In vitro interaction between paromomycin sulphate and four drugs with leishmanicidal activity against three New World Leishmania species

Abstract

OBJECTIVES: To evaluate in vitro interactions between paromomycin sulphate and the antileishmanial drugs meglumine antimoniate, amphotericin B, miltefosine and azithromycin against intracellular Leishmania (Leishmania) infantum chagasi, Leishmania (Viannia) braziliensis and Leishmania (Leishmania) amazonensis amastigotes in peritoneal mouse macrophages. METHODS: First, drug susceptibility was assessed in 3, 5 and 7 day assays, followed by drug interaction assays with a modified fixed-ratio method. An overall mean sum fractional inhibitory concentration (∑FIC) was calculated for each combination and each Leishmania species. The nature of the interactions was classified as synergistic if the mean ∑FIC was ≤ 0.5, indifferent if the mean ∑FIC was >0.5-4.0 and antagonistic if the mean ∑FIC was >4.0. RESULTS: In vitro synergism was observed for the combinations of paromomycin plus miltefosine [at 50% and 90% inhibitory concentrations (IC50 and IC90, respectively)] and paromomycin plus amphotericin B (at the IC90 level) against L. (L.) amazonensis, paromomycin plus meglumine antimoniate (at the IC50 and IC90 levels) and paromomycin plus amphotericin B (at the IC50 level) against L. (V.) braziliensis, and paromomycin plus miltefosine, paromomycin plus amphotericin B (both at the IC90 level) and paromomycin plus azithromycin (at the IC50 level) against L. (L) infantum chagasi. CONCLUSIONS: This work provides a preclinical dataset that supports future studies on multidrug treatment schedules against New World leishmaniasis.