Comparative efficacy of BMS-284756, a new fluoroquinolone, versus established antimicrobial regimens for the treatment of experimental intra-abdominal sepsis in rats

Abstract

Background: BMS-284756 is a new des-fluoro-(6)-quinolone with broad anti-microbial activity against gram-negative and gram-positive facultative and obligately anaerobic bacteria, including certain quinolone-resistant organisms. Objective: The purpose of this animal study was to examine the efficacy of BMS-284756 in a rat model of intra-abdominal sepsis. Methods: Five groups of 20 rats each were implanted with a gelatin capsule containing a mixed aerobe/anaerobe inoculum derived from the cecal contents of meat-fed rats. The inoculum was quantitatively and qualitatively examined to ensure that appropriate microbial species were present. Group 1 served as saline-treated controls; Group 2 received BMS-284756, 4 mg/d; Group 3 received BMS-284756, 9 mg/d; Group 4 received ampicillin plus sulbactam 77 mg TID; and Group 5 received a combination of gentamicin 2 mg TID plus clindamycin 15 mg TID. Dosage was determined for all antimicrobial agents based on peak and trough serum levels observed in previous tests, adjusting animal dosages according to a body surface area/body weight ratio and comparing these doses and levels to those from studies in humans. The end points were mortality during the first 2 to 4 days after initiation of sepsis and incidence of intraabdominal abscesses noted at necropsy. Results: The mortality rate was 65% in the control group versus 0% in the treatment groups ( P < 0.001). The incidence of abscess in survivors was 100% in the control group versus 10%, 10%, 5%, and 15% in Groups 2, 3, 4, and 5, respectively ( P < 0.001 vs control), with no significant differences between treatment groups. Conclusions: BMS-284756 is as effective as other established therapeutic regimens in reducing both mortality and the incidence of intra-abdominal abscesses in this animal model. These data suggest that BMS-284756 is an effective treatment for mixed intra-abdominal infections that involve both obligate anaerobes and facultative bacterial species.