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

Background Cefiderocol is a last resort option for carbapenem-resistant (CR) Gram-negative bacteria, especially metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa and CR Acinetobacter baumannii. Monitoring global levels of cefiderocol non-susceptibility (CFDC-NS) is important.

Objectives To systematically collate and examine studies investigating in-vitro CFDC-NS and estimate the global prevalence of CFDC-NS against major Gram-negative pathogens. Data sources PubMed and Scopus, up to May 2023. Study eligibility criteria Eligible were studies reporting CFDC-NS in Enterobacterales, P. aeruginosa, A. baumannii, or Stenotrophomonas maltophilia clinical isolates.

Methods Two independent reviewers extracted study data and assessed risk of bias on the population, setting and measurement (susceptibility testing) domains. Binomial-Normal mixed-effects models were applied to estimate CFDC-NS prevalence by species, co-resistance phenotype and breakpoint definition (EUCAST, CLSI, FDA). Sources of heterogeneity were investigated by subgroup and meta-regression analyses.

Results In 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 NDM-producing Enterobacterales (38.8%, 95%CI 22.6-58.0%), NDM-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.

Conclusions CFDC-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.