Clinical and parasite species risk factors for pentavalent antimonial treatment failure in cutaneous leishmaniasis in Peru
ABSTRACT Treatment for cutaneous leishmaniasis (CL) with standard pentavalent antimonial therapy is hampered by cumbersome administration, toxicity, and potential failure. Knowledge of factors influencing treatment outcome is essential for successful management.
A case-control study of incident cases was performed with patients experiencing their first CL episode. The standard treatment for CL for these patients was 20 mg/kg/day of sodium stibogluconate for 20 days. Clinical and epidemiological data were recorded, and parasite isolates were species typed. Patients were followed up for 6 months to assess treatment outcome. Clinical cure was defined as complete wound closure and re-epithelization without inflammation or infiltration; new lesions, wound reopening, or signs of activity were classified as treatment failure. Descriptive, bivariate, and logistic regression analyses were performed.
One hundred twenty-seven patients were recruited; 63 (49.6%) were infected with Leishmania (Viannia) peruviana, 29 (22.8%) were infected with Leishmania (Viannia) braziliensis, 27 (21.3%) were infected with Leishmania (Viannia) guyanensis, and 8 (6.3%) were infected with other species. Only patients infected with the 3 most common species were selected for risk-factor analysis (n=119). Final failure rate at 6 months was 24.4% (95% confidence interval [CI], 16.5%-32.1%), with 96% of failures occurring within the first 3 months of follow-up assessment. Risk factors for treatment failure identified in the final multivariate model were age (per year, odds ratio [OR], 0.95; 95% CI, 0.92-0.99; P=.017), stay of <72 months in area of disease acquisition (OR, 30.45; 95% CI, 2.38-389.25; P=.009), duration of disease <5 weeks (OR, 4.39; 95% CI, 1.12-17.23; P=.034), additional lesion (per lesion, OR, 2.06; 95% CI, 1.3-3.28; P=.002), infection with L. (V.) peruviana (OR, 9.85; 95% CI, 1.01-95.65; P=.049), and infection with L. (V.) braziliensis (OR, 22.36; 95% CI, 1.89-263.96; P=.014).
The identification of parasite species and clinical risk factors for antimonial treatment failure should lead to an improved management of CL in patients in Peru.
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ABSTRACT: Leishmaniasis is increasingly reported among travellers. Leishmania species vary in sensitivity to available therapies. Fast and reliable molecular techniques have made species-directed treatment feasible. Many treatment trials have been designed poorly, thus developing evidence-based guidelines for species-directed treatment is difficult. Published guidelines on leishmaniasis in travellers do not aim to be comprehensive or do not quantify overall treatment success for available therapies. We aimed at providing comprehensive species-directed treatment guidelines. English literature was searched using PubMed. Trials and observational studies were included if all cases were parasitologically confirmed, the Leishmania species was known, clear clinical end-points and time points for evaluation of treatment success were defined, duration of follow-up was adequate and loss to follow-up was acceptable. The proportion of successful treatment responses was pooled using mixed effects methods to estimate the efficacy of specific therapies. Final ranking of treatment options was done by an expert panel based on pooled efficacy estimates and practical considerations. 168 studies were included, with 287 treatment arms. Based on Leishmania species, symptoms and geography, 25 clinical categories were defined and therapy options ranked. In 12/25 categories, proposed treatment agreed with highest efficacy data from literature. For 5/25 categories no literature was found, and in 8/25 categories treatment advise differed from literature evidence. For uncomplicated cutaneous leishmaniasis, combination of intralesional antimony with cryotherapy is advised, except for L. guyanensis and L. braziliensis infections, for which systemic treatment is preferred. Treatment of complicated (muco)cutaneous leishmaniasis differs per species. For visceral leishmaniasis, liposomal amphotericin B is treatment of choice. Our study highlights current knowledge about species-directed therapy of leishmaniasis in returning travellers and also demonstrates lack of evidence for treatment of several clinical categories. New data can easily be incorporated in the presented overview. Updates will be of use for clinical decision making and for defining further research.PLoS Neglected Tropical Diseases 05/2014; 8(5):e2832. DOI:10.1371/journal.pntd.0002832 · 4.49 Impact Factor
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ABSTRACT: Background: Leishmaniasis remains a worldwide public health problem. The limited therapeutic options, drug toxicity and reports of resistance, reinforce the need for the development of new treatment options. Previously, we showed that 17( allylamino)-17-demethoxygeldanamycin (17-AAG), a Heat Shock Protein 90 (HSP90)-specific inhibitor, reduces L. (L.) amazonensis infection in vitro. Herein, we expand the current knowledge on the leishmanicidal activity of 17-AAG against cutaneous leishmaniasis, employing an experimental model of infection with L. (V.) braziliensis. Methodology/Principal findings: Exposure of axenic L. (V.) braziliensis promastigotes to 17-AAG resulted in direct dose-dependent parasite killing. These results were extended to L. (V.) braziliensis-infected macrophages, an effect that was dissociated from the production of nitric oxide (NO), superoxide (O-2) or inflammatory mediators such as TNF-alpha, IL-6 and MCP-1. The leishmanicidal effect was then demonstrated in vivo, employing BALB/c mice infected with L. braziliensis. In this model, 17-AAG treatment resulted in smaller skin lesions and parasite counts were also significantly reduced. Lastly, 17-AAG showed a similar effect to amphotericin B regarding the ability to reduce parasite viability. Conclusion/Significance: 17-AAG effectively inhibited the growth of L. braziliensis, both in vitro and in vivo. Given the chronicity of L. (V.) braziliensis infection and its association with mucocutaneous leishmaniasis, 17-AAG can be envisaged as a new chemotherapeutic alternative for cutaneous Leishmaniasis.PLoS neglected tropical diseases 10/2014; 8(10). DOI:10.1371/journal.pntd.0003275 · 4.72 Impact Factor
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ABSTRACT: Leishmaniasis, a disease caused by parasites of the Leishmania genus, constitutes a significant health and social problem in many countries and is increasing worldwide. The conventional treatment, meglumine antimoniate (MA), presents numerous disadvantages, including invasiveness, toxicity and frequent therapeutic failure, justifying the attempts at finding alternatives to the first-line therapy. We have studied the comparative long-term efficacy of MA against miltefosine (MF) in Leishmania infection in experimental mice. The criteria for efficacy evaluation were: footpad lesion size, anti-Leishmania antibodies level, histopathology of the site of inoculation (right footpad, RFP), splenic index (SI) and the presence of parasites in RFP, spleen and liver, determined by Polymerase Chain Reaction (PCR). Swiss mice, infected with L. (L.) amazonensis were treated, at different time points (5 and 40 days after infection) with either MA or MF. The efficacy of MF was better than that of MA for inhibiting lesions and for reducing tissue damage and presence/load of amastigotes in spleen and liver. Moreover, early administration of MF, produced a clear reduction in splenomegaly, and was equal in reducing antibody titles in comparison to MA. Our results demonstrated that MF is an effective and safe therapeutic alternative for leishmaniasis by L. (L.) amazonensis and is more efficacious than MA.Journal of Parasitology 12/2014; 100(6). DOI:10.1645/13-376.1 · 1.32 Impact Factor