A systematic review and individual bacterial species level meta-analysis of in vitro studies on the efficacy of ceftazidime/avibactam combined with other antimicrobials against carbapenem-resistant Gram-negative bacteria

Getnet M Assefa; Jason A Roberts; Abdullah T Aslan; Solomon A Mohammed; Fekade B Sime

doi:10.1093/jac/dkae451

A systematic review and individual bacterial species level meta-analysis of in vitro studies on the efficacy of ceftazidime/avibactam combined with other antimicrobials against carbapenem-resistant Gram-negative bacteria

J Antimicrob Chemother. 2024 Dec 17:dkae451. doi: 10.1093/jac/dkae451. Online ahead of print.

Authors

Getnet M Assefa^{1

2}, Jason A Roberts^{1

3

4

5

6}, Abdullah T Aslan¹, Solomon A Mohammed^{1

2}, Fekade B Sime¹

Affiliations

¹ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
² Department of Pharmacy, College of Medicine and Health Sciences, Wollo University, Dessie, Ethiopia.
³ Pharmacy Department, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
⁴ Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
⁵ Herston Infectious Disease Institute (HeIDI), Metro North Health, Brisbane, QLD, Australia.
⁶ Division of Anaesthesiology Critical Care Emerging and Pain Medicine, Nimes University Hospital, University of Montpellier, Nimes, France.

PMID: 39691958
DOI: 10.1093/jac/dkae451

Abstract

Background: Carbapenem-resistant Gram-negative bacteria (CR-GNB) develop resistance to many antimicrobials. To effectively manage infections caused by these organisms, novel agents and/or combinations of antimicrobials are required.

Objectives: Evaluated the in vitro efficacy of ceftazidime/avibactam in combination with other antimicrobials against CR-GNB.

Methods: PubMed, Web of Science, Embase and Scopus were searched. Study outcomes were quantified by counting the number of isolates exhibiting synergy, defined as a fractional inhibitory concentration index ≤ 0.5 for checkerboard and Etest, and a >2 log cfu/mL reduction for time-kill studies. The proportion of synergy was calculated as the ratio of isolates exhibiting synergy to the total number of isolates tested. These proportions were analysed using a random-effects model, following the Freeman-Tukey double-arcsine transformation.

Results: Forty-five in vitro studies were included. A total of 734 isolates were tested, and 69.3% of them were resistant to ceftazidime/avibactam. The combination of ceftazidime/avibactam with aztreonam showed a high synergy rate against carbapenem-resistant Klebsiella pneumoniae (effect size, ES = 0.91-0.98) and Escherichia coli (ES = 0.75-1.00). Ceftazidime/avibactam also demonstrated a high synergy rate (ES = 1) in time-kill studies when combined with azithromycin, fosfomycin and gentamicin against K. pneumoniae. Compared to ceftazidime/avibactam alone, a higher bactericidal rate was reported when ceftazidime/avibactam was combined with other antimicrobials against carbapenem-resistant K. pneumoniae (57% versus 31%) and E. coli (93% versus 0%).

Conclusions: Ceftazidime/avibactam frequently demonstrates synergistic bactericidal activity when combined with various antimicrobials against CR-GNB in in vitro tests. Further pre-clinical and clinical studies are warranted to validate the utility of ceftazidime/avibactam-based combination regimens for CR-GNB infections.