Cefepime-taniborbactam activity against antimicrobial-resistant clinical isolates of Enterobacterales and Pseudomonas aeruginosa: GEARS global surveillance programme 2018-22

Abstract

Objectives: Taniborbactam is a boronate-based β-lactamase inhibitor in clinical development in combination with cefepime.

Methods: Cefepime-taniborbactam and comparator broth microdilution MICs were determined for patient isolates of Enterobacterales (n = 20 725) and Pseudomonas aeruginosa (n = 7919) collected in 59 countries from 2018 to 2022. Taniborbactam was tested at a fixed concentration of 4 mg/L. Isolates with cefepime-taniborbactam MICs ≥ 16 mg/L underwent WGS. β-Lactamase genes were identified in additional meropenem-resistant isolates by PCR/Sanger sequencing.

Results: Taniborbactam reduced the cefepime MIC90 value for all Enterobacterales from >16 to 0.25 mg/L (>64-fold). At ≤16 mg/L, cefepime-taniborbactam inhibited 99.5% of all Enterobacterales isolates; >95% of isolates with MDR and ceftolozane-tazobactam-resistant phenotypes; ≥ 89% of isolates with meropenem-resistant and difficult-to-treat-resistant (DTR) phenotypes; >80% of isolates with meropenem-vaborbactam-resistant and ceftazidime-avibactam-resistant phenotypes; 100% of KPC-positive, 99% of OXA-48-like-positive, 99% of ESBL-positive, 97% of acquired AmpC-positive, 95% of VIM-positive and 76% of NDM-positive isolates. Against P. aeruginosa, taniborbactam reduced the cefepime MIC90 value from 32 to 8 mg/L (4-fold). At ≤16 mg/L, cefepime-taniborbactam inhibited 96.5% of all P. aeruginosa isolates; 85% of meropenem-resistant phenotype isolates; 80% of isolates with MDR and meropenem-vaborbactam-resistant phenotypes; >70% of isolates with DTR, ceftazidime-avibactam-resistant and ceftolozane-tazobactam-resistant phenotypes; and 82% of VIM-positive isolates. Multiple potential mechanisms of resistance, including carriage of IMP, or alterations in PBP3 (ftsI), porins (decreased permeability) and efflux (up-regulation) were present in most isolates with cefepime-taniborbactam MICs ≥ 16 mg/L.

Conclusions: Cefepime-taniborbactam exhibited potent in vitro activity against Enterobacterales and P. aeruginosa, and inhibited most carbapenem-resistant isolates, including those carrying serine carbapenemases or NDM/VIM MBLs.

Figure 1.

In vitro activity of cefepime–taniborbactam^a and comparator agents^b against carbapenem-resistant^c clinical isolates of Enterobacterales (CRE) and P. aeruginosa (CRPA) stratified by the presence and absence of molecularly identified carbapenemases. ^aFor comparative purposes only, % susceptible values for cefepime–taniborbactam correspond to the percentage of isolates inhibited at ≤16 mg/L. ^bCLSI and EUCAST susceptible breakpoints for ceftazidime–avibactam and ceftolozane–tazobactam are harmonized. As CLSI does not publish breakpoints for meropenem–vaborbactam against P. aeruginosa, the EUCAST susceptible breakpoint is used. ^cCarbapenem-resistant phenotypes for Enterobacterales and P. aeruginosa were based on meropenem susceptibility using CLSI 2023 breakpoints. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 2.

Global region diversity of carbapenemases detected among meropenem-resistant Enterobacterales^a. ^aIsolates that carried multiple carbapenemases were counted for each carbapenemase type. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 3.

Global region diversity of carbapenemases detected among meropenem-resistant P. aeruginosa^a. ^aIsolates that carried multiple carbapenemases were counted for each carbapenemase type. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.