Failure of fluconazole in treating cutaneous leishmaniasis caused by Leishmania guyanensis in the Brazilian Amazon: An open, nonrandomized phase 2 trial

Background: The treatment of Leishmaniasis caused by Leishmania (Viannia) guyanensis is based on a weak strength of evidence from very few clinical trials and some case series reports. Current treatment guidelines recommend pentamidine isethionate or meglumine antimoniate (Glucantime) as the first-line choices. Both are parenteral drugs with a low therapeutic indexes leading to a high risk of undesired effects. Imidazole derivatives interfere with the production of leishmanial ergosterol, an essential component of their membrane structure. One drug that has been studied in different clinical presentations of Leishmania is fluconazole, a hydrophilic bis-triazole, which is easily absorbed through the oral route with a low toxicity profile and is considered safe for children. This drug is readily available in poor countries with a reasonable cost making it a potential option for treating leishmaniasis. Methods and findings: An adaptive nonrandomized clinical trial with sequential groups with dose escalation of oral fluconazole was designed to treat adult men with localized cutaneous leishmaniasis (LCL) in Manaus, Brazil. Eligible participants were patients with LCL with confirmed Leishmania guyanensis infection. Results: Twenty adult male patients were treated with 450 mg of fluconazole daily for 30 days. One patient (5%) was cured within 30 days of treatment. Of the 19 failures (95%), 13 developed a worsening of ulcers and six evolved lymphatic spreading of the disease. Planned dose escalation was suspended after the disappointing failure rate during the first stage of the trial. Conclusion/Significance: Oral fluconazole, at the dose of 450mg per day, was not efficacious against LCL caused by Leishmania guyanensis in adult men. Trial registration: Brazilian Clinical Trial Registration (ReBec)—RBR-8w292w; UTN number—1158-2421 Author summary: The main agent causing localized cutaneous leishmaniasis in the Guianan Ecoregion Complex, a region that covers Guiana, Suriname, French Guiana, the southern portion of Venezuela and the northern portion of the Amazon Basin, is Leishmania (Viannia) guyanensis. The current treatment regimens for treating this parasite follow a weak strength of recommendation based on a low-quality evidence. All the drugs used are parenteral drugs with low therapeutic indexes and inadequate cure rates. Azoles are drugs that interfere with the production of leishmanial ergosterol and have been studied in other Leishmania species with promising results. Fluconazole is a hydrophilic bis-triazole that accumulates rapidly and extensively in the skin with a low toxicity profile. It is considered safe for children. Oral fluconazole is readily available and has a reasonable cost. In this work, we estimated the efficacy of fluconazole in treating localized cutaneous leishmaniasis caused by L. guyanensis in Manaus. The study had to be stopped due to the disappointing results, with only a 5% cure rate. Among the failures, 55% developed a marked worsening of their ulcers and 55% of those patients had lymphatic dissemination of the infection. In conclusion, fluconazole at the dose of 450mg per day is not efficacious in treating localized cutaneous leishmaniasis caused by L. guyanensis.