P-1079. Evaluation of cefepime/zidebactam (FPZ) dynamics in vitro using clinical Pseudomonas aeruginosa strains obtained from a patient treated with FPZ

TL;DR

This study evaluates how a new antibiotic combination works against drug-resistant Pseudomonas aeruginosa strains from a patient, showing it may still be effective even when resistance increases.

Contribution

The study provides novel insights into the pharmacodynamic activity of cefepime/zidebactam in strains with evolving high MICs.

Findings

FPZ MICs increased from 16 to >512 during treatment, but zidebactam MSCs remained 8-fold lower than MICs.

Strains with high FPZ MICs showed MECs near MIC values, suggesting retained bactericidal activity.

The study highlights the importance of analyzing PK/PD dynamics beyond MIC breakpoints for drug-resistant strains.

Abstract

Multidrug-resistant P. aeruginosa infections are a major global public health threat, often leaving clinicians with few to no treatment options. Here, we evaluated the activity of cefepime-zidebactam (FPZ), a novel β-lactam/β-lactam-enhancer agent, against 8 metallo-β-lactamase (NDM) producing P. aeruginosa strains longitudinally isolated from a patient treated with FPZ under compassionate use.

In 2024, the Clinical Laboratory and Standards Institute set an investigational, susceptible FPZ MIC breakpoint of ≤64µg/ml for P. aeruginosa, Acinetobacter and Enterobacterales. However, an FPZ MIC is only a proxy of the cefepime minimum elongation concentration (MEC) and zidebactam minimum spheroplast-forming concentration (MSC). Rather than FPZ MICs, MSCs and MECs drive pharmacokinetic/ pharmacodynamic (PK/PD) parameters. Additionally, there is a lack of in vitro, in vivo and clinical data on P. aeruginosa isolates with FPZ MICs >64.

Here, we tested 8 serial patient isolates showing a progressive increase in FPZ MICs on treatment. We aimed to assess correlation between FPZ pharmacodynamics and MIC values generated by reference antimicrobial susceptibility testing.

FPZ MICs of isolates were determined by broth microdilution per CLSI guidelines. Microscopy was used to determine cefepime MECs and zidebactam MSCs (i.e., morphological changes visualized after treating 106 CFU/mL of cells with each agent for 3h).

The isolates, except the index strain, were non-susceptible to all FDA-approved agents, including cefiderocol, ceftolozane/tazobactam, and ceftazidime/avibactam. FPZ MICs ranged from 16 to >512 over treatment. Strains with FPZ MICs of 16-32, which were isolated before FPZ therapy, had MECs of 64-128 (4x the MIC) and MSCs of 8-16 (1/2x the MIC). Strains with MICs of 128->512, which were isolated at the end of FPZ therapy, had MECs of 128-512 (near MIC) and MSCs of 16-128 (1/8x the MIC).

At high FPZ MICs, zidebactam MSCs remain 8-fold lower than MICs. This suggests that FPZ may retain bactericidal activity even when MICs exceed the investigational susceptibility breakpoint of 64. This study provides insight into FPZ's therapeutic potential and highlights the importance of dissecting PK/PD dynamics in strains showing evolution of high MICs.

All Authors: No reported disclosures