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

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, PAE_R, 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.

Keywords:

• In vivo post-antibiotic effect of a β²-lactam/β²-lactamase inhibitor combination
• post-antibiotic effect of ceftazidime-avibactam in vivo against Pseudomonas aeruginosa
• PAE of BL/BLI in vivo
• PAE of ceftazidime-avibactam in vivo against Pseudomonas aeruginosa

Acknowledgements

We acknowledge the extensive contributions of co-author J W Mouton, to the science of anti-infective PK/PD. Professor Mouton sadly passed away during the late stages of the preparation of this report.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

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

Notes on contributors

Johanna Berkhout

Johanna Berkhout is a clinical microbiologist at the Canisius-Wilhelmina Hospital and an associate scientist in PK/PD-studies at the Radboud University Medical Center, both in Nijmegen, The Netherlands.

Maria J. Melchers

Maria J. Melchers is a former graduate student in PK/PD-studies at the Radboud University Medical Center, Nijmegen, The Netherlands.

Anita C. van Mil

Anita C. van Mil is a technician in the Laboratory of Medical Microbiology at the Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.

Claudia M. Lagarde

Claudia M. Lagarde is a former biotechnician, currently training as a surgical assistant at the Radboud University Medical Center, Nijmegen, The Netherlands.

Wright W. Nichols

Wright W. Nichols is an independent consultant in Microbiology and is located in Manchester, UK.

Johan W. Mouton

Johan W. Mouton was a Professor of PK/PD-studies at the Radboud University Medical Center, Nijmegen and during the later stage of this article at the Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands.