Topical Treatment of Cutaneous Leishmaniasis Joseph EI-On, Ph.D., Rita Livshin, M.D., Zvi Even-Paz, M.D. , David Hamburger, Ph.D., and Louis Weinrauch, M. D . Department of Microbio logy and Immunology, Facult y of Hea lth Sciences, Dcn G urion University of the N cgev UE-O), Deer­ Sheva; Departmcnt of Dcrmatology, Hadassah Universi ty H ospital, Hebrcw University Had assa h Mcdical School (R L, ZE-P, LW), j erusalem; Teva Pharm aceutica l In dustries Ltd. (01-1 ), j erusa lem, Israel Six ty- seven patients, 19 fem :ll es and 48 m ales, 4-66 years develo pments did not affect the clinical he:ding process o ld , sufferin g fro m lesions o f cutaneous leishmaniasis which was generall y completed in a period of 10-30 d ays were treated to pica ll y with an o intme nt comprising 15% after termination of trea tment. In addition, 94% of the paro m o mycin sulfate and 12% m eth ylbenzethonium chl o­ treated lesio n s healed with little o r no scarring. N o adverse ride in white soft pa raffin (P-ointment, U .K . patent clinica l or laboratory side effe cts w ere observed except fo r GBll7237A). After 10 d ays of treatment, twice daily, the a burning sensation at the site of trea tment. Parasites iso_ lesio ns in 72% of the treated pati ents were free of parasites, lated fro m patients w ho failed to respond to topical treat_ 15% becam e free with in an additional 20 d ays, witho ut m ent were found to be susceptible to PR-MBC I in both further trea tment, and 13% failed to respond. Pig m entation in vitro infected m acrophages and in vivo in experimenta lly develo ped in 18% of the trea ted lesio n s and inA ammatio n infected BALE/c mice. J In vest Dennato/ 87:284-288, 1986 of varying degree was associated with t he treatm ent. T hese eishmania sis is a disorder produced by Aa gelbted pro­ prove to be a major antileishmani al th erapeutic advance against tozoa of the genus L eis/lll1 allia. Depending on the ca us­ both cutaneO Ll S and mucocutaneous leishmaniasis [1 0, 111. ative species, th e disease Ill ay m anifest itse lf as a sys­ Although C L is purely a skin disease, very fe w studies have tellli c, a destructive mucocutaneous, or a purely been made to devel op a simple topical application for its treat­ cutaneous chronic in fection. AII 3 forms are translilitted ment. Local treatment with imidazole derivatives was found to Lby species of sa ndAi es belong in g to the genus Phlevolo/III.IS (Old be in effective in curing CL ca used by either L. lIIajor or L. lIIexicana Worl d) or the genus LlIlz o/llia (New World). a/lla ZO Il ClIsis in both ex perimental anim.als and humans 11 21. H ow_ L eishlllania //"Iajor, one of the eti ologic agents of cutaneous lei sh­ ever, a chJ orpro l11a zin e-containing ointment was recentl y u sed mani as is (Cl) in the O ld World , produces in humans a se lf­ successfull y in hea lin g diffuse CL due to L. (/clhiop ica in hUlllan hea ling les ion fo ll owed by long-las ting immunity to reinfecti on 1 13J. 1"1] . The introducti on of the paras ite into the skin is fo ll owed by In a previous study, an ointment containing paromomycin and the development of a pap ul ar lesion w hi ch may enlarge and ul­ methylbenzeth onium chlo rid e was fou nd to be hi ghly effective ce rate and persist for up to 18 months. Spontaneous resolution in curing CL in experimental animals [14]. All mice infected w ith of a large lesion often lea ves an un sightl y sca r. Both sexes and L. lIIajor LRC-LJ37 were cured of the cutaneous disease after local all ages are susceptible. treatment applied twice dail y for 6-10 days. The paras ites were C utaneous leishmani as is is of clinica l importance beca use of its tota ll y eliminated from th e lesions, which rapidly healed. The chroni city and its potential for local des tructi on and disfigure­ present study describes the effi cacy of similar topica l treatlllent ment. N o sa ti sfactory systemicall y ad ministered drug against th e in humans against CL ca used by L. I/Iajor. disease has yet been developed; reli ance is on a few drugs w hi ch are sometimes in effecti ve and may be associated with side effec ts. The need for effi cacious, more easil y administered, and less toxic MATERIALS AND METHODS antiicishmania l agents is required. Rifampicin was the first orall y Patients, Treatment, and Evaluation of Responses Sixty_ effective antileishmanial agent introduced to clini ca l medi cin e 12-4]. seven patients of both sexes and different ages with ea rl y and Other oral medica ti on, sLi ch as metronidazole 15-7] and co-tri­ advanced infecti on were trea ted (Table I). The number of lesions moxazole [8,91 showed controversial effi cacy against the disease. per patient was '/-39. In most cases only one, th e largest and The development of the new antifungal agent ketoconazole may most active les ion , was trea ted while either one or more other untreated lesions on the sa me patient se rved as control. The le­ siollS were trea ted with an ointment containing 15% paromo­ m ycin sulphate (PR) and 12% mcthylbenzethonium chl oride (MBCI) in white soft paraffi n (P-ointmcnt), twice daily fOr a M anuscript received October 25, 1985; ~cceptcd for publi ca ti o n March peri od o f 1° day s. All ointment preparations were manufactured 3, 1986. and supplied by Teva Pharmaceutical Industries Ltd. , Jerusalem. RcpriIH requcsts to: j oseph E I-On, Ph.D. , DcpartmcntofMicro bi o logy In se veral cases th e treatment was extended for another 10 da and Immunology, Fa culty or Hea lth Sciences, Ben G urion Uni vcrsit y of and in one patient th e trea tment was given for a period of 2 the N egev, l3 ec r -S h cv~, 84 105 Israel. Abbreviatio ns: days. Treated lesions were generally left un covered, but in a few C L: cutancous Ici shman.ia sis cases the lesions were covered by adhes ive tape (Dermiciear) to LRC: Leis/lIl/fIIl ia I{cfcrcncc Ccnter prevent cl othing or dirt contamin ation. Between treatments the M 13 I: Ill cthylbcnzethonium chl orid e lesions were w iped clean. PR: paromomycin sul phate The res ults obtained were defined as follows: (1) rapidl y ef- 0022-202X/86/S03.50 Copyright © 1986 by T he Society for In vesti gative Dermatology, In c. 284 VOL. 87. NO.2 AUGUST 1986 TOPIC AL T ltEATMENT OF CUTANEOUS LE ISHMANIAS IS 285 Table I. Res ults of Topical T rea tment w ith P-Ointment on C utaneous Leish n1Jniasis Description of Patients Da ys from Appearance of Lesion ro O nset of Age (years) Treatment No. of Lesions per Patient Effect of Treatment 5ex N o. Percent Average ± 5D Ran ge Average ± 5D Ran ge Average ± 5D Range Rapidly effective M 34 50.7 24.34 ± 8.6 19- 55 86.09 ± 43.9 30-240 6.H7 ± 5.6 1- 19 F 14 20.8 23.23 ± 14.0 19-66 120.38 ± 77.3 30- 270 5.7 1 ± 3.5 1- 12 Less effective M 6 8.9 29.83 ± 12.2 19-4·<) 78.33 ± 58.4 60-180 10. 16 ± 9.8 3- 39 F 4 5.9 29.75 ± 20.2 19-60 100.00 ± 34.6 60-120 8.50 ± 8. 1 1-20 Ineffecti ve M 8 11. 9 21.1 5 ± 10.3 2- 36 96.25 ± 38.9 60- 180 8.25 ± 8.9 1- 29 F I 1.5 25.00 ± 0.0 25 250.00 ± 0.0 250 2.00 ± 0.0 2 fective: no parasites were detected in the treated les ion at th e cnd RESULTS of 10 days of treatment; (2) less rapidl y effective: para si tes werc still present in the treated lesion at the cnd ofl 0 days oftrea tl11 cnt, T he effcct of topica l treatment w ith P-ointmcnt as determined but disa ppeared w ithin the nex t 20 days; (3) in effe cti ve: paras ites by smcar and cul tu re techniques in 67 pati ents is summarized in still present in the lesions at least 1 month after the end of tre:J[­ Table I. After 10 da ys of treatment, rapid clearing was obtained in 48 (7 1.6%) patients. Less rapid clearing was demonstrated in ment. 10 (14.9%) and no effe ct was obscrved in 9 (13.4%) of the treated Diagnosis and Laboratory Examinations In all cases the di­ patients. In the rapidl y clearing group, parasites were totall y elim­ agnosis was based on positive smea r and/ or cultures . La rge les ions in ated from the lesions by the end of the treatment and the les ions were examined at several sites. Fo r smear and culture preparations were clinicall y hea led within an add itional 10-30 days.