Pharmacokinetic/pharmacodynamic evaluation of sulbactam against Acinetobacter baumannii in in vitro and murine thigh and lung infection models

Acinetobacter baumannii is a pathogen that has become globally associated with nosocomial infections. Sulbactam, a potent inhibitor of p-lactamases, was previously shown to be active against A. baumannii strains in vitro and effective against A. baumannii infections. However, a pharmacokinetic/pharmacodynamic (PK/PD) analysis of sulbactam against A. baumannii infections has not yet been performed. This is necessary because optimisation of dosing regimens should be based on PK/PD analysis. Therefore, in vitro and in vivo PK/PD analyses of sulbactam were performed using murine thigh and lung infection models of A. baumannii to evaluate the pharmacokinetics and pharmacodynamics of sulbactam. Sulbactam showed time-dependent bactericidal activity in vitro against A. baumannii. The PK/PD index that best correlated with its in vivo effects was the time that the free drug concentration remained above the minimum inhibitory concentration (ft(>MIC)) both in the thigh (R-2= 0.95) and lung (R-2= 0.96) infection models. Values of ft(>MIC) for a static effect and 1, 2 and 3 logio kill, respectively, were 21.0%, 32.9%, 43.6% and 57.3% in the thigh infection model and 20.4%, 24.5%, 29.3% and 37.3% in the lung infection model. Here we report the in vitro and in vivo time-dependent activities of sulbactam against A. baumannii infection and demonstrate that sulbactam was sufficiently bactericidal when anfr,HC of >60% against A. baumannii thigh infection and >40% against A. baumannii lung infection was achieved. (C) 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.