Antibacterial effect of seven days exposure to ceftolozane-tazobactam as monotherapy and in combination with fosfomycin or tobramycin against Pseudomonas aeruginosa with ceftolozane-tazobactam MICs at or above 4 mg/l in an in vitro pharmacokinetic model.
- Resource Type
- Academic Journal
- Authors
- Attwood M; Department of Infection Sciences, Bristol Centre for Antimicrobial Research & Evaluation, Southmead Hospital, Pathology Sciences Building, Phase 2, Westbury-on-Trym, Bristol BS10 5NB, UK.; Griffin P; Department of Infection Sciences, Bristol Centre for Antimicrobial Research & Evaluation, Southmead Hospital, Pathology Sciences Building, Phase 2, Westbury-on-Trym, Bristol BS10 5NB, UK.; Noel AR; Department of Infection Sciences, Bristol Centre for Antimicrobial Research & Evaluation, Southmead Hospital, Pathology Sciences Building, Phase 2, Westbury-on-Trym, Bristol BS10 5NB, UK.; Albur M; Department of Infection Sciences, Bristol Centre for Antimicrobial Research & Evaluation, Southmead Hospital, Pathology Sciences Building, Phase 2, Westbury-on-Trym, Bristol BS10 5NB, UK.; Macgowan AP; Department of Infection Sciences, Bristol Centre for Antimicrobial Research & Evaluation, Southmead Hospital, Pathology Sciences Building, Phase 2, Westbury-on-Trym, Bristol BS10 5NB, UK.
- Source
- Publisher: Oxford University Press Country of Publication: England NLM ID: 7513617 Publication Model: Print Cited Medium: Internet ISSN: 1460-2091 (Electronic) Linking ISSN: 03057453 NLM ISO Abbreviation: J Antimicrob Chemother Subsets: MEDLINE
- Subject
- Language
- English
Objectives: To use a pre-clinical pharmacokinetic infection model to assess the antibacterial effect of ceftolozane/tazobactam alone or in combination with fosfomycin or tobramycin against Pseudomonas aeruginosa strains with MICs at or higher than the clinical breakpoint (MIC ≥ 4 mg/L).
Methods: An in vitro model was used to assess changes in bacterial load and population profiles after exposure to mean human serum concentrations of ceftolozane/tazobactam associated with doses of 2 g/1 g q8h, fosfomycin concentrations associated with doses of 8 g q8h or tobramycin at doses of 7 mg/kg q24 h over 168 h.
Results: Simulations of ceftolozane/tazobactam at 2 g/1 g q8h alone produced 3.5-4.5 log reductions in count by 6 h post drug exposure for strains with MIC ≤32 mg/L. The antibacterial effect over the first 24 h was related to ceftolozane/tazobactam MIC. There was subsequent regrowth with most strains to bacterial densities of >106 CFU/mL. Addition of either fosfomycin or tobramycin resulted in suppression of regrowth and in the case of tobramycin more rapid initial bacterial killing up to 6 h. These effects could not be related to either fosfomycin or tobramycin MICs. Changes in population profiles were noted with ceftolozane/tazobactam alone often after 96 h exposure but such changes were suppressed by fosfomycin and almost abolished by the addition of tobramycin.
Conclusions: The addition of either fosfomycin or tobramycin to ceftolozane/tazobactam at simulated human clinically observed concentrations reduced P. aeruginosa bacterial loads and the risk of resistance to ceftolozane/tazobactam when strains had ceftolozane/tazobactam MIC values at or above the clinical breakpoint.
(© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)