Synergistic Effect of Clinically Available Beta-Lactamase Inhibitors Combined with Cefiderocol against Carbapenemase-Producing Gram-Negative Organisms

Abstract

The role of β-lactamases in reduced susceptibility or resistance to cefiderocol has been supported by recent reports. The purpose of this study was to investigate the in vitro impact of clinically available β-lactamase inhibitors on cefiderocol activity against characterized carbapenemase-producing Gram-negative isolates. A collection of 39 well-characterized Gram-negative isolates obtained from various clinical sources and countries were included. Cefiderocol antimicrobial susceptibility was evaluated via reference broth microdilution. The chequerboard microdilution method and time–kill assays were used to determine the synergy of tazobactam, avibactam, vaborbactam and relebactam in combination with cefiderocol. MICs of cefiderocol presented a 4- to 256-fold reduction against Klebsiella pneumoniae carbapenemase (KPC)-producing Gram-negative isolates (predominantly K. pneumoniae) when avibactam, vaborbactam and relebactam were combined individually. Notably, the KPC-inhibitors led to a 4- to 32-fold reduction in cefiderocol MICs in the four cefiderocol-resistant KPC-producing K. pneumoniae isolates, showing restoration of cefiderocol susceptibility (MIC ≤ 2 mg/L) in ten out of twelve cases. Tazobactam led to a 4- to 64-fold decrease in cefiderocol MICs only in K. pneumoniae strains harbouring blaKPC-41, blaKPC-31, blaKPC-53 and blaKPC-66. The synergistic effect of all serine-β-lactamase inhibitors on cefiderocol activity was also shown in OXA-48-like-producing Enterobacterales strains. Conversely, a combination of β-lactamases inhibitors with cefiderocol was not synergistic with all OXA-23-like-producing strains and most metallo-β-lactamases producers. In conclusion, the addition of clinically available serine β-lactamase inhibitors to cefiderocol might represent an important development in the formulation to increase its spectrum and therapeutic efficacy, and to limit in vivo resistance emergence.

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

“…In line with the current metaanalysis, a prior systematic review on mechanisms of CFDC-NS by the same authors, identified several β-lactamases (and various other mechanisms) that may result in higher MIC of cefiderocol, notably NDM and KPC variants conferring resistance for CZA [6]. Of interest, combination of cefiderocol with β-lactamases may be able to overcome resistance [6,110].…”

Treatment of critically ill patients with cefiderocol for infections caused by multidrug-resistant pathogens: review of the evidence

“…Moreover, disk diffusion can also be affected by remarkable variability depending on the various combinations of disks and agar media manufacturers [34,37]. Additional commercial systems for cefiderocol susceptibility testing have recently been developed, and evaluations of the available systems are underway with variable results [39][40][41][42][43].…”

Exploring Beta-Lactamase Inhibitory Potential of Common Medicinal Plants

“…The plant extract exhibiting highest synergistic activities was subjected to the time-kill assay to further analyze its β-Lactam amplifying potentials (López-Malo et al, 2020;Bianco et al, 2022). For this purpose, 200µl of MH broth, 20µl of meropenem, 10µl of Green tea extract and 20µl of freshly prepared bacterial culture in nutrient broth were added to the wells of microtiter plate.…”