Paromomycin topical cream with or without gentamicin is an effective treatment for ulcerative cutaneous leishmaniasis, according to the results of a phase 3, randomized, double-blind, parallel group–controlled trial.
Afif Ben Salah, MD, PhD, professor of preventive medicine at the School of Medicine of Tunis and head of epidemiology at the Institut Pasteur de Tunis, Tunisia, and colleagues report the results of the trial in the February 7 issue of the New England Journal of Medicine.
Leishmaniasis is endemic in 98 countries or territories worldwide, with the Leishmania major parasite found on the Eurasian and African continents. Cutaneous disease is characterized by a papule that enlarges to a nodule, often forms a large ulcer, and resolves in months to years.
The researchers conducted the study in an area of Tunisia where leishmaniasis is endemic. Patients aged between 5 and 65 years were eligible if they had 1 to 5 lesions, with an ulcerative index lesion from 1 to 5 cm in diameter. The researchers randomly assigned 375 patients to 1 of 3 treatments: 15% paromomycin, 15% paromomycin plus 0.5% gentamicin, or vehicle control (all from Teva Pharmaceuticals). About half of the participants were men. The participants had a mean age of 24 years (half were older than 17 years), and 58% had multiple lesions.
Clinicians applied the assigned study cream to each lesion once daily for 20 days. The primary endpoint of the trial was the cure rate of the index lesion, which was defined as a 50% or greater reduction in size by day 42, complete reepithelialization by day 98, and no relapse by day 168. Ninety-nine percent of patients completed all 20 days of treatment.
Adding Gentamicin?
Paromomycin alone achieved a cure rate of 82% (95% confidence interval [CI], 74% - 87%], and paromomycin-gentamicin produced a cure rate of 81% (95% CI, 73% - 87%) compared with a 58% cure rate in the control group (95% CI, 50% - 67%; P < .001 for each active drug vs control). Similar proportions of patients experienced cure of all lesions (81%, 80%, and 56%, respectively), and of these, most were healed by day 42. Relapses were rare: 4 in each of the drug groups and 2 in the control group.
Lack of improvement at 42 days was the most common reason for treatment failure (n = 16 and 19 in the drug groups; n = 39 in the control group).
Some mild to moderate skin reactions occurred at the application sites in all groups, some of which were attributed to the dressings. Small vesicles at the treatment site were more common in the drug groups (25% paromomycin vs 26% paromomycin-gentamicin vs 7% vehicle), whereas secondary bacterial infections were more common in the vehicle group (2% vs 0 vs 10%).
Although paromomycin was equally efficacious against L major compared with the combination cream, senior author Col. Max Grogl, PhD, division director of experimental therapeutics at Walter Reed Army Institute of Research in Silver Spring, Maryland, noted in an email that "the combination therapy could hold additional promise for global use since early research shows the combination therapy may be effective against the parasitic species found in Central and South America."
Asked for independent comment, Richard Pearson, MD, professor of medicine and pathology in the Division of Infectious Diseases and International Health at the University of Virginia School of Medicine, Charlottesville, told Medscape Medical News that the researchers are a "highly reputable group" and performed "an extremely well-organized, well-done, double-blind, prospective study.... So I think the findings are helpful."
He noted that it has been known for some time that topical paromomycin has activity in this setting, but the problem has been toxicity. "I think that has been attributed to the 12% methylbenzethonium chloride that was included in the preparation...to enhance skin penetration.... I think what's key here is that the Walter Reed vehicle that is licensed seems to be better tolerated and allow this group of patients to receive treatment for 20 days with compliance and a good rate of response."
Dr. Grogl had noted that the cream containing 15% paromomycin and 0.5% gentamicin has fast track approval status with the US Food and Drug Administration.
"I think this will provide, once it's available, a very attractive approach to treating of cutaneous lesions that are related to L major," Dr. Pearson concluded.
The study was supported by the US Department of the Army. The army holds a patent on the topical formulation of the drug. Dr. Grogl, and Dr. Pearson have disclosed no relevant financial relationships. One coauthor has reported receiving honoraria or consulting fees from Fast-Track Drugs & Biologics, LLC. Full conflict-of-interest information is available on the journal's Web site.
N Engl J Med. 2013;368:524-532. Abstract
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Cite this: Paromomycin Cream Cures Cutaneous Leishmaniasis - Medscape - Feb 07, 2013.
