1598. Antimicrobial Activity of the Novel β-Lactam Enhancer Combination Cefepime–Zidebactam (WCK-5222) Tested Against Gram-Negative Bacteria Isolated in United States Medical Centers from Patients with Bloodstream Infections

Abstract

BackgroundZidebactam (ZID) is a β-lactam enhancer antibiotic with a dual mechanism of action: high binding affinity to gram-negative PBP2 and β-lactamase (BL) inhibition. We evaluated the activity of cefepime (FEP) combined with ZID against contemporary clinical isolates of gram-negative bacilli (GNB) causing bloodstream infections (BSIs) in the US hospitals.Methods1,239 GNB were consecutively collected (1/patient) from 34 US medical centers in 2018. Susceptibility (S) testing against FEP-ZID (1:1 ratio) and comparators were performed by reference broth microdilution method in a central laboratory. The FEP S breakpoint of ≤ 8 mg/L (CLSI, high dose) was applied to FEP-ZID for comparison purposes. An FEP-ZID S breakpoint of ≤ 64 mg/L has been proposed for non-fermentative GNB based on pharmacokinetic/pharmacodynamic target attainment and was also applied. Selected Enterobacterales (ENT) isolates were evaluated by whole-genome sequencing.ResultsFEP-ZID was highly active against ENT (MIC50/MIC90, 0.03/0.12 mg/L; highest MIC, 4 mg/L; Table), including multidrug-resistant (MDR, MIC50/MIC90, 0.12/0.25 mg/L) and carbapenem-resistant isolates (n = 7; MIC50, 0.5 mg/L). The highest FEP-ZID MIC values among E. coli, K. pneumoniae, and E. cloacae were 1, 2, and 0.25 mg/L, respectively. The most active comparators tested against MDR ENT were ceftazidime–avibactam (CAZ-AVI; MIC50/MIC90, 0.25/1 mg/L; 98.0%S), meropenem (MEM; MIC50/MIC90, 0.03/0.12 mg/L; 93.1%S) and amikacin (AMK; MIC50/MIC90, 4/16 mg/L; 92.1%S). The most active agents tested against P. aeruginosa were FEP-ZID (MIC50/MIC90, 1/4 mg/L; highest MIC, 8 mg/L), colistin (MIC50/MIC90, 0.5/1 mg/L; 100.0%S), and AMK (MIC50/MIC90, 4/8 mg/L; 99.2%S); whereas CAZ-AVI and ceftolozane–tazobactam were active against 96.5–96.7% of isolates. FEP-ZID exhibited good activity against Acinetobacter spp. (MIC50/MIC90, 2/8 mg/L) and S. maltophilia (MIC50/MIC90, 4/32 mg/L). S. maltophilia displayed low S rates to most comparators.ConclusionFEP-ZID demonstrated potent activity against a large collection GNB from BSI, including isolates resistant to other BL inhibitor combinations and/or carbapenems. These results support further clinical development of FEP-ZID. Disclosures All authors: No reported disclosures.