期刊
ANTIBIOTICS-BASEL
卷 11, 期 8, 页码 -出版社
MDPI
DOI: 10.3390/antibiotics11081036
关键词
PKPD model; time-kill curve; prolonged infusion; continuous infusion; meropenem; beta-lactam; Pseudomonas aeruginosa; PK; PD index; pharmacometrics
资金
- Swedish Research Council [2018-03296]
- Swedish Research Council [2018-03296] Funding Source: Swedish Research Council
In this study, the impact of differently shaped clinical pharmacokinetic profiles of meropenem on the growth and killing patterns of Pseudomonas aeruginosa was investigated using a semi-mechanistic PKPD model and a PK/PD index-based approach. Continuous infusion plus loading dose and 3-hour infusions were found to be superior to standard 0.5-hour infusions in certain scenarios.
Pharmacokinetic-pharmacodynamic (PKPD) models have met increasing interest as tools to identify potential efficacious antibiotic dosing regimens in vitro and in vivo. We sought to investigate the impact of diversely shaped clinical pharmacokinetic profiles of meropenem on the growth/killing patterns of Pseudomonas aeruginosa (ARU552, MIC = 16 mg/L) over time using a semi-mechanistic PKPD model and a PK/PD index-based approach. Bacterial growth/killing were driven by the PK profiles of six patient populations (infected adults, burns, critically ill, neurosurgery, obese patients) given varied pathogen features (e.g., EC50, growth rate, inoculum), patient characteristics (e.g., creatinine clearance), and ten dosing regimens (including two dose levels and 0.5-h, 3-h and continuous-infusion regimens). Conclusions regarding the most favourable dosing regimen depended on the assessment of (i) the total bacterial load or fT(>MIC) (time that unbound concentrations exceed the minimum inhibitory concentration); (ii) the median or P-0.95 profile of the population; and (iii) 8 h or 24 h time points. Continuous infusion plus loading dose as well as 3-h infusions (3-h infusions: e.g., for scenarios associated with low meropenem concentrations, P-0.95 profiles, and MIC >= 16 mg/L) appeared superior to standard 0.5-h infusions at 24 h. The developed platform can serve to identify promising strategies of efficacious dosing for clinical trials.
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