Stability and low induction propensity of cefiderocol against chromosomal AmpC β-lactamases of Pseudomonas aeruginosa and Enterobacter cloacae

Abstract

ObjectivesThe siderophore cephalosporin cefiderocol possesses in vitro activity against MDR Gram-negative bacteria. The stability of cefiderocol against serine- and metallo-type carbapenemases has been reported previously, but little is known about how cefiderocol interacts with chromosomal AmpC β-lactamases. We investigated a number of features of cefiderocol, namely antibacterial activity against AmpC overproducers, stability against AmpC β-lactamases and propensity for AmpC induction using Pseudomonas aeruginosa and Enterobacter cloacae.MethodsMICs were determined by broth microdilution according to CLSI guidelines. The MIC of cefiderocol was determined in iron-depleted CAMHB. Hydrolysis of the antibiotics was determined by monitoring the changes in the absorbance in the presence of AmpC β-lactamase, and AmpC induction was evaluated by double disc diffusion and nitrocefin degradation assays.ResultsThe MICs of ceftazidime and cefepime for PAO1 increased 4- to 16-fold with inactivation of either ampD or dacB, whereas cefiderocol MICs were little affected by these inactivations (<2-fold increase). Cefiderocol has 40- and >940-fold lower affinity (higher Ki) to AmpCs of P. aeruginosa SR24-12 and E. cloacae P99, respectively, compared with ceftazidime. Both disc diffusion and nitrocefin degradation assays indicated that cefiderocol did not induce AmpC β-lactamases of P. aeruginosa PAO1 and ATCC 27853 and E. cloacae ATCC 13047, whereas imipenem did.ConclusionsCefiderocol showed in vitro activity against the AmpC-overproducing strains, low affinity for chromosomal AmpC β-lactamases, and a low propensity of temporal induction of AmpC β-lactamases of P. aeruginosa and E. cloacae. These features relating to chromosomal AmpC could explain the potent antibacterial activity of cefiderocol against drug-resistant strains producing AmpC β-lactamases.

Epidemiology and Treatment of Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa Infections

“…Cefiderocol acts by binding to ferric iron, which enables it to use bacterial iron transporters to penetrate the external bacterial membrane. It also has high stability against ␤-lactamases, including serine-dependent ␤-lactamases and MBLs (317,318). The ability of cefiderocol to neutralize AmpC overproduction, its stability against these enzymes, and its ability to induce AmpC in Enterobacter cloacae and P. aeruginosa have been studied (318).…”

“…It also has high stability against ␤-lactamases, including serine-dependent ␤-lactamases and MBLs (317,318). The ability of cefiderocol to neutralize AmpC overproduction, its stability against these enzymes, and its ability to induce AmpC in Enterobacter cloacae and P. aeruginosa have been studied (318). While the MICs of ceftazidime and cefepime for the P. aeruginosa PAO1 strain increased 4-to 16-fold due to the inactivation of AmpD and DacB, cefiderocol MICs were only slightly affected.…”

Potent Antibiotics Active against Multidrug-Resistant Gram-Negative Bacteria

“…In addition to its broad range of antimicrobial activity, the stability of cefiderocol against β-lactamases, including ESBL, KPC, and NDM-1, has been confirmed. [78][79][80] Cefiderocol has been evaluated in phase III clinical trials 81) and was submitted in a New Drug Application to the FDA in December 2018 and in a Marketing Authorization Application to the European Medicines Agency in March 2019.…”

Cefiderocol: A Novel Agent for the Management of Multidrug-Resistant Gram-Negative Organisms

“…In E. cloacae, enzyme affinities were [ 940-and [ 8fold lower for cefiderocol than for ceftazidime and cefepime, respectively. Double disc diffusion assays performed to detect the propensity for ampC induction of cefiderocol compared to imipenem demonstrated that cefiderocol did not induce ampC b-lactamases in P. aeruginosa or E. cloacae [19].…”