Cefepime-Zidebactam (WCK 5222) Activity Tested against Gram-negative Organisms Causing Bloodstream Infections Worldwide

Abstract

Background

Zidebactam (ZID), a bicyclo-acyl hydrazide, is a β-lactam enhancer with a dual mechanism of action involving selective and high binding affinity to Gram-negative (GN) PBP2 and β-lactamase inhibition. We evaluated the in vitro activity of cefepime (FEP) combined with ZID against GN organisms causing bloodstream infections (BSI) in hospitals worldwide.

Methods

A total of 2,094 isolates from 105 medical centers were evaluated. Isolates were collected from Europe (1,050), USA (331), Latin America (LA; 200) and the Asia-Pacific region (AP; 393) in 2015, and China (120) in 2013 by the SENTRY Program. Susceptibility (S) testing was performed by reference broth microdilution method against FEP-ZID (1:1 ratio) and comparators. The collection included 1,809 Enterobacteriaceae (ENT), 170 P. aeruginosa (PSA) and 115 Acinetobacter spp. (ASP).

Results

FEP-ZID was very active against ENT (MIC_50/90 of ≤0.03/0.12 μg/mL) with 99.9 and 100.0% of isolates inhibited at ≤4/4 and ≤8/8 μg/mL, respectively, and retained potent activity against carbapenem-resistant (CRE; n = 44; MIC_50/90, 1/4 μg/mL), multidrug-resistant (MDR), and extensively drug-resistant (XDR) isolates (Table). Amikacin (AMK; MIC_50/90, 2/4 μg/mL; 97.7% S) was also very active against ENT, and colistin (COL; MIC_50/90, 0.12/>8 μg/mL) inhibited only 87.3% of isolates at ≤2 μg/mL. FEP-ZID was highly active against PSA, including isolates resistant to other antipseudomonal β-lactams, MDR (MIC_50/90, 4/8 μg/mL) and XDR (MIC_50/90, 4/8 μg/mL) isolates. Among the comparators, COL (MIC_50/90 of ≤0.5/1 μg/mL; 100.0% S) and AMK (MIC_50/90, 4/16 μg/mL; 91.2% S) were the most active agents against PSA. FEP-ZID (MIC_50/90, 16/32 μg/mL) was 4-fold more active than FEP against ASP.

Conclusion

FEP-ZID (WCK 5222) exhibited potent in vitro activity against a large worldwide collection of GN isolates from BSI, including MDR and XDR isolates. These results support further clinical development of WCK 5222 for treating BSI.

Disclosures

H. S. Sader, Wockhardt Bio Ag: Research Contractor, Research grant; M. Castanheira, Wockhardt Bio Ag: Research Contractor, Research grant; J. M. Streit, Wockhardt Bio Ag: Research Contractor, Research grant; L. R. Duncan, Wockhardt Bio Ag: Research Contractor, Research grant; R. K. Flamm, Wock: Research Contractor, Research support