram-positive and gram-negative aerobic and facultative organisms. Infections derived from distal small-bowel perforations can be caused by gram-negative facultative and aerobic organisms with variable density. Perforations of this type often evolve into localized abscesses, with peritonitis developing only after rupture of the abscess. Anaerobes, such as B. fragilis, are commonly present. Colon-derived intra-abdominal infections can be caused by facultative and obligate anaerobic organisms. Streptococci and enterococci are also commonly present. By far the most common gram-negative facultative organism is Escherichia coli. Antibiotics used for empirical treatment of community-acquired intra-abdominal infections should, therefore, be active against enteric gram-negative aerobic and facultative bacilli and β-lactam–susceptible gram-positive cocci (A-1). Coverage against obligate anaerobic bacilli should be provided for distal small-bowel and colon-derived infections and for more-proximal gastrointestinal perforations when obstruction is present (A-1). Table 3 details agents and regimens that may be used to treat intra-abdominal infections and that have been adequately studied in clinical trials [45]. We note that studies in which sample sizes are too small to define equivalence or detect differences between various regimens provide little useful data. Studies that are not subject to peer review are, similarly, of little use. Agents and regimens that may be used for treatment of intra-abdominal infections and have been subjected to randomized, prospective clinical trials. The expanded gram-negative bacterial spectrum of some agents shown to be effective in clinical trials is not advantageous for patients with community-acquired infections, and unnecessary use of such agents may contribute to the emergence of antimicrobial resistance. In particular, agents that are used to treat nosocomial infections in the intensive care unit should not be routinely used to treat community-acquired infections (B-2) [7, 46]. For patients with mild-to-moderate community-acquired infections, agents that have a narrower spectrum of activity, such as ampicillin/sulbactam, cefazolin or cefuroxime/metronidazole, ticarcillin/clavulanate, and ertapenem are preferable to more costly agents that have broader coverage against gram-negative organisms and/or greater risk of toxicity (A-1). Generic agents have cost advantages. Aminoglycosides have relatively narrow therapeutic ranges and are associated with ototoxicity and nephrotoxicity. Because of the availability of less toxic agents demonstrated to be of equal efficacy, aminoglycosides are not recommended for routine use in community-acquired intra-abdominal infections (A-1). These agents should be reserved for patients with allergies to β-lactam agents and even then are second choices to quinolone-based regimens. Aminoglycosides may be first-choice agents for empirical treatment of health care–associated intra-abdominal infections, depending on local susceptibility patterns of nosocomial isolates. Individualized administration of aminoglycosides is the preferred dosing regimen for patients receiving these agents for intra-abdominal infections (A-1). Cefoxitin and cefotetan cannot be recommended for use, because B. fragilis group microorganisms have increasingly been found to be resistant to these agents. That outcomes are worse for patients infected with B. fragilis who are treated with agents to which the organisms are resistant has been demonstrated repeatedly [47–49]. Cost considerations may play an important role in the selection of initial empirical antimicrobial therapy. Precise calculation of the expenses associated with the use of different regimens is difficult, and these costs are specific to the particular institution. Costs may differ markedly between regimens, depending on the frequency of administration and the need to monitor serum drug concentrations. Completion of the antimicrobial course with oral forms of a quinolone plus metronidazole (A-1) or with oral amoxicillin/clavulanic acid (B-3) is acceptable for patients who are able to tolerate an oral diet [19, 26]. Several attempts have been made to identify clinical features in patients with peritonitis that increase the risk of adverse outcomes. These analyses have identified factors that are prognostic of death, rather of the risk of including disease, and to adequate of the of infection Similarly, patients with immunosuppression resulting from medical therapy for or inflammatory should therapy. Patients with other acute and chronic may also have although this is to For such use of antimicrobial regimens with expanded may be including meropenem, imipenem/cilastatin, ciprofloxacin plus metronidazole, or a third- or fourth-generation plus metronidazole (C-3). of and antimicrobial therapy are of antimicrobial failure to infection and that organisms resistant to the empirical antimicrobial regimen may be responsible for infection patients should be treated for nosocomial as in Health Intra-abdominal Infections (C-3). Antimicrobial therapy for established infections should be resolution of clinical signs of infection including of and and of gastrointestinal The risk of subsequent treatment failure appears to be for patients who have clinical evidence of infection at the time of of antimicrobial therapy For patients who have or clinical evidence of intra-abdominal infection after of therapy, appropriate should be This should include or and antimicrobial therapy effective against the organisms identified should be (C-3). For patients with or intra-abdominal infections, intervention likely will be to If a patient has clinical symptoms and but evidence of a or infection is after a of antimicrobial therapy is In community-acquired infections, the flora is routinely to recommended regimens. There is a case to be made against from patients with or Several studies have the impact of of such cultures on and have to identify any There are, that of this to other types of intra-abdominal infection The listed studies have been to with not failure in this to infection is This is due in part to of the inflamed remains abscess or other infected tissue. For other intra-abdominal infections, the failure rates are if empirical therapy is not active against any identified the regimen to identified isolates There are differences in susceptibility patterns within and between different These data are of in the most antimicrobial therapy for intra-abdominal infections. have an of in community-acquired appendicitis local hospital antimicrobial susceptibility patterns should be in initial empirical therapy. Identification and susceptibility testing of anaerobes and to be unnecessary if active anaerobic agents are used to treat infections in which anaerobes are with distal and colonic and if adequate or is Resistance repeatedly has been identified and found to be increasing for clindamycin, cefoxitin, cefotetan, and the quinolones of anaerobic susceptibility that used the recommended by the may be used as for therapy at the B. fragilis group This is not intended to from local resistance If this is the results should be published and with for previous years Susceptibility testing of individual anaerobic isolates should be considered when is of the when is and when therapy is In infections occurring after elective or emergent a more resistant flora is routinely is evidence that not empirical therapy active against the identified is associated with in mortality and treatment failure The organisms are similar to in other nosocomial infections, and anaerobes are not encountered. Antibiotic therapy for such infections should be by of the nosocomial flora at the particular hospital and its antimicrobial This may require the use of multidrug regimens an or quinolone or a and cultures not provide relevant for patients with community-acquired intra-abdominal infections and are, therefore, not recommended for such patients (A-1). from the intra-abdominal of infection should be of the associated with the clinical and is benefit to obtaining multiple aerobic and anaerobic cultures can be using a provided it is of of fluid or and is to the laboratory in an anaerobic system, rather on a not provide appropriate specimens for anaerobic For community-acquired infections, is in a of the infected For health care–associated infections, may be in the need for specific therapy for methicillin-resistant gram-positive organisms Local susceptibility patterns for and for enterococci might of to the regimen results of cultures and susceptibility testing are available. For enterococci, local should be monitored for and resistance. Candida or other are from of patients with acute perforations of the gastrointestinal tract when are agents are the patient has recently therapy for or inflammatory or has or intra-abdominal infection (B-2) therapy for Candida should be the infecting is identified (C-3). If is is an appropriate For Candida species, therapy with or is appropriate (B-3). The latter agents less toxicity and are indicated for patients with renal (A-1). and trials have regimens active against of routinely from patients with community-acquired infections. In at of these the regimen not have similar coverage none of these trials demonstrated an to infections. coverage against therefore, not for patients with community-acquired intra-abdominal infections (A-1). Antimicrobial therapy for enterococci should be when enterococci are from patients with health care–associated infections (B-3). The selection of appropriate antimicrobials should be by susceptibility The primary for this guideline is a drug utilization review for patients with community-acquired and with health care–associated intra-abdominal infection. reviews should the empirical therapy provided with local susceptibility There are of treatment of intra-abdominal infection that require The issue of appropriate specimen processing, including the role of antimicrobial susceptibility testing on a routine requires This may be by prospective This type of study also data on community resistance patterns and microbiologic findings an of of the appropriate duration of antimicrobial therapy is the most The impact of therapy, by the availability of oral regimens, may have a on the of resistant organisms in the community or in or chronic care to which such patients are from other to with health care–associated infections, clinical outcomes are Given the of such prospective trials are to be and other including prospective may be The of infecting organisms to be and the impact of empirical therapy should be In addition, duration of therapy for infections is an important variable that has and expenses for from and has and expenses as a for and as a for has been an in by and has been a with and provided by and have been by and of in has and expenses as a for and B. has and expenses for from and has and expenses for for has served as a local site in clinical trials by and has and expenses for from and has and expenses for from has and expenses for from and

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