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.
T. E. Asempa,
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 .