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

Disclosures:

K. Abdelraouf, None

S. Almarzoky Abuhussain, None

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

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