wr279396 and Leishmaniasis--Cutaneous

A 5-year-old boy from rural Afghanistan presented with a 1-year history of a skin lesion on his left knee, confirmed by polymerase chain reaction to be cutaneous leishmaniasis (Leishmania tropica). Conventional treatment of cutaneous leishmaniasis involves intravenous or intralesional pentavalent antimonials. The aim of this Critically Appraised Topic (CAT) is therefore to determine what alternative effective but less painful treatments (such as oral or topical therapies) can be used to treat cutaneous leishmaniasis in children. Embase and PubMed were searched for 'cutaneous leishmania*' AND 'treatment' AND 'children' in August 2014. All abstracts from April 2008 to August 2014 were reviewed. This search period was chosen to follow on from the Cochrane reviews on Old World and American leishmaniasis. Five randomized controlled trials met our inclusion criteria and have been included in this CAT. The study design and reporting quality in most of the trials included in both Cochrane reviews was found to be poor, and neither Cochrane review investigated the effect of patient age on response to treatment. This CAT identified two nonpainful treatments, topical paromomycin and oral miltefosine, whose effective use in children is supported in the literature. However, both of these treatments are currently unlicensed in the U.K. Our patient was successfully treated with miltefosine 20 mg twice daily for 4 weeks, leading to good resolution of the leishmaniasis plaque but with residual scarring.

Topics: Administration, Cutaneous; Ambulatory Care; Aminoglycosides; Antiprotozoal Agents; Child, Preschool; Humans; Leishmaniasis, Cutaneous; Male; Paromomycin; Phosphorylcholine; Randomized Controlled Trials as Topic

Cutaneous leishmaniasis (cl) is a disfiguring disease that confronts clinicians with a quandary: leave patients untreated or engage in a complex or toxic treatment. Topical treatment of CL offers a practical and safe option. Accordingly, the treatment of CL with WR279,396, a formulation of paromomycin and gentamicin in a hydrophilic base, was investigated in a phase 2 clinical study in Tunisia and France.. A phase 2, randomized, double blind, vehicle-controlled study was conducted to assess the safety and efficacy of topical WR279,396 when applied twice a day for 20 days as treatment for parasitologically confirmed CL. The study protocol established the primary efficacy end point as complete clinical response (CCR) defined as 50% or greater reduction in the ulceration size of an index lesion by day 50 (D50) followed by complete re-epithelialization by D100, and no relapse through D180.. Ninety-two subjects were randomized. Leishmania major was identified in 66 of 68 isolates typed (97%). In the intent-to-treat population, 47 of 50 WR279,396 treated participants (94%) met the definition of CCR, compared with 30 of 42 vehicle-placebo participants (71%) [p = 0.0045]. Erythema occurred in 30% and 24% of participants receiving WR279,396 and placebo, respectively [p = 0.64]. There was no clinical or laboratory evidence of systemic toxicity.. Application of WR279,396 for 20 days was found to be safe and effective in treating L. major CL, and offers great potential as a new, simple, easily applicable, and inexpensive topical therapy for this neglected disease.. ClinicalTrials.gov NCT00703924.

Topics: Adolescent; Adult; Aged; Aminoglycosides; Child; Child, Preschool; Double-Blind Method; France; Gentamicins; Humans; Leishmania major; Leishmaniasis, Cutaneous; Middle Aged; Ointments; Paromomycin; Placebos; Treatment Outcome; Trypanocidal Agents; Tunisia; Young Adult

We studied the efficacy of WR279396, a topical formulation of aminoglycosides that cures 100% of cutaneous leishmaniasis lesions in mice. We conducted what is to our knowledge the first controlled study of WR279396 therapy for clinical cutaneous leishmaniasis. A total of 45 Colombian soldiers, all men, were randomly assigned to treatment with WR279396 (33 patients) or placebo (12 patients). Each lesion was treated twice daily for 20 days. Lesions were measured at the end of therapy and at 45, 90, and 180 days after treatment began. A total of 17 (61%) of 28 assessable WR279396-treated patients were cured, and 5 (55%) of 9 assessable placebo-treated patients were cured (P = 0.9). For the 36 lesions treated with WR279396 that were cured, cure took a mean of 35 days, whereas for the 6 lesions that were cured in the group of patients receiving placebo, cure time took a mean of 56 days (P = 0.04). WR279396 is a nontoxic topical formulation that significantly accelerated cure time in patients with Leishmania panamensis cutaneous leishmaniasis.

Topics: Administration, Cutaneous; Adult; Aminoglycosides; Antiprotozoal Agents; Female; Humans; Leishmaniasis, Cutaneous; Male; Pilot Projects; Treatment Outcome

Topical therapy is an attractive approach for the treatment of Leishmania major cutaneous leishmaniasis (CL). WR279396, an expanded-spectrum aminoglycoside ointment, is now in phase 3 trials. Because the application of a cream is easier than the injection of pentavalent antimony, many patients with CL will likely be treated with WR279396 soon after the onset of a lesion. However, this new therapeutic approach may impair the acquisition of immunity. We evaluated the impact of early topical therapy on acquired immunity in an optimized mouse model of L. major-induced CL. The efficacy of the WR279396 ointment in this model has been established previously. Acquired immunity was defined as the absence of lesions upon reinoculation of the same parasite isolate at a different skin site. Bioluminescence-based follow-up of luciferase-expressing L. major loads was also performed. In this model, the control of L. major loads at the initial inoculation site and the acquisition of immunity are simultaneous (day 22 postinoculation). The clinical and parasitological efficacies of WR279396 applied as early as day 11 postinoculation, i.e., during the L. major multiplication phase, did not impair the acquisition of immunity to a second L. major challenge. This is reassuring from the perspective of the wide deployment of WR279396-based therapy in foci where L. major is endemic.

Topics: Administration, Cutaneous; Aminoglycosides; Animals; Antiprotozoal Agents; Dermis; Disease Models, Animal; Female; Humans; Immunity; Leishmania major; Leishmaniasis, Cutaneous; Mice; Mice, Inbred C57BL; Mice, Nude; Treatment Outcome

Because topical therapy is easy and usually painless, it is an attractive first-line option for the treatment of localized cutaneous leishmaniasis (LCL). Promising ointments are in the final stages of development. One main objective was to help optimize the treatment modalities of human LCL with WR279396, a topical formulation of aminoglycosides that was recently proven to be efficient and safe for use in humans.. C57BL/6 mice were inoculated in the ear with luciferase transgenic L. major and then treated with WR279396. The treatment period spanned lesion onset, and the evolution of clinical signs and bioluminescent parasite loads could be followed for several months without killing the mice. As judged by clinical healing and a 1.5-3 log parasite load decrease in less than 2 weeks, the 94% efficacy of 10 daily applications of WR279396 in mice was very similar to what had been previously observed in clinical trials. When WR279396 was applied with an occlusive dressing, parasitological and clinical efficacy was significantly increased and no rebound of parasite load was observed. In addition, 5 applications under occlusion were more efficient when done every other day for 10 days than daily for 5 days, showing that length of therapy is a more important determinant of treatment efficacy than the total dose topically applied.. Occlusion has a significant adjuvant effect on aminoglycoside ointment therapy of experimental cutaneaous leishmaniasis (CL), a concept that might apply to other antileishmanial or antimicrobial ointments. Generated in a laboratory mouse-based model that closely mimics the course of LCL in humans, our results support a schedule based on discontinuous applications for a few weeks rather than several daily applications for a few days.

Topics: Administration, Topical; Aminoglycosides; Animals; Animals, Genetically Modified; Antiprotozoal Agents; Disease Models, Animal; Ear; Female; Humans; Leishmania major; Leishmaniasis, Cutaneous; Mice; Mice, Inbred C57BL