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