In vitro activity of anti-leishmanial drugs against Leishmania donovani is host cell dependent

Abstract

Objectives: To evaluate the in vitro activity of anti-leishmanial drugs against intracellular Leishmania donovani amastigotes in different types of macrophages. Methods: Mouse peritoneal macrophages (PEMs), mouse bone marrow-derived macrophages (BMMΦ), human peripheral blood monocyte-derived macrophages (PBMΦ) and differentiated THP-1 cells were infected with L. donovani. Cultures were incubated with sodium stibogluconate, amphotericin B deoxycholate (Fungizone®), miltefosine or paromomycin sulphate over six concentrations in 3-fold serial dilutions for 5 days. Analysis was based on percentage inhibition of infected macrophages and EC50/EC90 values estimated using sigmoidal curve-fitting. Results: The rank order of drug activity was the same in the different macrophage populations: amphotericin B>miltefosine>sodium stibogluconate>paromomycin. However, significant (P<0.05) differences were observed between populations. Amphotericin B was more active in PEMs and BMMΦ (EC50 0.02-0.06 μM) compared with PBMΦ and differentiated THP-1 cells (EC50 0.08-0.40 μM) and miltefosine was more active in PBMΦ (EC50 0.16-0.74 μM) compared with PEMs and BMMΦ (EC50 2.60-7.67 μM). Sodium stibogluconate displayed highest activity in PBMΦ (EC50 1.38-1.89 μgSbv/mL), followed by PEMs (EC50 21.75-27.79 μgSbv/mL) and BMMΦ and differentiated THP-1 cells (EC50 28.96-112.77 μgSbv/mL). Paromomycin showed highest activity in PBMΦ (EC50 80.03-104.38 μM) and PEMs (EC50 75.42-201.63 μM). Conclusions: In vitro activity of anti-leishmanial drugs is host cell dependent. This has implications for: (i) the evaluation of in vitro drug activity; (ii) the evaluation of drug susceptibility of clinical isolates; and (iii) the standardization of anti-leishmanial drug assays. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.