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Leishmania resistant to sodium stibogluconate: drug-associated macrophage-dependent killing
M E Ibrahim1, M Hag-Ali, A M el-Hassan
1Center for Medical Parasitology, University of Copenhagen, Denmark.
Abstract:
A total of 17 Leishmania isolates, 6 of them isolated from antimony-resistant patients, were collected in the Sudan and tested for their sensitivity to sodium stibogluconate (Pentostam) as promastigotes. Six of those isolates were tested as amastigotes infecting a murine macrophage cell line. The results indicated that the conventional promastigote screening assay did not correlate with the clinical picture, whereas the amastigote/macrophage system produced results that pertained to the in vivo responses to the drug. A laboratory-generated resistant strain of L. major was adapted to grow at a high concentration of Pentostam (1000 micrograms/ml) as promastigotes but was quite sensitive to the drug at much lower concentrations in the amastigote/(macrophage system (20 micrograms/ml), thus suggesting that Pentostam's inhibitory action is mediated through the macrophage rather than through a direct toxic effect exerted on the parasite.
Insights
The amastigote/macrophage assay better predicts patient response to sodium stibogluconate (Pentostam) than promastigote screening. This suggests Pentostam
Area of Science:
- Parasitology
- Drug Resistance
- Leishmaniasis Treatment
Background:
- Sodium stibogluconate (Pentostam) is a primary treatment for leishmaniasis.
- Antimony resistance in Leishmania parasites poses a significant clinical challenge.
- Accurate in vitro sensitivity testing is crucial for effective treatment selection.
Purpose of the Study:
- To evaluate the correlation between in vitro drug sensitivity assays and clinical outcomes in Leishmania isolates.
- To compare the efficacy of promastigote and amastigote/macrophage assays for predicting Pentostam response.
- To elucidate the mechanism of Pentostam's action against Leishmania parasites.
Main Methods:
- Collected 17 Leishmania isolates from Sudan, including 6 from antimony-resistant patients.
- Tested parasite sensitivity to Pentostam using both promastigote and amastigote stages infecting murine macrophages.
- Adapted a laboratory-resistant L. major strain to high Pentostam concentrations.
Main Results:
- The conventional promastigote assay showed poor correlation with clinical resistance.
- The amastigote/macrophage system demonstrated results that correlated with in vivo drug responses.
- A resistant L. major strain was sensitive to low Pentostam concentrations in the amastigote/macrophage system.
Conclusions:
- The amastigote/macrophage assay is a more reliable predictor of Pentostam efficacy than the promastigote assay.
- Pentostam's inhibitory effect appears to be mediated through the host macrophage.
- This finding has implications for improving diagnostic strategies and treatment of leishmaniasis.