1368. Assessment of the In Vivo Efficacy of Human-simulated Epithelial Lining Fluid (ELF) Exposure of Meropenem/Nacubactam (MEM/NAC) Combination against ß-lactamase-producing Enterobacteriaceae in Neutropenic Lung Infection Model
Session: Poster Abstract Session: Novel Agents
Friday, October 5, 2018
Room: S Poster Hall
Posters
  • IDWeek Meropenem_Nacubactam KPC 9_24_2018.pdf (426.6 kB)
  • Background: NAC is a novel dual action β-lactamase inhibitor with in vitro activity against class A, class C, and some class D β-lactamases and antibacterial activity against Enterobactaeriaceae. NAC is being developed as a combination therapy with MEM for the treatment of serious Gram-negative bacterial infections. This study evaluated the efficacy of the human-simulated ELF exposure of MEM/NAC, compared with those of MEM or NAC alone against β-lactamase-producing Enterobacteriaceae isolates in the neutropenic murine lung infection model.

    Methods: Eight clinical MEM resistant Enterobacteriaceae isolates harboring various β-lactamases (IMI, KPC, OXA, TEM, SHV, AmpC) were utilized in the study. MEM and MEM:NAC (1:1) combination MICs were determined in triplicate via broth microdilution. ICR mice were rendered transiently neutropenic, and lungs were inoculated with 50 µL bacterial suspensions of 107 CFU/ml. Regimens in mice that simulated the human ELF exposures following doses of MEM 2g q8h and NAC 2g q8h (1.5h infusions) as monotherapies and in combination were established. Treatment mice received MEM human-simulated regimen (HSR), NAC HSR or MEM/NAC HSR and control mice were vehicle-dosed. Treatment was started 2h after inoculation and continued for 24h. Efficacy was assessed as the change in log10CFU/lung at 24h compared with 0h controls.

    Results: MEM and MEM/NAC MICs were 8 - 512 mg/L and 0.5 - 8 mg/L, respectively. The average log10CFU/lung at 0h across all isolates was 6.26 ± 0.26. Relative to 0h control, the mean bacterial growth at 24h in the untreated control mice, MEM HSR, and NAC HSR treatment groups were 2.93 ± 0.29, 2.72 ± 0.42, and 1.75 ± 0.80 log10CFU/lung, respectively. MEM/NAC HSR resulted in up to 2-log bacterial reduction in isolates with MEM/NAC MIC ≤4 mg/L.

    Conclusion: MEM/NAC human-simulated ELF exposure produced enhanced efficacy against MEM resistant β-lactamase-producing Enterobacteriaceae isolates with MEM/NAC MIC ≤4 mg/L. These data support a potential role for MEM/NAC for treatment of lung infections due to β-lactamase-producing Enterobacteriaceae and warrant further studies.

    Funding: This project has been funded in part under HHS BARDA Contract HHSO100201600038C.

    Tomefa E Asempa, PharmD1, Ana Motos, MSc1, Kamilia Abdelraouf, Ph.D.1, Caterina Bissantz, Ph.D.2, Claudia Zampaloni, Ph.D.3 and David P. Nicolau, PharmD, FCCP, FIDSA1,4, (1)Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, (2)Roche Pharma Research and Early Development Pharmaceutical Science, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland, (3)Roche Pharma Research and Early Development, Immunology, Inflammation and Infectious Diseases, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland, (4)Division of Infectious Diseases, Hartford Hospital, Hartford, CT

    Disclosures:

    T. E. Asempa, None

    A. Motos, None

    K. Abdelraouf, None

    C. Bissantz, F Hoffmann La Roche Ltd: Employee , Salary .

    C. Zampaloni, F. Hoffmann-La Roche Ltd.: Employee , Salary .

    D. P. Nicolau, Hoffmann-La Roche Ltd: Grant Investigator , Grant recipient .

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