A pharmacometric approach to define target site-specific breakpoints for bacterial killing and resistance suppression integrating microdialysis, time-kill curves and heteroresistance data: a case study with moxifloxacin.
Clin Microbiol Infect
; 26(9): 1255.e1-1255.e8, 2020 Sep.
Article
em En
| MEDLINE
| ID: mdl-32088331
ABSTRACT
OBJECTIVES:
Pharmacokinetic-pharmacodynamic (PK-PD) considerations are at the heart of defining susceptibility breakpoints for antibiotic therapy. However, current approaches follow a fragmented workflow. The aim of this study was to develop an integrative pharmacometric approach to define MIC-based breakpoints for killing and suppression of resistance development for plasma and tissue sites, integrating clinical microdialysis data as well as in vitro time-kill curves and heteroresistance information, exemplified by moxifloxacin against Staphylococcus aureus and Escherichia coli.METHODS:
Plasma and target site samples were collected from ten patients receiving 400 mg moxifloxacin/day. In vitro time-kill studies with three S. aureus and two E. coli strains were performed and resistant subpopulations were quantified. Using these data, a hybrid physiologically based (PB) PK model and a PK-PD model were developed, and utilized to predict site-specific breakpoints.RESULTS:
For both bacterial species, the predicted MIC breakpoint for stasis at 400 mg/day was 0.25 mg/L. Less reliable killing was predicted for E. coli in subcutaneous tissues where the breakpoint was 0.125 mg/L. The breakpoint for resistance suppression was 0.06 mg/L. Notably, amplification of resistant subpopulations was highest at the clinical breakpoint of 0.25 mg/L. High-dose moxifloxacin (800 mg/day) increased all breakpoints by one MIC tier.CONCLUSIONS:
An efficient pharmacometric approach to define susceptibility breakpoints was developed; this has the potential to streamline the process of breakpoint determination. Thereby, the approach provided additional insight into target site PK-PD and resistance development for moxifloxacin. Application of the approach to further drugs is warranted.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Staphylococcus aureus
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Escherichia coli
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Moxifloxacina
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Antibacterianos
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article