1405. Efficacy of the Human-Simulated Regimen (HSR) of Cefepime (FEP)/VNRX-5133 Combination against Serine β-lactamase-Producing Gram-negative Bacteria in the Neutropenic Murine Thigh Infection Model
Session: Poster Abstract Session: PK/PD Studies
Friday, October 5, 2018
Room: S Poster Hall
Background: VNRX-5133 is a new-generation β-lactamase inhibitor with potent activity against serine and metallo-β-lactamases. FEP/VNRX-5133 combination shows remarkable in vitro activity against multi-drug resistant gram-negative bacteria. The objective of this study was to assess the in vivo efficacy of HSR of the combination against a range of Enterobacteriaceae and Pseudomonas aeruginosa isolates expressing serine β-lactamases in the murine thigh infection model.

Methods: 24 Enterobacteriaceae and P. aeruginosa clinical isolates producing KPC and extended-spectrum ß-lactamases as well as P. aeruginosa with AmpC overexpression were utilized for in vivo studies. FEP and FEP/VNRX-5133 MIC ranges were 256 - >512 and 0.125 – 16 mg/L, respectively. ICR mice were rendered transiently neutropenic, and the thighs were inoculated with bacterial suspensions of 107 CFU/ml. HSR of FEP and VNRX-5133 equivalent to clinical doses of 2 g and 500 mg, respectively, each given q8h as 2 h infusion were developed in the murine model. Treatment mice were administered either FEP HSR alone, FEP HSR + VNRX-5133 HSR combination, or FEP HSR + 1/8th the doses of VNRX-5133 HSR. Control mice were vehicle-dosed. Efficacy was assessed as the change in log10CFU/thigh at 24 h compared with 0 h.

Results: The average log10CFU/thigh at 0 h across all isolates was 5.74 ± 0.53. At 24 h, the bacterial burden increased by an average of 3.27 ± 0.53 log10 CFU/thigh in the untreated control mice. Treatment with FEP alone was associated with average net growth of 2.76 ± 0.75 log10CFU/thigh. The co-administration of VNRX-5133 HSR was adequate to attain ≥ 2-log reduction in initial bacterial burdens at 24 h in 7 out of 24 isolates and ≥ 1-log reduction in the remaining 17 isolates. Furthermore, FEP HSR + 1/8th VNRX-5133 HSR resulted in ≥1- log reduction in the initial bacterial burden in 16 out of 24 isolates.

Conclusion: FEP/VNRX-5133 combination showed potent in vivo efficacy against serine ß–lactamase-producing gram-negative isolates. The extent of bacterial killing achieved with 1/8th VNRX-5133 HSR attested to the robustness of the inhibitor activity. These data support the consideration of FEP/VNRX-5133 combination for the treatment of serious infections due to these organisms in clinical trials.

Kamilia Abdelraouf, Ph.D., Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, Safa Almarzoky Abuhussain, PharmD, Department of Pharmacy, Um-alQura university, Makkah, Saudi Arabia and David P. Nicolau, PharmD, FCCP, FIDSA, Division of Infectious Diseases, Hartford Hospital, Hartford, CT


K. Abdelraouf, None

S. Almarzoky Abuhussain, None

D. P. Nicolau, VenatoRx Pharmaceuticals, Inc.: Grant Investigator , Research grant .

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