Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Cali, Colombia.
Universidad Icesi, Cali, Colombia.
Antimicrob Agents Chemother. 2022 Jan 18;66(1):e0142521. doi: 10.1128/AAC.01425-21. Epub 2021 Oct 25.
Failure of treatment of cutaneous leishmaniasis with antimonial drugs and miltefosine is frequent. Use of oral combination therapy represents an attractive strategy to increase efficacy of treatment and reduce the risk of drug resistance. We evaluated the potency of posaconazole, itraconazole, voriconazole, and fluconazole and the potential synergy of those demonstrating the highest potency, in combination with miltefosine (HePC), against infection with Leishmania (Viannia) panamensis. Synergistic activity was determined by isobolograms and calculation of the fractional inhibitory concentration index (FICI), based on parasite quantification using an model of human peripheral blood mononuclear cells (PBMCs) infected with a luciferase-transfected, antimony and miltefosine sensitive line of L. panamensis. The drug combination and concentrations that displayed synergy were then evaluated for antileishmanial effect in 10 clinical strains of L. panamensis by reverse transcription-quantitative (qRT-PCR) of 7SLRNA. High potency was substantiated for posaconazole and itraconazole against sensitive as well as HePC- and antimony-resistant lines of L. panamensis, whereas fluconazole and voriconazole displayed low potency. HePC combined with posaconazole (Poz) demonstrated evidence of synergy at free drug concentrations achieved in plasma during treatment (2 μM HePC plus 4 μM Poz). FICI, based on 70% and 90% reduction of infection, was 0.5 for the sensitive line. The combination of 2 μM HePC plus 4 μM Poz effected a significantly greater reduction of infection by clinical strains of L. panamensis than individual drugs. Orally administrable miltefosine/posaconazole combinations demonstrated synergistic antileishmanial capacity against L. panamensis, supporting their potential as a novel therapeutic strategy to improve efficacy and effectiveness of treatment.
皮肤利什曼病用锑剂和米替福新治疗失败很常见。口服联合治疗代表了一种提高疗效和降低耐药风险的有吸引力的策略。我们评估了泊沙康唑、伊曲康唑、伏立康唑和氟康唑的效力，并评估了那些显示最高效力的药物与米替福新（HePC）联合治疗感染的利什曼原虫（Viannia）panamensis 的潜力。协同活性通过棋盘法和基于使用感染人外周血单核细胞（PBMCs）的 Luciferase 转染、抗锑和米替福新敏感株的模型进行寄生虫定量的部分抑制浓度指数（FICI）来确定。然后，通过反转录-定量（qRT-PCR）检测 7SLRNA，评估在 10 株临床分离的利什曼原虫（Viannia）panamensis 中显示协同作用的药物组合和浓度的抗利什曼效果。泊沙康唑和伊曲康唑对敏感以及 HePC 和锑耐药株均具有高效力，而氟康唑和伏立康唑则显示低效力。HePC 与泊沙康唑（Poz）联合在治疗期间血浆中达到的游离药物浓度（2 μM HePC 加 4 μM Poz）显示出协同作用的证据。基于感染减少 70%和 90%的 FICI 分别为 0.5。2 μM HePC 加 4 μM Poz 的组合对临床分离株利什曼原虫（Viannia）panamensis 的感染减少作用明显大于单独用药。可口服的米替福新/泊沙康唑联合用药对利什曼原虫（Viannia）panamensis 显示出协同抗利什曼效果，支持其作为提高疗效和有效性的新型治疗策略的潜力。
