1395. Defining the Magnitude of AUC:MIC Driver for Efficacy of the β‑lactamase Inhibitor VNRX-5133 when combined with Cefepime against KPC- and VIM/NDM-producing Enterobacteriaceae and P. aeruginosa.
Session: Poster Abstract Session: PK/PD Studies
Friday, October 5, 2018
Room: S Poster Hall
Posters
  • 1395_IDWPOSTER_v2.jpg (2.7 MB)
  • Background: VNRX-5133 is a cyclic boronate β-lactamase inhibitor (BLI) in clinical development with cefepime for treatment of infections caused by ESBL- and carbapenemase producing Enterobacteriaceae and P. aeruginosa. It is a new generation broad-spectrum BLI with direct inhibitory activity against serine-active site and emerging metallo-β-lactamases (e.g. VIM/NDM). In previous in vivo and in vitro studies, the PK-PD driver of efficacy of VNRX-5133 was defined as AUC:MIC. Described herein are in vitro studies to assess the magnitude of VNRX-5133 exposure (AUC:MIC) required to restore efficacy of cefepime against a broad collection of KPC- and VIM/NDM-producing Enterobacteriaceae (ENT) and P. aeruginosa (PSA) clinical isolates.

    Methods: Dose-fractionation studies, consisting of four VNRX-5133 exposures fractionated into regimens administered every 4, 8, 12 and 24 h were performed in an in vitro infection model with simulated 2 g q8h dosing of cefepime against NDM-1 producing E. coli. A Hill-type model described the relationship between change in log10 CFU at 24 h and VNRX-5133 exposure (AUC:MIC), where cefepime MIC was determined with 4 µg/mL VNRX-5133. To evaluate variability of efficacy enabled by VNRX-5133 between isolates as well as between Serine-BL and Metallo-BL producers, dose-ranging studies were completed for eight isolates (7 ENT and 1 PSA) producing KPC or VIM/NDM metallo-β‑lactamases.

    Results: The PK-PD exposure parameter AUC:MIC accurately described the efficacy of VNRX-5133 in rescuing cefepime activity against KPC and VIM/NDM carbapenemase-producing isolates of ENT and PSA. The AUC:MIC ratios associated with net bacterial stasis, 1-, and 2-log10 reductions in bacterial burden from baseline were 6.1, 18.4 and 45 respectively for a collection of 5 VIM/NDM- and 3 KPC-producing isolates with cefepime MICs ranging from 4-8 µg/mL with no significant differences observed between Ser-BL and MBL producers.

    Conclusion: These data confirm the equivalent in vitro activity of cefepime/VNRX-5133 against organisms producing serine- and metallo- β-lactamases and provides an initial PK‑PD target for VNRX-5133 efficacy when used in combination with cefepime for the treatment of ESBL- and carbapenemase-producing ENT and PSA infections.

    Denis Daigle, Ph.D., Salvador Vernacchio, B.Sc., Luigi Xerri, Ph.D. and Daniel Pevear, Ph.D., VenatoRx Pharmaceuticals Inc., Malvern, PA

    Disclosures:

    D. Daigle, VenatoRx Pharmaceuticals Inc.: Employee and Shareholder , Salary .

    S. Vernacchio, VenatoRx Pharmaceuticals Inc.: Employee and Shareholder , Salary .

    L. Xerri, VenatoRx Pharmaceuticals Inc.: Employee and Shareholder , Salary .

    D. Pevear, VenatoRx Pharmaceuticals Inc.: Employee , Salary .

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