Background: PLZ is a next-generation aminoglycoside with potent in vitro activity against multidrug- and carbapenem-resistant EB. The objective of this study was to assess the efficacy of PLZ human-simulated exposure, alone and in combination with MEM or TGC, against EB in the I+ murine septicemia model.
Methods: ICR mice were inoculated intraperitoneally with bacterial suspensions of 10 6.5 CFU/ml. Eight EB isolates with PLZ, MEM and TGC MICs ranging from 2 - 16, ≤0.015 - >32 and ≤0.06 - 2 mg/L, respectively, were utilized to assess the efficacy of PLZ alone or in combination against isolates at the upper end of PLZ MIC distribution. PLZ, MEM and TGC doses in mice that mimic the human plasma exposures following the administration of the clinical doses summarized in the table were utilized.
15 mg/kg Q24H, 0.5 h infusion
2 g Q8H, 3 h infusion
50 mg Q12H
Treatment mice were administered PLZ, MEM or TGC human-equivalent doses alone or in combinations of PLZ/MEM and PLZ/TGC, while control mice were administered vehicle. Treatments were initiated 1 h post-infection and continued for 24 h. Efficacy was assessed by survival through 96 h. Survival was compared using Kaplan-Meier analysis and log-rank test.
Results: Compared with controls, human-simulated exposure of PLZ monotherapy produced significant improvement in survival for all isolates (P<0.05) and resulted in overall survival percentages of 86 (n=50) and 53.3 (n=30) for isolates with MIC ≤4 and ≥8 mg/L, respectively (P<0.05). Survival of MEM and TGC groups correlated well with their respective susceptibilities, with incremental increase in survival observed at lower MIC values. For isolate KP 561 (PLZ, MEM and TGC MICs of 8, >32 and 2 mg/L, respectively), PLZ/MEM and PLZ/TGC showed significant reduction in mortality compared with any of the single agents (P<0.05) (Fig 1).
Conclusion: PLZ monotherapy resulted in improved survival in the I+ murine septicemia model, notably for isolates with MIC ≤4. Moreover, some evidence suggests that co-administration of MEM or TGC could potentially lead to further improvement in survival. These preclinical data utilizing clinically relevant exposures support a role for PLZ in the management of septicemia due to EB, including carbapenem-resistant isolates.
K. M. Krause, Achaogen, Inc: Employee , Salary
D. P. Nicolau, Achaogen, Inc.: Grant Investigator , Research grant and Research support
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