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Chronic granulomatous disease: effect of sulfamethoxazole/trimethoprim on neutrophil microbicidal function
Abstract:
Normal and chronic granulomatous disease (CGD) neutrophils accumulated sulfamethoxazole (SMX) 3-fold and trimethoprim (TMP) 14-fold, possibly through a non-ionic diffusion and pH-partition mechanism. CGD neutrophils incubated with SMX/TMP after phagocytosis of S. aureus killed the bacteria. These findings explain the clinically observed beneficial effect of SMX/TMP in the treatment of infections in CGD and in other conditions characterized by impaired phagocyte microbicidal capacity.
Insights
Sulfamethoxazole (SMX) and trimethoprim (TMP) accumulate in neutrophils, enhancing bacterial killing in chronic granulomatous disease (CGD). This explains SMX/TMP efficacy in infections with impaired phagocyte function.
Area of Science:
- Pharmacology
- Immunology
- Microbiology
Background:
- Neutrophils are crucial for combating bacterial infections.
- Chronic granulomatous disease (CGD) impairs neutrophil microbicidal function.
- Sulfamethoxazole (SMX) and trimethoprim (TMP) are antibiotics often used to manage infections.
Purpose of the Study:
- To investigate the accumulation of SMX and TMP in normal and CGD neutrophils.
- To determine the effect of SMX/TMP on bacterial killing by CGD neutrophils.
- To elucidate the mechanism of SMX/TMP accumulation in neutrophils.
Main Methods:
- Quantification of SMX and TMP accumulation in neutrophils from healthy donors and CGD patients.
- Assessment of bacterial killing by SMX/TMP-treated CGD neutrophils after Staphylococcus aureus phagocytosis.
- Analysis of potential drug accumulation mechanisms, including non-ionic diffusion and pH-partition.
Main Results:
- CGD neutrophils demonstrated a 3-fold increase in SMX and a 14-fold increase in TMP accumulation compared to normal neutrophils.
- SMX/TMP treatment enhanced the killing of S. aureus by CGD neutrophils.
- Drug accumulation may be mediated by non-ionic diffusion and pH-partition mechanisms.
Conclusions:
- SMX and TMP accumulate significantly in CGD neutrophils, potentially via non-ionic diffusion and pH-partition.
- The enhanced accumulation of SMX/TMP contributes to improved bacterial killing in CGD neutrophils.
- These findings provide a mechanistic explanation for the clinical efficacy of SMX/TMP in treating infections in CGD and related conditions.