Ceftolozane/Tazobactam Plus Metronidazole for Complicated Intra-abdominal Infections in an Era of Multidrug Resistance: Results From a Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI)

Abstract

This phase 3 trial compared ceftolozane/tazobactam plus metronidazole vs meropenem for the treatment of complicated intra-abdominal infections. Ceftolozane/tazobactam plus metronidazole was noninferior to meropenem. High rates of presumed microbiological eradication of Enterobacteriaceae and Pseudomonas aeruginosa were found with both regimens.

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

“…Ceftolozane-tazobactam (in combination with metronidazole) was compared to meropenem for the treatment of complicated intra-abdominal infections in phase 2 [58] and phase 3 [59] trials that included 4 and 50 people, respectively, with ESBL-producing Enterobacteriaceae. Although the limited number of ESBLs precluded a robust analysis, this compound performed similarly against ESBL-producing and non-ESBL producing isolates.…”

What is the role of the new β-lactam/β-lactamase inhibitors ceftolozane/tazobactam and ceftazidime/avibactam?

“…In both studies, the non-inferiority end point (cure rate) was reached and the drugs were generally well tolerated [27,28]. Notably, cure rates were lower in patients with moderate kidney damage (creatinine clearance between 30 and 50 ml/min): this was probably because the reduced dose of BLBLI given to patients with renal failure was not appropriate, nor were subsequent posological changes, namely increasing the dose as renal function improved [27,28]. The non-inferiority of CAZ/AVI plus metronidazole versus meropenem was confirmed in a pooled analysis of two identical phase III clinical trials involving 1066 patients affected by cIAIs [29].…”

“…In the CAZ/AVI trial, which enrolled a small sample (135 patients), microbiological and clinical responses were comparable in the active versus comparator arm, and CAZ/AVI was well tolerated [25]. In the case of cIAIs, both TOL/TAZ and CAZ/AVI combined with metronidazole were compared with meropenem in two trials: 816 patients in the first [27] and 203 in the second (a phase II study) [28]. In both studies, the non-inferiority end point (cure rate) was reached and the drugs were generally well tolerated [27,28].…”

“…In the case of cIAIs, both TOL/TAZ and CAZ/AVI combined with metronidazole were compared with meropenem in two trials: 816 patients in the first [27] and 203 in the second (a phase II study) [28]. In both studies, the non-inferiority end point (cure rate) was reached and the drugs were generally well tolerated [27,28]. Notably, cure rates were lower in patients with moderate kidney damage (creatinine clearance between 30 and 50 ml/min): this was probably because the reduced dose of BLBLI given to patients with renal failure was not appropriate, nor were subsequent posological changes, namely increasing the dose as renal function improved [27,28].…”

Bacterial sepsis

“…MRSAcIAI is then additionally treated with vancomycin, tigecycline, or linezolid [183]. New escalation variations include ceftolozane/tazobactam or ceftazidime/ avibactam [184,185] in combination with metronidazole for cIAI with resistant gram-negative pathogens [186]. Provided effective surgical control of the infection is achieved and the patient's clinical condition improves, a treatment duration of 4-7 days is sufficient [149,153,183].…”