Literature Commentary by Dr. Bartlett: Cryptococcal Meningitis, Jan '08
Literature Commentary by Dr. Bartlett: Cryptococcal Meningitis, Jan '08
Bicanic T, Meintjes G, Wood R, et al. Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis. 2007;45:76-80. The purpose of the study was to determine early fungicidal activity (EFA) of amphotericin B vs fluconazole in the initial treatment of cryptococcal meningitis in people with AIDS in South Africa.
Methods: This is a prospective observational study done at the University of Cape Town, South Africa in 2005. Patients with a baseline Glasgow Coma Score (GCS) ≥ 10 received amphotericin B (1 mg/kg/d) for 7 days, followed by oral fluconazole (400 mg/d) for 8 weeks; this group is referred to as the "amphotericin B" group. Patients with a baseline GCS < 10 received oral fluconazole (400 mg/d) for 10 weeks. Beginning at week 10, the fluconazole dose was changed to 200 mg/d for all patients. The results were separately analyzed for those treated with amphotericin B vs fluconazole and those who were antiretroviral therapy (ART)-naive vs those that were receiving ART. Quantitative fungal cultures of cerebrospinal fluid (CSF) samples were obtained at baseline with follow-up CSF culture done on days 3, 7, and 14 to determine EFA.
Results: There were 49 patients in the amphotericin B group and 5 in the fluconazole group. The EFA was significantly greater with amphotericin B. The overall mortality was 17% at 2 weeks and 37% at 10 weeks with a median survival at 110 days. No difference was observed on the basis of ART-naive vs. ART-experienced patients in terms EFA, but those with ART treatment had a significantly greater 1-year survival rate. These results are summarized in the table .
Conclusion: The authors conclude that EFA is significantly better for amphotericin B compared with fluconazole for HIV-associated cryptococcal meningitis.
Comment: Cryptococcal meningitis is a major opportunistic infection in patients with AIDS in Africa. Data indicate that this is the most common cause of hospitalization and the cause of 44% of HIV-associated deaths in South Africa. More recent studies have also shown that cryptococcal immune reconstitution inflammatory syndrome (IRIS) is common and may be fatal. The study reported above does not address IRIS, but does suggest that amphotericin B is a preferred treatment for patients who have cryptococcal meningitis in Africa. The editorial comment is provided by Olivier Lortholary, MD, Institute Pasteur Paris, France, who noted that a prior "elegant" study in Thailand showed that clearance of cryptococci from CSF was significantly greater with amphotericin B + flucytosine compared with amphotericin B alone, with amphotericin B + fluconazole or with triple therapy. Furthermore, a 4-year French prospective study with 177 cases showed that lack of flucytosine during induction therapy was significantly associated with the lack of CSF sterilization at week 2. Lortholary goes on to note that intravenous infusions of amphotericin B are difficult to manage in Africa, the dose of fluconazole of 400 mg/day (as used in this study) may be inappropriately low, and that other studies have showed high dose fluconazole + flucytosine have been more effective than fluconazole alone. Thus, the conclusion is that the most important future trial to determine optimal management in Africa may be the study of oral high-dose fluconazole + flucytosine combined with optimal management of increased CSF pressure.
Bicanic T, Meintjes G, Wood R, et al. Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis. 2007;45:76-80. The purpose of the study was to determine early fungicidal activity (EFA) of amphotericin B vs fluconazole in the initial treatment of cryptococcal meningitis in people with AIDS in South Africa.
Methods: This is a prospective observational study done at the University of Cape Town, South Africa in 2005. Patients with a baseline Glasgow Coma Score (GCS) ≥ 10 received amphotericin B (1 mg/kg/d) for 7 days, followed by oral fluconazole (400 mg/d) for 8 weeks; this group is referred to as the "amphotericin B" group. Patients with a baseline GCS < 10 received oral fluconazole (400 mg/d) for 10 weeks. Beginning at week 10, the fluconazole dose was changed to 200 mg/d for all patients. The results were separately analyzed for those treated with amphotericin B vs fluconazole and those who were antiretroviral therapy (ART)-naive vs those that were receiving ART. Quantitative fungal cultures of cerebrospinal fluid (CSF) samples were obtained at baseline with follow-up CSF culture done on days 3, 7, and 14 to determine EFA.
Results: There were 49 patients in the amphotericin B group and 5 in the fluconazole group. The EFA was significantly greater with amphotericin B. The overall mortality was 17% at 2 weeks and 37% at 10 weeks with a median survival at 110 days. No difference was observed on the basis of ART-naive vs. ART-experienced patients in terms EFA, but those with ART treatment had a significantly greater 1-year survival rate. These results are summarized in the table .
Conclusion: The authors conclude that EFA is significantly better for amphotericin B compared with fluconazole for HIV-associated cryptococcal meningitis.
Comment: Cryptococcal meningitis is a major opportunistic infection in patients with AIDS in Africa. Data indicate that this is the most common cause of hospitalization and the cause of 44% of HIV-associated deaths in South Africa. More recent studies have also shown that cryptococcal immune reconstitution inflammatory syndrome (IRIS) is common and may be fatal. The study reported above does not address IRIS, but does suggest that amphotericin B is a preferred treatment for patients who have cryptococcal meningitis in Africa. The editorial comment is provided by Olivier Lortholary, MD, Institute Pasteur Paris, France, who noted that a prior "elegant" study in Thailand showed that clearance of cryptococci from CSF was significantly greater with amphotericin B + flucytosine compared with amphotericin B alone, with amphotericin B + fluconazole or with triple therapy. Furthermore, a 4-year French prospective study with 177 cases showed that lack of flucytosine during induction therapy was significantly associated with the lack of CSF sterilization at week 2. Lortholary goes on to note that intravenous infusions of amphotericin B are difficult to manage in Africa, the dose of fluconazole of 400 mg/day (as used in this study) may be inappropriately low, and that other studies have showed high dose fluconazole + flucytosine have been more effective than fluconazole alone. Thus, the conclusion is that the most important future trial to determine optimal management in Africa may be the study of oral high-dose fluconazole + flucytosine combined with optimal management of increased CSF pressure.