In Vivo Efficacy of Plazomicin Alone or in Combination with Meropenem or Tigecycline against Enterobacteriaceae Isolates Exhibiting Various Resistance Mechanisms in an Immunocompetent Murine Septicemia Model [PublishAheadOfPrint]

Background: Plazomicin is a next-generation aminoglycoside with potent in vitro activity against multidrug- and carbapenem-resistant Enterobacteriaceae. The objective of this study was to assess the efficacy of plazomicin exposure, alone and in combination with meropenem or tigecycline, against Enterobacteriaceae in the immunocompetent murine septicemia model.

Methods: ICR mice were inoculated intraperitoneally with bacterial suspensions. Eight Enterobacteriaceae isolates with wide ranges of plazomicin, meropenem and tigecycline MICs were utilized. Treatment mice were administered plazomicin, meropenem or tigecycline human-equivalent doses alone or in combinations of plazomicin/meropenem and plazomicin/tigecycline. Treatments were initiated 1h post-infection and continued for 24h. Efficacy was assessed by survival through 96h.

Results: Compared with controls, plazomicin monotherapy produced significant improvement in survival for all isolates (P<0.05) and resulted in overall survival of 86% (n=50) and 53.3% (n=30) for isolates with plazomicin MIC ≤4 and ≥8 mg/L, respectively (P<0.05). Survival of meropenem and tigecycline groups correlated well with their respective susceptibilities, with incremental increase in survival observed at lower MIC values. For isolate KP 561 (plazomicin, meropenem and tigecycline MICs of 8, >32 and 2 mg/L, respectively), combination therapies showed significant reduction in mortality compared with any monotherapy (P<0.05).

Conclusion: Plazomicin monotherapy resulted in improved survival in the immunocompetent murine septicemia model, notably for isolates with plazomicin MIC ≤4 mg/L. As evidenced by our current data, co-administration of meropenem or tigecycline could potentially lead to further improvement in survival. These data support a role for plazomicin in the management of septicemia due to Enterobacteriaceae with plazomicin MIC ≤4 mg/L, including carbapenem-resistant isolates.

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