1370. Cefepime/VNRX-5133 Broad-Spectrum Activity is Maintained against Emerging KPC- and PDC-Variants in Multidrug Resistant K. pneumoniae and P. aeruginosa.
Session: Poster Abstract Session: Novel Agents
Friday, October 5, 2018
Room: S Poster Hall
Posters
  • 1370_IDWPOSTER_v2.jpg (3.1 MB)
  • 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 US 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 5 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 >128 mg/L. Cefepime/VNRX-5133 was also active against all 5 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.

    Denis Daigle, Ph.D.1, Jodie Hamrick, B.Sc.1, Cassandra Chatwin, B.Sc.1, Natalia Kurepina, Ph.D.2, Barry N. Kreiswirth, PhD2, Ryan K. Shields, PharmD3, Antonio Oliver, PhD4, Cornelius J. Clancy, M.D.5, Minh-Hong Nguyen, MD3, Daniel Pevear, Ph.D.1 and Luigi Xerri, Ph.D.1, (1)VenatoRx Pharmaceuticals Inc., Malvern, PA, (2)Public Health Research Institute, Rutgers New Jersey Medical School, Newark, NJ, (3)University of Pittsburgh, School of Medicine, Pittsburgh, PA, (4)Hospital Son Espases, Palma de Mallorca, Spain, (5)Infectious Diseases, University of Pittsburgh, Pittsburgh, PA

    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 .

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