Combination therapy with fluconazole and flucytosine for pulmonary cryptococcosis
Abstract
We investigated, in vitro, the combined effects of fluconazole (FLCZ) and flucytosine (5-FC) against different strains of Cryptococcus neoformans, and retrospectively analyzed the clinical efficacy of combination therapy of FLCZ and 5-FC in patients with pulmonary cryptococcosis. The minimum inhibitory concentrations (MICs) of antifungal agents and drug interaction were determined by the broth microdilution method and checkerboard titration. FLCZ and 5-FC showed synergistic activity against 8 (32%) of 25 strains of C. neoformans. The clinical efficacy of the 2 drugs when combined together was good in 9 (90%) patients and fair in 1 (10%) patient with pulmonary cryptococcosis. Renal dysfunction occured in 1 patient. Our results suggest that a combination therapy using FLCZ and 5-FC is clinically useful in patients with pulmonary cryptococcosis who otherwise show a limited response to monotherapy.
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Expanding scope to all failed antifungal treatments, such as adding 5-FC or amphotericin B to fluconazole monotherapy, alleviates mortality rate and achieves up to 90% efficacy.
“Expanding the scope to all failed antifungal treatments, such as adding 5-FC or amphotericin B to fluconazole monotherapy, alleviates mortality rate and achieves up to 90% efficacy [177,178,179].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [177]
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Pappas, P. G., Perfect, J. R., Cloud, G. A., Larsen, R. A., Pankey, G. A., Lancaster, D. J., Henderson, H. M., Kauffman, C. A., Haas, D. W., Saccente, M., et al. (2001) · Clinical Infectious Diseases · doi:10.1086/322597 · Cited by 640 · see citing works
Combination antifungal therapy
Johnson, M. D., MacDougall, C., Ostrosky-Zeichner, L., Perfect, J. R., & Rex, J. H. (2004) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.48.3.693-715.2004 · Cited by 541 · see citing works
“However, more recent reports of investigations of triazole-flucytosine combinations most commonly have indicated synergy or indifference (3, 12, 14, 74, 138, 140, 223).”
BackgroundCombinatorial strategies for combating invasive fungal infections
Spitzer, M., Robbins, N., & Wright, G. D. (2016) · Virulence · doi:10.1080/21505594.2016.1196300 · Cited by 218 · see citing works
“Targeting of the fungal cell membrane by azoles and amphotericin B may explain synergism of these drugs with flucytosine.(56,57) Alternatively, 2 drugs that target different stages of the same biological pathway or even the”
BackgroundCryptococcus neoformans: Morphogenesis, infection, and evolution
Lin, X. (2009) · Infection Genetics and Evolution · doi:10.1016/j.meegid.2009.01.013 · Cited by 166 · see citing works
The past, present and future of antimycotic combination therapy
Polak, A. (1999) · Mycoses · doi:10.1046/j.1439-0507.1999.00475.x · Cited by 114 · see citing works
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Campitelli, M., Zeineddine, N., Samaha, G., & Maslak, S. (2017) · Journal of Clinical Medicine Research · doi:10.14740/jocmr2992w · Cited by 92 · see citing works
Antifungal Pharmacodynamics: Review of the Literature and Clinical Applications
Dodds, E. S., Drew, R. H., & Perfect, J. R. (2000) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1592/phco.20.17.1335.34901 · Cited by 46 · see citing works
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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
“Expanding the scope to all failed antifungal treatments, such as adding 5-FC or amphotericin B to fluconazole monotherapy, alleviates mortality rate and achieves up to 90% efficacy [177–179].”
Pulmonary Cryptococcosis in Late Pregnancy and Review of Published Literature
Nakamura, S., Izumikawa, K., Seki, M., Kakeya, H., Yamamoto, Y., Yanagihara, K., Miyazaki, Y., & Kohno, S. (2008) · Mycopathologia · doi:10.1007/s11046-008-9162-8 · Cited by 12 · see citing works
“Although combination therapy with AMPH-B and 5-FC is recommended for disseminated cryptococcosis [31], we treated with oral FLCZ and 5-FC since they exhibit good penetration to spinal fluid and because synergistic effects have been reported [ 32 , 33].”
BackgroundSelf-citationCarbon Dioxide Potentiates Flucytosine Susceptibility in Cryptococcus neoformans
Jezewski, A. J., Ristow, L. C., & Krysan, D. J. (2023) · Microbiology Spectrum · doi:10.1128/spectrum.04783-22 · Cited by 11 · see citing works
Singh, A., Agarwal, A. K., & Xu, Y.-J. (2017) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00734-17 · Cited by 10 · see citing works
“effect of HU through increased permeability of cell membrane and thus the bioavailability of HU, similar to that reported for azoles and flucytosine (41).”
ResultCombination therapy against human infections caused by Candida species
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MINIREVIEW Combination Antifungal Therapy
Johnson, J. R., Dougall, C. M., & Zeichner, L. O. (2004) · Cited by 7 · see citing works
Flucytosine: Site of Action, Mechanism of Resistance and Use in Combination Therapy
Chandra, J., Mohammad, S., & Ghannoum, M. A. (2009) · Antimicrobial Drug Resistance · doi:10.1007/978-1-59745-180-2_27 · Cited by 6 · see citing works
“In a separate study, Yamamoto et al. ( 76 ) retrospectively analyzed the clinical effi cacy of combination therapy of FLU and 5-FC in patients with pulmonary cryptococcosis.”
BackgroundJacobs, A. V., & Leaf, H. L. (1999) · Current Infectious Disease Reports · doi:10.1007/s11908-999-0015-5 · Cited by 5 · see citing works
“Pulmonary cryptococcosis in the healthy host may be treated, if treatment is warranted, with fluconazole 200 to 400 mg orally daily, or alternatively with flucanozole plus flucytosine [77] .”
BackgroundA Young Healthy Woman Presenting with Acute Meningitis and a Large Pleural-Based Mass
de Klerk, A. A. G., Bezuidenhout, J., & Bolliger, C. T. (2003) · Respiration · doi:10.1159/000075216 · Cited by 5 · see citing works
“Antifungal treatment consists of fluconazole 200–400 mg/day for 3–6 months. For those individuals who are unable to tolerate fluconazole, itraconazole (200–400 mg/day for 6–12 months) is an acceptable alternative. For patients with more severe disease, treatment with amphotericin B (0.5–1 mg/kg/day) may be necessary f…”
BackgroundInfluentialColín, I. F., Pérez Rosales, A., & Novelo-Retana (2003) · NCT Neumología y Cirugía de Tórax · Cited by 1 · see citing works
Combinatorial approach to combat drug resistance in human pathogenic fungi
Mir, M. A., Qadri, H., Aisha, S., & Shah, A. H. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-96127-1.00011-5
- Authors
- Yamamoto, Y., Maesaki, S., Kakeya, H., Yanagihara, K., Ohno, H., Ogawa, K., Hirakata, Y., Tomono, K., Koga, H., Tashiro, T., & Kohno, S.
- Affiliations
- Nagasaki University (JP)
- Venue
- Chemotherapy
- Publisher
- S. Karger AG
- Published
- 2009-09-11
- Volume
- 43
- Issue
- 6
- Pages
- 436-441
- ISSN
- 0009-3157 (ISSN-L)
- 1421-9794
- OpenAlex
- W1979400747
- Cited by
- 20
- References
- 0
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 1 · 2020: 1 · 2017: 2 · 2016: 1
- FWCI
- 0.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Chemotherapy (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Epidemiology › Pneumocystis jirovecii pneumonia detection and treatment
- Keywords
- pulmonary cryptococcosis, Cryptococcus neoformans, fluconazole, 5-fluorocytosine, combination antifungal therapy, drug synergy, minimum inhibitory concentration, drug interactions, renal dysfunction
- MeSH terms
- Adult, Aged, Antifungal Agents, Cryptococcosis, Drug Therapy, Combination, Female, Flucytosine, Humans, Lung Diseases, Fungal, Male, Middle Aged, Fluconazole
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