ArticleClinical infectious diseases : an official publication of the Infectious Diseases Society of America2020
Cerebrospinal Fluid Early Fungicidal Activity as a Surrogate Endpoint for Cryptococcal Meningitis Survival in Clinical Trials.
Article in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 2 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
22 citing papers in PubMed, 2 syntheses or guidelines pooled it, 28 citations in OpenAlex.
- Cryptococcosis-a systematic review to inform the World Health Organization Fungal Priority Pathogens List.Medical mycology · 2024Pooled it
- What Is the Most Appropriate Induction Regimen for the Treatment of HIV-Associated Cryptococcal Meningitis When the Recommended Regimen Is Not Available? Evidence From a Network Meta-Analysis.Frontiers in pharmacology · 2020Pooled it
- Evaluating the Use of Lower Dose Flucytosine for the Treatment of Cryptococcal Meningitis: A Clinical Trial.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2026Trial
- Oral Lipid Nanocrystal Amphotericin B for Cryptococcal Meningitis: A Randomized Clinical Trial.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2023Trial
- How Applicable Is the Single-Dose AMBITION Regimen for Human Immunodeficiency Virus-Associated Cryptococcal Meningitis to High-Income Settings?Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2023Trial
- Assessing Statistical Methods for Estimating the Cerebrospinal Fluid Early Fungicidal Activity as an Endpoint for Cryptococcal Meningitis Clinical Trials: A Systematic Review and Simulation Study.Open forum infectious diseases · 2026Article
- Analytical validation: Comparison of two laboratory-based methods for CSF quantitative cryptococcal cultures.Medical mycology · 2026Article
- Review of Risk Factors and Factors Influencing Outcomes of Cryptococcal Meningitis in Persons Living with HIV.Infection and drug resistance · 2026Review
- Target product profile and discovery and development path for novel cryptococcal disease treatments.The Journal of infection · 2025Review
- Comparison of Early Fungicidal Activity and Mortality Between Daily Liposomal Amphotericin B and Daily Amphotericin B Deoxycholate for Cryptococcal Meningitis.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2025Article
- Clinical importance of cerebrospinal fluid protein levels in HIV-associated cryptococcal meningitis: Insights from a prospective cohort study in Uganda.Medical mycology · 2024Article
- Evolution of Laboratory Diagnostics for Cryptococcosis and Missing Links to Optimize Diagnosis and Outcomes in Resource-Constrained Settings.Open forum infectious diseases · 2024Review
- Diagnosis and management of cryptococcal meningitis in HIV-infected adults.Clinical microbiology reviews · 2023Review
- Utility of Cerebrospinal Fluid Protein Levels as a Potential Predictive Biomarker of Disease Severity in HIV-Associated Cryptococcal Meningitis.medRxiv : the preprint server for health sciences · 2023Article
- 5-Flucytosine Longitudinal Antifungal Susceptibility Testing ofOpen forum infectious diseases · 2023Article
- Cryptococcal meningitis.Nature reviews. Disease primers · 2023Review
- Pharmacodynamics of ATI-2307 in a rabbit model of cryptococcal meningoencephalitis.Antimicrobial agents and chemotherapy · 2023Article
- Population pharmacokinetics and CSF penetration of flucytosine in adults with HIV-associated cryptococcal meningoencephalitis.The Journal of antimicrobial chemotherapy · 2023Article
- Article
- Noninvasive Testing and Surrogate Markers in Invasive Fungal Diseases.Open forum infectious diseases · 2022Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
24 authors at 4 institutions in 3 countries.
Funding
Abstract
backgroundIn cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of Cryptococcus clearance from cerebrospinal fluid (CSF) is used as a surrogate endpoint for all-cause mortality. The Food and Drug Administration allows for using surrogate endpoints for accelerated regulatory approval, but EFA as a surrogate endpoint requires further validation. We examined the relationship between rate of CSF Cryptococcus clearance (EFA) and mortality through 18 weeks.
methodsWe pooled individual-level CSF data from 3 sequential cryptococcal meningitis clinical trials conducted during 2010-2017. All 738 subjects received amphotericin + fluconazole induction therapy and had serial quantitative CSF cultures. The log10-transformed colony-forming units (CFUs) per mL CSF were analyzed by general linear regression versus day of culture over the first 10 days.
resultsMortality through 18 weeks was 37% for EFA > = 0.60 (n = 170), 36% for 0.40-0.59 (n = 182), 39% for 0.30-0.39 (n = 112), 35% for 0.20-0.29 (n = 87), and 50% for those with EFA < 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA < 0.20 to those with EFA > = 0.20, was 1.60 (95% confidence interval, 1.25, 2.04; P = .002). The lowest EFA group had lower median CD4 T-cell counts (P < .01) and lower proportion of patients with CSF pleocytosis (P < .001).
conclusionsEFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of > = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37%) compared to 50% mortality with EFA < 0.20. This EFA threshold may be considered a target for a surrogate endpoint. This builds upon existing studies to validate EFA as a surrogate endpoint.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.