Abstract. Clinical response to supervised treatment of Colombian patients with cutaneous leishmaniasis was evaluated in a randomized controlled trial comparing 10 days versus 20 days of treatment with meglumine antimonate (20 mg Sb/kg/day). Masked examiners evaluated clinical response defined as 100% re-epithelialization of all lesions at 13 weeks and no relapses during 52 weeks of follow-up. The efficacy of meglumine antimonate for 10 days' treatment was 61% (28 of 46) compared to 67% (24 of 36) for 20 days. There was a significantly lower clinical response for children Ͻ 5 years in both 10-day (11%) and 20-day (25%) groups compared to patients aged 5-14 years (67% and 75%, respectively) and 15 years or more (81% and 83%, respectively). Overall efficacy of treatment schedules was comparable, but lower than expected, mainly because of low efficacy in children. Pathogenicity of infection and pharmacokinetics may affect the treatment response in children. New therapeutic alternatives should be evaluated in trials that include children and women.
Plasmodium falciparum response mechanisms to the major artemisinin-based combination therapies (ACTs) are largely unknown. Multidrug-resistance protein (MRP)-like adenosine triphosphate (ATP)-binding cassette transporters are known to be related to multidrug resistance in many organisms. Therefore, we hypothesized that sequence variation in pfmrp1 can contribute to decreased parasite sensitivity to ACT. Through sequencing of the pfmrp1 open reading frame for 103 geographically diverse P. falciparum infections, we identified 27 single-nucleotide polymorphisms (SNPs), of which 21 were nonsynonymous and 6 synonymous. Analyses of clinical efficacy trials with artesunate-amodiaquine and artemether-lumefantrine detected a specific selection of the globally prevalent I876V SNP in recurrent infections after artemether-lumefantrine treatment. Additional in silico studies suggested an influence of variation in amino acid 876 on the ATP hydrolysis cycle of pfMRP1 with potential impact on protein functionality. Our data suggest for the first time, to our knowledge, the involvement of pfMRP1 in P. falciparum in vivo response to ACT.
The Leishmaniases are a group of diseases whose clinical presentation is in part determined by the infecting species. Until recently, mucosal leishmaniasis was attributed exclusively to Leishmania (Viannia ) braziliensis; however, the capacity of other species of the subgenus Viannia to invade mucosal tissue has been documented. This report examines the clinical characteristics of 23 parasitologically diagnosed patients with mucosal leishmaniasis due to L. (V.) panamensis from the Pacific Coast of Colombia seen at CIDEIM between 1985 and 1996. Most of the mucosal lesions 74% (17 of 23) were mild, with a short time of evolution (median ϭ 2.5 months) and were present concomitantly with an active cutaneous lesion in 61% (14 of 23) of the cases. The simultaneous presentation of mucosal and active cutaneous lesions contrast with classical descriptions of mucosal leishmaniasis caused by L. (V.) braziliensis, and highlights the importance of early diagnosis of mucosal disease by the examination of mucosa in all cases of cutaneous leishmaniasis.
IntroductionReports of therapeutic failure to meglumine antimoniate (MA) and miltefosine in cutaneous leishmaniasis (CL) varies between species, populations and geographic regions. This study aimed to determine the clinical, drug-related factors, and Leishmania species associated with treatment failure in children and adults with cutaneous leishmaniasis.MethodsA cohort study was performed with children (2–12 years old) and adults (18–65 years old) with CL, who have participated in clinical studies at CIDEIM Cali, Tumaco and Chaparral. Incidence of therapeutic failure was estimated by treatment and age groups. Descriptive, bivariate, and multiple logistic regression analyses were performed for the complete cohort and pediatric patients.ResultsTwo hundred and thirty patients were included (miltefosine: 112; MA: 118), of which 60.4% were children and 83.9% were infected with L.V. panamensis. Overall incidence of therapeutic failure was 15.65% (95%CI: 10.92–20.38), and was lower for miltefosine than for MA (8.92%, 95%CI: 3.59–14.26 versus 22.03%, 95%CI:14.48–29.58, p = 0.006). Treatment failure was associated with age ≤8 years (OR: 3.29; 95%CI: 1.37–7.89), disease duration ≤1 month (OR: 3.29; 95%CI: 1.37–7.89), regional lymphadenopathy (OR: 2.72; 95%CI: 1.10–6.70), treatment with MA (OR: 3.98; 95%CI: 1.66–9.50), and adherence <90% (OR: 3.59; 95%CI: 1.06–12.11). In children, higher Z-score of height/age was a protective factor (OR: 0.58; 95%CI: 0.36–0.93), while treatment with MA was a risk factor (OR: 40.82; 95%CI: 2.45–677.85), demonstrating significant interaction with age (p = 0.03).ConclusionsClinical and drug-related factors determine therapeutic failure in CL. High risk of failure in children treated with MA indicates the need to reconsider this drug as first line treatment in this population.Trial registrationClinical trial registration: NCT00487253Clinical trial registration: NCT01462500Clinical trial registration: NCT01464242
The potential role of polymorphisms in the pfcrt and pfmdr1 genes and in vitro susceptibility to amodiaquine and desethylamodiaquine were explored in 15 chloroquine-resistant Colombian Plasmodium falciparum isolates. Single nucleotide polymorphisms in the pfcrt gene, including a newly reported mutation (S334N), were seen in isolates with decreased susceptibility to amodiaquine and desethylamodiaquine. The lowest susceptibility found to amodiaquine was observed in an isolate carrying a pfcrt and pfmdr1 Dd2-like haplotype, whereas a pfcrt haplotype related to the 7G8 Brazilian strain was found in a Colombian isolate with the lowest susceptibility to desethylamodiaquine. This exploratory study suggests that polymorphisms in the pfcrt and pfmdr1 genes play a role in amodiaquine and desethylamodiaquine resistance and warrants further study.
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