Natural Resistance of Leishmania infantum to Miltefosine Contributes to the Low Efficacy in the Treatment of Visceral Leishmaniasis in Brazil
Natural Resistance of Leishmania infantum to Miltefosine Contributes to the Low Efficacy in the Treatment of Visceral Leishmaniasis in Brazil
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DOI：
10.4269/ajtmh.18-0949
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发表时间：
2019-01-01
影响因子：
3.3
通讯作者：
Dietze, Reynaldo
中科院分区：
文献类型：
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作者：
Carnielli, Juliana B. T.;Monti-Rocha, Renata;Dietze, Reynaldo
在印度，由杜氏利什曼原虫引起的内脏利什曼病（VL）已成功地用米替福新治疗，治愈率> 90%。为了评估口服米替福新对由婴儿利什曼原虫引起的巴西VL的疗效和安全性，在儿童（2-12岁）和成年人（13-60岁）中进行了口服米替福新的II期、开放标签、剂量递增研究。在6个月的随访访视时评估了持续治愈。推荐治疗28天的治愈率仅为42%（14例患者中的6例），延长治疗42天的治愈率为68%（28例患者中的19例）。在体外米替福新的敏感性资料的细胞内无鞭毛体阶段的预处理分离株，治愈和复发的患者，显示出正相关的临床结果。最终治愈的IC 50均值（SEM）为5.1（0.4）μ M，而最终失败的IC 50均值为12.8（1.9）μ M（P = 0.0002）。IC 50高于8.0 μ M预测失败，灵敏度为82%，特异性为100%。L.在来自最终治疗失败的患者的分离物中对米替福新具有抗性的婴儿无鞭毛体强烈地表明了对该药物的天然抗性，因为在进行该试验之前米替福新从未在巴西使用。
In India, visceral leishmaniasis (VL) caused by Leishmania donovani has been successfully treated with miltefosine with a cure rate of > 90%. To assess the efficacy and safety of oral miltefosine against Brazilian VL, which is caused by Leishmania infantum, a phase II, open-label, dose-escalation study of oral miltefosine was conducted in children (aged 2-12 years) and adolescent-adults (aged 13-60 years). Definitive cure was assessed at a 6-month followup visit. The cure rate was only 42% (6 of 14 patients) with a recommended treatment of 28 days and 68% (19 of 28 patients) with an extended treatment of 42 days. The in vitro miltefosine susceptibility profile of intracellular amastigote stages of the pretreatment isolates, from cured and relapsed patients, showed a positive correlation with the clinical outcome. The IC50 mean (SEM) of eventual cures was 5.1 (0.4) mu M, whereas that of eventual failures was 12.8 (1.9) mu M(P = 0.0002). An IC50 above 8.0 mu M predicts failure with 82% sensitivity and 100% specificity. The finding of L. infantum amastigotes resistant to miltefosine in isolates from patients who eventually failed treatment strongly suggests natural resistance to this drug, as miltefosine had never been used in Brazil before this trial was carried out.