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

• Published in: International journal of antimicrobial agents Vol. 43; no. 6; pp. 547 - 552
• Main Authors: Yokoyama, Yuta, Matsumoto, Kazuaki, Ikawa, Kazuro, Watanabe, Erika, Shigemi, Akari, Umezaki, Yasuhiro, Nakamura, Koyo, Ueno, Keiichiro, Morikawa, Norifumi, Takeda, Yasuo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2014
• Subjects: Abscess - drug therapy; Acinetobacter baumannii; Acinetobacter baumannii - drug effects; Acinetobacter Infections - drug therapy; Animals; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Bacterial Load; Disease Models, Animal; Female; Infection mouse model; Infectious Disease; Lung - pathology; Mice; Microbial Sensitivity Tests; Microbial Viability - drug effects; Pharmacokinetic/pharmacodynamic; Plasma - chemistry; Pneumonia, Bacterial - drug therapy; Sulbactam; Sulbactam - pharmacokinetics; Sulbactam - pharmacology; Sulbactam - therapeutic use; Thigh - pathology; Acinetobacter baumannii; Pharmacokinetic/pharmacodynamic; Sulbactam; Infection mouse model
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2014.02.012

Abstract Acinetobacter baumannii is a pathogen that has become globally associated with nosocomial infections. Sulbactam, a potent inhibitor of β-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 ( f T>MIC ) both in the thigh ( R2 = 0.95) and lung ( R2 = 0.96) infection models. Values of f T>MIC for a static effect and 1, 2 and 3 log10 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 an f T>MIC of >60% against A. baumannii thigh infection and >40% against A. baumannii lung infection was achieved.