Evaluation of the post-antibiotic effect in vivo for the combination of a β-lactam antibiotic and a β-lactamase inhibitor: ceftazidime-avibactam in neutropenic mouse thigh and lung infections

Johanna Berkhout, Maria J. Melchers, Anita C. van Mil, Claudia M. Lagarde, Wright W. Nichols*, Johan W. Mouton

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The post-antibiotic effect (PAE) of ceftazidime-avibactam in vivo was evaluated using models of thigh- and lung-infection with Pseudomonas aeruginosa in neutropenic mice. In thigh-infected mice, the PAE was negative (–2.18 to −0.11 h) for three of four strains: caused by a ‘burst’ of rapid bacterial growth after the drug concentrations had fallen below their pre-specified target values. With lung infection, PAE was positive, and longer for target drug concentrations in ELF (>2 h) than plasma (1.69–1.88 h). The time to the start of regrowth was quantified as a new parameter, PAER, which was positive (0.35–1.00 h) in both thigh- and lung-infected mice. In the context that measurements of the PAE of β-lactam/β-lactamase inhibitor combinations in vivo have not previously been reported, it is noted that the negative values were consistent with previous measurements of the PAE of ceftazidime-avibactam in vitro and of ceftazidime alone in vivo.

Original languageEnglish
Pages (from-to)400-408
Number of pages9
JournalJournal of Chemotherapy
Volume33
Issue number6
DOIs
Publication statusE-pub ahead of print - 6 Mar 2021

Bibliographical note

Funding Information:
This study was supported by an unrestricted grant from AstraZeneca. AstraZeneca’s rights to ceftazidime-avibactam were acquired by Pfizer in December 2016.

Publisher Copyright: © 2021 Edizioni Scientifi che per l'Informazione su Farmaci e Terapia.

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