Pharmacodynamics of Meropenem against Acinetobacter baumannii in a Neutropenic Mouse Thigh Infection Model
Mojgan Sabet1, Ziad Tarazi1, David C Griffith2
1Qpex Biopharma, Inc., San Diego, California, USA.
Abstract:
Acinetobacter baumannii infections are difficult to treat and have limited treatment options. Carbapenems, including meropenem, are currently considered the first-line agents for the treatment of infections caused by Acinetobacter spp. The percentage of a 24-hour period that the concentration of free drug in plasma is above the MIC (%24-h fT>MIC) to achieve stasis, 1 log CFU, or 2 log CFU of bacterial killing against A. baumannii has not been studied previously for meropenem. The objective of this study was to determine these parameters for meropenem against A. baumannii in a neutropenic mouse thigh infection model. Six A. baumannii clinical isolates with MICs ranging from 0.25 to 16 mg/liter were tested. Meropenem produced a bacteriostatic effect with a %24-h fT>MIC of 7 to 24% and produced 1 log CFU of bacterial killing with a %24-h fT>MIC of 15 to 37%.
Insights
Meropenem exhibits bacteriostatic effects against Acinetobacter baumannii infections at 7-24% of the dosing interval. Achieving 1 log CFU bacterial killing requires 15-37% of the dosing interval above the minimum inhibitory concentration.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Acinetobacter baumannii infections pose significant treatment challenges due to limited therapeutic options.
- Carbapenems, such as meropenem, are primary treatments for Acinetobacter spp. infections.
- Pharmacodynamic targets for meropenem against A. baumannii remain uncharacterized.
Purpose of the Study:
- To determine the pharmacokinetic/pharmacodynamic (PK/PD) targets for meropenem against A. baumannii.
- To establish the percentage of dosing interval required for meropenem to achieve stasis, 1 log CFU, and 2 log CFU bacterial killing of A. baumannii.
Main Methods:
- A neutropenic mouse thigh infection model was utilized.
- Six clinical isolates of A. baumannii with varying meropenem MICs (0.25–16 mg/L) were tested.
- The percentage of 24-hour free time above the MIC (%fT>MIC) was correlated with bacterial burden.
Main Results:
- Meropenem demonstrated bacteriostatic activity at %fT>MIC values ranging from 7% to 24%.
- A %fT>MIC of 15% to 37% was associated with 1 log CFU of bacterial killing.
- The study did not reach a 2 log CFU reduction threshold within tested parameters.
Conclusions:
- Meropenem requires specific %fT>MIC targets to achieve bacteriostatic and bactericidal effects against A. baumannii.
- These findings provide crucial PK/PD targets for optimizing meropenem therapy in A. baumannii infections.
- Further research is needed to define targets for greater bacterial killing.
