Efficacy of ceftolozane-tazobactam in combination with colistin against extensively drug-resistant Pseudomonas aeruginosa, including high-risk clones, in an in vitro pharmacodynamic model

María Montero*, Sandra Domene Ochoa, Carla López-Causapé, Brian VanScoy, Sonia Luque, Luisa Sorlí, Núria Campillo, Ariadna Angulo-Brunet, Eduardo Padilla, Núria Prim, Virginia Pomar, Alba Rivera, Santiago Grau, Paul G. Ambrose, Antonio Oliver, Juan P. Horcajada

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

Combination therapy is an attractive therapeutic option for extensively drug-resistant (XDR) Pseudomonas aeruginosa 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 P. aeruginosa 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 P. aeruginosa 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 in vitro pharmacodynamic chemostat model then was used to validate this combination against three selected XDR P. aeruginosa 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 in vitro 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 P. aeruginosa strains and particularly against C/T-resistant strains. C/T plus colistin may be a useful treatment for XDR P. aeruginosa infections, including those caused by high risk-clones resistant to C/T.

Original languageAmerican English
Article numbere02542-19
JournalAntimicrobial Agents and Chemotherapy
Volume64
Issue number4
DOIs
Publication statusPublished - 2020

Keywords

  • Ceftolozane-tazobactam
  • Colistin
  • Combination therapy
  • Pseudomonas aeruginosa

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