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Annals of Surgery:
Original Articles

Ertapenem Versus Piperacillin/Tazobactam in the Treatment of Complicated Intraabdominal Infections: Results of a Double-Blind, Randomized Comparative Phase III Trial

Solomkin, Joseph S. MD*; Yellin, Albert E. MD†; Rotstein, Ori D. MD‡; Christou, Nicolas V. MD§; Dellinger, E. Patchen MD¶; Tellado, Jose M. MD∥; Malafaia, Osvaldo MD|; Fernandez, Alvaro MD#; Choe, Kyuran A. MD*; Carides, Alexandra PhD**; Satishchandran, Vilas MS**; Teppler, Hedy MD**; the Protocol 017 Study Group

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Abstract

Objective: To examine the clinical efficacy and safety of ertapenem, a novel β-lactam agent with wide activity against common pathogens encountered in intraabdominal infection.

Summary Background Data: Ertapenem has a pharmacokinetic profile and antimicrobial spectrum that support the potential for use as a once-a-day agent for the treatment of common mixed aerobic and anaerobic infections.

Methods: This prospective, randomized, controlled, and double-blind trial was conducted to compare the safety and efficacy of ertapenem with piperacillin/tazobactam as therapy following adequate surgical management of complicated intraabdominal infections.

Results: Six hundred thirty-three patients were included in the modified intent-to-treat population, with 396 meeting all criteria for the evaluable population. Patients with a wide range of infections were enrolled; perforated or abscessed appendicitis was most common (approximately 60% in microbiologically evaluable population). A prospective, expert panel review was conducted to assess the adequacy of surgical source control in patients who were failures as a component of evaluability. For the modified intent-to-treat groups, 245 of 311 patients treated with ertapenem (79.3%) were cured, as were 232 of 304 (76.2) treated with piperacillin/tazobactam. One hundred seventy-six of 203 microbiologically evaluable patients treated with ertapenem (86.7%) were cured, as were 157 of the 193 (81.2%) treated with piperacillin/tazobactam.

Conclusions: In this study, the efficacy of ertapenem 1 g once a day was equivalent to piperacillin/tazobactam 3.375 g every 6 hours in the treatment of a range of intraabdominal infections. Ertapenem was generally well tolerated and had a similar safety and tolerability profile to piperacillin/tazobactam. A formal process for review of adequacy of source control was found to be of benefit. The results of this trial suggest that ertapenem may be a useful option that could eliminate the need for combination and/or multidosed antibiotic regimens for the empiric treatment of intraabdominal infections.

Complicated intraabdominal infections (i.e., those requiring both operative drainage and antimicrobial therapy) are among the most common infections in general surgery. Antimicrobial therapy is an important element in the management of these infections; there are convincing data that absent or inadequate empiric antibiotic therapy results in both increased failure rates and increased mortality. 1–4 The infecting flora seen with community-acquired intraabdominal infections is well known and consists of aerobic, facultative, and anaerobic gram-negative bacilli, various streptococci and enterococci, and a plethora of gram-positive anaerobes. 5–7 The synergistic interactions between endotoxin-bearing gram-negative organisms and Bacteroides fragilis define both groups as important targets for antimicrobial therapy. 8

Ertapenem (formerly MK-0826, Merck & Co., Inc.) is being investigated as a once-a-day parenteral β-lactam antimicrobial agent with the potential for use as monotherapy for the treatment of community-acquired mixed flora infections. This approach is based on its spectrum of activity, previously reported clinical studies that used once-a-day dosing, pharmacodynamic studies in animals, and pharmacokinetic studies in both humans and animals. 9,10 Ertapenem is highly active in vitro against gram-positive and gram-negative aerobic, facultative, and anaerobic bacteria, including the predominant pathogens responsible for intraabdominal infections. 11–13 However, it provides limited coverage against Pseudomonas aeruginosa, Acinetobacter spp, and enterococci, organisms generally associated with nosocomial infections.

The primary objectives of this study were to determine the clinical and microbiologic efficacy and safety of ertapenem for patients with complicated intraabdominal infections. The comparative agent was piperacillin/tazobactam, a β-lactam/β-lactamase inhibitor combination agent that has been well studied and is approved in the treatment of intraabdominal infection. 14 This agent is typically administered at 3.375 g every 6 hours in the United States.

This study also provided an opportunity to analyze an additional element of clinical trial design, the adequacy of surgical source control. Inadequate control of infection, through either incomplete drainage or incomplete management of enteric perforations, is an independent risk factor for treatment failure. 15,16 An expert panel review process was conducted to examine, under blinded conditions, the adequacy of surgical source control as a component of evaluability in a prospectively generated and well-documented group of patients.

© 2003 Lippincott Williams & Wilkins, Inc.

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