1370. Cefepime/VNRX-5133 Broad-Spectrum Activity Is Maintained Against Emerging KPC- and PDC-Variants in Multidrug-Resistant K. pneumoniae and P. aeruginosa
Authors: Daigle Denis , Hamrick Jodie , Chatwin Cassandra , Kurepina Natalia , Kreiswirth Barry N , Shields Ryan K , Oliver Antonio , Clancy Cornelius J , Nguyen Minh-Hong , Pevear Daniel , Xerri Luigi 
Published: November 2018

Abstract

Background
VNRX-5133 is a cyclic boronate β-lactamase inhibitor (BLI) currently in clinical development with cefepime to treat multidrug-resistant (MDR) infections caused by ESBL- and carbapenemase-producing Enterobacteriaceae (ENT) and P. aeruginosa (PSA). VNRX-5133 has direct inhibitory activity against serine-active site β-lactamases (Ser-BL) and emerging VIM/NDM metallo-β-lactamases (MBL). We show herein that cefepime/VNRX-5133 is highly active against MDR-K. pneumoniae and P. aeruginosa clinical isolates producing BL-variants evolved during therapy that compromise activity of ceftazidime/avibactam and ceftolozane/tazobactam.

Methods
Susceptibility testing was performed according to CLSI methods with cefepime, ceftolozane, and ceftazidime alone or in combination with VNRX-5133, avibactam, or tazobactam, respectively, fixed at 4 mg/L. Five clinical isolates of K. pneumoniae producing KPC variants impacting ceftazidime/avibactam and five clinical isolates of P. aeruginosa producing Pseudomonas-derived cephalosporinase variants impacting ceftolozane/tazobactam activity were collected in 2016 and 2017, respectively, from United States and Spanish hospitals. All other clinical isolates of Enterobacteriaceae and P. aeruginosa (n = 40) were collected in 2016.

Results
Cefepime/VNRX-5133 was highly active against five ceftazidime/avibactam-resistant K. pneumoniae clinical isolates producing KPC variants with MIC ranging from 0.5 to 4 mg/L relative to ceftazidime/avibactam MIC range of 16 to &gt;128 mg/L. Cefepime/VNRX-5133 was also active against all five clinical isolates of ceftolozane/tazobactam-resistant P. aeruginosa, where 4/5 isolates had MIC of 4–8 mg/L relative to ceftolozane/tazobactam MIC range of 32–128 mg/L. The elevated cefepime/VNRX-5133 MIC (16 mg/L) in the remaining P. aeruginosa isolate was not due to the PDC-221 variant, as an engineered strain of P. aeruginosa producing this enzyme had a cefepime/VNRX-5133 MIC of 1 mg/L.

Conclusion
VNRX-5133 is a potent BLI possessing a unique broad spectrum of activity, including Class A, C, and D Ser-BLs, clinically evolving variants of Ser-BLs (e.g., KPC, PDC) and emerging VIM/NDM-type MBLs. Cefepime/VNRX-5133 is highly active against emerging multidrug-resistant Enterobacteriaceae and P. aeruginosa.

Disclosures
D. Daigle, VenatoRx Pharmaceuticals Inc.: Employee and Shareholder, Salary. J. Hamrick, VenatoRx Pharmaceuticals Inc.: Employee, Salary. C. Chatwin, VenatoRx Pharmaceuticals Inc.: Employee, Salary. N. Kurepina, VenatoRx Pharmaceuticals Inc.: Research Contractor, Research support. B. N. Kreiswirth, VenatoRx Pharmaceuticals Inc.: Research Contractor, Research support. R. K. Shields, VenatoRx Pharmaceuticals Inc.: Research Contractor, Research support. A. Oliver, VenatoRx Pharmaceuticals Inc.: Research Contractor, Research support. C. J. Clancy, VenatoRx Pharmaceuticals Inc.: Research Contractor, Research support. M. H. Nguyen, VenatoRx Pharmaceuticals Inc.: Research Contractor, Research support. D. Pevear, VenatoRx Pharmaceuticals Inc.: Employee, Salary. L. Xerri, VenatoRx Pharmaceuticals Inc.: Employee and Shareholder, Salary.