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