Efficacy of Ceftolozane-Tazobactam in Combination with Colistin against Extensively Drug-Resistant Pseudomonas aeruginosa, Including High-Risk Clones, in an <i>In Vitro</i> Pharmacodynamic Model

Abstract

Combination therapy is an attractive therapeutic option for extensively drug-resistant (XDR) <i>Pseudomonas aeruginosa</i> infections. Colistin has been the only treatment available for these infections for many years, but its results are suboptimal. Ceftolozane-tazobactam (C/T) is a newly available therapeutic option that has shown good antipseudomonal activity, even against a number of XDR <i>P. aeruginosa</i> strains. However, data about combinations containing C/T are scarce. The aim of this study was to analyze the activity of C/T and colistin alone and in combination against a collection of XDR <i>P. aeruginosa</i> strains containing 24 representative clinical isolates from a multicentre Spanish study. Twenty-four time-kill experiments performed over 24 h were conducted in duplicate to determine the effects of colistin and C/T alone and combined. An <i>in vitro</i> pharmacodynamic chemostat model then was used to validate this combination against three selected XDR <i>P. aeruginosa</i> ST175 isolates with different susceptibility levels to C/T. Static time-kill assays demonstrated superior synergistic or additive effect for C/T plus colistin against 21 of the 24 isolates studied. In the <i>in vitro</i> dynamic pharmacokinetic/pharmacodynamic (PK/PD) model, the C/T regimen of 2/1 g every 8 h with a steady-state concentration of 2 mg/liter colistin effectively suppressed the bacterial growth at 24 h. Additive or synergistic interactions were observed for C/T plus colistin against XDR <i>P. aeruginosa</i> strains and particularly against C/T-resistant strains. C/T plus colistin may be a useful treatment for XDR <i>P. aeruginosa</i> infections, including those caused by high risk-clones resistant to C/T.