American Tegumentary Leishmaniasis: Is Antimonial Treatment Outcome Related to Parasite Drug Susceptibility?

Abstract

Antimony insensitivity might occur in a stepwise fashion (first to SbV and then to SbIII). Our data question the definition of true parasite resistance to antimonials. Further studies of treatment efficacy should apply standardized protocols and definitions and should also consider host factors.

Chronic exposure to arsenic in drinking water can lead to resistance to antimonial drugs in a mouse model of visceral leishmaniasis

“…Patients who experienced treatment failure in Peru were more likely to have had a short disease duration, have more than one CL lesion, have either Leishmania peruviana or Leishmania braziliensis isolated, and have lived in an area of endemicity for less than 72 mo (34). In vitro susceptibility to antimony was not determined, but a related study found no correlation between parasite resistance and clinical outcome to antimonial therapy (35). Detailed epidemiological work is underway to explore the relationship between arsenic exposure and antimonial treatment failure in VL in Bihar, including assessment of established clinical risk factors.…”

Comparison of gene expression patterns amongLeishmania braziliensisclinical isolates showing a differentin vitrosusceptibility to pentavalent antimony

“…Indeed, different epi-phenotypes to which the parasites could have developed specific adaptations might remain hidden in the in vitro Sb V susceptibility assays, but interfering with the gene expression patterns. For instance, (i) the variable adaptation to the macrophage effectors in the immunological context of the clinical infection (absent in the in vitro susceptibility assays) or (ii) the resistance to the reduced form of the drug, Sb III (Yardley et al 2006;Rijal et al 2007). These epi-phenotypes would explain the incongruences between the parasites' in vitro Sb V resistance and chemotherapy failure reported elsewhere (Yardley et al 2006;Rijal et al 2007) and illustrated in Table 1.…”

“…Isolates were essentially obtained before treatment of patients, typed by PCR-RFLP analysis of hsp70 and cpb genes (Garcia et al 2005) and tested as intracellular amastigotes for their in vitro susceptibility to Sb V (Yardley et al 2006) (see Table 1 for summary of isolate features). Promastigote forms were grown at 24°C in a biphasic medium consisting of rabbit blood agar overlaid with medium 199 (M199; Sigma) containing 20% heat-inactivated fetal bovine serum (FBS; Lonza Bioscience), 25 mM Hepes (pH 7·4), 100 units/ml penicillin and 100 μg/ml streptomycin (Lonza).…”

“…It is estimated that worldwide there is an annual incidence of 1·5-2 million new cases, with up to 350 million people at risk of infection (Murray et al 2005). Chemotherapy is the main control strategy for leishmaniasis and pentavalent antimonials (Sb V ) remain the mainstay, but their efficacy is threatened by the emergence of drugresistant Leishmania parasites, as described in several endemic regions (Lira et al 1999;Hadighi et al 2006;Rojas et al 2006;Yardley et al 2006).…”

Leishmaniases in Bolivia: Comprehensive Review and Current Status

“…67 Recently a study reported 7% of patients unresponsive to SbV. 68 Unresponsiveness could be caused by the use of subtherapeutic doses and substandard drugs, patient non-compliance with the treatment regimen, immunosuppression (e.g., because of HIV infection), and, of course, the real emergence of drug-resistant parasite strains. Of note is that, whereas SbV-resistant strains of L. For patients unresponsive to antimony (e.g., ML patients), amphotericin B deoxycholate (Fungizone , Bristol Myers Squibb, New York, NY) is the second-line drug in Bolivia.…”