Evaluating Empiric Treatment Options for Secondary Peritonitis Using Pharmacodynamic Profiling

Abstract

Selecting an appropriate agent for empiric antibiotic therapy for secondary peritonitis is challenging. The pathogens responsible, aerobic gram-negative bacilli in particular, are becoming more resistant to antibiotics. The purpose of this study was to predict the ability of common antimicrobial regimens to achieve optimal pharmacodynamic exposure against aerobic bacteria implicated in secondary peritonitis, while considering current national resistance trends. Monte Carlo simulation was used to model pharmacodynamic endpoints and compare the cumulative fraction of response (CFR) for imipenem-cilastatin, meropenem, ertapenem, piperacillin/tazobactam, ceftazidime, ceftriaxone, ciprofloxacin, and levofloxacin against isolates of species associated with secondary peritonitis. Minimum inhibitory concentration (MIC) distributions for isolates collected in North America were obtained from the 2004 MYSTIC database. Pharmacokinetic parameters were derived from the literature; the endpoints evaluated included free drug time above the MIC (fT(>MIC)) and the area under the concentration-time curve to MIC ratio (AUC:MIC). The simulation predicted that several compounds would have a superior probability of providing appropriate coverage of aerobic bacteria: Imipenem-cilastatin (98.6% CFR at 1 g q8h), meropenem (98.2% CFR at 1 g q8h), ertapenem (91.7% CFR at 1 g q24h), piperacillin/ tazobactam (93.7% CFR at 3.375 g q6h), ceftazidime (91.1% CFR at 2 g q8h), and cefepime (92.9% CFR at 1 g q12h and 95.8% CFR at 2 g q12h). Ceftriaxone, ciprofloxacin, and levofloxacin exhibited CFRs < 82%. Considering contemporary susceptibility data for aerobic bacteria, monotherapy with any of the three carbapenems or piperacillin/tazobactam 3.375 g q6h would provide optimal exposure for the pathogens commonly encountered in secondary peritonitis. Cefepime (in combination with metronidazole to provide anti-anaerobic coverage) also would be an acceptable choice, as would ceftazidime given at 2 g q8h (again in combination with metronidazole). Despite the popularity of combination therapy based on ciprofloxacin, levofloxacin, or ceftriaxone with metronidazole, these choices appear to be inferior to the other options because of emerging antibiotic resistance, particularly in E. coli.