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

Abstract

BackgroundThe 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 findingsAn 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.ResultsTwenty 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/SignificanceOral fluconazole, at the dose of 450mg per day, was not efficacious against LCL caused by Leishmania guyanensis in adult men.Trial registrationBrazilian Clinical Trial Registration (ReBec)—RBR-8w292w; UTN number—1158-2421

Favorable responses to treatment with 5 mg Sbv/kg/day meglumine antimoniate in patients with American tegumentary leishmaniasis acquired in different Brazilian regions

“…Leishmania (L.) amazonensis (1 case) and L. (V.) guyanensis (2 cases) were isolated from patients who acquired infections in the states of Maranhão and Amazonas, respectively, corroborating epidemiological data from these regions 2,36,37 . As 42% of the OS individuals came from the northern region, it is interesting to comment on the possibility of the presence of other species causing the lesions, especially L. (V.) shawi, and L. (V.) naiffi 38 , which could not be retrieved.…”

“…The only patient infected by L. (L.) amazonensis in this study presented with the classic localized cutaneous form with a single lesion, which usually responds satisfactorily to antimonial drugs 2 ; he was cured after the first course of treatment. Despite the poor expected response of L. (V.) guyanensis to MA 2,6,7,37 , one out of the two patients infected by this species was cured after the second treatment using 5 mg Sb v /kg/day. Although MA is the first-choice drug for treating ATL in Brazil, pentamidine has been the drug of choice in the Brazilian Amazon basin for the treatment of patients infected with this species 2 .…”

Identification of Clinical Infections of Leishmania Imported into Australia: Revising Speciation with Polymerase Chain Reaction-RFLP of the Kinetoplast Maxicircle

“…Leishmania (Viannia) species of the New World can lead to diverse clinical presentations and as such often have a diverse and unpredictable response to treatment. 54 Previous reports have demonstrated a strong correlation between inappropriately treated CL forms of the disease and the subsequent occurrence of MCL for both L. (V.) braziliensis and L. (V.) guyanensis. 55,56 Pentavalent antimonials are the most frequently used first-line treatment for both CL and VL.…”

“…52 However, the therapeutic response to antimonials in patients with CL is highly dependent on the L. (Viannia) etiological agent causing the infection. 57 Romero et al 57 demonstrated that patients infected with L. (V.) guyanensis had a higher failure rate in response to treatment with meglumine antimoniate than L. (V.) braziliensis, and Francesconi et al 54 also showed that fluconazole was not efficacious against CL caused by L. (V.) guyanensis in adult men. In addition, the Viannia species are susceptible not only to the drug of choice but also to the route of administration, with Christen et al 58 demonstrating that an intramuscular dosage of pentamidine isethionate in L. (V.) guyanensis-infected patients increased the risk of treatment failure.…”

Susceptibility testing of Leishmania spp. against amphotericin B and fluconazole using the Sensititre™ YeastOne™ YO9 platform

“…In a study of CL due to L. V. braziliensis, clinical cure was observed more rapidly and to a greater extent (mean duration of treatment 4-weeks; 100% cure) when FZ was prescribed at 8-mg/kg per day compared to a lower dose 5-mg/kg/day regimen (mean duration of treatment 7.5-weeks; 75% cure) [9]. Recent data surrounding the treatment of L. V. braziliensis and L. V. guyanensis from the Brazilian Amazon demonstrate sub-optimal cure rates with FZ 6.5-8 mg/kg/day for 28 days and 450 mg/day for 30 days, respectively [24][25][26], thus reinforcing the need for a standardized objective marker of expected clinical response, one component of which could be a drug susceptibility testing system that would be functional across species and geographic origins. The isolates tested in our study exhibited FZ MICs ≥256 μg/mL in every case, corroborating the observed clinical requirement of high concentrations of FZ for leishmanicidal effect.…”