- ABSTRACT.
- INTRODUCION
- MATERIALS AND METHODS
- STATISTICAL ANALYSES
- RESULTS
- Sequence types of C. neoformans isolates and their prognostic relationship with HIV-infected patients.
- Seasonal distribution analysis of cryptococcal infection in patients with HIV-infection.
- Antifungal susceptibility results.
- Distribution of antifungal susceptibility tests among different ST types.
- Antifungal susceptibility results and their prognostic relationship with HIV-infected patients.
- DISCUSSION
- ACKNOWLEDGMENT
- REFERENCES
ProCite
RefWorks
Reference Manager
BibTeX
Zotero
EndNote
-
1.
Hagen F, Khayhan K, Theelen B, Kolecka A, Polacheck I, Sionov E, Falk R, Parnmen S, Lumbsch HT, Boekhout T, 2015. Recognition of seven species in the Cryptococcus gattii/Cryptococcus neoformans species complex. Fungal Genet Biol 78: 16–48.
-
2.
Zhao Y, et al., 2023. Cryptococcus neoformans, a global threat to human health. Infect Dis Poverty 12: 20.
-
3.
Khayhan K, et al., 2013. Geographically structured populations of Cryptococcus neoformans variety grubii in Asia correlate with HIV status and show a clonal population structure. PLoS One 8: e72222.
-
4.
World Health Organization, 2022. WHO Fungal Priority Pathogens List to Guide Research, Development and Public Health Action. Available at: https://www.who.int/publications/i/item/9789240060241. Accessed February 20, 2023.
-
5.
Skipper CP, et al., 2022. Sterile cerebrospinal fluid culture at cryptococcal meningitis diagnosis is associated with high mortality. J Fungi (Basel) 9: 46.
-
6.
Lawrence DS, Boyer CT, Jarvis JN, 2019. Emerging concepts in HIV associated cryptococcal meningitis. Curr Opin Infect Dis 32: 16–23.
-
7.
Meyer W, et al., 2009. Consensus multi-locus sequence typing scheme for Cryptococcus neoformans and Cryptococcus gattii. Med Mycol 47: 561–570.
-
8.
Hong N, Chen M, Xu J, 2021. Molecular markers reveal epidemiological patterns and evolutionary histories of the human pathogenic Cryptococcus. Front Cell Infect Microbiol 11: 683670.
-
9.
Firacative C, et al., 2016. MLST and whole-genome-based population analysis of Cryptococcus gattii VGIII links clinical, veterinary and environmental strains, and reveals divergent serotype specifc sub-populations and distant ancestors. PLoS Negl Trop Dis 10: e0004861.
-
10.
Cogliati M, Roger F, Meyer W, Robert V, Bertout S, 2020. New multilocus sequence typing primers to enable genotyping of AD hybrids within the Cryptococcus neoformans species complex. Med Mycol 58: 1005–1009.
-
11.
Bive BZ, et al., 2022. Clinical epidemiology and high genetic diversity amongst Cryptococcus spp. isolates infecting people living with HIV in Kinshasa, Democratic Republic of Congo. PLoS One 17: e0267842.
-
12.
Cogliati M, et al., 2019. Genotypes and population genetics of Cryptococcus neoformans and Cryptococcus gattii species complexes in Europe and the mediterranean area. Fungal Genet Biol 129: 16–29.
-
13.
Xess I, et al., 2021. Multilocus sequence typing of clinical isolates of Cryptococcus from India. Mycopathologia 186: 199–211.
-
14.
Day JN, et al., 2011. Most cases of cryptococcal meningitis in HIV-uninfected patients in Vietnam are due to a distinct amplified fragment length polymorphism-defined cluster of Cryptococcus neoformans var. grubii VN1. J Clin Microbiol 49: 658–664.
-
15.
Mihara T, et al., 2013. Multilocus sequence typing of Cryptococcus neoformans in non-HIV associated cryptococcosis in Nagasaki, Japan. Med Mycol 51: 252–260.
-
16.
The European Committee on Antimicrobial Susceptibility Testing, 2020. Breakpoint Tables for Interpretation of MICs for Antifungal Agents Version 10.0. Available at: https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/AFST/Clinical_breakpoints/AFST_BP_v10.0_200204_updatd_links_200924.pdf. Accessed September 10, 2024.
-
17.
European Committee on Antimicrobial Susceptibility Testing, 2022. Overview of Antifungal ECOFFs and Clinical Breakpoints for Yeasts, Moulds and Dermatophytes Using the EUCAST E.Def 7.3, E.Def 9.4 and E.Def 11.0 Procedures. Version 3. Available at: https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/AFST/Clinical_breakpoints/EUCAST_BP_ECOFF_v_4.0.pdf. Accessed September 10, 2024.
-
18.
Espinel-Ingroff A, et al., 2012. Cryptococcus neoformans-Cryptococcus gattii species complex: An international study of wild-type susceptibility endpoint distributions and epidemiological cutoff values for fluconazole, itraconazole, posaconazole, and voriconazole. Antimicrob Agents Chemother 56: 5898–5906.
-
19.
National Health Commission of the People’s Republic of China, 2022. An Updated Catalogue of Microbial Pathogens Transmitted to Humans. Available at: http://www.nhc.gov.cn/wjw/yjzj/202112/94fcc4480ea2403e9c51c641645d6c20.shtml. Accessed February 20, 2023.
-
20.
Montoya MC, Magwene PM, Perfect JR, 2021. Associations between Cryptococcus genotypes, phenotypes, and clinical parameters of human disease: A review. J Fungi (Basel) 7: 260.
-
21.
Araújo MRB, Santos EGDM, Wolf V, Seabra LF, 2018. Identification of Cryptococcus neoformans by MALDI-TOF mass spectrometry in blood culture. Clin Biomed Res 38: 200–202.
-
22.
Tarumoto N, Sakai J, Kodana M, Kawamura T, Ohno H, Maesaki S, 2016. Identification of disseminated cryptococcosis using MALDI-TOF MS and clinical evaluation. Med Mycol J 57: E41–E46.
-
23.
Zhu N, Yu N, Zhu Y, Wei Y, Hou Y, Zhang H, Sun A-D, 2018. Identification of spoilage microorganisms in blueberry juice and their inactivation by a microchip pulsed electric field system. Sci Rep 8: 8160.
-
24.
Bongomin F, Oladele RO, Gago S, Moore CB, Richardson MD, 2018. A systematic review of fluconazole resistance in clinical isolates of Cryptococcus species. Mycoses 61: 290–297.
-
25.
Chang YC, Lamichhane AK, Cai H, Walter PJ, Bennett JE, Kwon-Chung KJ, 2021. Moderate levels of 5-fluorocytosine cause the emergence of high frequency resistance in cryptococci. Nat Commun 12: 3418.
-
26.
Clinical and Laboratory Standards Institute, 2023. Epidemiological Cutoff Values for Antifungal Susceptibility Testing, CLSI Suppl M59 Document. 2nd ed. Wayne, PA: Clinical and Laboratory Standards Institute.
-
27.
Clinical and Laboratory Standards Institute, 2023. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, 4th Suppl., M27-S4. Wayne, PA: Clinical and Laboratory Standards Institute.
-
28.
Fan X, et al., 2016. Predominance of Cryptococcus neoformans var. grubii multilocus sequence type 5 and emergence of isolates with non-wild-type minimum inhibitory concentrationsto fluconazole: A multi-Centre study in China. Clin Microbiol Infect 22: 887.e1–887.e9.
-
29.
Fang LF, Zhang PP, Wang J, Yang Q, Qu TT, 2020. Clinical and microbiological characteristics of cryptococcosis at an university hospital in China from 2013 to 2017. Braz J Infect Dis 24: 7–12.
-
30.
Zhang J, et al., 2022. Antifungal susceptibility and molecular characteristics of Cryptococcus spp. based on whole-genome sequencing in Zhejiang Province, China. Front Microbiol 13: 991703.
-
31.
Osawa R, Singh N, 2010. Colitis as a manifestation of infliximab-associated disseminated cryptococcosis. Int J Infect Dis 14: e436–e440.
-
32.
Nawabi DH, Ffolkes L, Bichere AO, 2005. Cryptococcal small-bowel obstruction in an HIV-positive patient. J R Soc Med 98: 513–514.
-
33.
Musubire AK, Meya DB, Lukande R, Kambugu A, Bohjanen PR, Boulware DR, 2015. Gastrointestinal cryptococcoma-immune reconstitution inflammatory syndrome or cryptococcal relapse in a patient with AIDS? Med Mycol Case Rep 8: 40–43.
-
34.
Araujo BS, Bay M, Reichert R, Goldani LZ, 2012. Intra-abdominal cryptococcosis by Cryptococcus gattii: Case report and review. Mycopathologia 174: 81–85.
-
35.
Tzimas D, Wan D, 2011. Small bowel perforation in a patient with AIDS. Diagnosis: Small bowel infection with Cryptococcus neoformans. Gastroenterology 140: 1882, 2150.
-
36.
Tian Y, Wang J, Shen Y, Zhao J, Hu J, Zhu X, Zhu M, Guan M, 2023. Characteristics and prognostic risk factors of patients with sequence type 5 lineage-associated cryptococcosis in China. Int J Infect Dis 128: 244–253.
-
37.
Liu ZY, et al., 2018. Expert consensus on the diagnosis and treatment of cryptococcal meningitis. Zhonghua Nei Ke Za Zhi 57: 317–323.
-
38.
Chen Y-C, Kuo S-F, Lin Y-S, Lin Y-S, Lee C-H, 2022. Epidemiological and clinical characteristics, antifungal susceptibility, and MLST-based genetic analysis of Cryptococcus isolates in southern Taiwan in 2013–2020. J Fungi (Basel) 8: 287.
-
39.
Wu T-S, Lin J-F, Cheng C-W, Huang P-Y, Yang JH, 2023. Lack of association between YEASTONE antifungal susceptibility tests and clinical outcomes of Cryptococcus meningitis. J Fungi (Basel) 9: 232.
| Past two years | Past Year | Past 30 Days | |
|---|---|---|---|
| Abstract Views | 4001 | 4001 | 94 |
| Full Text Views | 87 | 87 | 12 |
| PDF Downloads | 106 | 106 | 14 |
Multi-Locus Sequence Typing–Based Genetic Analysis, Antifungal Resistance, and Clinical Prognosis of Cryptococcus neoformans Infections in HIV-Infected Patients in Northern China
Fang-Fang Dai
Fang-Fang Dai
Department of Clinical Laboratory, Beijing Youan Hospital, Capital Medical University, Beijing, China;
Beijing Tongren Hospital, Capital Medical University, Beijing, China
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Beijing Tongren Hospital, Capital Medical University, Beijing, China
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Yan-Hua Yu
yyhs2005186@163.com
Yan-Hua Yu
Department of Clinical Laboratory, Beijing Youan Hospital, Capital Medical University, Beijing, China;
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Xin-Xin Lu
luxinxin2009@126.com
Xin-Xin Lu
Beijing Tongren Hospital, Capital Medical University, Beijing, China
Search for other papers by Xin-Xin Lu in
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Search for other papers by Xin-Xin Lu in
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PubMed
ABSTRACT.
This study aimed to investigate the molecular epidemiological characteristics and drug sensitivity of Cryptococcus from HIV-infected patients and their relationship with patients’ prognosis. Seventy-six strains were collected and identified to the species level by matrix-assisted laser desorption ionization–time of flight mass spectrometry, confirmed by internal transcribed spacer sequencing. Multi-locus sequence typing was used for the typing of Cryptococcus, and its antifungal susceptibility was tested using FUNGUS 3. The clinical outcomes of the patients were reviewed at 3-, 6-, 9-, and 12-month follow-ups. All strains were Cryptococcus neoformans var. grubii classified into seven sequence types (STs) dominated by ST5, ST31, and a new ST702 strain. The 6- and 9-month survival rates were highest for patients infected with ST31, ST32, and ST174. The antifungal resistant rates were 13.2%, 2.6%, and 1.4% for fluconazole, amphotericin B, and 5-fluorocytosine. Except itraconazole, the minimum inhibitory concentration (MIC) values and wild type (WT)/non–wild type (NWT) of Cryptococcus for antifungal drugs were not related to the clinical prognosis of HIV-infected patients with cryptococcal infection. ST5 was the main ST type, and the new ST702 type was found in a patient who died in a short period of time. Cryptococcus neoformans var. grubii had a relatively high antifungal drug resistance rate to fluconazole. The WT strain accounted for the highest proportions for 5-fluorocytosine, amphotericin B, fluconazole, voriconazole, and itraconazole. The MIC values of Cryptococcus for first-line antifungal drugs showed no relationship with clinical prognosis, implying that MIC values cannot be used to predict the clinical outcome of these patients.
Author Notes
Disclosures: The study was conducted in accordance with the guidelines of the Declaration of Helsinki and was approved by the Institutional Review Board of Beijing Youan Hospital, Capital Medical University. The requirement for informed consent was waived with the authorization of the Institutional Review Board of Beijing Youan Hospital of Capital Medical University because no intervention was performed.
Data availability: The data presented in this study are available upon request from the corresponding author.
Current contact information: Fang-Fang Dai, Department of Clinical Laboratory, Beijing Youan Hospital, Capital Medical University, Beijing, China, and Beijing Tongren Hospital, Capital Medical University, Beijing, China, E-mail: daifangfang1218@163.com. Yan-Hua Yu, Department of Clinical Laboratory, Beijing Youan Hospital, Capital Medical University, Beijing, China, E-mail: yyhs2005186@163.com. Xin-Xin Lu, Beijing Tongren Hospital, Capital Medical University, Beijing, China, E-mail: luxinxin2009@126.com.
- ABSTRACT.
- INTRODUCION
- MATERIALS AND METHODS
- STATISTICAL ANALYSES
- RESULTS
- Sequence types of C. neoformans isolates and their prognostic relationship with HIV-infected patients.
- Seasonal distribution analysis of cryptococcal infection in patients with HIV-infection.
- Antifungal susceptibility results.
- Distribution of antifungal susceptibility tests among different ST types.
- Antifungal susceptibility results and their prognostic relationship with HIV-infected patients.
- DISCUSSION
- ACKNOWLEDGMENT
- REFERENCES
ProCite
RefWorks
Reference Manager
BibTeX
Zotero
EndNote
-
1.
Hagen F, Khayhan K, Theelen B, Kolecka A, Polacheck I, Sionov E, Falk R, Parnmen S, Lumbsch HT, Boekhout T, 2015. Recognition of seven species in the Cryptococcus gattii/Cryptococcus neoformans species complex. Fungal Genet Biol 78: 16–48.
-
2.
Zhao Y, et al., 2023. Cryptococcus neoformans, a global threat to human health. Infect Dis Poverty 12: 20.
-
3.
Khayhan K, et al., 2013. Geographically structured populations of Cryptococcus neoformans variety grubii in Asia correlate with HIV status and show a clonal population structure. PLoS One 8: e72222.
-
4.
World Health Organization, 2022. WHO Fungal Priority Pathogens List to Guide Research, Development and Public Health Action. Available at: https://www.who.int/publications/i/item/9789240060241. Accessed February 20, 2023.
-
5.
Skipper CP, et al., 2022. Sterile cerebrospinal fluid culture at cryptococcal meningitis diagnosis is associated with high mortality. J Fungi (Basel) 9: 46.
-
6.
Lawrence DS, Boyer CT, Jarvis JN, 2019. Emerging concepts in HIV associated cryptococcal meningitis. Curr Opin Infect Dis 32: 16–23.
-
7.
Meyer W, et al., 2009. Consensus multi-locus sequence typing scheme for Cryptococcus neoformans and Cryptococcus gattii. Med Mycol 47: 561–570.
-
8.
Hong N, Chen M, Xu J, 2021. Molecular markers reveal epidemiological patterns and evolutionary histories of the human pathogenic Cryptococcus. Front Cell Infect Microbiol 11: 683670.
-
9.
Firacative C, et al., 2016. MLST and whole-genome-based population analysis of Cryptococcus gattii VGIII links clinical, veterinary and environmental strains, and reveals divergent serotype specifc sub-populations and distant ancestors. PLoS Negl Trop Dis 10: e0004861.
-
10.
Cogliati M, Roger F, Meyer W, Robert V, Bertout S, 2020. New multilocus sequence typing primers to enable genotyping of AD hybrids within the Cryptococcus neoformans species complex. Med Mycol 58: 1005–1009.
-
11.
Bive BZ, et al., 2022. Clinical epidemiology and high genetic diversity amongst Cryptococcus spp. isolates infecting people living with HIV in Kinshasa, Democratic Republic of Congo. PLoS One 17: e0267842.
-
12.
Cogliati M, et al., 2019. Genotypes and population genetics of Cryptococcus neoformans and Cryptococcus gattii species complexes in Europe and the mediterranean area. Fungal Genet Biol 129: 16–29.
-
13.
Xess I, et al., 2021. Multilocus sequence typing of clinical isolates of Cryptococcus from India. Mycopathologia 186: 199–211.
-
14.
Day JN, et al., 2011. Most cases of cryptococcal meningitis in HIV-uninfected patients in Vietnam are due to a distinct amplified fragment length polymorphism-defined cluster of Cryptococcus neoformans var. grubii VN1. J Clin Microbiol 49: 658–664.
-
15.
Mihara T, et al., 2013. Multilocus sequence typing of Cryptococcus neoformans in non-HIV associated cryptococcosis in Nagasaki, Japan. Med Mycol 51: 252–260.
-
16.
The European Committee on Antimicrobial Susceptibility Testing, 2020. Breakpoint Tables for Interpretation of MICs for Antifungal Agents Version 10.0. Available at: https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/AFST/Clinical_breakpoints/AFST_BP_v10.0_200204_updatd_links_200924.pdf. Accessed September 10, 2024.
-
17.
European Committee on Antimicrobial Susceptibility Testing, 2022. Overview of Antifungal ECOFFs and Clinical Breakpoints for Yeasts, Moulds and Dermatophytes Using the EUCAST E.Def 7.3, E.Def 9.4 and E.Def 11.0 Procedures. Version 3. Available at: https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/AFST/Clinical_breakpoints/EUCAST_BP_ECOFF_v_4.0.pdf. Accessed September 10, 2024.
-
18.
Espinel-Ingroff A, et al., 2012. Cryptococcus neoformans-Cryptococcus gattii species complex: An international study of wild-type susceptibility endpoint distributions and epidemiological cutoff values for fluconazole, itraconazole, posaconazole, and voriconazole. Antimicrob Agents Chemother 56: 5898–5906.
-
19.
National Health Commission of the People’s Republic of China, 2022. An Updated Catalogue of Microbial Pathogens Transmitted to Humans. Available at: http://www.nhc.gov.cn/wjw/yjzj/202112/94fcc4480ea2403e9c51c641645d6c20.shtml. Accessed February 20, 2023.
-
20.
Montoya MC, Magwene PM, Perfect JR, 2021. Associations between Cryptococcus genotypes, phenotypes, and clinical parameters of human disease: A review. J Fungi (Basel) 7: 260.
-
21.
Araújo MRB, Santos EGDM, Wolf V, Seabra LF, 2018. Identification of Cryptococcus neoformans by MALDI-TOF mass spectrometry in blood culture. Clin Biomed Res 38: 200–202.
-
22.
Tarumoto N, Sakai J, Kodana M, Kawamura T, Ohno H, Maesaki S, 2016. Identification of disseminated cryptococcosis using MALDI-TOF MS and clinical evaluation. Med Mycol J 57: E41–E46.
-
23.
Zhu N, Yu N, Zhu Y, Wei Y, Hou Y, Zhang H, Sun A-D, 2018. Identification of spoilage microorganisms in blueberry juice and their inactivation by a microchip pulsed electric field system. Sci Rep 8: 8160.
-
24.
Bongomin F, Oladele RO, Gago S, Moore CB, Richardson MD, 2018. A systematic review of fluconazole resistance in clinical isolates of Cryptococcus species. Mycoses 61: 290–297.
-
25.
Chang YC, Lamichhane AK, Cai H, Walter PJ, Bennett JE, Kwon-Chung KJ, 2021. Moderate levels of 5-fluorocytosine cause the emergence of high frequency resistance in cryptococci. Nat Commun 12: 3418.
-
26.
Clinical and Laboratory Standards Institute, 2023. Epidemiological Cutoff Values for Antifungal Susceptibility Testing, CLSI Suppl M59 Document. 2nd ed. Wayne, PA: Clinical and Laboratory Standards Institute.
-
27.
Clinical and Laboratory Standards Institute, 2023. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, 4th Suppl., M27-S4. Wayne, PA: Clinical and Laboratory Standards Institute.
-
28.
Fan X, et al., 2016. Predominance of Cryptococcus neoformans var. grubii multilocus sequence type 5 and emergence of isolates with non-wild-type minimum inhibitory concentrationsto fluconazole: A multi-Centre study in China. Clin Microbiol Infect 22: 887.e1–887.e9.
-
29.
Fang LF, Zhang PP, Wang J, Yang Q, Qu TT, 2020. Clinical and microbiological characteristics of cryptococcosis at an university hospital in China from 2013 to 2017. Braz J Infect Dis 24: 7–12.
-
30.
Zhang J, et al., 2022. Antifungal susceptibility and molecular characteristics of Cryptococcus spp. based on whole-genome sequencing in Zhejiang Province, China. Front Microbiol 13: 991703.
-
31.
Osawa R, Singh N, 2010. Colitis as a manifestation of infliximab-associated disseminated cryptococcosis. Int J Infect Dis 14: e436–e440.
-
32.
Nawabi DH, Ffolkes L, Bichere AO, 2005. Cryptococcal small-bowel obstruction in an HIV-positive patient. J R Soc Med 98: 513–514.
-
33.
Musubire AK, Meya DB, Lukande R, Kambugu A, Bohjanen PR, Boulware DR, 2015. Gastrointestinal cryptococcoma-immune reconstitution inflammatory syndrome or cryptococcal relapse in a patient with AIDS? Med Mycol Case Rep 8: 40–43.
-
34.
Araujo BS, Bay M, Reichert R, Goldani LZ, 2012. Intra-abdominal cryptococcosis by Cryptococcus gattii: Case report and review. Mycopathologia 174: 81–85.
-
35.
Tzimas D, Wan D, 2011. Small bowel perforation in a patient with AIDS. Diagnosis: Small bowel infection with Cryptococcus neoformans. Gastroenterology 140: 1882, 2150.
-
36.
Tian Y, Wang J, Shen Y, Zhao J, Hu J, Zhu X, Zhu M, Guan M, 2023. Characteristics and prognostic risk factors of patients with sequence type 5 lineage-associated cryptococcosis in China. Int J Infect Dis 128: 244–253.
-
37.
Liu ZY, et al., 2018. Expert consensus on the diagnosis and treatment of cryptococcal meningitis. Zhonghua Nei Ke Za Zhi 57: 317–323.
-
38.
Chen Y-C, Kuo S-F, Lin Y-S, Lin Y-S, Lee C-H, 2022. Epidemiological and clinical characteristics, antifungal susceptibility, and MLST-based genetic analysis of Cryptococcus isolates in southern Taiwan in 2013–2020. J Fungi (Basel) 8: 287.
-
39.
Wu T-S, Lin J-F, Cheng C-W, Huang P-Y, Yang JH, 2023. Lack of association between YEASTONE antifungal susceptibility tests and clinical outcomes of Cryptococcus meningitis. J Fungi (Basel) 9: 232.
| Past two years | Past Year | Past 30 Days | |
|---|---|---|---|
| Abstract Views | 4001 | 4001 | 94 |
| Full Text Views | 87 | 87 | 12 |
| PDF Downloads | 106 | 106 | 14 |