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The entry of meropenem into human macrophages and its immunomodulating activity
A M Cuffini1, V Tullio, A Allocco
1Institute of Microbiology, University of Turin, Torino, Italy.
Abstract:
The uptake of meropenem by human macrophages and its consequences upon subsequent phagocytosis and killing of intracellular staphylococci has been studied. The cellular to extracellular concentration ratios (C/E) of meropenem were always high (range 3-12) at extracellular concentrations ranging from 0.125 to 1 mg/L. The uptake was not energy-dependent, being similar when viable and formalin-killed cells were used and was influenced neither by environmental temperature nor by the addition of a metabolic inhibitor. Meropenem at half the MIC caused a significant enhancement of phagocytosis and a reduction in the survival of intracellular Staphylococcus aureus. Pre-exposure of either staphylococci or macrophages to sub-MIC concentrations of meropenem led to an increase in uptake of bacteria and intracellular bactericidal activity by macrophages.
Insights
Meropenem (a carbapenem antibiotic) concentrates highly within human macrophages, enhancing bacterial uptake and killing. This non-energy-dependent process boosts macrophage effectiveness against intracellular Staphylococcus aureus.
Area of Science:
- Pharmacology
- Immunology
- Microbiology
Background:
- Human macrophages play a crucial role in combating intracellular bacterial infections.
- Meropenem is a broad-spectrum carbapenem antibiotic commonly used to treat severe bacterial infections.
- Understanding antibiotic penetration into immune cells is vital for optimizing treatment strategies.
Purpose of the Study:
- To investigate the cellular uptake of meropenem by human macrophages.
- To determine the impact of meropenem on macrophage phagocytosis and intracellular killing of Staphylococcus aureus.
- To explore the mechanisms influencing meropenem uptake by macrophages.
Main Methods:
- Quantification of meropenem cellular to extracellular concentration ratios (C/E) in human macrophages.
- Assessment of meropenem uptake using both viable and formalin-killed macrophages.
- Evaluation of phagocytosis and intracellular bacterial survival following meropenem exposure.
- Investigation of the effects of temperature and metabolic inhibitors on meropenem uptake.
Main Results:
- Meropenem exhibited high cellular to extracellular concentration ratios (C/E: 3-12) in human macrophages.
- Meropenem uptake was independent of cellular energy, temperature, and metabolic inhibitors.
- Meropenem at sub-inhibitory concentrations significantly enhanced Staphylococcus aureus phagocytosis by macrophages.
- Pre-exposure to sub-MIC meropenem increased bacterial uptake and intracellular killing activity.
Conclusions:
- Meropenem efficiently concentrates within human macrophages through a non-energy-dependent mechanism.
- Meropenem exposure enhances macrophage phagocytic capacity and intracellular bactericidal activity against Staphylococcus aureus.
- These findings suggest a potential immunomodulatory role for meropenem, improving host defense against intracellular pathogens.