Evaluation of in vitro pharmacodynamic drug interactions of ceftazidime/avibactam and fosfomycin in Escherichia coli.
Journal
The Journal of antimicrobial chemotherapy
ISSN: 1460-2091
Titre abrégé: J Antimicrob Chemother
Pays: England
ID NLM: 7513617
Informations de publication
Date de publication:
03 10 2023
03 10 2023
Historique:
received:
24
03
2023
accepted:
31
07
2023
medline:
4
10
2023
pubmed:
25
8
2023
entrez:
25
8
2023
Statut:
ppublish
Résumé
Combination therapy can increase efficacy of antibiotics and prevent emergence of resistance. Ceftazidime/avibactam and fosfomycin may be empirically combined for this purpose, but a systematic and quantitative evaluation of this combination is needed. In this study, a systematic analysis of the pharmacodynamic interactions of ceftazidime/avibactam and fosfomycin in clinical and isogenic Escherichia coli strains carrying genes coding for several carbapenemases or ESBLs was performed and pharmacodynamic interactions were quantified by modelling and simulations. Pharmacodynamic interactions were evaluated in 'dynamic' chequerboard experiments with quantification of viable bacteria in eight isogenic and six clinical E. coli strains. Additionally, supplemental time-kill experiments were performed and genomic analyses were conducted on representative fosfomycin-resistant subpopulations. Models were fitted to all data using R and NONMEM®. Synergistic drug interactions were identified for 67% of the clinical and 75% of the isogenic isolates with a mean EC50 reduction of >50%. Time-kill experiments confirmed the interactions and modelling quantified EC50 reductions up to 97% in combination and synergy prevented regrowth of bacteria by enhanced killing effects. In 9 out of 12 fosfomycin-resistant mutants, genomic analyses identified previously reported mutations. The broad synergistic in vitro activity of ceftazidime/avibactam and fosfomycin confirms the potential of the application of this drug combination in clinics. The substantial reduction of the EC50 in combination may allow use of lower doses or treatment of organisms with higher MIC values and encourage further research translating these findings into the clinical setting.
Sections du résumé
BACKGROUND
Combination therapy can increase efficacy of antibiotics and prevent emergence of resistance. Ceftazidime/avibactam and fosfomycin may be empirically combined for this purpose, but a systematic and quantitative evaluation of this combination is needed.
OBJECTIVES
In this study, a systematic analysis of the pharmacodynamic interactions of ceftazidime/avibactam and fosfomycin in clinical and isogenic Escherichia coli strains carrying genes coding for several carbapenemases or ESBLs was performed and pharmacodynamic interactions were quantified by modelling and simulations.
METHODS
Pharmacodynamic interactions were evaluated in 'dynamic' chequerboard experiments with quantification of viable bacteria in eight isogenic and six clinical E. coli strains. Additionally, supplemental time-kill experiments were performed and genomic analyses were conducted on representative fosfomycin-resistant subpopulations. Models were fitted to all data using R and NONMEM®.
RESULTS
Synergistic drug interactions were identified for 67% of the clinical and 75% of the isogenic isolates with a mean EC50 reduction of >50%. Time-kill experiments confirmed the interactions and modelling quantified EC50 reductions up to 97% in combination and synergy prevented regrowth of bacteria by enhanced killing effects. In 9 out of 12 fosfomycin-resistant mutants, genomic analyses identified previously reported mutations.
CONCLUSIONS
The broad synergistic in vitro activity of ceftazidime/avibactam and fosfomycin confirms the potential of the application of this drug combination in clinics. The substantial reduction of the EC50 in combination may allow use of lower doses or treatment of organisms with higher MIC values and encourage further research translating these findings into the clinical setting.
Identifiants
pubmed: 37624929
pii: 7251081
doi: 10.1093/jac/dkad264
doi:
Substances chimiques
Ceftazidime
9M416Z9QNR
Fosfomycin
2N81MY12TE
avibactam
7352665165
Anti-Bacterial Agents
0
Azabicyclo Compounds
0
Drug Combinations
0
beta-Lactamases
EC 3.5.2.6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2524-2534Informations de copyright
© 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.