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Comparative uptake of rifampicin and rifapentine (DL473) by human neutrophils
Abstract:
Rifapentine, a new cyclopentyl rifamycin, was weight for weight less active than rifampicin against Staphylococcus aureus. It was, however, equally effective at reducing the survival of Staph. aureus within human neutrophils even at concentrations below the conventionally determined MIC. The intracellular survival of antibiotic-resistant Staph. aureus was affected by neither agent. The bactericidal activity of neutrophil sonicates after exposure to both antibiotics showed that rifapentine was concentrated three-fold more than rifampicin. Uptake was temperature dependent and rapidly reached a plateau within 10 min. Uptake of rifampicin was unaffected by pH whereas that of rifapentine was reduced when the pH was lowered from 7.3 to 5. Studies with the metabolic inhibitors, sodium cyanide and potassium fluoride, suggested a minor role for both oxidative and glycolytic metabolism in this process. However, neither inhibitor had any demonstrable effect on the intracellular killing of Staph. aureus by either rifapentine or rifampicin.
Insights
Rifapentine shows comparable efficacy to rifampicin in reducing Staphylococcus aureus survival within neutrophils, despite lower in vitro activity. This suggests potential for intracellular effectiveness against certain bacterial infections.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Rifampicin is a cornerstone antibiotic for Staphylococcus aureus infections.
- Rifapentine, a related rifamycin, offers a longer dosing interval but its intracellular activity requires further investigation.
Purpose of the Study:
- To compare the in vitro and intracellular activity of rifapentine and rifampicin against Staphylococcus aureus.
- To elucidate the mechanisms of antibiotic uptake and activity within human neutrophils.
Main Methods:
- Minimum Inhibitory Concentration (MIC) determination.
- Intracellular survival assays using human neutrophils.
- Antibiotic uptake studies by neutrophil sonicates.
- Assessment of pH and temperature dependence of antibiotic uptake.
- Evaluation of metabolic inhibitors' effects on intracellular killing.
Main Results:
- Rifapentine demonstrated lower weight-for-weight activity than rifampicin against Staphylococcus aureus in vitro.
- Both antibiotics were equally effective in reducing intracellular Staph. aureus survival, even below the MIC.
- Neither antibiotic affected the intracellular survival of antibiotic-resistant strains.
- Rifapentine exhibited three-fold greater concentration within neutrophils compared to rifampicin.
- Antibiotic uptake was temperature-dependent and rapid, reaching a plateau within 10 minutes.
- Rifapentine uptake was reduced at lower pH (5.0) unlike rifampicin.
- Metabolic inhibitors had a minor suggested role in uptake but no effect on intracellular killing.
Conclusions:
- Rifapentine possesses significant intracellular bactericidal activity against Staphylococcus aureus within neutrophils, comparable to rifampicin.
- The enhanced intracellular accumulation and pH-dependent uptake of rifapentine may contribute to its efficacy.
- Further research is warranted to explore rifapentine's role in treating Staph. aureus infections, particularly those involving intracellular pathogens.