Microbiological evaluation and antimicrobial treatment of complicated intra-abdominal infections

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1 Microbiological evaluation and antimicrobial treatment of complicated intra-abdominal s H van der Plas Helen van der Plas, FCP(SA), Cert ID(SA)Phys, DTM&H, Senior Specialist and Senior Lecturer Division Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town Helen van der Plas, helenvanderplas@gmail.com Keywords: complicated intra-abdominal s, microbiological evaluation, antimicrobial treatment Intra-abdominal is a major cause of morbidity and mortality. The principles of management of intra-abdominal s include adequate surgical procedures, as well as antimicrobial therapy. This review provides insights into the microbiology of complicated intra-abdominal s and offers an approach to the microbiological evaluation, as well as antimicrobial treatment strategies, in the South African context. Local antibiotic guidelines for the management of intra-abdominal s are urgently required to optimise clinical outcomes, while limiting the emergence of resistance, toxicity and the selection of pathogenic organisms. SAJEI 2012;27(2):53-57 Introduction The spectrum of intra-abdominal is wide, and can involve any intra-abdominal organ or space. In uncomplicated intraabdominal, the disease process is limited to the organ with no disruption of anatomical barriers, whereas with complicated intraabdominal there is extension beyond the organ of origin, e.g. intestinal wall perforation, with spillage of enteric organisms into the sterile peritoneal space. 1 Secondary peritonitis ensues, which may be localised and contained, or diffuse, carrying a high mortality in the absence of surgical intervention and appropriate antimicrobial therapy. Another sequelae of a perforated viscus is intra-abdominal abscesses, located in the intraperitoneal or retroperitoneal space, which occur in partially treated diffuse peritonitis, postoperatively, or in localised disease where the omentum has sealed off the perforation and formed an inflammatory barrier. If left untreated, a bacteremia may ensue with progression to generalised sepsis with shock. Peritonitis is classified as primary, secondary and tertiary. In primary peritonitis (spontaneous bacterial peritonitis) and continuous ambulatory peritoneal dialysis-associated peritonitis, the source of the is not due a breach in the gastrointestinal tract. Usually, it is caused by a single organism requiring medical management only. In contrast, secondary peritonitis is a polymicrobial following perforation of the gastrointestinal tract, or an originating in an intra-abdominal structure, e.g. the pancreas. Tertiary peritonitis is an ill-defined entity, which occurs despite adequate treatment of primary or secondary peritonitis. 1 Opportunistic organisms with low virulence are typically implicated. Only the management of secondary peritonitis will be reviewed. The key components of managing complicated intra-abdominal consist of initial fluid resuscitation, supportive measures to maintain vital function, e.g. oxygenation, antibiotic administration and surgical intervention. Appropriate source control procedures are critical to the management of complicated intra-abdominal. These include drainage of infected foci, control of ongoing peritoneal contamination by resection or diversion, as well as restoration of anatomical and physiological function. 2,3 Factors consistently associated with poor outcomes in patients with intra-abdominal s include increased illness severity, failed source control, inadequate empiric antimicrobial therapy and healthcare-acquired. 4 The purpose of this review is to provide insights into the microbiology of complicated intra-abdominal, offer an approach to the microbiological evaluation of, as well as antimicrobial treatment strategies for, complicated intra-abdominal, in the current South African setting. Microbiology More than 400 bacterial species form a complex ecosystem in the human gastrointestinal tract. The microflora differs according to the region of the gastrointestinal tract. The stomach and duodenum contain relatively few microorganisms, mostly representative of salivary Gram-positive facultative microorganisms such as lactobacilli, streptococci and Candida spp. The organism density increases towards the ileum containing Eschericha coli, enterococci and an equal number that are obligate anaerobic organisms, such as Bacteroides fragilis. Further on in the colon, obligate anaerobes, such as Bacteroides spp, anaerobic streptococci, and Clostridium spp. predominate, and far outnumber the mostly aerobic bacteria, ;27(2)

2 such as E. coli, Klebsiella spp., Proteus spp., Enterobacter spp., viridans streptococci and enterococci. Prevention of the implantation of pathogens, e.g. Shigella spp., Campylobacter spp. and Salmonella spp., and the equilibrium of enteric microflora is closely maintained through gastric acid, bile and peristalsis, as well as the microflora itself, by producing its own antibacterial substances, e.g. bacteriocins and fatty acids. 5 As anticipated, with bowel perforation, the contaminating organisms are diverse and the is typically polymicrobial. In addition, the composition of microorganisms in abdominal fluid obtained from patients following perforation varies, depending on the location of the perforation. However, selection processes, growth characteristics, adherence capacities, and the invasiveness of certain species and host defenses explain that only a small number of bacterial species, roughly four to six on average, out of the 400 different species, are isolated from the peritoneal exudate. 5 By far, the most commonly isolated two organisms are E. coli and the obligate anaerobe, B. fragilis. Bacterial synergism in intra-abdominal s was elegantly demonstrated in the 1970s by classic experiments in a rat model of fecal peritonitis, where it was shown that abscesses failed to form with the inoculation of single species. However, the combination of anaerobes and a facultative organism led to abscess formation. Furthermore, mortality appeared restricted to recipients of E.coli, and subsequently the role of Gram-negative lipopolysaccarides in the manifestations of sepsis and septic shock was elucidated, together with the importance of certain polysaccharides derived from B. fragilis in the development of abscess formation. 6 Complicated intra-abdominal s need to be further considered in the environment in which they occur. Characteristically, in community-acquired s, the microbiology consists of drug-susceptible organisms. In contrast to hospital-acquired intraabdominal sepsis, drug-resistant organisms from the hospital environment feature more prominently. Hospital-acquired intraabdominal is defined as an not present and not incubating at the time of admission to a healthcare setting, which becomes clinically evident after 48 hours of hospitalisation. 7 At-risk populations include the elderly and patients with chronic disease, organ dysfunction, malignancy, malnutrition and acquired immune deficiency syndrome. Relatively antibiotic-resistant microorganisms, such as P. aeruginosa, Acinetobacter spp., extensive ß-lactamase (ESBL)-producing enterobacteriaceae, enterococci and Candida spp., are frequently cultured from patients who received broad-spectrum antibiotics, or whose intra-abdominal s developed after hospital admission or postoperatively. Apart from considering the endogenous gut microflora when selecting appropriate empirical antibiotic cover, the primary process that caused the spontaneous perforation also requires deliberation. For instance, tuberculosis, typhoid and amebic ulcers, as well cytomegalovirus ulcers in immunocompromised patients, can cause spontaneous gastrointestinal perforation. The diagnosis is made during surgery and is supplemented by histology and tissue culture. 5 These s require targeted antimicrobial therapy. Microbiological evaluation Appropriate specimens for microbiological evaluation include representative material obtained intra-operatively from the site of clinical, preferably tissue or fluid. A minimum of 1 ml of fluid or tissue is required for optimal recovery of aerobic and anaerobic organisms from culture. Pus swabs, although commonly collected, are less desirable. Direct inoculation of peritoneal fluid into blood culture systems has shown enhanced yield. However, frank pus should not be directly inoculated into blood culture bottles. 3 Immediate Gram stains are of value for the early detection of Gram-positive cocci and yeasts in hospital-acquired s, and in patients who have received prior antibiotics. In that situation, additional empirical antifungal and enterococcal therapy can be added before definitive cultures become available. Shortcomings in specimen collection and transportation commonly result in unsuccessful culture of obligate anaerobes, particularly the fastidious ones. For optimal recovery of anaerobes, an anaerobic transport tube should be used, and the samples require rapid processing to avoid bacterial overgrowth. Most laboratories do not perform antimicrobial susceptibility testing of anaerobes because of the long and special incubation conditions required for isolation. Empirical anaerobe cover is based on local and national surveillance data collected periodically from clinically significant isolates. Overall, blood cultures have a very low yield in patients with complicated intra-abdominal in the absence of septicaemia. Aerobic blood cultures should be obtained in septic patients prior to commencement of antibiotics in all patients with healthcareassociated intra-abdominal s. Anaerobic blood cultures have a very low yield, and hence add very little value when considering the cost involved, and where empirical anaerobic antibiotic cover is standard of care. Thus, routine anaerobic blood cultures are not recommended for patients with intra-abdominal sepsis. There is controversy surrounding the routine intra-operative culture of community-acquired intra-abdominal. The microbiology represents drug-sensitive gut flora, and knowledge of culture results very rarely influences antibiotic therapy. 8,9 Two retrospective reviews of 363 and 104 patients who had undergone appendectomy for appendicitis found that therapy was not changed because of culture and susceptibility results. In the latter group, the results of cultures influenced antibiotic therapy in only seven per cent of cases. 9 The Infectious Diseases Society of America does not recommend routine culture in community-acquired intra-abdominal unless the patient is at risk of harbouring resistant pathogens or is immunocompromised. 3 However, surveillance systems need to be in place to monitor changes of resistance patterns of pathogens associated with these community- acquired s. The situation is reversed in patients with hospital-acquired intraabdominal, postoperative intra-abdominal, or highrisk patients [those with high Acute Physiology and Chronic Health Evaluation (APACHE) II scores, poor nutritional status, significant cardiovascular disease, inability to obtain adequate source control and immunosuppression], as they have a high rate of multidrugresistant pathogens, and initial empirical antibiotic choices may ;27(2)

3 be inappropriate. All patients with healthcare-associated intraabdominal require culture and drug susceptibility testing to guide antibiotic therapy in the postoperative period. Antimicrobial therapy selection Antibiotic therapy is a key adjunct to surgery, and needs to target Gram-negative, Gram-positive and anaerobe bacteria. In patients with uncomplicated intra-abdominal s, where the focus of is completely resected, and no peritonitis is present, only perioperative antibiotic prophylaxis is necessary. The surgeon is best placed to make this decision intra-operatively. Prophylactic antibiotics should be given for 24 hours only. Appropriate empirical antibiotic treatment is considered to cover all usual suspected pathogens in the case of established. It should be administered without delay, at the correct dose and dosing interval, is well tolerated, reaches the site of, and does not increase selection pressure for antibiotic-resistant microorganisms. Patient factors, such as existing co-morbidity, drug intolerance and prior antibiotic use, need to be taken into account when selecting an antibiotic regimen. Cost and ease of administration should also be considered in resource-poor settings. Most importantly, when selecting an antibiotic, the clinician needs to evaluate whether the was acquired in the community or in a healthcare facility. Community-acquired complicated intraabdominal A meta-analysis of 40 studies comparing 16 different comparative antibiotic regimens found that broad-spectrum single-agent or combination regimens are equally efficacious. 10 Effective broadspectrum single-agent therapy that targets Gram-positive and Gram-negative enterobacteriaceae, as well as the obligate anaerobe Bacteroides spp. group, includes cefoxitin, penicillin plus a betalactamase inhibitor, e.g. co-amoyclav or piperacillin-tazobactam, carbapenems, moxifloxacin and tigecycline (a glycylcycline). There are no existing guidelines for the management of complicated intra-abdominal in South Africa. Currently, the Antibiotic Guide for Academic Hospitals of the Western Cape recommends the use of penicillin, gentamicin and metronidazole to treat communityacquired intra-abdominal. 11 Co-amoxyclav is a convenient alternative in patients with severe sepsis and renal insufficiency. Two drug-regimens, such as a third-generation cephalosporin or a fluoroquinolone, e.g. ciprofloxacin, combined with metronidazole, are also handy options. Unfortunately, quinolone-resistant E. coli are becoming increasingly common in some communities. The findings of a six-year surveillance study evaluating resistance among aerobic and facultative anaerobic Gram-negative bacilli isolates from complicated intra-abdominal from 59 private hospitals in South Africa, reports 7.6% ESBL production among E.coli, and 41.2% of all K. pneumoniae were ESBL producers. Ertapenem was the most active agent (94%), followed by amikacin (91,9%), piperacillin-tazobactam (89.3%), and imipenem-cilastin (87.1%). High rates of resistance in the range of % were reported for ceftriaxone, cefotaxime, ciprofloxacin and levofloxacin. 12 The major limitation of this study was that there was no distinction between hospital- and community-acquired. Prior antibiotic use and risk factors for resistant GNB were not determined. Despite these findings, empirical use of carbapenems for community-acquired intra-abdominal should be discouraged, as there is concern that broad use may hasten the appearance of carbapenem-resistant Enterobacteriaceae, Pseudomonas and Acinetobacter spp. Resistance patterns among obligate anaerobes are underappreciated as drug susceptibility testing it is not routinely performed, and there is reliance on local surveillance data. Recent data from Johannesburg show that there is an increasing trend of metronidazole resistance (12.3%) among B. fragils. Fortunately, no resistance to co-amoxyclav was demonstrated. 13 Table I lists useful antimicrobial agents, as determined by the setting. Table I: Antimicrobial agents for use in initial empirical treatment of extrabiliary community-acquired complicated intra-abdominal Communityacquired Regimen Comment complicated intra-abdominal Single agent Co-amoxiclav Superb anaerobe and enterococcal cover and safety profile. Cefoxitin Effective against anaerobes, no enterococcal cover. Moxifloxacin Broad-spectrum cover which includes anaerobes and enterococci. Ertapenem Restrict use to patients with risk of being colonised with extensive ß-lactamase-producing organisms. Combination therapy Penicillin or ampicillin, metronidazole plus gentamycin Ceftriaxone or cefuroxime plus metronidazole Ciprofloxacin plus metronidazole Avoid this combination in elderly patients, and in patients with renal impairment. Alternative in patients with renal dysfunction. No enterococcal cover. Increasing fluoroquinolone resistance among Eschericha coli may limit this option in future. Hospital-acquired complicated intra-abdominal Multidrug-resistant pathogens are more commonly seen in hospitalacquired and postoperative intra-abdominal. Therefore, broader spectrum antimicrobial regimens are recommended for these patients. Empirical treatment needs to be guided by the resistance patterns of Enterobacteriaceae, non-fermenters such as Pseudomonas and Acinetobacter spp., and enterococci isolated from the healthcare facility. Tailoring or de-escalation of the initial broad antimicrobial regimen to a narrower spectrum agent should be undertaken once definitive culture results are available. Recent drug susceptibility patterns of K. pneumoniae isolates from South African academic hospitals show ESBL production was reported as high as 50%, rendering cephalosporins or a ß-lactam/- lactamase inhibitor combination useless. ESBL production was less ;27(2)

4 frequently observed among E. coli strains (6-16%). 14 Furthermore, these isolates were frequently multi-resistant, with high rates of associated quinolone and aminoglycoside resistance. Carbapenems are the drug of choice where these resistant isolates are prevalent. The worldwide emergence and spread of carbapenem resistance among K. pneumoniae, which includes reports from South Africa, is cause for alarm and poses a major threat to the viability of currently available antibiotics. 15,16 Multi-drug resistance among non-fermenters is the rule, and knowledge of local nosocomial non-fermenter resistance patterns should guide empirical cover for hospital-acquired intra-abdominal s in each institution. Drug combinations are required for empirical coverage. These include a carbapenem, piptazobactam or fourth-generation cephalosporins (cefepime or ceftazidime) with amikacin or colistin. Tigecycline, a novel agent approved for complicated intra-abdominal, has expanded broad-spectrum antibacterial activity against Enterobacteriaceae, anaerobes, including methicillinresistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. Reduced activity of tigecycline has been observed for Proteus spp., Providencia spp. and Morganella spp. P. aeruginosa is also not reliably inhibited. 17 Empirical monotherapy is a consideration in patients with renal dysfunction and/or ß-lactam allergy, where ESBL-producing strains or polymicrobial multidrug-resistant organisms are likely, and there is a very low risk of acquiring an due to Pseudomonas spp. This agent can also be considered for targeted therapy against mixed s of MRSA- or ESBLproducing organisms. This drug should be used within an antibiotic stewardship programme or in consultation with a microbiologist. Anti-enterococcal therapy and antifungal therapy In addition to coverage of more resistant Gram-negative bacilli and anaerobes, use of agents that are effective against enterococci, resistant staphylococci and Candida should also be considered. Routine anti-enterococcal therapy is not a requirement in patients with mild-to-moderate community-aquired intra-abdominal s. Numerous studies have compared therapeutic regimens that are active against enterococci, to regimens without coverage against enterococci. These studies did not show an advantage for treating enterococci. However, there is general consensus that enterococcal coverage is recommended in patients with prior cephalosporin or quinolone use (which select for enterococci), in immunocompromised patients, in patients with prosthetic heart valves or vascular heart disease, and in hospital-acquired intraabdominal s. 3 Empirical anti-enterococcal therapy should be directed against the susceptibility pattern of Enterococcus faecalis. The organism is sensitive to ampicillin, piperacillin-tazobactam, imipenem and vancomycin. If ampicillin resistance is high among nosocomial isolates, vancomycin should be the empirical agent of choice to cover enterococci. Antifungal therapy is recommended if candida is grown from intraabdominal specimens in patients with severe community-acquired intra-abdominal s and hospital-acquired intra-abdominal s. 3 Amphotericin B is the empirical agent of choice as it has broad activity against all Candida spp., and once C. albicans is isolated, therapy can be safely de-escalated to fluconazole. Echinacandins are attractive alternatives in critically ill patients, particularly with renal dysfunction. However, at this stage, cost is still prohibitive. Antibiotic treatment duration Prolonged antimicrobial therapy results in excess cost, has the potential for drug-related toxicity, as well as the development of C. difficile, and leads to the emergence of antibiotic-resistant pathogens. When the source of the infectious process has been controlled and there is a clinical response (as determined by the maintenance of an afebrile state for 48 hours, normal white blood cell count, the absence of abdominal tenderness, and the return of peristalsis), the antibiotic regimen may be discontinued as soon as five days after initiation. The Surgical Infection Society and the Infectious Disease Society of America recommend limiting the treatment duration to 4-7 days. 3 A systemic review carried out in evaluating treatment duration in children with advanced appendicitis found that limiting antibiotic use to three days was not associated with higher rates of intra-abdominal abscess or wound. 18 Currently, there is a randomised trial underway comparing two short three-day regimens in patients presenting with community-acquired intra-abdominal of mild-to-moderate severity. 19 These results will guide treatment duration in this patient group. Patients with a poor clinical response usually have poor source control with possible abscess formation. However, extra-abdominal sources of and noninfectious inflammatory conditions should also be looked for. Conclusion Early appropriate surgical intervention and effective antimicrobial therapy limit the local and haematogenous spread of the and reduce late complications and mortality. Selection of appropriate antibiotic therapy needs to be considered with care, and within the context in which the occurs. Currently, there are no South African antibiotic guidelines for the management of complicated intra-abdominal s. Antibiotic guidelines are urgently required to guide antibiotic selection for intra-abdominal s in the private, as well as the public sector. Acknowledgments The author would like to thank Dr Adrian Brink for reviewing the manuscript. Conflicts of interest The author has no conflicts of interest to declare. References 1. Blot S, De Waele JJ. 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