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

摘要

Plazomicin is a novel 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. 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 at 1 h postinfection and continued for 24 h. Efficacy was assessed by determination of mouse survival through 96 h. Compared with the survival of the controls, plazomicin monotherapy produced a significant improvement in survival for all mice infected with the isolates (P 0.05) and resulted in overall survival rates of 86% (n = 50) and 53.3% (n = 30) for mice infected with isolates with plazomicin MICs of = 4 and = 8 mg/liter, respectively (P 0.05). The survival of the meropenem and tigecycline groups correlated well with susceptibilities of their respective isolates, with incremental increases in survival being observed at lower MIC values. For mice infected with isolate Klebsiella pneumoniae 561 (plazomicin, meropenem, and tigecycline MICs, 8, 32, and 2 mg/liter, respectively), combination therapies showed a significant reduction in mortality compared with that achieved with any monotherapy (P 0.05). Plazomicin monotherapy resulted in improved survival in the immunocompetent murine septicemia model, notably, for mice infected with isolates with plazomicin MICs of = 4 mg/liter. As evidenced by our current data, coadministration of meropenem or tigecycline could potentially lead to a further improvement in survival. These data support a role for plazomicin in the management of septicemia due to Enterobacteriaceae with plazomicin MICs of = 4 mg/liter, including carbapenem-resistant isolates.