Pharmacokinetics-Pharmacodynamics of Enmetazobactam Combined with Cefepime in a Neutropenic Murine Thigh Infection Model

Abstract

Third-generation cephalosporin (3GC)-resistant Enterobacteriaceae are classified as critical priority pathogens, with extended-spectrum β-lactamases (ESBLs) as principal resistance determinants. Enmetazobactam (formerly AAI101) is a novel ESBL inhibitor developed in combination with cefepime for empirical treatment of serious Gram-negative infections in settings where ESBLs are prevalent. Cefepime-enmetazobactam has been investigated in a phase 3 trial in patients with complicated urinary tract infections or acute pyelonephritis. This study examined pharmacokinetic-pharmacodynamic (PK-PD) relationships of enmetazobactam, in combination with cefepime, for ESBL-producing isolates of Klebsiella pneumoniae in 26-h murine neutropenic thigh infection models. Enmetazobactam dose fractionation identified the time above a free threshold concentration (fT > CT) as the PK-PD index predictive of efficacy. Nine ESBL-producing isolates of K. pneumoniae, resistant to cefepime and piperacillin-tazobactam, were included in enmetazobactam dose-ranging studies. The isolates encoded CTX-M-type, SHV-12, DHA-1, and OXA-48 β-lactamases and covered a cefepime-enmetazobactam MIC range from 0.06 to 2 μg/ml. Enmetazobactam restored the efficacy of cefepime against all isolates tested. Sigmoid curve fitting across the combined set of isolates identified enmetazobactam PK-PD targets for stasis and for a 1-log10 bioburden reduction of 8% and 44% fT > 2 μg/ml, respectively, with a concomitant cefepime PK-PD target of 40 to 60% fT > cefepime-enmetazobactam MIC. These findings support clinical dose selection and breakpoint setting for cefepime-enmetazobactam.

Antimicrobial Resistance Conferred by OXA-48 β-Lactamases: Towards a Detailed Mechanistic Understanding

“…An example of a β-lactam inhibitor is enmetazobactam, which is a penicillanic acid sulfone currently developed in combination with cefepime. 92,93 This combination was found to be effective against OXA-48 producers, but the efficacy is most likely again attributed to the activity of cefepime and not to efficient inhibition by enmetazobactam, which is active primarily against ESBLs. 93,94 On the other hand, boronates show promise as broad-spectrum β-lactamase inhibitors.…”

“…92,93 This combination was found to be effective against OXA-48 producers, but the efficacy is most likely again attributed to the activity of cefepime and not to efficient inhibition by enmetazobactam, which is active primarily against ESBLs. 93,94 On the other hand, boronates show promise as broad-spectrum β-lactamase inhibitors. In particular, cyclic boronates can act as analogues of the tetrahedral acylation transition state of SBLs, 95 and have potential for at least moderate activity against MBLs.…”

Pharmacokinetics and pharmacodynamics of enrofloxacin treatment of Escherichia coli in a murine thigh infection modeling

“…The correlation between the host, pathogens, and the drug is usually determined via the neutropenic mice thigh infection model [ 10 , 11 ]. The stability, maturity, and avoidance of the host immune system’s impact on the antibacterial effect are all major advantages of this model.…”

Studies on enmetazobactam clarify mechanisms of widely used β-lactamase inhibitors

“…In accord with prior studies ( 20 , 34 ), we observed only small differences in potency for enmetazobactam compared to the closely related tazobactam ( SI Appendix , Tables S1–S3 ). The reported significantly enhanced potential of enmetazobactam against class A ESBLs in cells ( 33 , 34 ) and in vivo ( 41 ) may thus result from improved properties with respect to variables other than potency against isolated SBLs, e.g., outer membrane permeability or efflux pump susceptibility.…”