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Updated: Jun 2, 2026
An Intravital Microscopy-Based Approach to Assess Intestinal Permeability and Epithelial Cell Shedding Performance
Published on: December 3, 2020
Meropenem penetration into epithelial lining fluid in mice and humans and delineation of exposure targets
G L Drusano1, T P Lodise, D Melnick
1Ordway Research Institute, Albany, New York 12208, USA. gdrusano@ordwayresearch.org
Abstract:
Pseudomonas aeruginosa pneumonia remains a most-difficult-to-treat nosocomial bacterial infection. We used mathematical modeling to identify drug exposure targets for meropenem in the epithelial lining fluid (ELF) of mice with Pseudomonas pneumonia driving substantial [2 to 3 log(10) (CFU/g)] killing and which suppressed resistant subpopulation amplification. We bridged to humans to estimate the frequency with which the largest licensed meropenem dose would achieve these exposure targets. Cell kills of 2 and 3 log(10) (CFU/g) and resistant subpopulation suppression were mediated by achieving time > MIC in ELF of 32%, 50%, and 50%. Substantial variability in meropenem's ability to penetrate into ELF of both mice and humans was observed. Penetration variability and high exposure targets combined to prevent even the largest licensed meropenem dose from achieving the targets at an acceptable frequency. Even a highly potent agent such as meropenem does not adequately suppress resistant subpopulation amplification as single-agent therapy administered at maximal dose and optimal schedule. Combination chemotherapy is likely required in humans if we are to minimize resistance emergence in Pseudomonas aeruginosa pneumonia. This combination needs evaluation both in the murine pneumonia model and in humans.
Insights
Meropenem monotherapy fails to suppress resistant Pseudomonas aeruginosa pneumonia. Combination therapy is likely required to effectively treat this difficult-to-treat nosocomial infection and prevent further resistance.
Area of Science:
- Pharmacology
- Infectious Diseases
- Mathematical Biology
Background:
- Pseudomonas aeruginosa pneumonia is a challenging nosocomial infection.
- Effective treatment requires understanding drug exposure in epithelial lining fluid (ELF).
Purpose of the Study:
- To identify meropenem exposure targets in mouse ELF for treating Pseudomonas pneumonia.
- To evaluate the potential of meropenem monotherapy in humans based on these targets.
Main Methods:
- Mathematical modeling was used to determine meropenem exposure targets in mouse ELF.
- These targets were linked to substantial bacterial killing and suppression of resistant subpopulations.
- Human dosing was extrapolated to assess target achievement frequency.
Main Results:
- Achieving 32-50% time above the minimum inhibitory concentration (MIC) in ELF mediated bacterial killing and resistance suppression.
- Significant variability in meropenem penetration into ELF was observed in both mice and humans.
- The highest licensed meropenem dose frequently failed to achieve these targets.
Conclusions:
- Meropenem monotherapy, even at maximal doses, is insufficient to suppress resistant Pseudomonas aeruginosa pneumonia.
- Combination chemotherapy is likely necessary to combat this infection and minimize resistance.
- Further evaluation of combination therapies in both murine models and human trials is warranted.
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