Abstract: We included 38 trials involving 2728 participants. Results are based on individual studies or limited pooled analyses. There was good evidence in: Leishmania braziliensis and L. panamensis infections: Intramuscular (IM) meglumine antimoniate (MA) was better than oral allopurinol for 28 days (1RCT n=127, RR 0.39; 95% CI 0.26, 0.58). Intravenous (IV)MA for 20-days was better than 3-day and 7-day IVMA plus 15% paromomycin plus 12% methylbenzethonium chloride (PR-MBCL) or 7-day IVMA (1RCT n= 150, RR 0.24; 95% CI 0.11, 0.50; RR 0.69; 95% CI 0.53, 0.90; RR 0.64; 95% CI 0.44, 0.92 respectively). Oral allopurinol plus antimonials was better than IV antimonials (2RCT n= 168, RR 1.90; 95% CI 1.40, 2.59; I2=0%). L. braziliensis infections: Oral pentoxifylline plus IV sodium stibogluconate (SSG) was better than IVSSG (1RCT n= 23, RR 1.66; 95% CI 1.03, 2.69); IVMA was better than IM aminosidine sulphate (1RCT n= 38, RR 0.05; 95% CI 0.00, 0.78) and better than IV pentamidine isethionate (1RCT n= 80, RR 0.45; 95% CI 0.29, 0.71). Intramuscular MA was better than Bacillus Calmette-Guérin (1RCT n= 93, RR 0.46; 95% CI 0.32, 0.65). L .panamensis infections: Oral allopurinol was better than IVMA (1RCT n= 58, RR 2.20; 95% CI 1.34, 3.60). Aminosidine sulphate at doses of 12mg/kg/day and 18mg/kg/day for 14 days were better than aminosidine sulphate 12mg/kg/day for 7 days (1RCT n= 60, RR 0.23; 95% CI 0.07, 0.73; RR 0.23; 95% CI 0.07, 0.73 respectively). Oral ketoconazole for 28 days, oral miltefosine and topical PR-MBCL were better than placebo. Most trials have been designed and reported so poorly that they are inconclusive. There is a need for large well conducted studies that evaluate long-term effects of current therapies to improve quality and standardization of methods.

Plain-language summary: There was reasonable randomised controlled trial (RCT) evidence in L. braziliensis infections that oral pentoxifylline plus IVSSG was better than IVSSG alone; IVMA was better than IM aminosidine sulphate and IV pentamidine isethionate; and IMMA was better than the Bacillus Calmette-Guérin vaccine. Regarding L. panamensis infections, oral ketoconazole for 28 days and oral miltefosine and topical PR-MBCL were all better than placebo; oral allopurinol better than IVMA, aminosidine sulphate 12mg/kg/day and 18mg/kg/day for 14 days were better than aminosidine sulphate 12mg/kg/day for 7 days. There was complete absence of RCT evidence on alternative treatments, surgery, oral itraconazole and fluconazole, oral antibiotics like rifampicin, metronidazole and cotrimoxazole, intravenous or topical amphotericin B, oral dapsone, photodynamic therapy, promoting healing therapies, laser, and cryotherapy treatments. Moreover, none of the studies reported quality of life, "microbiological or histopathological cure of skin lesions", changes in ability to detect the parasite by diagnostic methods (e.g. smear or culture) or mortality. No general consensus on optimal treatment has been achieved but alternatives to intramuscular or intravenous treatments are under active investigation. The evidence base for the treatment of American cutaneous and mucocutaneous leishmaniasis has many limitations due to poor design and reporting of clinical trials. Because resources are limited for clinical research into neglected diseases, there is a need for prioritising properly designed clinical trials. Therefore, we suggest the creation of an international strategy to improve the quality and standardization of future trials for a better evidence-based strategic approach in the future.