Rethinking treatment of complicated intra-abdominal infections

Issue: January 2016

ByDonald Kaye, MD, MACP

ByLarry M. Bush, MD, FACP

Intra-abdominal infections, or IAIs, include a variety of entities resulting from disease or trauma to both hollow and solid organs located in either the peritoneal cavity or retroperitoneal space. The designation of “complicated” IAI applies to those conditions that extend beyond the involved organ with subsequent development of secondary peritonitis or abscess formation. Approximately 80% of IAIs are community-acquired, while others, termed health care-associated, generally arise as complications of previous elective or emergency intra-abdominal operations. The later frequently involve nosocomial isolates specific to the site of the operation and individual health care setting. Based upon the patient’s comorbid conditions, immune status and accepted physiologic scoring systems (ie, APACHE-II), IAIs can be graded from mild to moderate to more severe forms. Rapid recognition, optimal hemodynamic restoration, source control and perhaps most importantly, the rapid administration of adequate antimicrobial therapy, best serve to temper morbidity, complications and mortality associated with complicated IAIs. These measures are reflective of what is commonly believed or proven in the management of serious infections leading to sepsis.

Selecting the best therapy for IAI

CT scans with oral and IV contrast material provide superior detail of intra-abdominal processes and have proved especially well-suited for the diagnosis of IAIs. Except for detecting processes suspected to be localized in the right upper quadrant, retroperitoneum or pelvis where ultrasonography is more helpful, CT scans are frequently obtained as the initial imaging study and have essentially eliminated the need for exploratory laparotomy surgery. Once a specific complicated IAI (cIAI) diagnosis is suspected or made, antimicrobial therapy targeting gram-negative aerobic and anaerobic bacilli (GNB) as well as gram-positive aerobic cocci is essential. Although it is clear that the chosen regimen does not need to be active against every potential or isolated pathogen to ensure a successful outcome, the need for an antimicrobial regimen specific for some isolated organisms still remains controversial. For example, enterococci are found in about one-fifth of cIAIs and have emerged as major nosocomial pathogens. However, there is no credible evidence that antimicrobial regimens possessing anti-enterococcal activity either improve clinical outcomes or effectively prevent the emergence of enterococcal superinfection. Currently, the available evidence suggests that routine coverage against enterococcus is not necessary for patients with community-acquired cIAIs, but it should be considered for those patients with prior cephalosporin or fluoroquinolone use, immunocompromised conditions and hospital-acquired cIAIs, including postoperative peritonitis and abscess formation. Likewise, most authorities agree that even though Candida spp. are cultured from about 20% of patients with acute perforations of the gastrointestinal tract, antifungal therapy is not needed except in instances where the yeast is isolated from blood cultures, found to be a predominant organism, or in patients undergoing immunosuppressive therapy. Agents with anti-MRSA activity are warranted as part of an initial empiric antimicrobial regimen for health care-associated cIAIs in individuals known to be colonized or who are at increased risk for MRSA infection because of failed prior therapies and broad antimicrobial exposure.

Complications due to drug resistance

The rise in bacterial resistance among aerobic GNB involved in health care-associated and, to an increasingly greater extent, community-acquired cIAIs, adversely affects outcomes resulting in lengthened hospital stays, escalating costs and increased morbidity and mortality. This has made for new challenges when selecting an adequate antimicrobial regimen for cIAI treatment, especially in those instances where the infection is considered to be highly severe. For the most part, the burgeoning resistance of aerobic GNB against agents generally used in cIAIs is driven by the increased prevalence of extended-spectrum beta-lactamase (ESBL) production by common Enterobacteriaceae isolates involved in these infections. The 2011 Study for Monitoring Antimicrobial Resistance trends (SMART) found that Escherichia coli and Klebsiella pneumoniae constituted 55% of the aerobic GNB in IAIs, and that 12.7% of K. pneumoniae and 9.7% of E. coli isolates produced ESBL. Furthermore, in a recent large multicenter worldwide observational study of cIAIs, ESBL production was detected in 20% and 40% of all E. coli and Klebsiella spp., respectively. Although the signature phenotypic property of ESBL enzymes is the hydrolysis of extended-spectrum cephalosporins, the overexpression of other beta-lactamases such as AmpC (the genetics of which typically are chromosomal but capable of transfer to other bacteria via plasmids) further limits effective treatment of cIAIs since antibiotic resistance mediated by this enzyme (increasingly prevalent in Enterobacteriaceae) is not overcome by the addition of beta-lactamase inhibitors, such as clavulanate or tazobactam. Complicating matters more, additional resistance mechanisms such as altered drug targets, decreased outer membrane porin expression, and efflux pump regulation frequently coexist in beta-lactamase–producing isolates leading to multidrug-resistant (MDR) and at times, extremely drug-resistant, pathogens.

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Reliance on previous minimal inhibitory concentration (MIC) breakpoints to detect advanced cephalosporin resistance in Enterobacteriaceae isolates was hampered by values that were too high by pharmacodynamic parameters. Instead, clinicians were dependent on the clinical laboratory’s reporting of ESBL positive isolates. Specific additional tests to confirm the presence of beta-lactamase has been eliminated by the Clinical Laboratory Standards Institute’s lowering of MIC clinical breakpoints that are currently employed by most microbiology laboratories for cephalosporins and monobactams. However, because such breakpoints for beta-lactam-beta-lactamase inhibitor combination antibiotics (BLBLIs), in particular piperacillin-tazobactam (P-T), remain high (ie, susceptible < 16/4 mg/L, resistant > 128/4 mg/L), this agent is commonly chosen with confidence to treat cIAIs based on reported in-vitro susceptibility data. This discounts the concern that the pharmacodynamic parameter of time above the MIC (40% to 50% of the dosing interval) needed to optimize bacterial killing may not be achievable for higher MIC isolates. In fact, the combined published guideline by the Surgical Infection Society and the Infectious Diseases Society of America for the diagnosis and management of cIAIs recommends the use of P-T when ESBL-producing Enterobacteriaceae are known or suspected to be present. Nevertheless, there is limited proven clinical efficacy of BLBLIs against ESBL producers when treating high inoculum infections that may overcome the action supplied by the beta-lactamase inhibitor. Fluoroquinolone agents (ciprofloxacin, levofloxacin and moxifloxacin) continue to be empirically selected and (with the exception of moxifloxacin, which has activity against anaerobes) combined with metronidazole for cIAI antibiosis. However, in light of the rapid increase in E. coli resistance, fluoroquinolones should not be used for the treatment of cIAIs of high severity unless local and hospital microbiologic surveys indicate more than 90% of E. coli strains remain susceptible to these agents. Tigecycline often remains active against MDR Enterobacteriaceae; however, one trial on cIAI demonstrated an increased risk for death among patients receiving tigecycline compared with patients receiving comparator antibiotics, leading to a recommendation against the use of this glycylcycline antibiotic in severe infection. As a consequence of these growing resistance issues, the carbapenem antibiotics have become the “go-to drugs” when confronted with a cIAI of high severity. Not unexpectedly, this increased dependency on carbapenems has created selection pressure for carbapenem resistance. An analysis of The Surveillance Network database for U.S. hospitals from 2000 to 2009 found that in cIAIs, approximately 15% of Pseudomonas aeruginosa strains demonstrated MDR, and 2% of aerobic GNB were carbapenem-resistant Enterobacteriaceae(CRE) — mostly K. pneumoniae carbapenemase (KPC)-producing strains.

Two new BLBLI antibiotics — Zerbaxa (ceftolozane-tazobactam, Merck; C-T) and Avycaz (ceftazidime-avibactam, Forest Pharmaceuticals; C-A) — recently have been approved for the treatment of cIAIs. An oxyimino-aminothiazolyl cephalosporin, ceftolozane’s unique chemical structure improves its antimicrobial activity against AmpC beta-lactamase–producing Enterobacteriaceae while the beta-lactamase inhibitor tazobactam component affords activity against class A and C beta-lactamases. However, C-T remains susceptible to degradation by carbapenemases. By evading efflux pumps and having a greater affinity for attachment to penicillin-binding proteins on isolates exhibiting diminished outer membrane porin expression, which lessens drug uptake, ceftolozane is afforded activity against MDR strains of P. aeruginosa. C-A is the first BLBLI with activity against KPC-producing aerobic GNB, but lacks activity against those CRE capable of metallo-beta-lactamase production. Owing to their insufficient activity against anaerobic bacteria, both agents require the addition of metronidazole in treating IAIs and both have proved noninferior vs. meropenem in phase 3 cIAI treatment clinical trials. Although costly, these drugs are welcome additions when confronted with a patient with restricted or no other treatment options.

Advantages of shorter treatment courses

Granted an absence of proven evidence, source control of IAIs — defined as all adequate measures to control active contamination, physical elimination of the infection source and re-establishment of anatomic function either by surgical intervention or invasive radiologic technique — is believed to be paramount in the management of cIAIs. Immediate surgical intervention even in the medically unstable septic patient has been supported by a recent prospective observational study where those patients with gastrointestinal perforations and associated septic shock who underwent surgery within 2 hours of admission had a significant survival advantage at 60 days. For years expert guideline recommendations have stated that the duration of antimicrobial therapy should be limited to 4 to 7 days except in situations where the source of infection cannot be adequately controlled. However, it has remained common clinical practice for treating physicians to continue antibiotics for 10 to 14 days, or until the resolution of all abnormal clinical and laboratory parameters. This issue has now been firmly addressed by the recently published multicenter Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial, in which patients with cIAIs and satisfactory source control were randomly assigned to receive antimicrobial therapy for 4 full days (experimental group) or until 2 days (control patients) after the normalization of clinical and laboratory abnormalities (median, 8 days). The primary outcomes of surgical site infections, recurrent IAI or death did not differ between either group, thus supporting shorter courses of antibiotic administration. One criticism of this trial could be its lack of microbiologic and specific treatment information. Shortened treatment courses also provide the added advantages of decreased costs and hopeful prevention of the potential adverse effects and development of resistance associated with unwarranted prolonged antibiotic utilization.

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For more information:
Larry M. Bush, MD, FACP, is an affiliated professor of biomedical sciences at the Charles E. Schmidt College of Medicine, Florida Atlantic University, and affiliated associate professor of medicine at the University of Miami Miller School of Medicine, JFK Medical Center, Palm Beach County, Florida.
Donald Kaye, MD, is a professor of medicine at Drexel University College of Medicine, associate editor of the International Society for Infectious Diseases’ ProMED-mail, section editor of news for Clinical Infectious Diseases and an Infectious Disease News Editorial Board member.

Disclosures: Bush and Kaye report no relevant financial disclosures.