Fluconazole Monotherapy Is a Suboptimal Option for Initial Treatment of Cryptococcal Meningitis Because of Emergence of Resistance
Open accessAbstract
Cryptococcal meningitis is a lethal disease with few treatment options. The incidence remains high and intricately linked with the HIV/AIDS epidemic. In many parts of the world, fluconazole is the only agent that is available for the initial treatment of cryptococcal meningitis despite considerable evidence that it is associated with suboptimal microbiological and clinical outcomes. Fluconazole has a fungistatic mode of action: it predominantly inhibits growth rather than causing fungal killing. Our work shows that the pattern of fluconazole activity is caused by the emergence of resistance in Cryptococcus not detected by standard susceptibility tests, with chromosomal duplication/aneuploidy as the main mechanism. Resistance emergence is related to drug exposure and occurs with the use of clinically relevant regimens. Hence, fluconazole (and potentially other agents that target 14-alpha-demethylase) is compromised by an intrinsic property that limits its effectiveness. However, this resistance may be potentially overcome by dosage escalation or the use of combination therapy.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Other research suggested feasibility of fluconazole dose escalation and combination therapy in treatment of cryptococcal meningitis but also revealed limitations in combination options, for which only 5-FC was widely available.
“Other research suggested the feasibility of fluconazole dose escalation and combination therapy in the treatment of cryptococcal meningitis but also revealed limitations in combination options, for which only 5-FC was widely available [165].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [165]
The Discussion supports considering dose escalation and says combination choices are limited to 5FC, while cautioning that the efficacy and tolerability of escalation require further study. But the Introduction says fluconazole—not 5FC—is the only drug available in much of Africa, contrary to the claim that 5FC was widely available. (LLM, conf=0.87)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredConventional antifungal susceptibility testing methods, such as broth microdilution and disk diffusion assays, may not detect heteroresistant subpopulations.
“Conventional antifungal susceptibility testing methods, such as broth microdilution and disk diffusion assays, may not detect heteroresistant subpopulations [165,166].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [165]
The Introduction says a small fluconazole-heteroresistant subpopulation in C. neoformans may be missed by conventional MIC testing, and the Results identify broth microdilution as an MIC method used in the study. The paper does not address disk diffusion assays, so that specific example is not supported by our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHeteroresistant subpopulations may exist at low frequencies or exhibit resistance only under specific conditions, such as prolonged exposure to antifungal agents or within certain host environments.
“This limitation arises because heteroresistant subpopulations may exist at low frequencies or exhibit resistance only under specific conditions, such as prolonged exposure to antifungal agents or within certain host environments [153,165,167,168].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [165]
The Introduction states that fluconazole-resistant C. neoformans subpopulations are often below 1% and expand or persist during drug exposure. The murine Results report resistant chromosome 1 disomy after more than 96 hours of fluconazole exposure, but the paper does not establish that these subpopulations exhibit resistance only within particular host environments or that the finding applies to antifungal agents generally. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMisclassification of heteroresistant infections as susceptible can lead to selection of antifungal therapies ineffective against resistant subpopulations, resulting in treatment failure, persistent infections, or emergence of fully resistant strains.
“This misclassification can lead to the selection of antifungal therapies that are ineffective against resistant subpopulations, resulting in treatment failure, persistent infections, or even the emergence of fully resistant strains [99,165].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [165]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredMonotherapy 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 <i>Cryptococcus neoformans</i> highlights key roles in stress tolerance and virulence (2022) · cites this paper as Hope et al. 2019
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Fast and accurate short read alignment with Burrows-Wheeler transform
Li, H., & Durbin, R. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp324 · Cited by 58,607 · see citing works
Cutadapt removes adapter sequences from high-throughput sequencing reads
Martin, M. (2011) · EMBnet.journal · doi:10.14806/ej.17.1.200 · Cited by 33,889 · see citing works
The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., Altshuler, D., Gabriel, S., Daly, M., et al. (2010) · Genome Research · doi:10.1101/gr.107524.110 · Cited by 27,895 · see citing works
A framework for variation discovery and genotyping using next-generation DNA sequencing data
DePristo, M. A., Banks, E., Poplin, R. E., Garimella, K. V., Maguire, J., Hartl, C., Philippakis, A., del Angel, G., Rivas, M. A., Hanna, M., et al. (2011) · Nature Genetics · doi:10.1038/ng.806 · Cited by 11,216 · see citing works
Reference method for broth dilution antifungal susceptibility testing of yeasts : Approved standard
Rex, J. H., & Clinical (2008) · Clinical and Laboratory Standards Institute eBooks · Cited by 1,052 · see citing works
Boeva, V., Popova, T. G., Kevin Bleakley, A., Chiche, P., Cappo, J., Schleiermacher, G., Janoueix‐Lerosey, I., Delattre, O., & Barillot, E. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr670 · Cited by 1,012 · see citing works
Saag, M. S., Powderly, W. G., Cloud, G. A., Robinson, P. A., Grieco, M. H., Sharkey, P. K., Thompson, S. E., Sugar, A. M., Tuazon, C. U., Fisher, J. F., et al. (1992) · New England Journal of Medicine · doi:10.1056/nejm199201093260202 · Cited by 625 · see citing works
Sionov, E., Lee, H., Chang, Y. C., & Kwon-Chung, K. J. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1000848 · Cited by 479 · see citing works
Neely, M. N., Guilder, M. V., Yamada, W. M., et al. (2012) · Therapeutic Drug Monitoring · doi:10.1097/ftd.0b013e31825c4ba6 · Cited by 470 · see citing works
Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa
Molloy, S. F., Kanyama, C., Heyderman, R. S., Loyse, A., Kouanfack, C., Chanda, D. M., Mfinanga, S., Temfack, E., Lakhi, S., Kivuyo, S. L., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1710922 · Cited by 397 · see citing works
Self-citationHsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy
Chen, G., Bradford, W. D., Seidel, C. W., & Li, R. (2012) · Nature · doi:10.1038/nature10795 · Cited by 274 · see citing works
Bicanic, T. A., Meintjes, G., Wood, R., Hayes, M., Rebe, K. B., Bekker, L., & Harrison, T. S. (2007) · Clinical Infectious Diseases · doi:10.1086/518607 · Cited by 271 · see citing works
Self-citationBicanic, T. A., Harrison, T. S., Niepieklo, A., Dyakopu, N., & Meintjes, G. (2006) · Clinical Infectious Diseases · doi:10.1086/507895 · Cited by 222 · see citing works
Self-citationLongley, N., Muzoora, C. K., Taseera, K., Mwesigye, J., Rwebembera, J., Chakera, A. J., Wall, E. C., Andia, I., Jaffar, S. S., & Harrison, T. S. (2008) · Clinical Infectious Diseases · doi:10.1086/593194 · Cited by 201 · see citing works
Self-citationNussbaum, J. C., Jackson, A., Namarika, D., Phulusa, J., Kenala, J., Kanyemba, C., Jarvis, J. N., Jaffar, S. S., Hosseinipour, M. C., Kamwendo, D., et al. (2009) · Clinical Infectious Diseases · doi:10.1086/649861 · Cited by 192 · see citing works
Self-citationA Tetraploid Intermediate Precedes Aneuploid Formation in Yeasts Exposed to Fluconazole
Harrison, B. D., Hashemi, J., Bibi, M., Pulver, R., Bavli, D., Nahmias, Y., Wellington, M., Sapiro, G., & Berman, J. (2014) · PLoS Biology · doi:10.1371/journal.pbio.1001815 · Cited by 174 · see citing works
Correlation of Fluconazole MICs with Clinical Outcome in Cryptococcal Infection
Aller, A. I., Martín‐Mazuelos, E., Lozano, F., Gómez-Mateos, J. M., Steele‐Moore, L., Holloway, W. J., Gutiérrez, M. J., Recio, F., & Espinel-Ingroff, A. V. (2000) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.44.6.1544-1548.2000 · Cited by 171 · see citing works
Dynamic ploidy changes drive fluconazole resistance in human cryptococcal meningitis
Stone, N. R. H., Rhodes, J., Fisher, M. C., Mfinanga, S., Kivuyo, S., Rugemalila, J., Segal, E. S., Needleman, L., Molloy, S. F., Kwon-Chung, J., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci124516 · Cited by 167 · see citing works
Self-citationHeteroresistance to Fluconazole and Voriconazole in <i>Cryptococcus neoformans</i>
Mondon, P., Petter, R., Amalfitano, G., Luzzati, R., Concia, E., Polacheck, I., & Kwon-Chung, K. J. (1999) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.43.8.1856 · Cited by 139 · see citing works
Witt, M. D., Lewis, R. J., Larsen, R. A., Milefchik, E. N., Leal, M. A. E., Haubrich, R., Richie, J., Edwards, J. E., & Ghannoum, M. A. (1996) · Clinical Infectious Diseases · doi:10.1093/clinids/22.2.322 · Cited by 136 · see citing works
Mayanja‐Kizza, H., Oishi, K., Mitarai, S., Yamashita, H., Nalongo, K., Watanabe, K., Izumi, T., Ococi-Jungala, Augustine, K., Mugerwa, R. D., et al. (1998) · Clinical Infectious Diseases · doi:10.1086/516372 · Cited by 128 · see citing works
Sionov, E., Chang, Y. C., & Kwon-Chung, K. J. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00694-13 · Cited by 112 · see citing works
Dannaoui, É., Abdul, M., Arpin, M., Michel-Nguyen, A., Piens, M. A., Favel, A., Lortholary, O., Dromer, F., & the French Cryptococcosis Study Group (2006) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01520-05 · Cited by 102 · see citing works
Loyse, A., Burry, J., Cohn, J., Ford, N., Chiller, T., Ribeiro, I., Koulla-Shiro, S., Mghamba, J., Ramadhani, A., Nyirenda, R., et al. (2019) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(18)30493-6 · Cited by 90 · see citing works
Self-citationSuppression of Emergence of Resistance in Pathogenic Bacteria: Keeping Our Powder Dry, Part 1
Drusano, G. L., Louie, A., MacGowan, A. P., et al. (2015) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02177-15 · Cited by 62 · see citing works
Sudan, A., Livermore, J., Howard, S. J., Al-Nakeeb, Z., Sharp, J., Goodwin, J., Gregson, L., Warn, P. A., Felton, T., Perfect, J. R., et al. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00216-13 · Cited by 59 · see citing works
Self-citationNixon, G. L., McEntee, L., Johnson, A., Farrington, N., Whalley, S., Livermore, J., Natal, C., Washbourn, G., Bibby, J., Berry, N. G., et al. (2018) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01909-17 · Cited by 48 · see citing works
Self-citationAltamirano, S., Fang, D., Simmons, C., Sridhar, S., Wu, P., Sanyal, K., & Kozubowski, L. (2017) · mSphere · doi:10.1128/msphere.00205-17 · Cited by 46 · see citing works
Chang, Y. C., Khanal Lamichhane, A., & Kwon-Chung, K. J. (2018) · mBio · doi:10.1128/mbio.01290-18 · Cited by 34 · see citing works
Arechavala, A. I., Ochiuzzi, M. E., Borgnia, M. D., & Santiso, G. (2009) · Revista Iberoamericana de Micología · doi:10.1016/j.riam.2009.02.001 · Cited by 29 · see citing works
Wiederhold, N. P., Xu, X., Wang, A., et al. (2018) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01315-18 · Cited by 24 · see citing works
Stott, K. E., Beardsley, J., Kolamunnage‐Dona, R., Castelazo, A. S., Kibengo, F., Hoang, N. T., Tung, N. L. N., Cuc, N. T. K., Day, J., & Hope, W. W. (2018) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00885-18 · Cited by 20 · see citing works
Self-citationStott, K. E., Beardsley, J., Whalley, S., Kibengo, F., Hoang, N. T., Tung, N. L. N., Cuc, N. T. K., Kolamunnage‐Dona, R., Hope, W. W., & Day, J. (2018) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02526-17 · Cited by 12 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- [1]WHO. 2018 WHO guidelines for the diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children. WHO, Geneva, Switzerland http://www.who.int/hiv/pub/guidelines/cryptococcal-disease/en/. 30285342
Cited by
Sorted by citations
Loyse, A., Burry, J., Cohn, J., Ford, N., Chiller, T., Ribeiro, I., Koulla-Shiro, S., Mghamba, J., Ramadhani, A., Nyirenda, R., et al. (2019) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(18)30493-6 · Cited by 90 · see citing works
Self-citationFu, C., Beattie, S. R., Jezewski, A. J., Robbins, N., Whitesell, L., Krysan, D. J., & Cowen, L. E. (2022) · Genetics · doi:10.1093/genetics/iyab164 · Cited by 31 · see citing works
Moreira, I. D. M. B., Cortez, A. C. A., de Souza, É. S., Pinheiro, S. B., de Souza Oliveira, J. G., Sadahiro, A., Cruz, K. S., Matsuura, A. B. J., Melhem, M. D. S. C., Frickmann, H., et al. (2022) · Medical Mycology · doi:10.1093/mmy/myac005 · Cited by 22 · see citing works
Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance
Su, Y., Li, Y., Yi, Q., Xu, Y., Sun, T., & Li, Y. (2025) · Journal of Fungi · doi:10.3390/jof11020143 · Cited by 18 · see citing works
“This limitation arises because heteroresistant subpopulations may exist at low frequencies or exhibit resistance only under specific conditions, such as prolonged exposure to antifungal agents or within certain host environments [153,165,167,168].”
InfluentialHuang, Y., Zhang, Y., Yang, S., Lu, H., Yu, H., Wang, X., Jia, X., Tang, D., Wu, L., Huang, S., et al. (2024) · Microbiology Spectrum · doi:10.1128/spectrum.00725-24 · Cited by 12 · see citing works
Novel ABC Transporter Associated with Fluconazole Resistance in Aging of Cryptococcus neoformans
Oliveira, N. K., Bhattacharya, S., Gambhir, R., Joshi, M., & Fries, B. C. (2022) · doi:10.20944/preprints202201.0263.v1 · Cited by 24 · see citing works
- Authors
- Hope, W., Stone, N. R. H., Johnson, A., McEntee, L., Farrington, N., Santoro-Castelazo, A., Liu, X., Lucaci, A., Hughes, M., Oliver, J. D., Giamberardino, C., Mfinanga, S., Harrison, T. S., Perfect, J. R., & Bicanic, T.
- Affiliations
- University of Liverpool (GB)
- Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, Liverpool Health Partners, Liverpool, United Kingdom
- F2G (United Kingdom) (GB)
- Duke University (US)
- National Institute for Medical Research (TZ)
- St George's, University of London (GB)
- Corresponding author
- Hope, William
- ORCID
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2019-12-24
- Volume
- 10
- Issue
- 6
- ISSN
- 2150-7511 (ISSN-L)
- 2161-2129
- PMC
- PMC6890991
- OpenAlex
- W2994239937
- Cited by
- 70
- References
- 33
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 15 · 2023: 6 · 2022: 18 · 2021: 8 · 2020: 9 · 2018: 1
- FWCI
- 6.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- St George's Online Research Archive (St George's University of London) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Wellcome (097377/Z/11/Z)
- UK Research and Innovation | Medical Research Council (G1001760)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- cryptococcal meningitis, fluconazole, antifungal resistance, Cryptococcus, aneuploidy, chromosomal duplication, HIV/AIDS, dose escalation, combination antifungal therapy, susceptibility testing
- MeSH terms
- Adult, Animals, Antifungal Agents, Cryptococcus neoformans, Female, Humans, Male, Meningoencephalitis, Microbial Sensitivity Tests, Middle Aged, Fluconazole, Meningitis, Cryptococcal, Drug Resistance, Fungal, Mice, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
