Efficacy of azole therapy for tegumentary leishmaniasis: A systematic review and meta-analysis

Abstract

BackgroundSeveral controlled and uncontrolled studies addressing azole antifungal drugs for cutaneous and mucosal leishmaniasis have been published with inconclusive results. We conducted a systematic literature review of studies evaluating the efficacy and toxicity associated with azole therapy for tegumentary leishmaniasis.MethodologyPRISMA guidelines for systematic reviews and the Cochrane manual were followed, and the review methodology was registered (PROSPERO; CRD42016048668). Sources included the EMBASE, Web of Science, MEDLINE, LILACS, and IBECS databases along with a manual search of references from evaluated studies. Additional resources such as Google Scholar and clinicaltrials.gov were also searched. We included all studies reporting cure rate after cutaneous or mucosal leishmaniasis treatment with systemic azole drugs, regardless of their design. R software was used to estimate global rates of success and adverse events with each drug. The main outcome of interest was clinical cure, defined as complete re-epithelialization of all lesions.ResultsA total of 37 studies involving 1259 patients that reported outcomes after fluconazole (9), ketoconazole (14) and itraconazole (15) treatments were included. Only 14 (38%) were randomized controlled trials (RCT). The pooled azole final efficacy rate was 64% (CI95%: 57–70%) for all studies and 60% (CI95%: 50–70%) (p = 0.41) if only RCTs studies were considered. Twenty-four studies were conducted in the Old World and 13 studies in the Americas. The final efficacy rate according to New and Old World were 62% (CI95%: 43–77%) and 66% (CI95%: 58–73%), respectively. The final efficacy rate of azoles according to species were 89% (CI95%: 50–98%) for L. mexicana; 88% for L. infantum (CI95%: 27–99%); 80% for L. donovani; 53% (CI95%: 29–76%) for L. major; 49% for L. braziliensis (CI95%: 21–78%); and 15% (CI95%: 1–84%) for L. tropica. The cure rates were similar among the fluconazole, ketoconazole and itraconazole group arms (p = 0.89), specifically 61% (CI95%: 48–72%), 64% (CI95%: 44–80%) 65% (CI95%: 56–72%), respectively. Adverse events during fluconazole, itraconazole and ketoconazole therapy were reported in 7% (CI95%: 3–14%), 12% (CI95% 8–19%) and 13% (CI95%: 6–29%) of treated patients, respectively, without difference among them (p = 0.35). This systematic review included studies with small samples and both non-comparative and non-randomized studies and the main limitation was the low quality of the available studies.ConclusionsAvailable evidence suggests that fluconazole, ketoconazole and itraconazole have similar and modest efficacy rates for tegumentary leishmaniasis treatment. There is insufficient evidence to support the exclusive use of azole therapy as a single agent for leishmaniasis treatment.

Intraläsionale Therapie einer lokalisierten Leishmaniose mit Meglumin‐Antimonat

“…Azole haben gegen L. mexicana eine Wirksamkeit von 89 %. Die Heilungsraten durch Fluconazol, Itraconazol und Ketoconazol betragen 61 %, 65 % beziehungsweise 64 % [10]. Zusätzlich zu anderen verfügbaren Therapien hat Imiquimod als Adjuvans zusätzlich zu MA ein gutes Ansprechen ohne Therapieversagen oder Rezidiv gezeigt.…”

Leishmaniasis cutánea causada por Leishmania braziliensis y uso de anfotericina B liposomal. Comunicación de un caso clínico importado

“…Un meta-análisis demostró una eficacia de 60% para los azoles. La eficacia se redujo a 49% para L. brazilensis6 . Por estas razones, los azoles no deben ser usados como terapia inicial en leishmaniasis del Nuevo Mundo 1 .…”

Uso da anfotericina B lipossomal e de outras drogas no tratamento de pacientes com leishmaniose mucosa: análise da experiência em um serviço de referência para o diagnóstico e tratamento das leishmanioses, 2000-2015

“…Este estudo demonstra uma frequência de IRA próxima a encontrada por Wortmann et al (2010) e Guery et al (2017) (Galvão et al, 2017). Os eventos adversos mais frequentemente relatados como razões para a interrupção da terapia com azóis foram as elevações de enzimas hepáticas, dor epigástrica, náuseas e vômitos, aumento da creatinina, dores de cabeça, erupções cutâneas e icterícia (Galvão et al, 2017).…”

“…Este estudo demonstra uma frequência de IRA próxima a encontrada por Wortmann et al (2010) e Guery et al (2017) (Galvão et al, 2017). Os eventos adversos mais frequentemente relatados como razões para a interrupção da terapia com azóis foram as elevações de enzimas hepáticas, dor epigástrica, náuseas e vômitos, aumento da creatinina, dores de cabeça, erupções cutâneas e icterícia (Galvão et al, 2017). Ao avaliar estudos que abordaram apenas pacientes com LM, entre 38 tratados com itraconazol não houve relato da ocorrência de efeito adverso (Amato et al, 2000b;Calvopina et al, 2004;Amato et al, 2009).…”

“…Leishmania, com piores respostas para L. braziliensis 49% e L. tropica 15%(Galvão et a.,;. Os resultados, entretanto, quando abordado tratamento com azóis apenas para a forma mucosa, são muito discrepantes, e envolvem apenas 3 estudos publicados até o momento.…”