Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-abdominal Infection: Results From a Randomized, Controlled, Double-Blind, Phase 3 Program

Abstract

In this randomized phase 3 trial, ceftazidime-avibactam plus metronidazole was noninferior to meropenem in treating complicated intra-abdominal infection, with similar efficacy against ceftazidime-resistant and ceftazidime-susceptible pathogens and no new safety concerns observed.

The Use of Noncarbapenem β-Lactams for the Treatment of Extended-Spectrum β-Lactamase Infections

“…The MIC 50 /MIC 90 of this agent for ESBL-producing E. coli and K. pneumoniae are 0.12/0.25 µg/mL and 0.5/1 µg/mL, respectively [60]. Similar to ceftolozane-tazobactam, phase 2 [61] and phase 3 studies [62] compared ceftazidime-avibactam (plus metronidazole) vs meropenem for intra-abdominal infections, but did not specifically compare outcomes of ESBL-confirmed pathogens. Data from a phase 3 study comparing ceftazidime-avibactam and doripenem in UTIs showed similar microbiological response for ceftazidime-resistant Enterobacteriaceae, most of which were ESBL producers [63].…”

Ceftazidime/Avibactam: Who Says You Can’t Teach an Old Drug New Tricks?

“…While there were SAEs, the majority of adverse events were mild. (42). The most commonly reported events for ceftazidime/avibactam plus metronidazole were gastrointestinal related (diarrhea, nausea, vomiting) ranging from 4.5-7.6% and fever 4.5%; which was similar to meropenem.…”

“…The RECLAIM 1 and 2 trials are the first phase III clinical trials in which ceftazidime/avibactam was evaluated for the treatment of complicated intraabdominal infections (cIAIs) (42). These trials were identical and combined for submission to the US FDA and European Medicines Agency (EMA).…”

“…Overall, ceftazidime/avibactam appears relatively safe from the completed Phase II and III trials for adult and pediatric patients (40)(41)(42)(43)(44). However, the majority of additional safety concerns are from the avibactam component given significant historical safety data with ceftazidime alone.…”

“…In regards to activity, clinical trials in complicated UTIs and IAIs demonstrated non-inferiority; however, there were several caveats. The first being in cIAIs patients with a CrCl <50 mL/min, where clinical cure was 45.2% for ceftazidime/avibactam plus metronidazole vs 74.3% meropenem in the mMITT group and 72% vs 88% in the CE group at TOC (42). The second concern being no CRE isolates were included in any of the clinical trials.…”