title: Cerebrospinal Fluid Culture Positivity and Clinical Outcomes After Amphotericin-Based Induction Therapy for Cryptococcal Meningitis.
abstract: Background.  Amphotericin-based combination antifungal therapy reduces mortality from human immunodeficiency virus (HIV)-associated cryptococcal meningitis. However, 40%-50% of individuals have positive cerebrospinal fluid (CSF) fungal cultures at completion of 2 weeks of amphotericin induction therapy. Residual CSF culture positivity has historically been associated with poor clinical outcomes. We investigated whether persistent CSF fungemia was associated with detrimental clinical outcomes in a contemporary African cohort. Methods.  Human immunodeficiency virus-infected individuals with cryptococcal meningitis in Uganda and South Africa received amphotericin (0.7-1.0 mg/kg per day) plus fluconazole (800 mg/day) for 2 weeks, followed by "enhanced consolidation" therapy with fluconazole 800 mg/day for at least 3 weeks or until cultures were sterile, and then 400 mg/day for 8 weeks. Participants were randomized to receive antiretroviral therapy (ART) either 1-2 or 5 weeks after diagnosis and observed for 6 months. Survivors were classified as having sterile or nonsterile CSF based on 2-week CSF cultures. Mortality, immune reconstitution inflammatory syndrome (IRIS), and culture-positive relapse were compared in those with sterile or nonsterile CSF using Cox regression. Results.  Of 132 participants surviving 2 weeks, 57% had sterile CSF at 2 weeks, 23 died within 5 weeks, and 40 died within 6 months. Culture positivity was not significantly associated with mortality (adjusted 6-month hazard ratio, 1.2; 95% confidence interval, 0.6-2.3; P = .28). Incidence of IRIS or relapse was also not significantly related to culture positivity. Conclusions.  Among patients, all treated with enhanced consolidation antifungal therapy and ART, residual cryptococcal culture positivity was not found to be associated with poor clinical outcomes.
authors.affiliation: Department of Medicine , Medical School, University of Minnesota.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Rolfes
authors.affiliation: Department of Medicine , Medical School, University of Minnesota ; Infectious Diseases Institute, Makerere University , Kampala , Uganda.
authors.forename: Joshua
authors.initials: J
authors.lastname: Rhein
authors.affiliation: Institute of Infectious Disease and Molecular Medicine and Department of Medicine , University of Cape Town , South Africa.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Schutz
authors.affiliation: Internal Medicine, Faculty of Medicine , Mbarara University of Science and Technology, Mbarara , Uganda.
authors.forename: Kabanda
authors.initials: K
authors.lastname: Taseera
authors.affiliation: Infectious Diseases Institute, Makerere University , Kampala , Uganda.
authors.forename: Henry W
authors.initials: HW
authors.lastname: Nabeta
authors.affiliation: Division of Biostatistics , School of Public Health, University of Minnesota , Minneapolis.
authors.forename: Kathy
authors.initials: K
authors.lastname: Huppler Hullsiek
authors.affiliation: Infectious Diseases Institute, Makerere University , Kampala , Uganda ; Department of Microbiology , College of Health Sciences, Makerere University , Kampala , Uganda.
authors.forename: Andrew
authors.initials: A
authors.lastname: Akampuira
authors.affiliation: Department of Medicine , Medical School, University of Minnesota ; Infectious Diseases Institute, Makerere University , Kampala , Uganda.
authors.forename: Radha
authors.initials: R
authors.lastname: Rajasingham
authors.affiliation: Infectious Diseases Institute, Makerere University , Kampala , Uganda.
authors.forename: Abdu
authors.initials: A
authors.lastname: Musubire
authors.affiliation: Department of Medicine , Medical School, University of Minnesota ; Infectious Diseases Institute, Makerere University , Kampala , Uganda.
authors.forename: Darlisha A
authors.initials: DA
authors.lastname: Williams
authors.affiliation: Institute of Infectious Disease and Molecular Medicine and Department of Medicine , University of Cape Town , South Africa.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Thienemann
authors.affiliation: Department of Medicine , Medical School, University of Minnesota ; Infectious Diseases Institute, Makerere University , Kampala , Uganda.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Bohjanen
authors.affiliation: Internal Medicine, Faculty of Medicine , Mbarara University of Science and Technology, Mbarara , Uganda.
authors.forename: Conrad
authors.initials: C
authors.lastname: Muzoora
authors.affiliation: Institute of Infectious Disease and Molecular Medicine and Department of Medicine , University of Cape Town , South Africa ; Department of Medicine , Imperial College London , United Kingdom.
authors.forename: Graeme
authors.initials: G
authors.lastname: Meintjes
authors.affiliation: Department of Medicine , Medical School, University of Minnesota ; Infectious Diseases Institute, Makerere University , Kampala , Uganda ; School of Medicine, College of Health Sciences, Makerere University , Kampala , Uganda.
authors.forename: David B
authors.initials: DB
authors.lastname: Meya
authors.affiliation: Department of Medicine , Medical School, University of Minnesota.
authors.forename: David R
authors.initials: DR
authors.lastname: Boulware
keywords: HIV; amphotericin; clinical outcome; cryptococcal meningitis