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Published on: June 22, 2019
Cerebrospinal Fluid Culture Positivity and Clinical Outcomes After Amphotericin-Based Induction Therapy for
Melissa A Rolfes1, Joshua Rhein2, Charlotte Schutz3
1Department of Medicine , Medical School, University of Minnesota.
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.
Insights
Persistent fungal presence in cerebrospinal fluid (CSF) after initial treatment for human immunodeficiency virus (HIV)-associated cryptococcal meningitis did not increase mortality risks in a recent African study. Enhanced antifungal therapy and timely antiretroviral treatment mitigated negative outcomes.
Area of Science:
- Infectious Diseases
- Mycology
- Immunology
Background:
- Amphotericin-based combination therapy is crucial for reducing mortality in HIV-associated cryptococcal meningitis.
- A significant proportion (40%-50%) of patients exhibit positive cerebrospinal fluid (CSF) fungal cultures after 2 weeks of amphotericin induction.
- Historically, residual CSF positivity has been linked to adverse clinical outcomes.
Purpose of the Study:
- To investigate the association between persistent CSF fungemia and clinical outcomes in a contemporary African cohort with HIV-associated cryptococcal meningitis.
- To evaluate the impact of residual fungal culture positivity on mortality, immune reconstitution inflammatory syndrome (IRIS), and relapse.
Main Methods:
- A cohort of HIV-infected individuals with cryptococcal meningitis in Uganda and South Africa received amphotericin and fluconazole induction therapy.
- Patients were subsequently treated with enhanced consolidation therapy (fluconazole) and randomized to receive antiretroviral therapy (ART) at 1-2 weeks or 5 weeks post-diagnosis.
- Outcomes including mortality, IRIS, and relapse were compared between patients with sterile versus non-sterile CSF cultures at 2 weeks using Cox regression.
Main Results:
- Of 132 survivors at 2 weeks, 57% had sterile CSF; 40-day mortality was 17% (23/132) and 6-month mortality was 30% (40/132).
- Residual CSF culture positivity at 2 weeks was not significantly associated with 6-month mortality (adjusted HR, 1.2; 95% CI, 0.6-2.3; P = .28).
- Incidence of IRIS or culture-positive relapse was also not significantly related to 2-week CSF culture status.
Conclusions:
- In patients receiving enhanced consolidation antifungal therapy and ART, residual cryptococcal positivity in CSF was not associated with adverse clinical outcomes.
- This suggests that modern treatment strategies may overcome the negative prognostic implications of persistent fungemia in HIV-associated cryptococcal meningitis.
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