Global prevalence of cefiderocol non-susceptibility in Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia: a systematic review and meta-analysis

Abstract

BackgroundCefiderocol is a last resort option for carbapenem-resistant (CR) Gram-negative bacteria, especially metallo-β-lactamase-producing Pseudomonas aeruginosa and CR Acinetobacter baumannii. Monitoring global levels of cefiderocol non-susceptibility (CFDC-NS) is important. ObjectivesTo systematically collate and examine studies investigating in vitro CFDC-NS and estimate the global prevalence of CFDC-NS against major Gram-negative pathogens. Data sourcesPubMed and Scopus, up to May 2023. Study eligibility criteriaEligible were studies reporting CFDC-NS in Enterobacterales, P. aeruginosa, A. baumannii, or Stenotrophomonas maltophilia clinical isolates. Risk-of-bias assessmentTwo independent reviewers extracted study data and assessed the risk of bias on the population, setting, and measurement (susceptibility testing) domains. Data synthesisBinomial-Normal mixed-effects models were applied to estimate CFDC-NS prevalence by species, coresistance phenotype, and breakpoint definition (EUCAST, CLSI, and FDA). Sources of heterogeneity were investigated by subgroup and meta-regression analyses. ResultsIn all, 78 studies reporting 82 035 clinical isolates were analysed (87% published between 2020 and 2023). CFDC-NS prevalence (EUCAST breakpoints) was low overall but varied by species (S. maltophilia 0.4% [95% CI 0.2–0.7%], Enterobacterales 3.0% [95% CI 1.5–6.0%], P. aeruginosa 1.4% [95% CI 0.5–4.0%]) and was highest for A. baumannii (8.8%, 95% CI 4.9–15.2%). CFDC-NS was much higher in CR Enterobacterales (12.4%, 95% CI 7.3–20.0%) and CR A. baumannii (13.2%, 95% CI 7.8–21.5%), but relatively low for CR P. aeruginosa (3.5%, 95% CI 1.6–7.8%). CFDC-NS was exceedingly high in New Delhi metallo-β-lactamase-producing Enterobacterales (38.8%, 95% CI 22.6–58.0%), New Delhi metallo-β-lactamase-producing A. baumannii (44.7%, 95% CI 34.5–55.4%), and ceftazidime/avibactam-resistant Enterobacterales (36.6%, 95% CI 22.7–53.1%). CFDC-NS varied considerably with breakpoint definition, predominantly among CR bacteria. Additional sources of heterogeneity were single-centre investigations and geographical regions. ConclusionsCFDC-NS prevalence is low overall, but alarmingly high for specific CR phenotypes circulating in some institutions or regions. Continuous surveillance and updating of global CFDC-NS estimates are imperative while cefiderocol is increasingly introduced into clinical practice. The need to harmonize EUCAST and CLSI breakpoints was evident.