Anfotericina B no tratamento da neurocriptococose em pacientes submetidos a transplante renal

Nóbrega, J. P. S.

doi:10.1590/S0004-282X1988000200002

Resumos

Foram estudados 35 casos de neurocriptococose, 17 dos quais em pacientes submetidos a transplante renal. O objetivo foi avaliar a resposta terapêutica observada no grupo de pacientes transplantados renais com neurocriptococose, com ênfase à função renal, submetidos a esquema medicamentoso que inclui a anfotericina B. A resposta observada foi comparada aos resultados obtidos no grupo dos demais pacientes com a mesma infecção, submetidos ao mesmo esquema medicamentoso, porém sem insuficiência renal prévia. Dos 35 pacientes, 10 faleceram nos primeiros dias do tratamento e, assim, 25 foram efetivamente tratados para neurocriptococose. Destes 25, 18 apresentavam outra condição clínica associada, sendo esta transplante renal em 15 deles. Os medicamentos utilizados basicamente foram a anfotericina B intravenosa e intra-raqueana associada à 5-fluorocitosina via oral. Sete pacientes faleceram durante o tratamento. Assim, dos 35 pacientes que inicialmente compunham a casuística, 17 faleceram (48,57%) e 18 foram tratados com sucesso, nenhum deles apresentando recidiva. As intercorrências observadas durante o tratamento são discutidas e é feita correlação dos dados obtidos neste estudo aos disponíveis na literatura. A análise dos resultados obtidos permite ressaltar: a necessidade do surgimento de medicamentos mais eficazes e menos tóxicos para a terapêutica da neurocriptococose, sendo até o momento a anfotericina B o principal medicamento existente; o esquema terapêutico atualmente indicado consiste na associação anfotericina B e 5-fluorocitosina, havendo vantagens na utilização simultânea da anfotericina B pelas vias intravenosa e intra-raqueana. A análise dos resultados permite concluir por não haver contra-indicação ao uso da anfotericina B por via intravenosa em transplantados renais com neurocriptococose.

Thirty-five cases of cryptococcosis of the central nervous system (CNS) were studied, 17 of them submitted to renal transplantation. The objective was to evaluate the therapeutic responses observed in the group of kidney transplant patients with CNS cryptococcosis. They were submitted to amphotericin B therapy, with emphasis to the renal function. The results in this group were compared with the outcome in the group of patients with the same infection, submitted to the same therapeutic scheme, but without previous impairment of renal function. Among the 35 patients, 20 were male; the age varied between 4 and 76 years. Associated clinical conditions were noticed in 25 patients, 17 of them with renal transplantation. Among 35 patients, 10 died in the first days of the treatment; 25 patients were effectively treated for CNS cryptococcosis, 18 of them with associated clinical conditions; 15 were kidney transplant patients. The drugs used in the treatment of CNS cryptococcosis were, as possible, the amphotericin B by intravenous and intrathecal route (lumbar puncture) associated with 5-fluorocytosine. Seven patients died during the treatment; then, of the 35 patients who were initially evaluated, 17 died and 18 were successfully treated, with a death rate of 48.57%. Various intercurrences were observed with the use of amphotericin B and 5-fluorocytosine. The clinical and therapeutic results recorded in this study were compared with the information met in literature. The analysis of the results emphasizes the need of the discovery of better and less toxic drugs than those currently used. Amphotericin B still is the most important drug in the treatment of CNS cryptococcosis and the therapeutic scheme currently recommended consists in the association of amphotericin B and 5-fluorocytosine, and there has been also advantage in the simultaneous use of intravenous and intrathecal amphotericin B. Statistical analysis of the results showed that there is no harm with the use of intravenous amphotericin b in renal transplanted patients with cryptococcosis of the central nervous system.

J. P. S. Nóbrega

Clínica Neurológica do Hospital das Clínicas da Faculdade de Medicina da Universidade ao Departamento de Neurologia da FMUSP em 1987

RESUMO

Foram estudados 35 casos de neurocriptococose, 17 dos quais em pacientes submetidos a transplante renal. O objetivo foi avaliar a resposta terapêutica observada no grupo de pacientes transplantados renais com neurocriptococose, com ênfase à função renal, submetidos a esquema medicamentoso que inclui a anfotericina B. A resposta observada foi comparada aos resultados obtidos no grupo dos demais pacientes com a mesma infecção, submetidos ao mesmo esquema medicamentoso, porém sem insuficiência renal prévia. Dos 35 pacientes, 10 faleceram nos primeiros dias do tratamento e, assim, 25 foram efetivamente tratados para neurocriptococose. Destes 25, 18 apresentavam outra condição clínica associada, sendo esta transplante renal em 15 deles. Os medicamentos utilizados basicamente foram a anfotericina B intravenosa e intra-raqueana associada à 5-fluorocitosina via oral. Sete pacientes faleceram durante o tratamento. Assim, dos 35 pacientes que inicialmente compunham a casuística, 17 faleceram (48,57%) e 18 foram tratados com sucesso, nenhum deles apresentando recidiva. As intercorrências observadas durante o tratamento são discutidas e é feita correlação dos dados obtidos neste estudo aos disponíveis na literatura. A análise dos resultados obtidos permite ressaltar: a necessidade do surgimento de medicamentos mais eficazes e menos tóxicos para a terapêutica da neurocriptococose, sendo até o momento a anfotericina B o principal medicamento existente; o esquema terapêutico atualmente indicado consiste na associação anfotericina B e 5-fluorocitosina, havendo vantagens na utilização simultânea da anfotericina B pelas vias intravenosa e intra-raqueana. A análise dos resultados permite concluir por não haver contra-indicação ao uso da anfotericina B por via intravenosa em transplantados renais com neurocriptococose.

SUMMARY

Thirty-five cases of cryptococcosis of the central nervous system (CNS) were studied, 17 of them submitted to renal transplantation. The objective was to evaluate the therapeutic responses observed in the group of kidney transplant patients with CNS cryptococcosis. They were submitted to amphotericin B therapy, with emphasis to the renal function. The results in this group were compared with the outcome in the group of patients with the same infection, submitted to the same therapeutic scheme, but without previous impairment of renal function. Among the 35 patients, 20 were male; the age varied between 4 and 76 years. Associated clinical conditions were noticed in 25 patients, 17 of them with renal transplantation. Among 35 patients, 10 died in the first days of the treatment; 25 patients were effectively treated for CNS cryptococcosis, 18 of them with associated clinical conditions; 15 were kidney transplant patients. The drugs used in the treatment of CNS cryptococcosis were, as possible, the amphotericin B by intravenous and intrathecal route (lumbar puncture) associated with 5-fluorocytosine. Seven patients died during the treatment; then, of the 35 patients who were initially evaluated, 17 died and 18 were successfully treated, with a death rate of 48.57%. Various intercurrences were observed with the use of amphotericin B and 5-fluorocytosine. The clinical and therapeutic results recorded in this study were compared with the information met in literature. The analysis of the results emphasizes the need of the discovery of better and less toxic drugs than those currently used. Amphotericin B still is the most important drug in the treatment of CNS cryptococcosis and the therapeutic scheme currently recommended consists in the association of amphotericin B and 5-fluorocytosine, and there has been also advantage in the simultaneous use of intravenous and intrathecal amphotericin B. Statistical analysis of the results showed that there is no harm with the use of intravenous amphotericin b in renal transplanted patients with cryptococcosis of the central nervous system.

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Centro de Investigações em Neurologia, FMUSP - Caixa Postal 5199 - 01051 São Paulo SP - Brasil.

1. Atkinson AJ Jr, Bindschadler DD - Pharmacokinetics of intrathecally administered amphotericin B. Amer Rev Resp Dis 99: 917, 1969.
2. Bell WE - Treatment of fungal infections of the central nervous system. Ann Neurol 9: 417, 1981.
3. Bennett JE - Flucytosine. Ann Intern Med 86: 319, 1977.
4. Bennett JE, Dismukes WE, Duma RJ, Medofff G, Sande MA, Gallis H, Leonard J, Fields BT, Bradshaw M, Haywood H, McGee ZA, Cate TR, Cobbs CG, Warner JF, Ailing DW - A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. N Engl J Med 301: 126, 1979.
5. Block ER, Bennett JE - The combined effect of 5-fluorocytosine and amphotericin B in the therapy of murine cryptococcosis (37049). Proc Soc Exp Biol 142: 476, 1973.
6. Burgess JL, Birchall R - Nephrotoxicity of amphotericin B, with emphasis on changes in tubular function. Amer J Med 53: 77, 1972.
7. Butler WT, Ailing DW, Spickard A, Utz JP - Diagnostic and prognostic value of clinical and laboratory findings in cryptococcal meningitis: a follow-up study of forty patients. N Engl J Med 270: 59, 1964.
8. Butler WT, Bennett JE, Ailing DW, Wertlake PT, Utz JP, Hill II GJ - Nephrotoxicity of amphotericin B: early and late effects in 81 patients. Ann Intern Med 61: 175, 1964.
9. Campbell GD, Currier RD, Busey JF - Survival in untreated cryptococcal meningitis. Neurology 31: 1154, 1981.
10. Carton CA - Treatment of central nervous system cryptococcosis: a review and report of four cases treated with actidione. Ann Intern Med 37: 123, 1952.
11. Codish SD, Tobias JS, Monaco AP - Recent advances in the treatment of systemic mycotic infections. Surg Gynec Obstet 148: 435, 1979.
12. Dawborn JK, Page MD, Schiavone DJ - Use of 5-fluorocytosine in patients with impaired renal function. Br Med J 4: 382, 1973.
13. Diamond RD, Bennett JE - Prognostic factors in cryptococcal meningitis: a study in 111 cases. Ann Intern Med 80:176, 1974.
14. Dureux JB, Canton Ph, Neiman L, Etienne Y, Houppe JP - Cryptococcose neuroméningée: considérations diagnostiques et thérapeutiques: à propos de 5 observations personnelles et d'une revue de la littérature. Med Mal Infect 11:573, 1979.
15. Edwars VE, Sutherland JM, Tyrer JH - Cryptococcosis of the central nervous system: epidemiological, clinical, and therapeutic features. J Neurol Neurosurg Psychiat 33: 415, 1970.
16. Fetter BF, Klintworth GK, Hendry WS - Mycoses of the central nervous system. Williams & Wilkins, Baltimore, 1967.
17. Gallis HA, Berman RA, Cate TR, Hamilton JD, Gunnells JC, Stickel DL - Fungal infection following renal transplantation. Arch Intern Med 135: 1163, 1975.
18. Goodman JS, Koenig MG - Amphotericin B: specifics of administration. Mod Treat 7: 581, 1970.
19. Gosseye-Lissoir F, Laterre E-C, Vandepitte J, Blaton H, Yourassowsky E, Schouttens E - Cryptococcose cérébroméningée: rôle favorisant de la thérapeutique immunosuppressive chez les transplantés rénaux. Path Biol 23: 211, 1975.
20. Hart PD, Russell E Jr, Remington JS - The compromised host and infection: II. Deep fungal infection. J Infect Dis 120: 169, 1969.
21. Hermans PE, Keys TF - Antifungal agents used for deep-seated mycotic infections. Mayo Clin Proc 58: 223, 1983.
22. Hooper DC, Pruitt AA, Rubin RH - Central nervous system infection in the chronically immunosuppressed. Medicine 61: 166, 1982.
23. Howard RJ, Simmons RL, Najarian JS - Fungal infections in renal transplant recipients. Ann Surg 188: 598, 1978.
24. Kauffman CA, Frame PT - Bone marrow toxicity associated with 5-fluorocytosine therapy. Antimicrob Agents Chemother 11: 244, 1977.
25. Littman ML - Cryptococcosis (Torulosis): current concepts and therapy. Am J Med 27: 976, 1959.
26. Littman ML, Walter JE - Cryptococcosis: current status. Am J Med 45: 922, 1968.
27. McChesney JA, Marquardt JF - Hypokalemic paralysis induced by amphotericin B. JAMA 189: 1029, 1964.
28. Medoff G, Comfort M, Kobayashi GS - Synergistic action of amphotericin B and 5-fluorocytosine against yeast-like organisms. Proc Soc Exp Biol 138: 571, 1971.
29. Medoff, Kobayashi GS, Kwan CN, Schiessinger D, Venkov P - Potentiation of rifampicin and 5-fluorocytosine as antifungal antibiotics by amphotericin B. Proc Nat Acad Sci 69:196, 1972.
30. Meunier-Carpentier F - Cryptococcal meningitis: a caso report and review of diagnostic procedures and therapy. Acta Clin Belg 36: 360, 1981.
31. Miller RP, Bates JH - Amphotericin B toxicity: a follow-up report of 53 patients. Ann Intern Med 71: 1089, 1969.
32. Nóbrega JPS, Livramento JA, Machado LR, Spina-França A - Criptococose do sistema nervoso central: avaliação da terapêutica por anfotericina-B, 5-fluorocitosina e miconazole em 18 casos. Arq Neuro-Psiquiat (São Paulo) 37: 28, 1979.
33. Nóbrega JPS, Livramento JA, Spina-França A - 5-fluorocitosina e anfotericina-B no tratamento da criptococose do sistema nervoso central. Arq Neuro-Psiquiat (São Paulo) 33: 210, 1975.
34. Rifkind D, Marchioro TL, Schneck SA, Hill RB Jr - Systemic fungal infections complicating renal transplantation and immunosupressive therapy: clinical, microbiologic, neurologic and pathologic features. Am J Med 43: 28, 1967.
35. Sabbaga E - Micoses por fungos oportunistas nos transplantes renais. In Lacaz CS (ed): Infecções por Agentes Oportunistas. Ed Univ S Paulo, São Paulo, 1977, pg 93.
36. Sarosi GA, Parker JD, Doto IL, Tosh FE - Amphotericin B in cryptococcal meningitis: long-term results of treatment. Ann Intern Med 71: 1679, 1969.
37. Schonebeck J, Polak A, Fernex M, Scholer HJ - Pharmacokinetic studies on the oral antimycotic agent 5-fluorocytosine in individuals with normal and impaired kidney function. Chemotherapy (Basel) 18: 321, 1973.
38. Schroter GPJ, Temple DR, Husberg BS, Weil III R, Starzl TE - Cryptococcosis after renal transplantation: report of ten cases. Surgery 79: 268, 1976.
39. Snider WD, Simpson DM, Nielsen S, Gold JWM, Metroka CE, Posner JB - Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients. Ann Neurol 14: 403, 1983.
40. Spickard A, Butler WT, Andriole V, Utz JP - The improved prognosis of cryptococcal meningitis with amphotericin B therapy. Ann Intern Med 58: 66, 1963.
41. Spina-França A - Terapêutica das neuromicoses oportunísticas. In Lacaz CS (ed): Infecções por Agentes Oportunistas. Ed Univ S Paulo, São Paulo, 1977, pg 155.
42. Symers WStC - Amphotericin pharmacophobia. Br Med J 4: 460, 1973.
43. Turcotte JG - Infection and renal transplantation. Surg Clin N Am 52: 1501, 1972.
44. Utz JP - Current and future chemotherapy of central nervous system fungal infections. In Thompson RA, Green JR (eds): Advances in Neurology, 6: 127, Raven, New York, 1974.
45. Utz JP - New drugs for the systemic mycoses: flucytosine and clotrimazole. Bull N Y Acad Med 51: 1103, 1975.
46. Utz JP, Garriques IL, Sande MA, Warner JF, Mandell GL, McGehee RF, Duma RJ, Shadomy S - Therapy of cryptococcosis with a combination of flucytosine and amphotericin B. J Infect Dis 132: 368, 1975.
47. Weenink HR, Bruyn GW - Cryptococcosis of the nervous system. In Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology, 35: 459. North-Holland, Amsterdam, 1978.
48. Yoshikawa TT, Fujita N, Grinnell V, Edwards JE, Feldman RA - Management of central nervous system cryptococcosis. West Med J 132: 123, 1980.
49. Zylstra W - Cryptococcosis and 5-fluorocytosine. Austr N Z J Med 4: 296, 1974.

Anfotericina B no tratamento da neurocriptococose em pacientes submetidos a transplante renal

Amphotericin B in the treatment of central nervous system cryptococcosis in patients submitted to renal transplantation

Datas de Publicação

Publicação nesta coleção
21 Jun 2011
Data do Fascículo
Jun 1988

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. Atkinson AJ Jr, Bindschadler DD - Pharmacokinetics of intrathecally administered amphotericin B. Amer Rev Resp Dis 99: 917, 1969.

[2] 2. Bell WE - Treatment of fungal infections of the central nervous system. Ann Neurol 9: 417, 1981.

[3] 3. Bennett JE - Flucytosine. Ann Intern Med 86: 319, 1977.

[4] 4. Bennett JE, Dismukes WE, Duma RJ, Medofff G, Sande MA, Gallis H, Leonard J, Fields BT, Bradshaw M, Haywood H, McGee ZA, Cate TR, Cobbs CG, Warner JF, Ailing DW - A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. N Engl J Med 301: 126, 1979.

[5] 5. Block ER, Bennett JE - The combined effect of 5-fluorocytosine and amphotericin B in the therapy of murine cryptococcosis (37049). Proc Soc Exp Biol 142: 476, 1973.

[6] 6. Burgess JL, Birchall R - Nephrotoxicity of amphotericin B, with emphasis on changes in tubular function. Amer J Med 53: 77, 1972.

[7] 7. Butler WT, Ailing DW, Spickard A, Utz JP - Diagnostic and prognostic value of clinical and laboratory findings in cryptococcal meningitis: a follow-up study of forty patients. N Engl J Med 270: 59, 1964.

[8] 8. Butler WT, Bennett JE, Ailing DW, Wertlake PT, Utz JP, Hill II GJ - Nephrotoxicity of amphotericin B: early and late effects in 81 patients. Ann Intern Med 61: 175, 1964.

[9] 9. Campbell GD, Currier RD, Busey JF - Survival in untreated cryptococcal meningitis. Neurology 31: 1154, 1981.

[10] 10. Carton CA - Treatment of central nervous system cryptococcosis: a review and report of four cases treated with actidione. Ann Intern Med 37: 123, 1952.

[11] 11. Codish SD, Tobias JS, Monaco AP - Recent advances in the treatment of systemic mycotic infections. Surg Gynec Obstet 148: 435, 1979.

[12] 12. Dawborn JK, Page MD, Schiavone DJ - Use of 5-fluorocytosine in patients with impaired renal function. Br Med J 4: 382, 1973.

[13] 13. Diamond RD, Bennett JE - Prognostic factors in cryptococcal meningitis: a study in 111 cases. Ann Intern Med 80:176, 1974.

[14] 14. Dureux JB, Canton Ph, Neiman L, Etienne Y, Houppe JP - Cryptococcose neuroméningée: considérations diagnostiques et thérapeutiques: à propos de 5 observations personnelles et d'une revue de la littérature. Med Mal Infect 11:573, 1979.

[15] 15. Edwars VE, Sutherland JM, Tyrer JH - Cryptococcosis of the central nervous system: epidemiological, clinical, and therapeutic features. J Neurol Neurosurg Psychiat 33: 415, 1970.

[16] 16. Fetter BF, Klintworth GK, Hendry WS - Mycoses of the central nervous system. Williams & Wilkins, Baltimore, 1967.

[17] 17. Gallis HA, Berman RA, Cate TR, Hamilton JD, Gunnells JC, Stickel DL - Fungal infection following renal transplantation. Arch Intern Med 135: 1163, 1975.

[18] 18. Goodman JS, Koenig MG - Amphotericin B: specifics of administration. Mod Treat 7: 581, 1970.

[19] 19. Gosseye-Lissoir F, Laterre E-C, Vandepitte J, Blaton H, Yourassowsky E, Schouttens E - Cryptococcose cérébroméningée: rôle favorisant de la thérapeutique immunosuppressive chez les transplantés rénaux. Path Biol 23: 211, 1975.

[20] 20. Hart PD, Russell E Jr, Remington JS - The compromised host and infection: II. Deep fungal infection. J Infect Dis 120: 169, 1969.

[21] 21. Hermans PE, Keys TF - Antifungal agents used for deep-seated mycotic infections. Mayo Clin Proc 58: 223, 1983.

[22] 22. Hooper DC, Pruitt AA, Rubin RH - Central nervous system infection in the chronically immunosuppressed. Medicine 61: 166, 1982.

[23] 23. Howard RJ, Simmons RL, Najarian JS - Fungal infections in renal transplant recipients. Ann Surg 188: 598, 1978.

[24] 24. Kauffman CA, Frame PT - Bone marrow toxicity associated with 5-fluorocytosine therapy. Antimicrob Agents Chemother 11: 244, 1977.

[25] 25. Littman ML - Cryptococcosis (Torulosis): current concepts and therapy. Am J Med 27: 976, 1959.

[26] 26. Littman ML, Walter JE - Cryptococcosis: current status. Am J Med 45: 922, 1968.

[27] 27. McChesney JA, Marquardt JF - Hypokalemic paralysis induced by amphotericin B. JAMA 189: 1029, 1964.

[28] 28. Medoff G, Comfort M, Kobayashi GS - Synergistic action of amphotericin B and 5-fluorocytosine against yeast-like organisms. Proc Soc Exp Biol 138: 571, 1971.

[29] 29. Medoff, Kobayashi GS, Kwan CN, Schiessinger D, Venkov P - Potentiation of rifampicin and 5-fluorocytosine as antifungal antibiotics by amphotericin B. Proc Nat Acad Sci 69:196, 1972.

[30] 30. Meunier-Carpentier F - Cryptococcal meningitis: a caso report and review of diagnostic procedures and therapy. Acta Clin Belg 36: 360, 1981.

[31] 31. Miller RP, Bates JH - Amphotericin B toxicity: a follow-up report of 53 patients. Ann Intern Med 71: 1089, 1969.

[32] 32. Nóbrega JPS, Livramento JA, Machado LR, Spina-França A - Criptococose do sistema nervoso central: avaliação da terapêutica por anfotericina-B, 5-fluorocitosina e miconazole em 18 casos. Arq Neuro-Psiquiat (São Paulo) 37: 28, 1979.

[33] 33. Nóbrega JPS, Livramento JA, Spina-França A - 5-fluorocitosina e anfotericina-B no tratamento da criptococose do sistema nervoso central. Arq Neuro-Psiquiat (São Paulo) 33: 210, 1975.

[34] 34. Rifkind D, Marchioro TL, Schneck SA, Hill RB Jr - Systemic fungal infections complicating renal transplantation and immunosupressive therapy: clinical, microbiologic, neurologic and pathologic features. Am J Med 43: 28, 1967.

[35] 35. Sabbaga E - Micoses por fungos oportunistas nos transplantes renais. In Lacaz CS (ed): Infecções por Agentes Oportunistas. Ed Univ S Paulo, São Paulo, 1977, pg 93.

[36] 36. Sarosi GA, Parker JD, Doto IL, Tosh FE - Amphotericin B in cryptococcal meningitis: long-term results of treatment. Ann Intern Med 71: 1679, 1969.

[37] 37. Schonebeck J, Polak A, Fernex M, Scholer HJ - Pharmacokinetic studies on the oral antimycotic agent 5-fluorocytosine in individuals with normal and impaired kidney function. Chemotherapy (Basel) 18: 321, 1973.

[38] 38. Schroter GPJ, Temple DR, Husberg BS, Weil III R, Starzl TE - Cryptococcosis after renal transplantation: report of ten cases. Surgery 79: 268, 1976.

[39] 39. Snider WD, Simpson DM, Nielsen S, Gold JWM, Metroka CE, Posner JB - Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients. Ann Neurol 14: 403, 1983.

[40] 40. Spickard A, Butler WT, Andriole V, Utz JP - The improved prognosis of cryptococcal meningitis with amphotericin B therapy. Ann Intern Med 58: 66, 1963.

[41] 41. Spina-França A - Terapêutica das neuromicoses oportunísticas. In Lacaz CS (ed): Infecções por Agentes Oportunistas. Ed Univ S Paulo, São Paulo, 1977, pg 155.

[42] 42. Symers WStC - Amphotericin pharmacophobia. Br Med J 4: 460, 1973.

[43] 43. Turcotte JG - Infection and renal transplantation. Surg Clin N Am 52: 1501, 1972.

[44] 44. Utz JP - Current and future chemotherapy of central nervous system fungal infections. In Thompson RA, Green JR (eds): Advances in Neurology, 6: 127, Raven, New York, 1974.

[45] 45. Utz JP - New drugs for the systemic mycoses: flucytosine and clotrimazole. Bull N Y Acad Med 51: 1103, 1975.

[46] 46. Utz JP, Garriques IL, Sande MA, Warner JF, Mandell GL, McGehee RF, Duma RJ, Shadomy S - Therapy of cryptococcosis with a combination of flucytosine and amphotericin B. J Infect Dis 132: 368, 1975.

[47] 47. Weenink HR, Bruyn GW - Cryptococcosis of the nervous system. In Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology, 35: 459. North-Holland, Amsterdam, 1978.

[48] 48. Yoshikawa TT, Fujita N, Grinnell V, Edwards JE, Feldman RA - Management of central nervous system cryptococcosis. West Med J 132: 123, 1980.

[49] 49. Zylstra W - Cryptococcosis and 5-fluorocytosine. Austr N Z J Med 4: 296, 1974.