Antifungal heteroresistance causes prophylaxis failure and facilitates breakthrough Candida parapsilosis infections
Open accessAbstract
Breakthrough fungal infections in patients on antimicrobial prophylaxis during allogeneic hematopoietic cell transplantation (allo-HCT) represent a major and often unexplained cause of morbidity and mortality. Candida parapsilosis is a common cause of invasive candidiasis and has been classified as a high-priority fungal pathogen by the World Health Organization. In high-risk allo-HCT recipients on micafungin prophylaxis, we show that heteroresistance (the presence of a phenotypically unstable, low-frequency subpopulation of resistant cells (~1 in 10,000)) underlies breakthrough bloodstream infections by C. parapsilosis. By analyzing 219 clinical isolates from North America, Europe and Asia, we demonstrate widespread micafungin heteroresistance in C. parapsilosis. Standard antimicrobial susceptibility tests, such as broth microdilution or gradient diffusion assays, which guide drug selection for invasive infections, fail to detect micafungin heteroresistance in C. parapsilosis. To facilitate rapid detection of micafungin heteroresistance in C. parapsilosis, we constructed a predictive machine learning framework that classifies isolates as heteroresistant or susceptible using a maximum of ten genomic features. These results connect heteroresistance to unexplained antifungal prophylaxis failure in allo-HCT recipients and demonstrate a proof-of-principle diagnostic approach with the potential to guide clinical decisions and improve patient care.
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The prevalent use of caspofungin in a given setting may select for caspofungin-heteroresistant C. glabrata, whereas micafungin-predominant pressure or intrinsic species factors can lead to micafungin heteroresistance.
“Consequently, the prevalent use of caspofungin in a given setting may select for caspofungin‐heteroresistant C. glabrata, whereas micafungin‐predominant pressure or intrinsic species factors can lead to micafungin heteroresistance [49].”
From Calcineurin‐Dependent Stress Adaptation Enables Caspofungin Heteroresistance Leading to Stable Resistance in <i>Candida Glabrata</i> (2026) · cites this paper as [49]
The Results section, “Micafungin heteroresistance marks breakthrough infections” (page unavailable), shows that micafungin exposure made an existing resistant subpopulation of C. parapsilosis dominant. It does not establish that predominant drug use produces heteroresistance, or address caspofungin-driven selection in C. glabrata or intrinsic species factors as a cause of micafungin heteroresistance. (LLM, conf=0.82)
Experimental — accuracy not yet measuredExposure of C. parapsilosis to tunicamycin did not reveal any relationship between aneuploidy and heteroresistance.
“However, unlike C. neoformans, exposure of C. parapsilosis to tunicamycin did not reveal any relationship between aneuploidy and heteroresistance [3,153].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [3]
The Results section (Association between heteroresistance and genomic variations; page not provided) says this study lacked power to confirm or reject a relationship between aneuploidy and micafungin heteroresistance in C. parapsilosis. It does not report a tunicamycin-exposure test; instead, it notes prior reports of aneuploidy in C. parapsilosis tolerance to tunicamycin. The claim changes the exposure and overstates the inconclusive result as no relationship. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn C. parapsilosis, heteroresistance facilitates breakthrough infections in immunocompromised patients and may cause prophylaxis failure.
“In C. parapsilosis, multi-center studies have shown that heteroresistance facilitates breakthrough infections in immunocompromised patients and may cause prophylaxis failure [3].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [3]
The Discussion reports that micafungin heteroresistance promotes breakthrough C. parapsilosis infections during prophylaxis in allo-HCT recipients, supporting the clinical claim. But the breakthrough-infection cohort was studied at one center, MSKCC (Results, “C. parapsilosis causes micafungin breakthrough infections”); isolates from multiple hospitals were used to assess the spread of heteroresistance, not to establish the breakthrough finding in multi-center studies. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe heteroresistance landscape is shaped by both the specific drug and the pathogen species.
“highlighting how the heteroresistance landscape is shaped by both the specific drug and the pathogen species.”
From Calcineurin‐Dependent Stress Adaptation Enables Caspofungin Heteroresistance Leading to Stable Resistance in <i>Candida Glabrata</i> (2026) · cites this paper as [49]
The Results section ('Micafungin heteroresistance marks breakthrough infections'; page unavailable) shows that heteroresistance varies by drug: some C. parapsilosis isolates had different phenotypes for micafungin, caspofungin and anidulafungin. It also reports micafungin heteroresistance in C. auris, but does not compare species in a way that establishes how pathogen species shapes the heteroresistance landscape. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAntifungal heteroresistance causes prophylaxis failure and facilitates breakthrough Candida parapsilosis infections in patients during allogeneic hematopoietic cell transplantation.
“Moreover, a recent study found that antifungal heteroresistance causes prophylaxis failure and facilitates breakthrough Candida parapsilosis infections in patients during allogeneic hematopoietic cell transplantation [30].”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [30]
C. auris exhibits heteroresistance towards echinocandins, the first-line treatment for C. auris infection.
“For highly resistant pathogen C. auris, Zhai et al. reported heteroresistance towards echinocandins, the first-line treatment for C. auris infection [3].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [3]
Prior to onset of infection, antifungal heteroresistance can facilitate breakthrough infection or result in prophylaxis failure.
“Prior to the onset of infection, this can facilitate breakthrough infection or result in prophylaxis failure [3].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [3]
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“In C. parapsilosis , multi-center studies have shown that heteroresistance facilitates breakthrough infections in immunocompromised patients and may cause prophylaxis failure [3].”
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- Authors
- Zhai, B., Liao, C., Jaggavarapu, S., Tang, Y., Rolling, T., Ning, Y., Sun, T., Bergin, S. A., Gjonbalaj, M., Miranda, E., Babady, N. E., Bader, O., Taur, Y., Butler, G., Zhang, L., Xavier, J. B., Weiss, D. S., & Hohl, T. M.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Emory University (US)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- University College Dublin (IE)
- Universitätsmedizin Göttingen (DE)
- Corresponding author
- Zhai, Bing
- Weiss, David S.
- Hohl, Tobias M.
- ORCID
- Venue
- Nature Medicine
- Published
- 2024-08-02
- Volume
- 30
- Issue
- 11
- Pages
- 3163-3172
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC11840754
- OpenAlex
- W4401264619
- Cited by
- 62
- References
- 59
- Citations by year
- 2026: 22 · 2025: 32 · 2024: 5 · 2023: 3
- FWCI
- 20.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- Funders
- Memorial Sloan-Kettering Cancer Center (CA008748, P30 CA008748)
- Science Foundation Ireland (19/FFP/6668, 18/CRT/6214)
- Deutsche Forschungsgemeinschaft (RO-5328/1-2, P30 CA008748)
- Chinese Academy of Medical Sciences (2021-I2M-1-044)
- National Institutes of Health (1p01ai179406-01, 1k99ai175599-01a1, CA008748, AI158080, AI148661)
- Ludwig Center at Harvard (P30 CA008748)
- National Key Research and Development Program of China (2021YFA0911300, P30 CA008748)
- National Cancer Institute (P30CA008748)
- National Institute of Allergy and Infectious Diseases (R01AI139632, R21AI105617, R21AI156157, R01AI148661, R01AI141883, K99 AI175599, P01 AI179406, R01AI137269, U01AI124275, R37AI093808, R00AI175599, U19AI158080)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- Candida parapsilosis, micafungin, heteroresistance, allogeneic hematopoietic stem cell transplantation, bloodstream infection, antimicrobial susceptibility testing, machine learning classification, genomic features, invasive candidiasis
- MeSH terms
- Machine Learning, Candida parapsilosis, Micafungin, Antifungal Agents, Candidiasis, Humans, Microbial Sensitivity Tests, Hematopoietic Stem Cell Transplantation, Drug Resistance, Fungal
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