Effects of Fluconazole Singly and in Combination with 5-Fluorocytosine or Amphotericin B in the Treatment of Cryptococcal Meningoencephalitis in an Intracranial Murine Model

Abstract In this study we developed a highly reproducible intracranial murine model of cryptococcosis. Mice (Balb/c, 5-7 weeks old) were challenged intracranially and treated with intermediate (30 mg/kg) or high (90 mg/kg) dose fluconazole, and amphotericin B (0.75 mg/kg), administered singly or in combination with flucytosine (100 mg/kg). Survival and brain CFU analyses were performed. Effect of fluconazole prophylaxis was also determined. Our data show that the developed model mimics clinical signs of cryptococcal meningitis. In single treatment, fluconazole (30 mg/kg) was more efficacious than amphotericin B or flucytosine (P <0.0001). Combination treatment led to significantly increased anticryptococcal activity, which was highest for high dose fluconazole + flucytosine (P <0.0001). However, no significant difference was observed between high dose fluconazole treatment with and without flucytosine (P >0.05). Fluconazole prophylaxis led to a significant decrease in brain CFU. In conclusion, high dose fluconazole administered post-infection, or as prophylaxis, may be highly efficacious in the treatment and prevention of meningoencephalitis.

[1]  S. Pileri,et al.  The changing face of AIDS-related opportunism: Cryptococcosis in the highly active antiretroviral therapy (HAART) era. Case reports and literature review , 1999, Mycopathologia.

[2]  K. Sepkowitz.  Opportunistic infections in patients with and patients without Acquired Immunodeficiency Syndrome. , 2002, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[3]  C. O'Daniels,et al.  Human papillomavirus-associated oral warts among human immunodeficiency virus-seropositive patients in the era of highly active antiretroviral therapy: an emerging infection. , 2002, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[4]  H. Furrer,et al.  Opportunistic infections: an update. , 2002, Journal of HIV therapy.

[5]  B. Haynes,et al.  Immune reconstitution in patients with HIV infection. , 2002, Annual review of medicine.

[6]  J. Laurence.  Immune reconstitution and HAART: an update. , 2001, The AIDS reader.

[7]  S. Cinti,et al.  Case Report. Recurrence of increased intracranial pressure with antiretroviral therapy in an AIDS patient with cryptococcal meningitis , 2001, Mycoses.

[8]  P. Price,et al.  Immune dysfunction and immune restoration disease in HIV patients given highly active antiretroviral therapy. , 2001, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[9]  M. Ghannoum,et al.  Reintroduction of the PLB1 gene into Candida albicans restores virulence in vivo. , 2001, Microbiology.

[10]  R. M. Warren,et al.  Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[11]  P. Sax.  Opportunistic infections in HIV disease: down but not out. , 2001, Infectious disease clinics of North America.

[12]  B. Gazzard,et al.  The changing pattern of AIDS-defining illnesses with the introduction of highly active antiretroviral therapy (HAART)in a London clinic. , 2001, The Journal of infection.

[13]  W. Coulson,et al.  Histopathology of cryptococcosis and other fungal infections in patients with acquired immunodeficiency syndrome. , 2001, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases.

[14]  E. Fung,et al.  Cryptococcosis: clinical and biological aspects. , 2000, Medical mycology.

[15]  M. Ghannoum,et al.  The Exciting Future of Antifungal Therapy , 2000, European Journal of Clinical Microbiology and Infectious Diseases.

[16]  N. Rojanasthien,et al.  Pharmacokinetics and bioequivalence testing of generic fluconazole preparations in healthy thai volunteers. , 2000, International journal of clinical pharmacology and therapeutics.

[17]  J. Perfect,et al.  Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. , 2000, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[18]  J. Aberg.  Reconstitution of immunity against opportunistic infections in the era of potent antiretroviral therapy. , 2000, AIDS clinical review.

[19]  W. Powderly.  Immune reconstitution and the consequences for opportunistic infection treatment and prevention , 1999, Current infectious disease reports.

[20]  J. Graybill,et al.  An Alternative Animal Model for Comparison of Treatments for Cryptococcal Meningitis , 1999, Antimicrobial Agents and Chemotherapy.

[21]  F. Raffi,et al.  Opportunistic infections occurring during highly active antiretroviral treatment , 1998, AIDS.

[22]  M. Woods,et al.  HIV combination therapy: partial immune restitution unmasking latent cryptococcal infection , 1998, AIDS.

[23]  A. Penk,et al.  [Value of high dosage fluconazole in therapy of candida infections in intensive care medicine]. , 1998, Anaesthesiologie und Reanimation.

[24]  I. Marino,et al.  Successful treatment of disseminated cryptococcosis in a liver transplant recipient with fluconazole and flucytosine, an all oral regimen , 1998, Transplant international : official journal of the European Society for Organ Transplantation.

[25]  A. Penk,et al.  High‐dose therapy with fluconazole ≥ 800 mg day‐1 , 1997, Mycoses.

[26]  M. Saag,et al.  Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. , 1997, The New England journal of medicine.

[27]  C. Y. Yu,et al.  Combination therapy with fluconazole and flucytosine in the murine model of cryptococcal meningitis , 1997, Antimicrobial agents and chemotherapy.

[28]  J. Graybill,et al.  Effect of fluconazole on fungicidal activity of flucytosine in murine cryptococcal meningitis , 1996, Antimicrobial agents and chemotherapy.

[29]  A. Casadevall,et al.  Monoclonal antibodies to Cryptococcus neoformans glucuronoxylomannan enhance fluconazole efficacy , 1995, Antimicrobial agents and chemotherapy.

[30]  Claude Carbón,et al.  In vivo activity of interferon-gamma in combination with amphotericin B in the treatment of experimental cryptococcosis. , 1994, The Journal of infectious diseases.

[31]  J. McCutchan,et al.  Fluconazole combined with flucytosine for treatment of cryptococcal meningitis in patients with AIDS. , 1994, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[32]  M. Burroughs,et al.  Pharmacokinetics of fluconazole in cerebrospinal fluid and serum of rabbits: validation of an animal model used to measure drug concentrations in cerebrospinal fluid , 1994, Antimicrobial Agents and Chemotherapy.

[33]  S. Boyle.  HIV positive patients. , 1993, AORN journal.

[34]  M. Prenna,et al.  Pharmacokinetics of fluconazole in normal volunteers. , 1993, Chemotherapy.

[35]  C. Cirrincione,et al.  Cryptococcal meningitis: outcome in patients with AIDS and patients with neoplastic disease. , 1992, The Journal of infectious diseases.

[36]  M. Saag,et al.  A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. The NIAID AIDS Clinical Trials Group and Mycoses Study Group. , 1992, The New England journal of medicine.

[37]  D. Peterson,et al.  Primary prophylaxis with fluconazole against systemic fungal infections in HIV‐positive patients , 1992, AIDS.

[38]  M. Saag,et al.  Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group. , 1992, The New England journal of medicine.

[39]  T. Walsh,et al.  Systemically administered antifungal agents. A review of their clinical pharmacology and therapeutic applications. , 1992, Drugs.

[40]  R. Allendoerfer,et al.  Combined therapy with fluconazole and flucytosine in murine cryptococcal meningitis , 1991, Antimicrobial Agents and Chemotherapy.

[41]  G. Chindemi,et al.  Cryptococcal meningoencephalitis in a patient with Hodgkin's lymphoma: successful treatment with fluconazole , 1991, Mycoses.

[42]  L. Chan,et al.  Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in AIDS. A randomized trial. , 1990, Annals of internal medicine.

[43]  R. M. Tucker,et al.  Pharmacokinetics of fluconazole in cerebrospinal fluid and serum in human coccidioidal meningitis , 1988, Antimicrobial Agents and Chemotherapy.

[44]  R. Selik,et al.  Opportunistic diseases reported in AIDS patients: frequencies, associations, and trends. , 1987, AIDS.

[45]  P. Troke,et al.  Efficacy of fluconazole (UK-49,858) against experimental aspergillosis and cryptococcosis in mice. , 1987, The Journal of antimicrobial chemotherapy.

[46]  J. Graybill,et al.  Treatment of murine cryptococcosis with liposome-associated amphotericin B. , 1982, The Journal of infectious diseases.

[47]  D. Bindschadler,et al.  Guide to use of amphotericin B. , 1970, Geriatrics.

[48]  W. Butler.  Pharmacology, toxicity, and therapeutic usefulness of amphotericin B. , 1966, JAMA.