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In vivo and in vitro study of several pharmacodynamic effects of meropenem
F Fuentes1, M M Martín, J Izquierdo
1Department of Microbiology, Faculty of Medicine, Complutense University of Madrid, Spain.
Abstract:
Several pharmacodynamic parameters are being studied and applied to the design of dosage regimens. The thigh infection model in neutropenic mice has been used in this study to investigate the in vivo postantibiotic effect (PAE) of meropenem against S. aureus, E. coli and P. aeruginosa. The sub-minimum inhibitory concentration (sub-MIC) postantibiotic effect (PA SME) of 1/2, 1/4 and 1/8 x MIC was also determined in vitro on S. aureus and E. coli after pre-exposure of these microorganisms to 10 x MIC of meropenem. The in vitro PAE was also determined. In vivo killing curves using 2 different short dosage regimens were also studied to relate the lethal effect to the time that serum levels were above the MIC. No significant in vivo and in vitro PAEs were observed. The PA SMEs were higher for S. aureus than for E. coli. The 2 short dosage regimens, in vivo, were equally effective in killing S. aureus, but not E. coli. These results suggest that the pharmacodynamics of meropenem on Gram-negative strains may need further study to elucidate the mechanisms and characteristics of these parameters. On the other hand, we need to standardize a reliable in vitro method to monitor regrowth with a good correlation with the in vivo conditions.
Insights
Meropenem showed no significant postantibiotic effect (PAE) in vivo or in vitro against S. aureus and Gram-negative bacteria. Sub-MIC postantibiotic effects (PASMEs) were observed, suggesting further study of meropenem pharmacodynamics in Gram-negative infections is needed.
Area of Science:
- Pharmacology
- Microbiology
- Infectious Diseases
Background:
- Pharmacodynamic (PD) parameters are crucial for optimizing antibiotic dosage regimens.
- Meropenem is a broad-spectrum carbapenem antibiotic used for serious bacterial infections.
Purpose of the Study:
- To investigate the in vivo and in vitro postantibiotic effect (PAE) of meropenem against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa.
- To determine the sub-minimum inhibitory concentration postantibiotic effect (PASME) of meropenem.
- To evaluate the efficacy of different meropenem dosage regimens in a murine thigh infection model.
Main Methods:
- Utilized a neutropenic mouse thigh infection model to assess in vivo PAE.
- Determined in vitro PAE and PASME after exposing S. aureus and E. coli to meropenem.
- Conducted in vivo killing curves with two short dosage regimens.
Main Results:
- No significant in vivo or in vitro PAEs were observed for meropenem against the tested bacteria.
- PASMEs were more pronounced in S. aureus compared to E. coli.
- Two short meropenem dosage regimens demonstrated equal efficacy against S. aureus but not E. coli in vivo.
Conclusions:
- Meropenem's pharmacodynamics, particularly against Gram-negative bacteria like E. coli, require further investigation.
- Standardization of reliable in vitro methods correlating with in vivo conditions is necessary for monitoring bacterial regrowth.