CED
Clinical dermatology • Concise report
Clinical and Experimental Dermatology
Intermediate cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis successfully treated with fluconazole K. Daly,1 H. De Lima,2 H. Kato,3 E. M. Sordillo,4 J. Convit,5 O. Reyes-Jaimes,5 O. Zerpa2 and A. E. Paniz-Mondolfi1,5,6 Fundacion Jacinto Convit, Caracas, Venezuela; 2Division of Leishmaniasis, Instituto de Biomedicina, Caracas, Venezuela; 3Laboratory of Parasitology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan; 4Department of Pathology and Laboratory Medicine and the Infectious Diseases Developmental Laboratory (Department of Medicine), St. Luke’s Roosevelt Hospital Center, University Hospital of Columbia University College of Physicians and Surgeons, New York, NY, USA; 5Laboratory of Biochemistry and Dermatopathology, Instituto de Biomedicina, UCV/MPPS/IVSS, Caracas, Venezuela; and 6Medical Microbiology Laboratory, Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA 1
doi:10.1111/ced.12359
Summary
American cutaneous leishmaniasis is an endemic anthropozoonosis that exhibits a broad spectrum of clinical presentations. Intermediate/borderline disseminated cutaneous leishmaniasis is a distinct clinical condition that comprises cutaneous disease of a chronic nature, usually occurring as multiple lesions with or without mucosal involvement. The disease is usually caused by parasites of the subgenus Viannia, frequently occurs in context of an underlying disease, and is often resistant to standard antileishmanial therapy. We report a case that was refractory to standard therapy and other second-line drugs, but resolved after treatment with fluconazole, and review the use of fluconazole as a second-line drug in children.
Intermediate or borderline disseminated cutaneous leishmaniasis (ICL) is an uncommon variant of American cutaneous leishmaniasis. The disease usually presents in children or in patients with underlying comorbid conditions1 and an aberrant immune response to the parasite, leading to development of multiple, variegated disseminated lesions, a varied and sometimes exaggerated delayed-type hypersensitivity reaction to leishmanin, and a predominance of parasitized vacuolated macrophages in the upper dermis.1 ICL may be accompanied by mucosal disease, tends towards chronicity and relapse, and shows resistance to standard treatment regimens.1 We report an exceptionally interesting case of ICL successfully treated with fluconazole after several first-line and second-line Correspondence: Dr Alberto E. Paniz Mondolfi, Department of Microbiology, Yale University School of Medicine/Yale-New Haven Hospital, (PS656) 55 Park Street, New Haven CT 06511, USA E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 26 January 2014
ª 2014 British Association of Dermatologists
chemotherapeutic approaches were exhausted, and we review the use of fluconazole for ICL treatment in the subpopulation of children who may be particularly susceptible.
Report A 12-year-old girl presented with a 6-month history of cutaneous lesions. She was from a western Venezuelan region endemic for leishmaniasis. The initial lesion was an erythematous papule on the middle of the patient’s right forearm, which evolved into a plaque with an ulcerated centre (Fig. 1a). Subsequently 8–10 nodular erythematous lesions developed on her face and limbs, some with a scaly or crusty surface, or ulcerated centre (Fig. 1a). She also had an erythematous infiltrated plaque over her left scapula, and an erythematous, ulcerated, right nasal mucosal lesion. Montenegro test (leishmanial intradermal reaction) was positive (10 mm). Full blood count, blood chemistry and hepatic transaminase tests were normal, and serology testing for human immunodeficiency virus was negative. A biopsy was consistent with
Clinical and Experimental Dermatology
1
Intermediate cutaneous leishmaniasis treated with fluconazole A. E. Paniz Mondolfi et al.
Figure 1 (a) Erythematous raised plaques on the face and right forearm, and ulcerated plaque on the face. (b) Laminar hyperkeratosis,
orthokeratosis, irregular epidermis with moderate acanthosis, and an ill-defined lymphoplasmacytic infiltrate with numerous vacuolated macrophages containing abundant amastigotes (haematoxylin and eosin, original magnification 9 400). (c) Typical star-shaped depressed scar on the nose; and (d) completely healed lesion on right forearm.
leishmaniasis (Fig. 1b). Species-specific typing by the rRNA internal transcriber region of the cytochrome B gene2 revealed Leishmania (Viannia) braziliensis. Local treatments used for localized cutaneous leishmaniasis (LCL) management were not an option for our patient because she had multiple lesions, mucosal involvement and a lesion measuring > 40 mm.3 She was enrolled in a trial of miltefosine (Aeterna; Zentaris, Frankfurt, Germany) 50 mg twice daily for 71 days, which resulted in a partial response, but she developed nausea, vomiting and severe diffuse abdominal pain, and her alkaline phosphatase level increased to 932 U/L (normal range 50–200 U/L), prompting treatment suspension. Her lesions persisted, and 1 month later she was started on treatment with a
2
Clinical and Experimental Dermatology
pentavalent antimonial drug (meglumine antimoniate; Rhone-Poulenc, Paris, France) Glucantime; 20 mg/kg/day intramuscularly. However, this had to be stopped after 13 days, when a severe local and painful skin rash developed. Although rare, skin reactions can occur during antimonial treatment because of the altered physicochemical composition of the drug and contamination with heavy metals.4 Giemsa-stained lymph smears remained positive despite these interventions, and 20 days after the antimonial treatment was discontinued, the patient was started on oral fluconazole 200 mg daily (5 mg/kg/day) for 12 days. Within 48 h, the lesions started to re-epithelialize, and the infiltration diminished substantially. The patient did not experience any side effects,
ª 2014 British Association of Dermatologists
ª 2014 British Association of Dermatologists
M
Hand and foot NR
Limbs and face Scalp
Face
Face and ankle
Face
NR NR NR NR NR NR Left arm
Site of lesion
Ulcers, 1.5 and 2 cm NR
3 cm, papular
NR NR NR NR NR NR 3 erythematous lesions 3.5 cm raised erythematous lesion with crusted centre 3 cm lesions on face and ankle, and 2 cm lesion on face. 2 cm lesion with central scab and surrounding erythema Ulcerated plaque
Characteristic of lesions
NR
3
18
3
NR
1
7
3.5 3.5 5 3.5 3 5 5
Duration of disease, months
*Suspected organism. CR, case report; CS, case series; CT, clinical trial. NR, not reported.
3 years
CT
F
F
F
F
8 years
3 years
F
11 years
11 years
CR
Sklavost et al., 201010 Baront et al., 200411 Toubianat et al., 200612 Sousat et al., 20116
F
9 months
CR
CS
Crogant et al., 20109
F M F M F F F
Sex
1 year 5 years 10 years 1 year 8 years 9 years 12 years
2 years
CS
Morizot et al., 20077
Age
CR
Study type
Reference/Type of study
7 mg/kg/day
5 mg/kg/day
100 mg once daily
150 mg once daily
5 mg/kg/day
5 mg/kg/day
5 mg/kg/day
2.5 mg/kg/day 2.5 mg/kg/day 2.5 mg/kg/day 2.5 mg/kg/day 2.5 mg/kg/day 2.5 mg/kg/day 5 mg/kg/day
Dose
Table 1 Reports of paediatric patients with cutaneous leishmaniasis treated with oral fluconazole.
weeks weeks weeks weeks weeks weeks months
8 weeks
20 days
3 weeks
6 weeks
1 month
2 months
2 months
6 6 6 6 6 6 7
Length of treatment
L. braziliensis*
L. major MON 26
NR
L. major*
NR
NR
L.major* L. major MON 25 L. major MON 74 L. major MON 25 L. major* L.major* NR
Species
Healed
Complete healing
Light scarring
Scarring
Failure
Failure
Failure
Resolution Resolution Resolution Failure Failure Failure Resolution
Outcome
NR
3 months
NR
NR
NR
NR NR NR
Follow-up
Intermediate cutaneous leishmaniasis treated with fluconazole A. E. Paniz Mondolfi et al.
Clinical and Experimental Dermatology
3
Intermediate cutaneous leishmaniasis treated with fluconazole A. E. Paniz Mondolfi et al.
and her laboratory values remained normal. At day 10, biopsies of the lesions with inoculation of laboratory animals were negative. Her lesions regressed (Fig. 1c,d) with no signs of infiltration. No new lesions have developed during a follow-up of >3 years after treatment cessation. Leishmaniasis is endemic in 88 countries. Over 350 million people are at risk,5 an estimated 12 million are infected, and about 1.5 million new cases occur yearly, yet leishmaniasis remains one of the most neglected tropical diseases.5 The clinical appearance and response to treatment1,5 are determined both by the infecting Leishmania species and by host immune response. A frequent agent of New World cutaneous leishmaniasis, L. (V.) braziliensis, causes both intermediate/borderline disseminated cutaneous leishmaniasis and mucocutaneous leishmaniasis, and is a major health problem in Latin American countries such as Brazil, Bolivia, Peru, Venezuela and Guatemala.1,5 Lesions may spontaneously heal with scarring, but later reappear elsewhere, especially as destructive mucocutaneous lesions. Mucocutaneous leishmaniasis (also called Espundia) never heals spontaneously and requires early, aggressive treatment.1,5 The risk of mucosal involvement when the initial stages of leishmaniasis are not managed aggressively has meant that local paramomycin and intralesional pentavalent antimonials, which are effective in Old World leishmaniasis, have limited utility for management of New World leishmaniasis.5 Although pentavalent antimonials remain the firstline therapy for most cases of leishmaniasis, including New World cutaneous leishmaniasis caused by L. (V) braziliensis,5 they are not effective against all Leishmania species, require parenteral administration, and have significant systemic toxicity. Other agents, including pentamidine, miltefosine, amphotericin B deoxycholate, and liposomal amphotericin B, are also limited by variable efficacy and severe side effects, prompting the search for more effective, bettertolerated options.5,6 The imidazoles and the structurally related triazoles have demonstrated activity against some types of cutaneous leishmaniasis.1,5,6 Fluconazole, a well-tolerated, orally active, synthetic triazole with a long half-life, achieves 10 times its plasma concentration in skin,6 and has shown promise in some clinical trials of leishmaniasis treatment, notably in Old World complex species infections,6,7 but less consistently in New World
4
Clinical and Experimental Dermatology
leishmaniasis. Sousa et al.6 reported cure rates of 89–100%, depending on dose (5 and 8 mg/kg/day respectively) for fluconazole treatment of cutaneous leishmaniasis in patients from the State of Cear a, Brazil, where L. (V) braziliensis is endemic. However, Schnedl et al.8 reported three cases of cutaneous leishmaniasis, imported from Belize and assumed to be due to New World Leishmania species, which showed no response to 200 mg/day of oral fluconazole. Antileishmanial use of fluconazole in children is mostly anecdotal; successful treatment was reported in some cases, including several L. major cases and one case of L. braziliensis infection (Table 1).9–12 An important limitation of many reports is that the parasites were not characterized molecularly, as it seems that species differences among Leishmania are critical in determining azole susceptibility. In vitro susceptibility results may also be assay-dependent. For example, Rangel et al.13 found L. braziliensis 2903 to be naturally resistant to ketoconazole and to other sterol C14a–demethylase inhibitors (e.g. bis-triazole D0870), whereas Leishmania mexicana was extremely azole-susceptible, with therapeutic concentrations achieving complete growth arrest and cell lysis of the parasites. Beach et al.14 observed that of 36 references strains representing 7 Leishmania species, L. (V) braziliensis isolates were the most susceptible to azoles, with > 90% inhibition of proliferation by ketoconazole 0.1 lg/mL at day 5 of incubation. Furthermore, as azoles such as fluconazole concentrate in skin, in vitro assays may not adequately predict clinical efficacy. Our report of successful fluconazole treatment of a patient with ICL due to L. (V) braziliensis (confirmed by molecular testing), in conjunction with the cases reported by Sousa et al., supports the potential use of oral fluconazole for treatment of L. (V) braziliensis infections, particularly in children and other susceptible patients developing intermediate leishmaniasis. Although the previous treatment measures in our patient could have influenced parasite viability, the persistence of high parasite loads on skin smears prior to beginning fluconazole suggests that fluconazole was pivotal in eradicating the infection. Alternatively, the apparent parasitocidal effect of fluconazole in our case may reflect strain-specific azole susceptibility. Future randomized controlled trials are necessary to confirm our results, and in such trials, molecular characterization will be essential to evaluate the efficacy of antileishmanial azole drugs against different Leishmania species.
ª 2014 British Association of Dermatologists
Intermediate cutaneous leishmaniasis treated with fluconazole A. E. Paniz Mondolfi et al.
Learning points ● Intermediate and mucocutaneous forms of
leishmaniasis occur primarily in the tropics of South America. ● L. (V.) braziliensis is one of the most common agents of cutaneous leishmaniasis in the New World. ● Intermediate and mucocutaneous leishmaniasis is often relatively resistant to standard treatment regimens. ● Intermediate/borderline disseminated leishmaniasis usually presents in children or in patients with a comorbid condition. ● The treatment of choice for all forms of leishmaniasis is a type of drug containing antimonials, such as sodium stibogluconate or meglumin antimoniate. ● Standard treatments for leishmaniasis usually have marked side effects. ● Increasing data supports the potential use of oral azoles for treatment of L. (V) braziliensis infections in cases of recalcitrant clinical presentations of the disease, as in this case.
References 1 Paniz Mondolfi AE, Duffey GB, Horton LE et al. Intermediate/borderline disseminated cutaneous leishmaniasis. Int J Dermatol 2013; 52: 446–55. 2 Kato H, Watanabe J, Mendoza Nieto I et al. Leishmania species identification using FTA card sampling directly from patients’ cutaneous lesions in the state of Lara, Venezuela. Trans R Soc Trop Med Hyg 2011; 105: 561–7. 3 Blum J, Lockwood DN, Visser L et al. Local or systemic treatment for New World cutaneous leishmaniasis? Re-evaluating the evidence for the risk of mucosal leishmaniasis. Int Health 2012; 4: 153–63.
ª 2014 British Association of Dermatologists
4 Romero GA, Flore MRM, Noronha EF, Mac^edo Vde O. High frequency of skin reactions in patients with leishmaniasis treated with meglumine antimoniate contaminated with heavy metals. A comparative approach using historical controls. Mem Inst Oswaldo Cruz 2003; 98: 145–9. 5 Gonz alez U, Pinart M, Renginfo-Pardo M et al. Interventions for American cutaneous and mucocutaneous leishmaniasis. Cochrane Database Syst Rev 2009; 2: CD004834. 6 Sousa AQ, Frutuoso MS, Moraes E et al. High-dose oral fluconazole therapy effective for cutaneous leishmaniasis due to Leishmania (Vianna) braziliensis. Clin Infect Dis 2011; 53: 693–5. 7 Morizot G, Delgiudice P, Caumes E et al. Healing of Old World cutaneous leishmaniasis in travelers treated with fluconazole: drug effect or spontaneous evolution? Am J Trop Med Hyg 2007; 76: 48–52. 8 Schnedl J, Auer H, Fischer M et al. Cutaneous leishmaniasis—an import from Belize. Wien Klin Wochenschr 2007; 119: 102–5. 9 Crogan J, Gunasekera H, Wood N et al. Management of old world cutaneous leishmaniasis in refugee children. Pediatr Infect Dis J 2010; 29: 357–9. 10 Sklavos AV, Walls T, Webber MT, Watson AB. Cutaneous leishmaniasis in a child treated with oral fluconazole. Australas J Dermatol 2010; 51: 195–7. 11 Baron S, Laube S, Raafat F, Moss C. Cutaneous leishmaniasis in a Kosovan child treated with oral fluconazole. Clin Exp Dermatol 2004; 29: 546–7. 12 Toubiana J, Armengaud JB, Dupouy Camet J, Gendrel D. Oral fluconazole treatment for extensive cutaneous leishmaniasis in an 11-year-old child. Pediatr Infect Dis J 2006; 25: 1083–4. 13 Rangel H, Dagger F, Hernandez A et al. Naturally azole-resistant Leishmania braziliensis promastigotes are rendered susceptible in the presence of terbinafine: comparative study with azole-susceptible Leishmania mexicana promastigotes. Antimicrob Agents Chemother 1996; 40: 2785–91. 14 Beach DH, Goad LJ, Holz GG. Effects of antimycotic azoles on growth and sterol biosynthesis of Leishmania promastigotes. Mol Biochem Parasitol 1988; 31: 149–62.
Clinical and Experimental Dermatology
5
Clinical dermatology • Concise report
Clinical and Experimental Dermatology
Intermediate cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis successfully treated with fluconazole K. Daly,1 H. De Lima,2 H. Kato,3 E. M. Sordillo,4 J. Convit,5 O. Reyes-Jaimes,5 O. Zerpa2 and A. E. Paniz-Mondolfi1,5,6 Fundacion Jacinto Convit, Caracas, Venezuela; 2Division of Leishmaniasis, Instituto de Biomedicina, Caracas, Venezuela; 3Laboratory of Parasitology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan; 4Department of Pathology and Laboratory Medicine and the Infectious Diseases Developmental Laboratory (Department of Medicine), St. Luke’s Roosevelt Hospital Center, University Hospital of Columbia University College of Physicians and Surgeons, New York, NY, USA; 5Laboratory of Biochemistry and Dermatopathology, Instituto de Biomedicina, UCV/MPPS/IVSS, Caracas, Venezuela; and 6Medical Microbiology Laboratory, Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA 1
doi:10.1111/ced.12359
Summary
American cutaneous leishmaniasis is an endemic anthropozoonosis that exhibits a broad spectrum of clinical presentations. Intermediate/borderline disseminated cutaneous leishmaniasis is a distinct clinical condition that comprises cutaneous disease of a chronic nature, usually occurring as multiple lesions with or without mucosal involvement. The disease is usually caused by parasites of the subgenus Viannia, frequently occurs in context of an underlying disease, and is often resistant to standard antileishmanial therapy. We report a case that was refractory to standard therapy and other second-line drugs, but resolved after treatment with fluconazole, and review the use of fluconazole as a second-line drug in children.
Intermediate or borderline disseminated cutaneous leishmaniasis (ICL) is an uncommon variant of American cutaneous leishmaniasis. The disease usually presents in children or in patients with underlying comorbid conditions1 and an aberrant immune response to the parasite, leading to development of multiple, variegated disseminated lesions, a varied and sometimes exaggerated delayed-type hypersensitivity reaction to leishmanin, and a predominance of parasitized vacuolated macrophages in the upper dermis.1 ICL may be accompanied by mucosal disease, tends towards chronicity and relapse, and shows resistance to standard treatment regimens.1 We report an exceptionally interesting case of ICL successfully treated with fluconazole after several first-line and second-line Correspondence: Dr Alberto E. Paniz Mondolfi, Department of Microbiology, Yale University School of Medicine/Yale-New Haven Hospital, (PS656) 55 Park Street, New Haven CT 06511, USA E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 26 January 2014
ª 2014 British Association of Dermatologists
chemotherapeutic approaches were exhausted, and we review the use of fluconazole for ICL treatment in the subpopulation of children who may be particularly susceptible.
Report A 12-year-old girl presented with a 6-month history of cutaneous lesions. She was from a western Venezuelan region endemic for leishmaniasis. The initial lesion was an erythematous papule on the middle of the patient’s right forearm, which evolved into a plaque with an ulcerated centre (Fig. 1a). Subsequently 8–10 nodular erythematous lesions developed on her face and limbs, some with a scaly or crusty surface, or ulcerated centre (Fig. 1a). She also had an erythematous infiltrated plaque over her left scapula, and an erythematous, ulcerated, right nasal mucosal lesion. Montenegro test (leishmanial intradermal reaction) was positive (10 mm). Full blood count, blood chemistry and hepatic transaminase tests were normal, and serology testing for human immunodeficiency virus was negative. A biopsy was consistent with
Clinical and Experimental Dermatology
1
Intermediate cutaneous leishmaniasis treated with fluconazole A. E. Paniz Mondolfi et al.
Figure 1 (a) Erythematous raised plaques on the face and right forearm, and ulcerated plaque on the face. (b) Laminar hyperkeratosis,
orthokeratosis, irregular epidermis with moderate acanthosis, and an ill-defined lymphoplasmacytic infiltrate with numerous vacuolated macrophages containing abundant amastigotes (haematoxylin and eosin, original magnification 9 400). (c) Typical star-shaped depressed scar on the nose; and (d) completely healed lesion on right forearm.
leishmaniasis (Fig. 1b). Species-specific typing by the rRNA internal transcriber region of the cytochrome B gene2 revealed Leishmania (Viannia) braziliensis. Local treatments used for localized cutaneous leishmaniasis (LCL) management were not an option for our patient because she had multiple lesions, mucosal involvement and a lesion measuring > 40 mm.3 She was enrolled in a trial of miltefosine (Aeterna; Zentaris, Frankfurt, Germany) 50 mg twice daily for 71 days, which resulted in a partial response, but she developed nausea, vomiting and severe diffuse abdominal pain, and her alkaline phosphatase level increased to 932 U/L (normal range 50–200 U/L), prompting treatment suspension. Her lesions persisted, and 1 month later she was started on treatment with a
2
Clinical and Experimental Dermatology
pentavalent antimonial drug (meglumine antimoniate; Rhone-Poulenc, Paris, France) Glucantime; 20 mg/kg/day intramuscularly. However, this had to be stopped after 13 days, when a severe local and painful skin rash developed. Although rare, skin reactions can occur during antimonial treatment because of the altered physicochemical composition of the drug and contamination with heavy metals.4 Giemsa-stained lymph smears remained positive despite these interventions, and 20 days after the antimonial treatment was discontinued, the patient was started on oral fluconazole 200 mg daily (5 mg/kg/day) for 12 days. Within 48 h, the lesions started to re-epithelialize, and the infiltration diminished substantially. The patient did not experience any side effects,
ª 2014 British Association of Dermatologists
ª 2014 British Association of Dermatologists
M
Hand and foot NR
Limbs and face Scalp
Face
Face and ankle
Face
NR NR NR NR NR NR Left arm
Site of lesion
Ulcers, 1.5 and 2 cm NR
3 cm, papular
NR NR NR NR NR NR 3 erythematous lesions 3.5 cm raised erythematous lesion with crusted centre 3 cm lesions on face and ankle, and 2 cm lesion on face. 2 cm lesion with central scab and surrounding erythema Ulcerated plaque
Characteristic of lesions
NR
3
18
3
NR
1
7
3.5 3.5 5 3.5 3 5 5
Duration of disease, months
*Suspected organism. CR, case report; CS, case series; CT, clinical trial. NR, not reported.
3 years
CT
F
F
F
F
8 years
3 years
F
11 years
11 years
CR
Sklavost et al., 201010 Baront et al., 200411 Toubianat et al., 200612 Sousat et al., 20116
F
9 months
CR
CS
Crogant et al., 20109
F M F M F F F
Sex
1 year 5 years 10 years 1 year 8 years 9 years 12 years
2 years
CS
Morizot et al., 20077
Age
CR
Study type
Reference/Type of study
7 mg/kg/day
5 mg/kg/day
100 mg once daily
150 mg once daily
5 mg/kg/day
5 mg/kg/day
5 mg/kg/day
2.5 mg/kg/day 2.5 mg/kg/day 2.5 mg/kg/day 2.5 mg/kg/day 2.5 mg/kg/day 2.5 mg/kg/day 5 mg/kg/day
Dose
Table 1 Reports of paediatric patients with cutaneous leishmaniasis treated with oral fluconazole.
weeks weeks weeks weeks weeks weeks months
8 weeks
20 days
3 weeks
6 weeks
1 month
2 months
2 months
6 6 6 6 6 6 7
Length of treatment
L. braziliensis*
L. major MON 26
NR
L. major*
NR
NR
L.major* L. major MON 25 L. major MON 74 L. major MON 25 L. major* L.major* NR
Species
Healed
Complete healing
Light scarring
Scarring
Failure
Failure
Failure
Resolution Resolution Resolution Failure Failure Failure Resolution
Outcome
NR
3 months
NR
NR
NR
NR NR NR
Follow-up
Intermediate cutaneous leishmaniasis treated with fluconazole A. E. Paniz Mondolfi et al.
Clinical and Experimental Dermatology
3
Intermediate cutaneous leishmaniasis treated with fluconazole A. E. Paniz Mondolfi et al.
and her laboratory values remained normal. At day 10, biopsies of the lesions with inoculation of laboratory animals were negative. Her lesions regressed (Fig. 1c,d) with no signs of infiltration. No new lesions have developed during a follow-up of >3 years after treatment cessation. Leishmaniasis is endemic in 88 countries. Over 350 million people are at risk,5 an estimated 12 million are infected, and about 1.5 million new cases occur yearly, yet leishmaniasis remains one of the most neglected tropical diseases.5 The clinical appearance and response to treatment1,5 are determined both by the infecting Leishmania species and by host immune response. A frequent agent of New World cutaneous leishmaniasis, L. (V.) braziliensis, causes both intermediate/borderline disseminated cutaneous leishmaniasis and mucocutaneous leishmaniasis, and is a major health problem in Latin American countries such as Brazil, Bolivia, Peru, Venezuela and Guatemala.1,5 Lesions may spontaneously heal with scarring, but later reappear elsewhere, especially as destructive mucocutaneous lesions. Mucocutaneous leishmaniasis (also called Espundia) never heals spontaneously and requires early, aggressive treatment.1,5 The risk of mucosal involvement when the initial stages of leishmaniasis are not managed aggressively has meant that local paramomycin and intralesional pentavalent antimonials, which are effective in Old World leishmaniasis, have limited utility for management of New World leishmaniasis.5 Although pentavalent antimonials remain the firstline therapy for most cases of leishmaniasis, including New World cutaneous leishmaniasis caused by L. (V) braziliensis,5 they are not effective against all Leishmania species, require parenteral administration, and have significant systemic toxicity. Other agents, including pentamidine, miltefosine, amphotericin B deoxycholate, and liposomal amphotericin B, are also limited by variable efficacy and severe side effects, prompting the search for more effective, bettertolerated options.5,6 The imidazoles and the structurally related triazoles have demonstrated activity against some types of cutaneous leishmaniasis.1,5,6 Fluconazole, a well-tolerated, orally active, synthetic triazole with a long half-life, achieves 10 times its plasma concentration in skin,6 and has shown promise in some clinical trials of leishmaniasis treatment, notably in Old World complex species infections,6,7 but less consistently in New World
4
Clinical and Experimental Dermatology
leishmaniasis. Sousa et al.6 reported cure rates of 89–100%, depending on dose (5 and 8 mg/kg/day respectively) for fluconazole treatment of cutaneous leishmaniasis in patients from the State of Cear a, Brazil, where L. (V) braziliensis is endemic. However, Schnedl et al.8 reported three cases of cutaneous leishmaniasis, imported from Belize and assumed to be due to New World Leishmania species, which showed no response to 200 mg/day of oral fluconazole. Antileishmanial use of fluconazole in children is mostly anecdotal; successful treatment was reported in some cases, including several L. major cases and one case of L. braziliensis infection (Table 1).9–12 An important limitation of many reports is that the parasites were not characterized molecularly, as it seems that species differences among Leishmania are critical in determining azole susceptibility. In vitro susceptibility results may also be assay-dependent. For example, Rangel et al.13 found L. braziliensis 2903 to be naturally resistant to ketoconazole and to other sterol C14a–demethylase inhibitors (e.g. bis-triazole D0870), whereas Leishmania mexicana was extremely azole-susceptible, with therapeutic concentrations achieving complete growth arrest and cell lysis of the parasites. Beach et al.14 observed that of 36 references strains representing 7 Leishmania species, L. (V) braziliensis isolates were the most susceptible to azoles, with > 90% inhibition of proliferation by ketoconazole 0.1 lg/mL at day 5 of incubation. Furthermore, as azoles such as fluconazole concentrate in skin, in vitro assays may not adequately predict clinical efficacy. Our report of successful fluconazole treatment of a patient with ICL due to L. (V) braziliensis (confirmed by molecular testing), in conjunction with the cases reported by Sousa et al., supports the potential use of oral fluconazole for treatment of L. (V) braziliensis infections, particularly in children and other susceptible patients developing intermediate leishmaniasis. Although the previous treatment measures in our patient could have influenced parasite viability, the persistence of high parasite loads on skin smears prior to beginning fluconazole suggests that fluconazole was pivotal in eradicating the infection. Alternatively, the apparent parasitocidal effect of fluconazole in our case may reflect strain-specific azole susceptibility. Future randomized controlled trials are necessary to confirm our results, and in such trials, molecular characterization will be essential to evaluate the efficacy of antileishmanial azole drugs against different Leishmania species.
ª 2014 British Association of Dermatologists
Intermediate cutaneous leishmaniasis treated with fluconazole A. E. Paniz Mondolfi et al.
Learning points ● Intermediate and mucocutaneous forms of
leishmaniasis occur primarily in the tropics of South America. ● L. (V.) braziliensis is one of the most common agents of cutaneous leishmaniasis in the New World. ● Intermediate and mucocutaneous leishmaniasis is often relatively resistant to standard treatment regimens. ● Intermediate/borderline disseminated leishmaniasis usually presents in children or in patients with a comorbid condition. ● The treatment of choice for all forms of leishmaniasis is a type of drug containing antimonials, such as sodium stibogluconate or meglumin antimoniate. ● Standard treatments for leishmaniasis usually have marked side effects. ● Increasing data supports the potential use of oral azoles for treatment of L. (V) braziliensis infections in cases of recalcitrant clinical presentations of the disease, as in this case.
References 1 Paniz Mondolfi AE, Duffey GB, Horton LE et al. Intermediate/borderline disseminated cutaneous leishmaniasis. Int J Dermatol 2013; 52: 446–55. 2 Kato H, Watanabe J, Mendoza Nieto I et al. Leishmania species identification using FTA card sampling directly from patients’ cutaneous lesions in the state of Lara, Venezuela. Trans R Soc Trop Med Hyg 2011; 105: 561–7. 3 Blum J, Lockwood DN, Visser L et al. Local or systemic treatment for New World cutaneous leishmaniasis? Re-evaluating the evidence for the risk of mucosal leishmaniasis. Int Health 2012; 4: 153–63.
ª 2014 British Association of Dermatologists
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