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Integration of pharmacokinetics and pharmacodynamics of imipenem in a human-adapted mouse model
U Flückiger1, C Segessenmann, A U Gerber
1Division of Medicine, Regionalspital Burgdorf, Switzerland.
Abstract:
The relationship between the pharmacokinetics and bactericidal activity of imipenem against Pseudomonas aeruginosa and Escherichia coli was investigated in a neutropenic mouse thigh infection model. To circumvent the problem of short elimination time in small animals, imipenem was administered in fractionized, decreasing doses such that the pharmacokinetic profiles as observed in humans after intravenous and intramuscular injections were approximated in mice. The human-simulated kinetic profile corresponding to an intramuscular injection of 500 mg at 12-h intervals proved to be as effective as the human-simulated profile of the same dose injected intravenously every 6 h. In contrast, the human-simulated profile corresponding to only one intravenous injection every 12 h resulted in bacterial breakthrough growth between 8 and 12 h after the onset of treatment. The results of our investigations confirm the hypothesis that the bactericidal effect of imipenem against P. aeruginosa and E. coli in vivo depends mainly on the time during which drug levels remain above the MIC rather than on the plasma peak/MIC ratio.
Insights
Imipenem
Area of Science:
- Pharmacology
- Microbiology
- Infectious Diseases
Background:
- Imipenem is a broad-spectrum carbapenem antibiotic.
- Understanding its pharmacokinetic/pharmacodynamic (PK/PD) relationship is crucial for optimizing treatment efficacy.
- Neutropenic animal models are essential for studying antibiotic activity against bacterial infections.
Purpose of the Study:
- To investigate the relationship between imipenem pharmacokinetics and its bactericidal activity against Pseudomonas aeruginosa and Escherichia coli.
- To simulate human dosing regimens in a neutropenic mouse thigh infection model to overcome limitations of small animal pharmacokinetics.
- To determine whether time above the minimum inhibitory concentration (MIC) or peak plasma concentration/MIC ratio is the primary driver of imipenem's efficacy.
Main Methods:
- A neutropenic mouse thigh infection model was utilized.
- Fractionized, decreasing doses of imipenem were administered to mimic human pharmacokinetic profiles (intravenous and intramuscular).
- Bacterial growth and drug concentrations were monitored over time to assess efficacy and PK/PD relationships.
Main Results:
- A human-simulated imipenem pharmacokinetic profile mimicking intramuscular injection every 12 hours was as effective as an intravenous profile every 6 hours.
- A less frequent intravenous dosing regimen (every 12 hours) resulted in bacterial breakthrough growth, indicating treatment failure.
- Bacterial breakthrough was observed between 8 and 12 hours after treatment initiation with the less frequent intravenous regimen.
Conclusions:
- The duration of imipenem concentration above the MIC is the key determinant of its bactericidal effect against P. aeruginosa and E. coli in vivo.
- The peak plasma concentration/MIC ratio is a less important predictor of imipenem efficacy compared to the time above MIC.
- Optimizing imipenem dosing strategies based on time above MIC can improve treatment outcomes in infections caused by these bacteria.