An open label randomized clinical trial comparing the safety and effectiveness of one, two or three weekly pentamidine isethionate doses (seven milligrams per kilogram) in the treatment of cutaneous leishmaniasis in the Amazon Region

Abstract

BackgroundAmerican Cutaneous Leishmaniasis (ACL), a vector borne disease, is caused by various species of Leishmania and in the Amazonas, Leishmania guyanensis is predominant. The recommended drugs for treatment of cutaneous leishmaniasis (CL) in Brazil are pentavalent antimonials, pentamidine isethionate (PI) and amphotericin B. Pentamidine was initially used as metanolsulfonate or mesylate (Lomidine) at a dose of 4 mg/kg/daily, containing 2.3mg of base. This drug was withdrawn from the market in the eighties, and currently is available as PI. The PI dose required to achieve an equivalent dose of pentamidine base is 7 mg/kg, rather than the 4 mg/kg that is currently recommended in Brazil.ObjectivesThe aim of this study was to evaluate the efficacy and safety of PI in a single dose, two or three doses of 7 mg/kg body weight, intramuscularly, with an interval of seven days between each dose.Materials and methodsThis study was conducted as a controlled, randomized, open–label clinical trial for a total number of 159 patients with CL. Individuals aged 16–64 years with one to six lesions of confirmed CL based on amastigotes visualization in direct examination of Giemsa stained of dermal scraping from the border of the lesion with no previous treatment for CL and no abnormal values for liver enzymes were eligible to participate in the study. Patients with history of diabetes, cardiac, renal, and hepatic disease as well as pregnant women were excluded. Cure was defined as complete healing in the diameters of the ulcers and lesions skin six months after the end of the treatment.ResultsFrom November 2013 to December 2015, 159 patients were screened and allocated in three groups for treatment with PI: i) 53 patients were treated with a single dose intramuscularly injection of 7 mg/kg body weight; ii) 53 received two doses of 7 mg/kg within an interval of seven days; and iii) 53 were treated with three doses of 7mg/kg with an interval of seven days between each dose. In 120 patients, L. guyanensis was identified. A cure rate of 45%, 81.1% and 96.2% were observed in the first, second and third group, respectively. The cure in the three PI dose group was higher compared to the single-dose (p<0.0001) and two-dose groups (p = 0.03). No serious adverse events occurred.ConclusionThe present study shows that PI is a safe drug and its efficacy varied with the number of doses. The administration of PI in patients with ACL, predominantly caused by L. guyanensis, was mostly efficient in three or two doses of 7 mg/kg.Trial registrationClinicalTrials.gov NCT02919605

Cutaneous Leishmaniasis: A 2022 Updated Narrative Review into Diagnosis and Management Developments

“…Although MCL due to L. guyanensis is not as rare as formerly thought, in patients with a few uncomplicated CL lesions, local therapy can also be considered [ 137 ]. Nonetheless, in Suriname and Brazil, systemic pentamidine is the preferred treatment option for L. guyanensis infections [ 138 , 139 ], even though in Manaus, Brazil, efficacy proved lower with 50–60% success rates [ 140 ]. As a rule of thumb, strict follow-up is advisable in patients with American CL, to exclude treatment failure or progression towards MCL manifestations [ 141 , 142 ].…”

Association of miltefosine with granulocyte and macrophage colony-stimulating factor (GM-CSF) in the treatment of cutaneous leishmaniasis in the Amazon region: A randomized and controlled trial

“…Therefore, the identification of new drugs is necessary to improve the cure rate, decrease the high healing time, reducing the absenteeism, and stigmatization. Although in a recent open trial, pentamidine in three weekly doses of 7 mg/kg was associated with a high cure rate (Gadelha et al, 2018), its parenteral use requires further visits to the clinics, which indicate the need for more practical therapeutic strategies, including oral drugs.…”

“…In the Amazon region, the efficacy of meglumine antimoniate is low and pentamidine has been used as the first choice drug. While the cure rate of CL caused by L. guyanensis with antimony versus pentamidine in a single dose of 4 mg/Kg/weight was similar, 58.1% and 55.5%, respectively (Neves et al 2011); pentamidine (7 mg/Kg/ weight) applied in 3 doses had a cure rate of 96.2% (Gadelha et al 2018). Both meglumine antimoniate and pentamidine have a high rate of adverse reactions that are dose-dependent (Chrusciak-Talhari et al 2011;Gadelha et al 2015).…”

Treatment of Cutaneous Leishmaniasis and Insights into Species-Specific Responses: A Narrative Review

“…Furthermore, in an effort to minimize the number of treatment sessions, a Colombian study on CL revealed that four injections on alternate days of 2 mg pentamidine/kg and 3 mg pentamidine/kg could give rise to 84% and 96% CRs, respectively, with even lesser side effects [ 86 ]. It was also found that L. guyanensis treatment with weekly pentamidine at a dose of 7 mg/kg could result in increasing efficacies with the number of treatment sessions, up to a CR of 96% [ 87 ]. However, the intramuscular administration of pentamidine isethionate tended to fail more than the intravenous administration of pentamidine, in the treatment of CL due to L. guyanensis [ 31 ].…”