Fernández Olga Lucía, Diaz-Toro Yira, Ovalle Clemencia, Valderrama Liliana, Muvdi Sandra, Rodríguez Isabel, Gomez María Adelaida, Saravia Nancy Gore
Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Cali, Colombia.
Centro Dermatológico Federico Lleras Acosta (CDFLLA), Bogotá, Colombia.
PLoS Negl Trop Dis. 2014 May 22;8(5):e2871. doi: 10.1371/journal.pntd.0002871. eCollection 2014 May.
Pentavalent antimonials have been the first line treatment for dermal leishmaniasis in Colombia for over 30 years. Miltefosine is administered as second line treatment since 2005. The susceptibility of circulating populations of Leishmania to these drugs is unknown despite clinical evidence supporting the emergence of resistance.
METHODOLOGY/PRINCIPAL FINDINGS: In vitro susceptibility was determined for intracellular amastigotes of 245 clinical strains of the most prevalent Leishmania Viannia species in Colombia to miltefosine (HePC) and/or meglumine antimoniate (Sb(V)); 163, (80%) were evaluated for both drugs. Additionally, susceptibility to Sb(V) was examined in two cohorts of 85 L. V. panamensis strains isolated between 1980-1989 and 2000-2009 in the municipality of Tumaco. Susceptibility to each drug differed among strains of the same species and between species. Whereas 68% of L. V. braziliensis strains presented in vitro resistance to HePC, 69% were sensitive to Sb(V). Resistance to HePC and Sb(V) occurred respectively, in 20% y 21% of L. panamensis strains. Only 3% of L. V. guyanensis were resistant to HePC, and none to Sb(V). Drug susceptibility differed between geographic regions and time periods. Subpopulations having disparate susceptibility to Sb(V) were discerned among L. V. panamensis strains isolated during 1980-1990 in Tumaco where resistant strains belonged to zymodeme 2.3, and sensitive strains to zymodeme 2.2.
CONCLUSIONS/SIGNIFICANCE: Large scale evaluation of clinical strains of Leishmania Viannia species demonstrated species, population, geographic, and epidemiologic differences in susceptibility to meglumine antimoniate and miltefosine, and provided baseline information for monitoring susceptibility to these drugs. Sensitive and resistant clinical strains within each species, and zymodeme as a proxy marker of antimony susceptibility for L. V. panamensis, will be useful in deciphering factors involved in susceptibility and the distribution of sensitive and resistant populations.
30多年来，五价锑化合物一直是哥伦比亚治疗皮肤利什曼病的一线药物。自2005年起，米替福新作为二线治疗药物使用。尽管有临床证据支持耐药性的出现，但利什曼原虫循环种群对这些药物的敏感性尚不清楚。
方法/主要发现：测定了哥伦比亚最常见的维氏利什曼原虫245株临床菌株的细胞内无鞭毛体对米替福新（HePC）和/或葡甲胺锑酸盐（Sb(V)）的体外敏感性；其中163株（80%）对两种药物都进行了评估。此外，在图马科市1980 - 1989年和2000 - 2009年分离的两组85株巴拿马利什曼原虫菌株中检测了对Sb(V)的敏感性。同一物种的不同菌株以及不同物种之间对每种药物的敏感性存在差异。巴西利什曼原虫菌株中有68%对HePC表现出体外耐药性，而69%对Sb(V)敏感。巴拿马利什曼原虫菌株中对HePC和Sb(V)的耐药率分别为20%和21%。圭亚那利什曼原虫只有3%对HePC耐药，对Sb(V)均不耐药。药物敏感性在不同地理区域和时间段有所不同。在图马科1980 - 1990年分离的巴拿马利什曼原虫菌株中，发现了对Sb(V)敏感性不同的亚群，其中耐药菌株属于酶谱型2.3，敏感菌株属于酶谱型2.2。
结论/意义：对维氏利什曼原虫临床菌株的大规模评估表明，该物种在对葡甲胺锑酸盐和米替福新的敏感性上存在物种、种群、地理和流行病学差异，并为监测这些药物的敏感性提供了基线信息。每个物种内的敏感和耐药临床菌株，以及作为巴拿马利什曼原虫锑敏感性替代标志物的酶谱型，将有助于解读敏感性相关因素以及敏感和耐药种群的分布情况。
