É relatado um caso de rinoentomoftoramicose por Conidiobolus coronatus em mulher de 61 anos submetida a tratamento com todos os antifúngicos disponíveis no mercado brasileiro, durante 8 anos, sem sucesso, incluindo iodeto de potássio por 1 mês, sulfametoxazol associado ao trimetoprim por 2 meses, anfotericina B em dose total de 1130 mg, cetoconazol, 400 mg/dia por 6 meses, fluconazol, 200 mg/dia, por pelo menos 2 meses, e itraconazol, 400 mg/dia, por 2 meses, seguido de 200 mg/dia por mais 4 meses. A cura clínica e micológica completa foi obtida com a associação de itraconazol 400mg/dia com fluconazol 200 mg/dia, durante 24 meses. Após a cura a paciente foi submetida a cirurgia restauradora. Atualmente a paciente encontra-se há 59 meses sem medicação específica permanecendo clínica e micologicamente curada.Rhinoentomophthoramycosis caused by Conidiobolus coronatus in a 61-year old woman was unsuccessfully treated during 8 years with all the antifungals available in the Brazilian market, including potassium iodide for 1 month, sulfamethoxazole plus trimethoprim for 2 months, amphotericin B, total dose of 1130 mg, cetoconazole, 400 mg/day for 6 months, fluconazole, 200 mg/day, for at least 2 months and, itraconazole, 400 mg/day for 2 months, followed by 200 mg/day for 4 more months. Complete clinical and mycological cure was achieved using itraconazol 400 mg/day in association with fluconazol 200 mg/day during 24 months. After cure she was submitted to plastic surgery to repair her facial deformation. Today she remains clinically and mycologically cured after 59/60 months (5 years!) without any specific antifungal. We thus suggest the use of the combination of itraconazole and fluconazole as an additional option for the treatment of this mycosis

LAZÉRA, Márcia dos Santos

MONTEIRO, Paulo Cezar Fialho

VALLE, Antonio Carlos Francesconi do

VIEGAS, Maria de Lourdes

WANKE, Bodo

English

Rhinoentomophthoramycosis caused by Conidiobolus coronatus in a 61-year old woman was unsuccessfully treated during 8 years with all the antifungals available in the Brazilian market, including potassium iodide for 1 month, sulfamethoxazole plus trimethoprim for 2 months, amphotericin B, total dose of 1130 mg, cetoconazole, 400 mg/day for 6 months, fluconazole, 200 mg/day, for at least 2 months and, itraconazole, 400 mg/day for 2 months, followed by 200 mg/day for 4 more months. Complete clinical and mycological cure was achieved using itraconazol 400 mg/day in association with fluconazol 200 mg/day during 24 months. After cure she was submitted to plastic surgery to repair her facial deformation. Today she remains clinically and mycologically cured after 59/60 months (5 years!) without any specific antifungal. We thus suggest the use of the combination of itraconazole and fluconazole as an additional option for the treatment of this mycosis.É relatado um caso de rinoentomoftoramicose por Conidiobolus coronatus em mulher de 61 anos submetida a tratamento com todos os antifúngicos disponíveis no mercado brasileiro, durante 8 anos, sem sucesso, incluindo iodeto de potássio por 1 mês, sulfametoxazol associado ao trimetoprim por 2 meses, anfotericina B em dose total de 1130 mg, cetoconazol, 400 mg/dia por 6 meses, fluconazol, 200 mg/dia, por pelo menos 2 meses, e itraconazol, 400 mg/dia, por 2 meses, seguido de 200 mg/dia por mais 4 meses. A cura clínica e micológica completa foi obtida com a associação de itraconazol 400mg/dia com fluconazol 200 mg/dia, durante 24 meses. Após a cura a paciente foi submetida a cirurgia restauradora. Atualmente a paciente encontra-se há 59 meses sem medicação específica permanecendo clínica e micologicamente curada

Cadernos Espinosanos (E-Journal)

Rev. Inst. Med. trop. S. Paulo43 (4):233-236, July-August, 2001.(1) Laboratory of Clinical Research, Research Center Evandro Chagas Hospital, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, RJ, Brazil.(2) Laboratory of Medical Mycology, Research Center Evandro Chagas Hospital, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, RJ, Brazil.(3) Hospital da Lagoa, Instituto Nacional de Seguridade Social (INSS),Rio de Janeiro, RJ, Brazil.Correspondence to: Antonio Carlos Francesconi do Valle, Rua Machado de Assis, 24/903, Flamengo, 22220-060 Rio de Janeiro, RJ, Brasil. E-mail: afvalle@cpqhec.fiocruz.brENTOMOPHTHORAMYCOSIS BY Conidiobolus coronatus. REPORT OF A CASE SUCCESSFULLYTREATED WITH THE COMBINATION OF ITRACONAZOLE AND FLUCONAZOLEAntonio Carlos Francesconi do VALLE(1), Bodo WANKE(2), Márcia dos Santos LAZÉRA(2), Paulo Cezar Fialho MONTEIRO(2) & Maria de Lourdes VIEGAS(3)SUMMARYRhinoentomophthoramycosis caused by Conidiobolus coronatus in a 61-year old woman was unsuccessfully treated during 8years with all the antifungals available in the Brazilian market, including potassium iodide for 1 month, sulfamethoxazole plustrimethoprim for 2 months, amphotericin B, total dose of 1130 mg, cetoconazole, 400 mg/day for 6 months, fluconazole, 200 mg/day,for at least 2 months and, itraconazole, 400 mg/day for 2 months, followed by 200 mg/day for 4 more months. Complete clinical andmycological cure was achieved using itraconazol 400 mg/day in association with fluconazol 200 mg/day during 24 months. Aftercure she was submitted to plastic surgery to repair her facial deformation. Today she remains clinically and mycologically cured after59/60 months (5 years!) without any specific antifungal. We thus suggest the use of the combination of itraconazole and fluconazoleas an additional option for the treatment of this mycosis.KEYWORDS: Entomophthoramycosis; Zygomycosis; Combination triazole treatment; Rhinoentomophthoramycosis.INTRODUCTIONEntomophthoramycosis affects individuals with an apparently intactimmunological status and occurs primarily in tropical areas. Twozygomycetes belonging to the order Entomophthorales are the etiologicagents of subcutaneous entomophthoramycosis: Basodiobolus ranarum(= B. haptosporus) and Conidiobolus coronatus3,7. C. coronatus hasalready been isolated from soil samples, rotting plant matter, insects,and the gastrointestinal contents of lizards and frogs, especially in tropicaland subtropical regions11.Infection by B. ranarum manifests itself as a subcutaneoustumefaction located on the trunk, buttocks, or proximal portion of thelimbs. Invasion of the abdominal and thoracic cavities by extension ofthe subcutaneous tumor mass has been reported. More recently therehave been case reports with frankly visceral manifestations, with gastricand intestinal tumoral lesions, presenting as acute abdomen3,7.Lesions by C. coronatus begin as infiltration of the nasal mucosaand submucosa, extending to the adjacent tissues of the paranasal sinuses,nasal dorsum, upper lip, and face, with no delimitation to their growth.The tumefaction, with a nodular or polipose infiltrative appearance, iscovered by erythematous, hard skin, displaying continuity with theunderlying tissues. The clinical manifestations result from the expansionof the tumor mass. Because of its initially central facial presentationaffecting the nose first, the disease is also known as rhinoentomo-phthoramycosis. In the more advanced cases, the lesions can also affectthe nasopharynx, oropharynx, palate, cervical region, and even themediastinum3,7. The first mycologically proven cases in humans weredescribed independently and simultaneously in 1965 in Jamaica4 andAfrica12.Cases of rhinoentomophthoramycosis have been described in Africa,Asia, and the Americas, ranging between the tropics of Cancer andCapricorn. The disease is essentially chronic, evolving over the courseof years. No incubation period or cases of spontaneous involution areknown. Diagnosis is made by clinical, histopathological, and mycologicalexamination2.According to the medical literature, treatment can be applied withsatisfactory results using potassium iodide, amphotericin B, andcetoconazole. However, the literature provides little information on long-term follow-up and/or relapses. We present a case of rhinoentomo-phthoramycosis caused by C. coronatus in which all the availableantifungals, including itraconazole and fluconazole, had been used singlywithout success. However, the patient evolved to complete cure afterlong-term combination therapy with these two triazoles.CASE REPORTA 61 year-old white woman, domestic, living in the state ofMaranhão, northeast Brazil, presented a history of a disease lasting 8234VALLE, A.C.F.; WANKE, B.; LAZÉRA, M.S.; MONTEIRO, P.C.F. & VIEGAS, M.L. - Entomophthoramycosis by Conidiobolus coronatus. Report of a case successfully treated with thecombination of itraconazole and fluconazole. Rev. Inst. Med. trop. S. Paulo, 43(4):233-236, 2001.years (Fig. 1). During this period she was examined at several hospitals,and after obtaining the diagnosis of entomophthoramycosis based onclinical, mycological and histopathological findings, treated with thefollowing drugs:- potassium iodide for 1 month, with worsening of the lesions;- sulfamethoxazole plus trimethoprim for 2 months, with notherapeutic response;- amphotericin B, total dose of 1130 mg, with partial improvement;- cetoconazole, 400 mg/day for 6 months, with a favorable clinicalresponse. Treatment was interrupted because the patient could notafford the medication. After a relapse, she resumed use of thismedication, with no therapeutic response;- fluconazole, 200 mg/day, for at least 2 months, with no therapeuticresponse;- itraconazole, 400 mg/day for 2 months, followed by 200 mg/day for4 more months, with no therapeutic response.The patient was referred to the Evandro Chagas Hospital at theOswaldo Cruz Foundation in Rio de Janeiro for specific treatment, wherethe diagnosis of rhinoentomophthoramycosis by C. coronatus wasconfirmed on clinical, histopathological, and mycological examination(Fig. 2a and 2b). At the beginning of April 28, 1993, due to the lack ofother treatment options, we initiated combined oral fluconazole 200 mg/day and itraconazole 400 mg/day until April 1995. The patient evolvedto clinical and mycological cure in 3 months (Fig. 3). Throughouttreatment she was monitored every 2 months with clinical andmycological examination, complete blood count, and blood biochemicaltests and presented no side effects or signs of toxicity. After the specificclinical treatment during 24 months, restorative surgery was performedto correct sequelae (Fig. 4). At the last clinical assessment, in March2000, the patient had been off medication for 59 months and remainedclinically cured.DISCUSSIONEntomophthoramycosis occurs sporadically in tropical regions ofAsia, Africa, and the Americas. The disease is caused by fungi livingsaprophytically in organic debris in the environment. So far only fewcases of rhinoentomophthoramycosis caused by C. coronatus werereported. In Brazil, the first case was described by ANDRADE et al. in19671, only two years after the first reports on this mycosis in casesfrom Africa and Jamaica. Later on, cases were reported from the statesof the North9,10 and more frequently from the Northeast of Brazil (statesof Bahia, Piauí, Maranhão, and Sergipe)1,2,6,8,14,17. In the present case thepatient was a native of the state of Maranhão, reinforcing the Northeastas the main focus of this mycosis in Brazil.Clinical and histopathological findings are quite suggestive, butdefinitive diagnosis is only possible by isolating and identifying thefungus in appropriate culture media. Clinically, the differential diagnosisFig. 1 - Aspect of the patient at admission.Fig. 2a - Culture of Conidiobolus coronatus. Fig. 2b - Microphotograph showing sporangiola producing secondary multiplicative spores.VALLE, A.C.F.; WANKE, B.; LAZÉRA, M.S.; MONTEIRO, P.C.F. & VIEGAS, M.L. - Entomophthoramycosis by Conidiobolus coronatus. Report of a case successfully treated with thecombination of itraconazole and fluconazole. Rev. Inst. Med. trop. S. Paulo, 43(4):233-236, 2001.235should consider scleroma, rhynosporidiosis, and benign and malignanttumors of the nasal cavity 8. Histopathological examination shows aninflammatory granulomatous reaction, with a predominantlymononuclear infiltrate consisting of lymphocytes, histiocytes, and somemultinucleated giant cells, along with plasma cells and eosinophils. Thecentral portion shows broad, thin-walled, irregular branching hyphae,frequently approaching right angles. These hyphae do not usually displaysepta and are surrounded by a peculiar eosinophilic mass (the Splendore-Hoeppli phenomenon). The appearance is similar to that of subcutaneousentomophthoramycosis caused by B. ranarum. In our clinical case thediagnosis was based on clinical and histopathological examinationconfirmed by mycological identification of C. coronatus.According to the literature, treatment of rhinoentomophthoramycosishas been performed successfully with potassium iodide3, combinationsulfamethoxazole-trimethoprim5, amphotericin B3,5, and cetoconazole8,17.All of these drugs were used unsuccessfully in the present case.Itraconazole and fluconazole, broad-spectrum triazolic derivativeantifungals were used effectively against various other mycoses, hadalso been used singly to treat the patient, initially producing regressionof the lesions, but with reactivation of the infection shortly afterwards.All the antifungals available in Brazil in 1993 failed to cure the patient.Saperconazole, a new broad-spectrum imidazolic derivative, also wasnot available at that time because it has been removed from the marketdue to the development of tumors in laboratory animals. For lack ofother options and based on reports of the successful use of multidrugtherapy in various infectious diseases, we used a combination ofitraconazole and fluconazole obtaining an excellent therapeutic response.In fact, the response was similar to that found by other authors in treatingother mycoses with this combination therapy13,15,16. No side effects ordrug-related toxicity were observed. We thus suggest the use of thecombination of itraconazole and fluconazole as an additional option forthe treatment of this mycosis. Possibly this may be also valid for otherdisseminated or opportunistic mycoses, especially in cases followingtreatment failure with the classic drug regimens.Itraconazole and fluconazole are triazoles with similar mechanisms,acting especially on the fungal cell wall’s cytochrome p450. However,the underlying mechanism of a possible synergism between both drugsis so far unknown. We didn’t find reports of antagonism between thesetwo drugs.Due to the lack of criteria for control of biological cure in this mycosisand the small number of cases reported in the literature, treatment issomewhat empirical, since the precise dosage and duration of treatmentare unknown. In our case, as in others reported in the literature, therehad been an initially favorable response to certain drugs, but their removal,perhaps too early, had led to in vivo resistance. Therefore, even with aclinical cure after 3 months, we maintained this combination drug therapyfor over 19 months. There is a report of cure in this mycosis followingsurgical treatment, but in our case surgery was performed to correctsequelae, and the successive histopathological and mycological tests ofthe operatory specimens were negative.ACKNOWLEDGEMENTSThe authors thank Dr. Alberto Thomaz Londero, Emeritus Professorof the Federal University of Santa Maria, RS-Brazil, for revising thetext and helpful suggestions and, Professor Dr. Karel De Beule, JanssenResearch Foundation, Beerse, Belgium, for comments and providingreferences.Fig. 4 - Aspect of the patient after 24 months of successful therapy and restorative surgery.Fig. 3 - Aspect of patient’s lesion 90 days after the use of thecombination of itraconazole and fluconazole.236VALLE, A.C.F.; WANKE, B.; LAZÉRA, M.S.; MONTEIRO, P.C.F. & VIEGAS, M.L. - Entomophthoramycosis by Conidiobolus coronatus. Report of a case successfully treated with thecombination of itraconazole and fluconazole. Rev. Inst. Med. trop. S. Paulo, 43(4):233-236, 2001.RESUMOEntomoftoramicose por Conidiobolus coronatus. Relato de umcaso tratado com a associação de itraconazol com fluconazolÉ relatado um caso de rinoentomoftoramicose por Conidioboluscoronatus em mulher de 61 anos submetida a tratamento com todos osantifúngicos disponíveis no mercado brasileiro, durante 8 anos, semsucesso, incluindo iodeto de potássio por 1 mês, sulfametoxazol associadoao trimetoprim por 2 meses, anfotericina B em dose total de 1130 mg,cetoconazol, 400 mg/dia por 6 meses, fluconazol, 200 mg/dia, por pelomenos 2 meses, e itraconazol, 400 mg/dia, por 2 meses, seguido de 200mg/dia por mais 4 meses. A cura clínica e micológica completa foi obtidacom a associação de itraconazol 400mg/dia com fluconazol 200 mg/dia,durante 24 meses. Após a cura a paciente foi submetida a cirurgiarestauradora. Atualmente a paciente encontra-se há 59 meses semmedicação específica permanecendo clínica e micologicamente curada.REFERENCES1. ANDRADE, Z.A.; PAULA, L.A.; SHERLOCK I.A. & CHEEVER A.W. - Nasalgranuloma caused by Entomophthora coronata. Amer. J. trop. Med. Hyg., 16: 31-33, 1967.2. ANDRADE, Z.A. & ANDRADE, S.G. - A entomoftorose nasal. Rev. Soc. bras. Med.trop., 6: 239-249, 1972.3. BANDEIRA, V. & LASCET, I.G. - Zigomicose. In: TALHARI, S. & NEVES, R.G., ed.Dermatologia tropical. São Paulo, Medsi, 1995. p. 191–202.4. BRAS, G.; GORDON, C.C.; EMMONS, C.W.; PRENDEGAST, K.M. & SUGAR, M. -A case of phycomycosis observed in Jamaica; infection with Entomophthora coronata.Amer. J. trop. Med. Hyg., 14: 141-145, 1965.5. CAMPBELL, I. & GOUVEIA, J. - Zigomicose. In: ZAITZ, C.; CAMPBELL, I.;MARQUES, A.S.; RUIZ, L.R.B. & SOUZA, V.M., ed. Compêndio de micologiamédica. Rio de Janeiro, Medsi, 1998. p. 205-218,6. COSTA, E.F.; PORTUGAL, F.M.; PIVA, N. & AGUIAR, K.V.M. - Zigomicose rinofacial:apresentação de um caso. An. bras. Derm., 74: 265-268, 1999.7. ELLIS, D.H. - The zygomycetes. In: AJELLO, L. & HAY, R.J. - Medical Mycology. 9.ed. London, Arnold; New York, Oxford University Press, 1998. p. 247-276.(COLLIER, L.; BALOWS, A. & SUSSMAN, M. - Topley and Wilson’s Microbiologyand Microbial Infections v.4.)8. FONSECA, A.P.M.; FONSECA, W.S.M.; LEAL, M.J.S. & ARAÚJO, R.C. -Rinoentomoftoromicose: relato de quatro casos. An. bras. Derm., 64: 261-265, 1989.9. MORAES, M.A.P.; ARNAUD, M.C.V. & ALMEIDA, M.M.R. - Zigomicose nasofacialno Estado do Pará: registro de dois casos. Rev. Soc. bras. Med. trop., 30: 329-331,1997.10. MORAES, M.A.; ALMEIDA, M.M.R.; VEIGA, R.C.C. & SILVEIRA F.T. - Zigomicosenasofacial. Relato de um caso no estado do Pará, Brasil. Rev. Inst. Med. trop. S.Paulo, 36: 171-174, 1994.11. PORTO, E.; MELO, N.T.; HEINS-VACCARI, E.M.; LACAZ, C.S. & ASSIS, C.M. -Isolamento de Conidiobolus coronatus (Costantin) Batko, 1964, de amostras de terracom e sem detritos vegetais. An. bras. Derm., 62: 303-307, 1987.12. RENOIRTE, R.; VANDEPITTE, J.; GATTI, F. & WERTH, R. - Phycomycose nasofaciale(rhinophycomycose) due a Entomophtora coronata. Bull. Soc. Path. exot., 58: 847-862, 1965.13. SHICAMURA, I. - Evaluation of keratomycosis experienced in Ehime University forrecent three years. In: JAPANESE ASSOCIATION FOR OCULAR INFECTION,32., Japan, 1995. p. 50.14. SILVA, J.F.; SILVA, W.M.; DANTAS, J.C.; ASSUNÇÃO, A.C.R. & OLIVEIRA,M.M.S.T. - Rinoentomoftorose. Registro de um caso. Rev. Pat. trop., 4: 101-106,1975.15. TAKAMATSU, K. & OHTA, Y. - One case with cryptogenic severe sub-acute meningitissuccessfully treated with cerebral ventricle-peritoneal shunt combined with antifungaltreatment. In: MEETING OF THE JAPANESE SOCIETY OF NEUROLOGICALTHERAPEUTICS, 13., Japan, 1995. p. 56.16. TELLES, F.Q.; FILLUS, J.N.; SAAD, L.M. et al. - Successful treatment of cerebralphaeohyphomycosis with azole combined therapy. In: SYMPOSIUM ON TOPICSIN MYCOLOGY: FUNGAL DIMORPHISM, 4., Cambridge, 1992. p. 284.17. TOWERSEY, L.; WANKE, B.; ESTRELLA, R.R. et al. - Conidiobolus coronatus infectiontreated with ketoconazole. Arch. Derm., 124: 1392-1396, 1988.Received: 27 October 2000Accepted: 15 March 2001

Entomophthoramycosis by Conidiobolus coronatus. Report of a case successfully treated with the combination of itraconazole and fluconazole

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Entomoftoramicose por Conidiobolus coronatus. Relato de um caso tratado com a associação de itraconazol com fluconazol

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Entomoftoramicose por Conidiobolus coronatus. Relato de um caso tratado com a associação de itraconazol com fluconazol

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