Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients

Bicanic, Tihana; Muzoora, Conrad; Brouwer, Annemarie E.; Meintjes, Graeme; Longley, Nicky; Taseera, Kabanda; Rebe, Kevin; Loyse, Angela; Jarvis, Joseph; Bekker, Linda‐Gail; Wood, Robin; Limmathurotsakul, Direk; Chierakul, Wirongrong; Stepniewska, Kasia; White, Nicholas J.; Jaffar, Shabbar; Harrison, Thomas S.

doi:10.1086/604716

Cited by 227Fungal Infections and StudiesAntifungal resistance and susceptibilityInfectious Diseases and Tuberculosis

Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients

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Bicanic, Tihana, Muzoora, Conrad, Brouwer, Annemarie E., Meintjes, Graeme, Longley, Nicky, Taseera, Kabanda, Rebe, Kevin, Loyse, Angela +9 more·2009·Clinical Infectious Diseases

DOI 10.1086/604716PMC PMC2965403

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Abstract

BACKGROUND: Progress in therapy for cryptococcal meningitis has been slow because of the lack of a suitable marker of treatment response. Previously, we demonstrated the statistical power of a novel endpoint, the rate of clearance of infection, based on serial quantitative cultures of cerebrospinal fluid, to differentiate the fungicidal activity of alternative antifungal drug regimens. We hypothesized that the rate of clearance of infection should also be a clinically meaningful endpoint. METHODS: We combined data from cohorts of patients with human immunodeficiency virus-associated cryptococcal meningitis from Thailand, South Africa, and Uganda, for whom the rate of clearance of infection was determined, and clinical and laboratory data prospectively collected, and explored the association between the rate of clearance of infection and mortality by Cox survival analyses. RESULTS: The combined cohort comprised 262 subjects. Altered mental status at presentation, a high baseline organism load, and a slow rate of clearance of infection were independently associated with increased mortality at 2 and 10 weeks. Rate of clearance of infection was associated with antifungal drug regimen and baseline cerebrospinal fluid interferon-gamma levels. CONCLUSIONS: The results support the use of the rate of clearance of infection or early fungicidal activity as a means to explore antifungal drug dosages and combinations in phase II studies. An increased understanding of how the factors determining outcome interrelate may help clarify opportunities for intervention.

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Monotherapy with fluconazole results in poor outcome relative to amphotericin B and flucytosine combination therapy due to lack of early fungicidal activity and development of resistance.
“Monotherapy with fluconazole also results in poor outcome relative to amphotericin B and flucytosine combination therapy due to the lack of early fungicidal activity for fluconazole resulting in the development of resistance (Bicanic et al. 2009; Hope et al. 2019).”
From Genetic analysis of Hsp90 function in Cryptococcus neoformans highlights key roles in stress tolerance and virulence (2022) · cites this paper as Bicanic et al. 2009

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Authors: Bicanic, T., Muzoora, C., Brouwer, A. E., Meintjes, G., Longley, N., Taseera, K., Rebe, K., Loyse, A., Jarvis, J., Bekker, L., Wood, R., Limmathurotsakul, D., Chierakul, W., Stepniewska, K., White, N. J., Jaffar, S., & Harrison, T. S.
Affiliations: University of Cape Town (ZA)
St George's, University of London (GB)
Institute of Infectious Disease and Molecular Medicine (ZA)
Mahidol University (TH)
London School of Hygiene & Tropical Medicine (GB)
Corresponding author: Harrison, Thomas S.
ORCID: Bicanic, Tihana
Muzoora, Conrad
Meintjes, Graeme
Taseera, Kabanda
Rebe, Kevin
Loyse, Angela
Jarvis, Joseph
Bekker, Linda‐Gail
Wood, Robin
Limmathurotsakul, Direk
Chierakul, Wirongrong
Stepniewska, Kasia
White, Nicholas J.
Jaffar, Shabbar
Harrison, Thomas S.
Venue: Clinical Infectious Diseases
Publisher: Oxford University Press (OUP)
Published: 2009-09
Volume: 49
Issue: 5
Pages: 702-709
ISSN: 1058-4838 (ISSN-L)
1537-6591
DOI: 10.1086/604716
PMC: PMC2965403
OpenAlex: W2143928313
Cited by: 227
References: 22
Citations by year: 2026: 6 · 2025: 8 · 2024: 9 · 2023: 12 · 2022: 11 · 2021: 11 · 2020: 9 · 2019: 13 · 2018: 15 · 2017: 12 · 2016: 12 · 2015: 18 · 2014: 23 · 2013: 22 · 2012: 20
FWCI: 10.07
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Clinical Infectious Diseases (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Radboud Repository (Radboud University) (submittedVersion)
Funders: Wellcome Trust (077166, 081794, 069991, 84323)
British Infection Society
Mahidol University
Medical Research Council
Topics: Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Health Sciences › Medicine › Surgery › Infectious Diseases and Tuberculosis
Keywords: HIV-associated cryptococcal meningitis, mortality, fungicidal activity, altered mental status, prognostic factors
MeSH terms: Adult, Antifungal Agents, Cerebrospinal Fluid, Dose-Response Relationship, Drug, Drug Therapy, Combination, Female, Humans, Interferon-gamma, Male, Prognosis, Prospective Studies, South Africa, Thailand, Time Factors, Uganda, Colony Count, Microbial, Cohort Studies, Fluconazole, Proportional Hazards Models, Randomized Controlled Trials as Topic, Treatment Outcome, Meningitis, Cryptococcal, AIDS-Related Opportunistic Infections

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Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients

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