In Vitro Activity of Cefepime-Taniborbactam and Comparators against Clinical Isolates of Gram-Negative Bacilli from 2018 to 2020: Results from the Global Evaluation of Antimicrobial Resistance via Surveillance (GEARS) Program

Abstract

Taniborbactam is a novel cyclic boronate β-lactamase inhibitor in clinical development in combination with cefepime. We assessed the in vitro activity of cefepime-taniborbactam and comparators against a 2018-2020 collection of Enterobacterales (n = 13,731) and Pseudomonas aeruginosa (n = 4,619) isolates cultured from infected patients attending hospitals in 56 countries. MICs were determined by CLSI broth microdilution. Taniborbactam was tested at a fixed concentration of 4 μg/mL. Isolates with cefepime-taniborbactam MICs of ≥16 μg/mL underwent whole-genome sequencing. β-lactamase genes were identified in meropenem-resistant isolates by PCR/Sanger sequencing. Against Enterobacterales, taniborbactam reduced the cefepime MIC₉₀ value by >64-fold (from >16 to 0.25 μg/mL). At ≤16 μg/mL, cefepime-taniborbactam inhibited 99.7% of all Enterobacterales isolates; >97% of isolates with multidrug-resistant (MDR) and ceftolozane-tazobactam-resistant phenotypes; ≥90% of isolates with meropenem-resistant, difficult-to-treat-resistant (DTR), meropenem-vaborbactam-resistant, and ceftazidime-avibactam-resistant phenotypes; 100% of VIM-positive, AmpC-positive, and KPC-positive isolates; 98.7% of extended-spectrum β-lactamase (ESBL)-positive; 98.8% of OXA-48-like-positive; and 84.6% of NDM-positive isolates. Against P. aeruginosa, taniborbactam reduced the cefepime MIC₉₀ value by 4-fold (from 32 to 8 μg/mL). At ≤16 μg/mL, cefepime-taniborbactam inhibited 97.4% of all P. aeruginosa isolates; ≥85% of isolates with meropenem-resistant, MDR, and meropenem-vaborbactam-resistant phenotypes; >75% of isolates with DTR, ceftazidime-avibactam-resistant, and ceftolozane-tazobactam-resistant phenotypes; and 87.4% of VIM-positive isolates. Multiple potential mechanisms, including carriage of IMP, certain alterations in PBP3, permeability (porin) defects, and possibly, upregulation of efflux were present in most isolates with cefepime-taniborbactam MICs of ≥16 μg/mL. We conclude that 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 metallo-β-lactamases (MBLs).

Keywords: Enterobacterales; Gram-negative; Pseudomonas aeruginosa; carbapenem resistant; multidrug resistant; taniborbactam; β-lactamase inhibitor.

FIG 1

Cefepime (white bars) and cefepime-taniborbactam (black bars) MIC frequency distributions for 627 isolates of carbapenemase-positive Enterobacterales. The 627 isolates of carbapenemase-positive Enterobacterales included 230 KPC-positive, 207 NDM-positive, 168 OXA-48 group-positive, and 22 VIM-positive isolates (note: several isolates carried multiple carbapenemases). IMP-positive isolates (n = 6) were excluded from the data set as IMP is outside the spectrum of taniborbactam inhibition.

FIG 2

Occurrence and cooccurrence of mechanisms of antimicrobial resistance identified in 22/24 isolates of E. coli with cefepime-taniborbactam MICs of ≥16 μg/mL. Major porin genes, ompC and ompF, were screened for alterations that code for a truncated, presumably nonfunctional protein. PBP3 sequence mutation includes ftsI sequences predicted to code insertions known to reduce cefepime binding. Predicted efflux upregulation includes genetic changes that likely enhance drug extrusion.

FIG 3

Cefepime (white bars) and cefepime-taniborbactam (black bars) MIC frequency distributions for 216 isolates of carbapenemase-positive P. aeruginosa. The 216 isolates of carbapenemase-positive P. aeruginosa included 159 VIM-positive, 33 GES-positive (GES-5, GES-6, GES-19/20, GES-20 [GES enzymes with reported carbapenemase activity]), and 17 NDM-positive isolates (note: several isolates carried multiple carbapenemases). IMP-positive isolates (n = 33) were excluded from the data set as IMP is outside the spectrum of taniborbactam inhibition.

FIG 4

Occurrence and cooccurrence of mechanisms of antimicrobial resistance identified in 204/267 isolates of P. aeruginosa with cefepime-taniborbactam MICs of ≥16 μg/mL. Resistance factors include the presence of IMP family MBLs, mutation in the ftsI sequence predicted to code for PBP3 variants with reduced cefepime binding, and predicted efflux upregulation that includes genetic changes that likely enhance drug extrusion.