Understanding the environmental drivers of clinical azole resistance in Aspergillus species


  • Pooja Sen Antimycotic and Drug Susceptibility Laboratory, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, Uttar Pradesh - India https://orcid.org/0000-0002-0819-1599
  • Mukund Vijay Antimycotic and Drug Susceptibility Laboratory, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, Uttar Pradesh - India https://orcid.org/0000-0002-7359-7093
  • Shweta Singh Amity Institute of Biotechnology, Amity University Haryana, Gurugram (Manesar) - India https://orcid.org/0000-0001-9403-4890
  • Saif Hameed Amity Institute of Biotechnology, Amity University Haryana, Gurugram (Manesar) - India https://orcid.org/0000-0002-6477-1870
  • Pooja Vijayaraghvan Antimycotic and Drug Susceptibility Laboratory, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, Uttar Pradesh - India




Aspergillus, Azole resistance, Biofilm, cyp51A gene, Environmental origin, Triazoles


 Aspergilli are ubiquitous fungal pathogens associated with severe life-threatening infections, especially in immunocompromised patients. Azoles are the first line of defence in the fight against most Aspergillus -related infections. However, resistance to these therapeutic compounds has developed, which is mainly due to the existence of mutations in lanosterol 14 alpha-demethylase (Cyp51A), a crucial enzyme in the pathway that produces ergosterol and is the target of azole antifungals. Azole-based antifungal medications are ineffective because of infections brought on by azole-resistant Aspergillus  species, leading to a high fatality rate. However, resistant Aspergillus  isolates have also been isolated from azole-naïve patients. Global agricultural practices promote the use of azole fungicides to protect crops from phytopathogens. Usage of azole fungicides on a large scale has been linked to the development of resistance among Aspergillus  species prevalent in the environment. The infections caused by these azoleresistant Aspergillus  species cannot be treated by the available azole drugs, in turn leading to high morbidity and mortality rates. Thus, knowledge of the environmental drivers and comprehending the genetic basis of fungal drug resistance evolution is pertinent, considering increasing numbers of patients with COVID-19 infections who are sensitive to opportunistic fungal infections. This article emphasises the prevalence and underlying mechanisms of azole resistance in Aspergillus  species, with a focus on environmental triggers and resistance development. It also highlights the need for regular surveillance of pesticide use in agriculture, detection of triazole-resistant Aspergillus  species in environmental and clinical settings and development of new antifungal drugs.


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Author Biographies

Pooja Sen, Antimycotic and Drug Susceptibility Laboratory, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, Uttar Pradesh - India

Research Scholar

Antimycotic and Drug Susceptibility Laboratory, Lab 120, J3 block, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Sector-125, NOIDA, Uttar Pradesh, India

Mukund Vijay, Antimycotic and Drug Susceptibility Laboratory, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, Uttar Pradesh - India

Research Scholar

Antimycotic and Drug Susceptibility Laboratory, Lab 120, J3 block, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Sector-125, NOIDA, Uttar Pradesh, India

Shweta Singh, Amity Institute of Biotechnology, Amity University Haryana, Gurugram (Manesar) - India

Postdoctoral fellow

Amity Institute of Biotechnology, Amity University Haryana, Gurugram (Manesar)-122413, India

Pooja Vijayaraghvan, Antimycotic and Drug Susceptibility Laboratory, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, Uttar Pradesh - India


Antimycotic and Drug Susceptibility Laboratory, Lab 120, J3 block, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Sector-125, NOIDA, Uttar Pradesh, India


Patterson TF, Kirkpatrick WR, White M, et al. Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes. I3 Aspergillus Study Group. Medicine (Baltimore). 2000;79(4):250-260. https://doi.org/10.1097/00005792-200007000-00006 PMID:10941354 DOI: https://doi.org/10.1097/00005792-200007000-00006

Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis. 2001;32(3):358-366. https://doi.org/10.1086/318483 PMID:11170942 DOI: https://doi.org/10.1086/318483

Verweij PE, Chowdhary A, Melchers WJ, Meis JF. Azole resistance in A. fumigatus: can we retain the clinical use of mold-active antifungal azoles? Clin Infect Dis. 2016;62(3):362-368. https://doi.org/10.1093/cid/civ885 PMID:26486705 DOI: https://doi.org/10.1093/cid/civ885

Hagiwara D, Watanabe A, Kamei K, Goldman GH. Epidemiological and genomic landscape of azole resistance mechanisms in Aspergillus fungi. Front Microbiol. 2016;7:1382. https://doi.org/10.3389/fmicb.2016.01382 PMID:27708619 DOI: https://doi.org/10.3389/fmicb.2016.01382

Dabas Y, Xess I, Bakshi S, Mahapatra M, Seth R. Emergence of azole-resistant Aspergillus fumigatus from immunocompromised hosts in India. Antimicrob Agents Chemother. 2018;62(8):e02264-e17. https://doi.org/10.1128/AAC.02264-17 PMID:29891597 DOI: https://doi.org/10.1128/AAC.02264-17

Denning DW, Cadranel J, Beigelman-Aubry C, et al; European Society for Clinical Microbiology and Infectious Diseases and European Respiratory Society. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Eur Respir J. 2016;47(1):45-68. https://doi.org/10.1183/13993003.00583-2015 PMID:26699723 DOI: https://doi.org/10.1183/13993003.00583-2015

Denning DW, Pleuvry A, Cole DC. Global burden of allergic bronchopulmonary aspergillosis with asthma and its complication chronic pulmonary aspergillosis in adults. Med Mycol. 2013;51(4):361-370. https://doi.org/10.3109/13693786.2012.738312 PMID:23210682 DOI: https://doi.org/10.3109/13693786.2012.738312

Armstead J, Morris J, Denning DW. Multi-country estimate of different manifestations of aspergillosis in cystic fibrosis. PLoS One. 2014;9(6):e98502. https://doi.org/10.1371/journal.pone.0098502 PMID:24914809 DOI: https://doi.org/10.1371/journal.pone.0098502

Denning DW. The ambitious ‘95-95 by 2025’ roadmap for the diagnosis and management of fungal diseases. Thorax. 2015;70(7):613-614. https://doi.org/10.1136/thoraxjnl-2015-207305PMID:26024686 DOI: https://doi.org/10.1136/thoraxjnl-2015-207305

Kosmidis C, Denning DW. The clinical spectrum of pulmonary aspergillosis. Thorax. 2015;70(3):270-277. https://doi.org/10.1136/thoraxjnl-2014-206291 PMID:25354514 DOI: https://doi.org/10.1136/thoraxjnl-2014-206291

McCarthy MW, Walsh TJ. Special considerations for the diagnosis and treatment of invasive pulmonary aspergillosis. Expert Rev Respir Med. 2017;11(9):739-748. https://doi.org/10.1080/17476348.2017.1340835 PMID:28595486 DOI: https://doi.org/10.1080/17476348.2017.1340835

Komase Y, Kunishima H, Yamaguchi H, Ikehara M, Yamamoto T, Shinagawa T. Rapidly progressive invasive pulmonary aspergillosis in a diabetic man. J Infect Chemother. 2007;13(1):46-50. https://doi.org/10.1007/s10156-006-0481-8 PMID:17334729 DOI: https://doi.org/10.1007/s10156-006-0481-8

Yan X, Li M, Jiang M, Zou LQ, Luo F, Jiang Y. Clinical characteristics of 45 patients with invasive pulmonary aspergillosis: retrospective analysis of 1711 lung cancer cases. Cancer. 2009;115(21):5018-5025. https://doi.org/10.1002/cncr.24559 PMID:19637340 DOI: https://doi.org/10.1002/cncr.24559

Prattes J, Hoenigl M, Krause R, et al. Invasive aspergillosis in patients with underlying liver cirrhosis: a prospective cohort study. Med Mycol. 2017;55(8):803-812. https://doi.org/10.1093/mmy/myx011 PMID:28431001 DOI: https://doi.org/10.1093/mmy/myx011

Agarwal R, Denning DW, Chakrabarti A. Estimation of the burden of chronic and allergic pulmonary aspergillosis in India. PLoS One. 2014;9(12):e114745. https://doi.org/10.1371/journal.pone.0114745 PMID:25478929 DOI: https://doi.org/10.1371/journal.pone.0114745

Jabeen K, Farooqi J, Mirza S, Denning D, Zafar A. Serious fungal infections in Pakistan. Eur J Clin Microbiol Infect Dis. 2017;36(6):949-956. https://doi.org/10.1007/s10096-017-2919-6PMID:28161741 DOI: https://doi.org/10.1007/s10096-017-2919-6

Gugnani HC, Denning DW, Rahim R, Sadat A, Belal M, Mahbub MS. Burden of serious fungal infections in Bangladesh. Eur J Clin Microbiol Infect Dis. 2017;36(6):993-997. https://doi.org/10.1007/s10096-017-2921-z PMID:28161744 DOI: https://doi.org/10.1007/s10096-017-2921-z

Khwakhali US, Denning DW. Burden of serious fungal infections in Nepal. Mycoses. 2015;58(suppl 5):45-50. https://doi.org/10.1111/myc.12393 PMID:26449506 DOI: https://doi.org/10.1111/myc.12393

Jayasekera PI, Denning DW, Perera PD, Fernando A. The burden of serious fungal infections in Sri Lanka. Mycoses. 2013;56:103

Stevens DA, Moss RB, Kurup VP, et al; Participants in the Cystic Fibrosis Foundation Consensus Conference. Allergic bronchopulmonary aspergillosis in cystic fibrosis – state of the art: Cystic Fibrosis Foundation Consensus Conference. Clin Infect Dis. 2003;37(s3)(suppl 3):S225-S264. https://doi.org/10.1086/376525 PMID:12975753 DOI: https://doi.org/10.1086/376525

Al-Mobeireek AF, Al-Hedaithy SS, Alasali K, Al-Majed S, Joharjy I, Joharjy I; El-Rab MOGAD. Allergic bronchopulmonary mycosis in patients with asthma: period prevalence at a university hospital in Saudi Arabia. Respir Med. 2001;95(5):341-347. https://doi.org/10.1053/rmed.2001.1047 PMID:11392574 DOI: https://doi.org/10.1053/rmed.2001.1047

Lass-Flörl C. Triazole antifungal agents in invasive fungal infections: a comparative review. Drugs. 2011;71(18):2405-2419. https://doi.org/10.2165/11596540-000000000-00000PMID:22141384 DOI: https://doi.org/10.2165/11596540-000000000-00000

Russell PE. A century of fungicide evolution. J Agric Sci. 2005;143(1):11-25. https://doi.org/10.1017/S0021859605004971 DOI: https://doi.org/10.1017/S0021859605004971

Gupta AK, Sauder DN, Shear NH. Antifungal agents: an overview. Part I. J Am Acad Dermatol. 1994;30(5 Pt 1):677-698. https://doi.org/10.1016/S0190-9622(08)81495-8PMID:8176006 DOI: https://doi.org/10.1016/S0190-9622(08)81495-8

Heeres J, Backx LJ, Mostmans JH, Van Cutsem J. Antimycotic imidazoles. Part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agent. J Med Chem. 1979;22(8):1003-1005. https://doi.org/10.1021/jm00194a023 PMID:490531 DOI: https://doi.org/10.1021/jm00194a023

Johnson LB, Kauffman CA. Voriconazole: a new triazole antifungal agent. Clin Infect Dis. 2003;36(5):630-637. https://doi.org/10.1086/367933 PMID:12594645 DOI: https://doi.org/10.1086/367933

Maertens JA. History of the development of azole derivatives. Clin Microbiol Infect. 2004;10(s1)(suppl 1):1-10. https://doi.org/10.1111/j.1470-9465.2004.00841.x PMID:14748798 DOI: https://doi.org/10.1111/j.1470-9465.2004.00841.x

Scott LJ, Simpson D. Voriconazole: a review of its use in the management of invasive fungal infections. Drugs. 2007;67(2):269-298. https://doi.org/10.2165/00003495-200767020-00009PMID:17284090 DOI: https://doi.org/10.2165/00003495-200767020-00009

Gothard P, Rogers TR. Voriconazole for serious fungal infections. Int J Clin Pract. 2004;58(1):74-80. https://doi.org/10.1111/j.1368-5031.2004.0099.x PMID:14994974 DOI: https://doi.org/10.1111/j.1368-5031.2004.0099.x

Pasqualotto AC, Thiele KO, Goldani LZ. Novel triazole antifungal drugs: focus on isavuconazole, ravuconazole and albaconazole. Curr Opin Investig Drugs. 2010;11(2):165-174. PMID:20112166

Allen D, Wilson D, Drew R, Perfect J. Azole antifungals: 35 years of invasive fungal infection management. Expert Rev Anti Infect Ther. 2015;13(6):787-798. https://doi.org/10.1586/14787210.2015.1032939 PMID:25843556 DOI: https://doi.org/10.1586/14787210.2015.1032939

Snelders E, Karawajczyk A, Schaftenaar G, Verweij PE, Melchers WJ. Azole resistance profile of amino acid changes in Aspergillus fumigatus CYP51A based on protein homology modeling. Antimicrob Agents Chemother. 2010;54(6):2425-2430. https://doi.org/10.1128/AAC.01599-09 PMID:20385860 DOI: https://doi.org/10.1128/AAC.01599-09

Georgopapadakou NH, Walsh TJ. Antifungal agents: chemotherapeutic targets and immunologic strategies. Antimicrob Agents Chemother. 1996;40(2):279-291. https://doi.org/10.1128/AAC.40.2.279 PMID:8834867 DOI: https://doi.org/10.1128/AAC.40.2.279

White TC, Marr KA, Bowden RA. Clinical, cellular, and molecular factors that contribute to antifungal drug resistance. Clin Microbiol Rev. 1998;11(2):382-402. https://doi.org/10.1128/CMR.11.2.382 PMID:9564569 DOI: https://doi.org/10.1128/CMR.11.2.382

Koltin Y, Hitchcock CA. The search for new triazole antifungal agents. Curr Opin Chem Biol. 1997;1(2):176-182. https://doi.org/10.1016/S1367-5931(97)80007-5 PMID:9667858 DOI: https://doi.org/10.1016/S1367-5931(97)80007-5

Maschmeyer G, Haas A, Cornely OA. Invasive aspergillosis: epidemiology, diagnosis and management in immunocompromised patients. Drugs. 2007;67(11):1567-1601. https://doi.org/10.2165/00003495-200767110-00004 PMID:17661528 DOI: https://doi.org/10.2165/00003495-200767110-00004

Walsh TJ, Anaissie EJ, Denning DW, et al; Infectious Diseases Society of America. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(3):327-360. https://doi.org/10.1086/525258 PMID:18177225 DOI: https://doi.org/10.1086/525258

Howard SJ, Pasqualotto AC, Denning DW. Azole resistance in allergic bronchopulmonary aspergillosis and Aspergillus bronchitis. Clin Microbiol Infect. 2010;16(6):683-688. https://doi.org/10.1111/j.1469-0691.2009.02911.x PMID:19673966 DOI: https://doi.org/10.1111/j.1469-0691.2009.02911.x

Mukherjee PK, Sheehan D, Puzniak L, Schlamm H, Ghannoum MA. Echinocandins: are they all the same? J Chemother. 2011;23(6):319-325. https://doi.org/10.1179/joc.2011.23.6.319PMID:22233814 DOI: https://doi.org/10.1179/joc.2011.23.6.319

Azevedo MM, Faria-Ramos I, Cruz LC, Pina-Vaz C, Rodrigues AG. Genesis of azole antifungal resistance from agriculture to clinical settings. J Agric Food Chem. 2015;63(34):7463-7468. https://doi.org/10.1021/acs.jafc.5b02728 PMID:26289797 DOI: https://doi.org/10.1021/acs.jafc.5b02728

Morton V, Staub T. A Short History of Fungicides. APSnet Features. doi: 10.1094/APSnet Feature-2008-0308. Online https://www.apsnet.org/edcenter/apsnetfeatures/Pages/Fungicides.aspx DOI: https://doi.org/10.1094/APSnetFeature-2008-0308

Price CL, Parker JE, Warrilow AG, Kelly DE, Kelly SL. Azole fungicides – understanding resistance mechanisms in agricultural fungal pathogens. Pest Manag Sci. 2015;71(8):1054-1058. https://doi.org/10.1002/ps.4029 PMID:25914201 DOI: https://doi.org/10.1002/ps.4029

Singh N, Dureja P. Persistence of hexaconazole, a triazole fungicide in soils. J Environ Sci Health B. 2000;35(5):549-558. https://doi.org/10.1080/03601230009373291 PMID:10968606 DOI: https://doi.org/10.1080/03601230009373291

FRAC Code List. Fungal control agents sorted by cross resistance pattern and mode of action. Fungicide Resistance Action Committee; 2019.

Messer SA, Jones RN, Fritsche TR. International surveillance of Candida spp. and Aspergillus spp.: report from the SENTRY Antimicrobial Surveillance Program (2003). J Clin Microbiol. 2006;44(5):1782-1787. https://doi.org/10.1128/JCM.44.5.1782-1787.2006 PMID:16672407 DOI: https://doi.org/10.1128/JCM.44.5.1782-1787.2006

Gomez-Lopez A, Garcia-Effron G, Mellado E, Monzon A, Rodriguez-Tudela JL, Cuenca-Estrella M. In vitro activities of three licensed antifungal agents against Spanish clinical isolates of Aspergillus spp. Antimicrob Agents Chemother. 2003;47(10):3085-3088. https://doi.org/10.1128/AAC.47.10.3085-3088.2003 PMID:14506013 DOI: https://doi.org/10.1128/AAC.47.10.3085-3088.2003

Lelièvre L, Groh M, Angebault C, Maherault AC, Didier E, Bougnoux ME. Azole resistant Aspergillus fumigatus: an emerging problem. Med Mal Infect. 2013;43(4):139-145. https://doi.org/10.1016/j.medmal.2013.02.010 PMID:23562488 DOI: https://doi.org/10.1016/j.medmal.2013.02.010

Mellado E, Garcia-Effron G, Alcázar-Fuoli L, Cuenca-Estrella M, Rodriguez-Tudela JL. Substitutions at methionine 220 in the 14α-sterol demethylase (Cyp51A) of Aspergillus fumigatus are responsible for resistance in vitro to azole antifungal drugs. Antimicrob Agents Chemother. 2004;48(7):2747-2750. https://doi.org/10.1128/AAC.48.7.2747-2750.2004 PMID:15215142 DOI: https://doi.org/10.1128/AAC.48.7.2747-2750.2004

Mellado E, Garcia-Effron G, Alcázar-Fuoli L, et al. A new Aspergillus fumigatus resistance mechanism conferring in vitro cross-resistance to azole antifungals involves a combination of cyp51A alterations. Antimicrob Agents Chemother. 2007;51(6):1897-1904. https://doi.org/10.1128/AAC.01092-06 PMID:17371828 DOI: https://doi.org/10.1128/AAC.01092-06

Alanio A, Sitterlé E, Liance M, et al. Low prevalence of resistance to azoles in Aspergillus fumigatus in a French cohort of patients treated for haematological malignancies. J Antimicrob Chemother. 2011;66(2):371-374. https://doi.org/10.1093/jac/dkq450 PMID:21131690 DOI: https://doi.org/10.1093/jac/dkq450

Mortensen KL, Jensen RH, Johansen HK, et al. Aspergillus species and other molds in respiratory samples from patients with cystic fibrosis: a laboratory-based study with focus on Aspergillus fumigatus azole resistance. J Clin Microbiol. 2011;49(6):2243-2251. https://doi.org/10.1128/JCM.00213-11 PMID:21508152 DOI: https://doi.org/10.1128/JCM.00213-11

Escribano P, Recio S, Peláez T, Bouza E, Guinea J. Aspergillus fumigatus strains with mutations in the cyp51A gene do not always show phenotypic resistance to itraconazole, voriconazole, or posaconazole. Antimicrob Agents Chemother. 2011;55(5):2460-2462. https://doi.org/10.1128/AAC.01358-10 PMID:21321141 DOI: https://doi.org/10.1128/AAC.01358-10

Jeurissen A, Cooreman S, Van Kerckhoven W, et al. Invasive pulmonary aspergillosis due to a multi-azole resistant Aspergillus fumigatus. Acta Clin Belg. 2012;67(1):46-48. PMID:22480040

Alastruey-Izquierdo A, Mellado E, Peláez T, et al; FILPOP Study Group. Population-based survey of filamentous fungi and antifungal resistance in Spain (FILPOP Study). Antimicrob Agents Chemother. 2013;57(7):3380-3387. https://doi.org/10.1128/AAC.00383-13PMID:23669377 DOI: https://doi.org/10.1128/AAC.00383-13

Steinmann J, Hamprecht A, Vehreschild MJ, et al. Emergence of azole-resistant invasive aspergillosis in HSCT recipients in Germany. J Antimicrob Chemother. 2015;70(5):1522-1526. https://doi.org/10.1093/jac/dku566 PMID:25630644 DOI: https://doi.org/10.1093/jac/dku566

van der Linden JW, Arendrup MC, Warris A, et al. Prospective multicenter international surveillance of azole resistance in Aspergillus fumigatus. Emerg Infect Dis. 2015;21(6):1041-1044. https://doi.org/10.3201/eid2106.140717 PMID:25988348 DOI: https://doi.org/10.3201/eid2106.140717

Lavergne RA, Morio F, Favennec L, et al. First description of azole-resistant Aspergillus fumigatus due to TR46/Y121F/T289A mutation in France. Antimicrob Agents Chemother. 2015;59(7):4331-4335. https://doi.org/10.1128/AAC.00127-15 PMID:25918139 DOI: https://doi.org/10.1128/AAC.00127-15

Brillowska-Dąbrowska A, Mroczyńska M, Nawrot U, Włodarczyk K, Kurzyk E. Examination of cyp51A and cyp51B expression level of the first Polish azole resistant clinical Aspergillus fumigatus isolate. Acta Biochim Pol. 2015;62(4):837-839. https://doi.org/10.18388/abp.2015_1143 PMID:26636140 DOI: https://doi.org/10.18388/abp.2015_1143

Lazzarini C, Esposto MC, Prigitano A, Cogliati M, De Lorenzis G, Tortorano AM. Azole resistance in A. fumigatus clinical isolates from an Italian culture collection. Antimicrob Agents Chemother. 2015;60(1):682-685. https://doi.org/10.1128/AAC.02234-15 PMID:26552980 DOI: https://doi.org/10.1128/AAC.02234-15

Pelaez T, Monteiro MC, Garcia-Rubio R, Bouza E, Gomez-Lopez A, Mellado E. First detection of Aspergillus fumigatus azole-resistant strain due to Cyp51A TR46/Y121F/T289A in an azole-naive patient in Spain. New Microbes New Infect. 2015;6:33-34. https://doi.org/10.1016/j.nmni.2015.04.005 PMID:26082842 DOI: https://doi.org/10.1016/j.nmni.2015.04.005

Özmerdiven GE, Ak S, Ener B, et al. First determination of azole resistance in Aspergillus fumigatus strains carrying the TR34/L98H mutations in Turkey. J Infect Chemother. 2015;21(8):581-586. https://doi.org/10.1016/j.jiac.2015.04.012 PMID:26048062 DOI: https://doi.org/10.1016/j.jiac.2015.04.012

Jensen RH, Hagen F, Astvad KM, Tyron A, Meis JF, Arendrup MC. Azole-resistant Aspergillus fumigatus in Denmark: a laboratory-based study on resistance mechanisms and genotypes. Clin Microbiol Infect. 2016 Jun;22(6):570.e1-e9. https://doi.org/10.1016/j.cmi.2016.04.001 PMID:27091095 DOI: https://doi.org/10.1016/j.cmi.2016.04.001

Lavergne RA, Chouaki T, Hagen F, et al. Home environment as a source of life-threatening azole-resistant A. fumigatus in immunocompromised patients. Clin Infect Dis. 2017;64(1):76-78. https://doi.org/10.1093/cid/ciw664 PMID:27682064 DOI: https://doi.org/10.1093/cid/ciw664

Prigitano A, Esposto MC, Biffi A, et al. Triazole resistance in Aspergillus fumigatus isolates from patients with cystic fibrosis in Italy. J Cyst Fibros. 2017;16(1):64-69. https://doi.org/10.1016/j.jcf.2016.06.006 PMID:27356848 DOI: https://doi.org/10.1016/j.jcf.2016.06.006

Abdolrasouli A, Petrou MA, Park H, et al. Surveillance for azole-resistant Aspergillus fumigatus in a centralized diagnostic mycology service, London, United Kingdom, 1998-2017. Front Microbiol. 2018;9:2234. https://doi.org/10.3389/fmicb.2018.02234 PMID:30294314 DOI: https://doi.org/10.3389/fmicb.2018.02234

Wu CJ, Liu WL, Lai CC, et al. Multicenter study of azole-resistant Aspergillus fumigatus clinical isolates, Taiwan. Emerg Infect Dis. 2020;26(4):804-806. https://doi.org/10.3201/eid2604.190840 PMID:32186508 DOI: https://doi.org/10.3201/eid2604.190840

Chen J, Li H, Li R, Bu D, Wan Z. Mutations in the cyp51A gene and susceptibility to itraconazole in Aspergillus fumigatus serially isolated from a patient with lung aspergilloma. J Antimicrob Chemother. 2005;55(1):31-37. https://doi.org/10.1093/jac/dkh507 PMID:15563516 DOI: https://doi.org/10.1093/jac/dkh507

Hsueh PR, Lau YJ, Chuang YC, et al. Antifungal susceptibilities of clinical isolates of Candida species, Cryptococcus neoformans, and Aspergillus species from Taiwan: surveillance of multicenter antimicrobial resistance in Taiwan program data from 2003. Antimicrob Agents Chemother. 2005;49(2):512-517. https://doi.org/10.1128/AAC.49.2.512-517.2005PMID:15673726 DOI: https://doi.org/10.1128/AAC.49.2.512-517.2005

Bueid A, Howard SJ, Moore CB, et al. Azole antifungal resistance in Aspergillus fumigatus: 2008 and 2009. J Antimicrob Chemother. 2010;65(10):2116-2118. https://doi.org/10.1093/jac/dkq279 PMID:20729241 DOI: https://doi.org/10.1093/jac/dkq279

Howard SJ, Cerar D, Anderson MJ, et al. Frequency and evolution of azole resistance in Aspergillus fumigatus associated with treatment failure. Emerg Infect Dis. 2009;15(7):1068-1076. https://doi.org/10.3201/eid1507.090043 PMID:19624922 DOI: https://doi.org/10.3201/eid1507.090043

Meis JF, Chowdhary A, Rhodes JL, Fisher MC, Verweij PE. Clinical implications of globally emerging azole resistance in Aspergillus fumigatus. Philos Trans R Soc Lond B Biol Sci. 2016;371(1709):20150460. https://doi.org/10.1098/rstb.2015.0460 PMID:28080986 DOI: https://doi.org/10.1098/rstb.2015.0460

Bunskoek PE, Seyedmousavi S, Gans SJ, et al. Successful treatment of azole-resistant invasive aspergillosis in a bottlenose dolphin with high-dose posaconazole. Med Mycol Case Rep. 2017;16:16-19. https://doi.org/10.1016/j.mmcr.2017.03.005 PMID:28409094 DOI: https://doi.org/10.1016/j.mmcr.2017.03.005

Hof H. Critical annotations to the use of azole antifungals for plant protection. Antimicrob Agents Chemother. 2001;45(11):2987-2990. https://doi.org/10.1128/AAC.45.11.2987-2990.2001PMID:11600346 DOI: https://doi.org/10.1128/AAC.45.11.2987-2990.2001

Snelders E, Camps SM, Karawajczyk A, et al. Triazole fungicides can induce cross-resistance to medical triazoles in Aspergillus fumigatus. PLoS One. 2012;7(3):e31801. https://doi.org/10.1371/journal.pone.0031801 PMID:22396740 DOI: https://doi.org/10.1371/journal.pone.0031801

Chowdhary A, Kathuria S, Xu J, et al. Clonal expansion and emergence of environmental multiple-triazole-resistant Aspergillus fumigatus strains carrying the TR₃₄/L98H mutations in the cyp51A gene in India. PLoS One. 2012;7(12):e52871. https://doi.org/10.1371/journal.pone.0052871 PMID:23285210 DOI: https://doi.org/10.1371/journal.pone.0052871

Mortensen KL, Mellado E, Lass-Flörl C, Rodriguez-Tudela JL, Johansen HK, Arendrup MC. Environmental study of azole-resistant Aspergillus fumigatus and other aspergilli in Austria, Denmark, and Spain. Antimicrob Agents Chemother. 2010;54(11):4545-4549. https://doi.org/10.1128/AAC.00692-10 PMID:20805399 DOI: https://doi.org/10.1128/AAC.00692-10

Chowdhary A, Kathuria S, Xu J, Meis JF. Emergence of azole-resistant Aspergillus fumigatus strains due to agricultural azole use creates an increasing threat to human health. PLoS Pathog. 2013;9(10):e1003633. https://doi.org/10.1371/journal.ppat.1003633 PMID:24204249 DOI: https://doi.org/10.1371/journal.ppat.1003633

Verweij PE, Mellado E, Melchers WJ. Multiple-triazole-resistant aspergillosis. N Engl J Med. 2007;356(14):1481-1483. https://doi.org/10.1056/NEJMc061720 PMID:17409336 DOI: https://doi.org/10.1056/NEJMc061720

Van der Linden JW, Camps SM, Kampinga GA, et al. Aspergillosis due to voriconazole highly resistant A. fumigatus and recovery of genetically related resistant isolates from domestic homes. Clin Infect Dis. 2013;57(4):513-520. https://doi.org/10.1093/cid/cit320 PMID:23667263 DOI: https://doi.org/10.1093/cid/cit320

Thind TS. Changing cover of fungicide umbrella in crop protection. Indian Phytopathol. 2007;60:421-433.

Snelders E, Huis in t Veld RA, Rijs AJ, Kema GH, Melchers WJ, Verweij PE. Possible environmental origin of resistance of A. fumigatus to medical triazoles. Appl Environ Microbiol. 2009;75(12):4053-4057. https://doi.org/10.1128/AEM.00231-09 PMID:19376899 DOI: https://doi.org/10.1128/AEM.00231-09

Zhang J, Snelders E, Zwaan BJ, et al. A novel environmental azole resistance mutation in A. fumigatus and a possible role of sexual reproduction in its emergence. MBio. 2017;8(3):e00791-e17. https://doi.org/10.1128/mBio.00791-17 PMID:28655821 DOI: https://doi.org/10.1128/mBio.00791-17

Badali H, Vaezi A, Haghani I, et al. Environmental study of azole-resistant Aspergillus fumigatus with TR34/L98H mutations in the cyp51A gene in Iran. Mycoses. 2013;56(6):659-663. https://doi.org/10.1111/myc.12089 PMID:23668594 DOI: https://doi.org/10.1111/myc.12089

Ahmad S, Khan Z, Hagen F, Meis JF. Occurrence of triazole-resistant Aspergillus fumigatus with TR34/L98H mutations in outdoor and hospital environment in Kuwait. Environ Res. 2014;133:20-26. https://doi.org/10.1016/j.envres.2014.05.009 PMID:24906064 DOI: https://doi.org/10.1016/j.envres.2014.05.009

Chowdhary A, Sharma C, Hagen F, Meis JF. Exploring azole antifungal drug resistance in Aspergillus fumigatus with special reference to resistance mechanisms. Future Microbiol. 2014;9(5):697-711. https://doi.org/10.2217/fmb.14.27 PMID:24957095 DOI: https://doi.org/10.2217/fmb.14.27

van der Linden JW, Snelders E, Kampinga GA, et al. Clinical implications of azole resistance in Aspergillus fumigatus, The Netherlands, 2007-2009. Emerg Infect Dis. 2011;17(10):1846-1854. https://doi.org/10.3201/eid1710.110226 PMID:22000354 DOI: https://doi.org/10.3201/eid1710.110226

Dauchy C, Bautin N, Nseir S, et al. Emergence of Aspergillus fumigatus azole resistance in azole-naïve patients with chronic obstructive pulmonary disease and their homes. Indoor Air. 2018;28(2):298-306. https://doi.org/10.1111/ina.12436 PMID:29082624 DOI: https://doi.org/10.1111/ina.12436

Lescar J, Meyer I, Akshita K, et al. Aspergillus fumigatus harbouring the sole Y121F mutation shows decreased susceptibility to voriconazole but maintained susceptibility to itraconazole and posaconazole. J Antimicrob Chemother. 2014;69(12):3244-3247. https://doi.org/10.1093/jac/dku316 PMID:25125676 DOI: https://doi.org/10.1093/jac/dku316

Sharma C, Hagen F, Moroti R, Meis JF, Chowdhary A. Triazole-resistant Aspergillus fumigatus harbouring G54 mutation: is it de novo or environmentally acquired? J Glob Antimicrob Resist. 2015;3(2):69-74. https://doi.org/10.1016/j.jgar.2015.01.005 PMID:27873672 DOI: https://doi.org/10.1016/j.jgar.2015.01.005

Wang HC, Huang JC, Lin YH, Chen YH. Prevalence, mechanisms, and genetic relatedness of the human pathogenic fungus A. fumigatus sex inhibiting resistance to medical azoles in the environment of Taiwan. Appl Environ Microbiol. 2008;20:270-280. DOI: https://doi.org/10.1111/1462-2920.13988

Jeanvoine A, Rocchi S, Reboux G, Crini N, Crini G, Millon L. Azole-resistant Aspergillus fumigatus in sawmills of Eastern France. J Appl Microbiol. 2017;123(1):172-184. https://doi.org/10.1111/jam.13488 PMID:28497646 DOI: https://doi.org/10.1111/jam.13488

Alvarez-Moreno C, Lavergne RA, Hagen F, Morio F, Meis JF, Le Pape P. Azole-resistant Aspergillus fumigatus harboring TR34/L98H, TR46/Y121F/T289A and TR53 mutations related to flower fields in Colombia. Sci Rep. 2017;7(1):45631. https://doi.org/10.1038/srep45631PMID:28358115 DOI: https://doi.org/10.1038/srep45631

Chowdhary A, Sharma C, Kathuria S, Hagen F, Meis JF. Prevalence and mechanism of triazole resistance in Aspergillus fumigatus in a referral chest hospital in Delhi, India and an update of the situation in Asia. Front Microbiol. 2015;6:428. https://doi.org/10.3389/fmicb.2015.00428 PMID:26005442 DOI: https://doi.org/10.3389/fmicb.2015.00428

Hoda S, Agarwal H, Ahluwalia SK, Vermani M, Vijayaraghavan P. Antifungal resistance analysis of environmental isolates of Aspergillus in North India. J Pure Appl Microbiol. 2019;13(1):385-392. https://doi.org/10.22207/JPAM.13.1.42 DOI: https://doi.org/10.22207/JPAM.13.1.42

Mann PA, Parmegiani RM, Wei SQ, et al. Mutations in Aspergillus fumigatus resulting in reduced susceptibility to posaconazole appear to be restricted to a single amino acid in the cytochrome P450 14α-demethylase. Antimicrob Agents Chemother. 2003;47(2):577-581. https://doi.org/10.1128/AAC.47.2.577-581.2003 PMID:12543662 DOI: https://doi.org/10.1128/AAC.47.2.577-581.2003

Tashiro M, Izumikawa K, Hirano K, et al. Correlation between triazole treatment history and susceptibility in clinically isolated Aspergillus fumigatus. Antimicrob Agents Chemother. 2012;56(9):4870-4875. https://doi.org/10.1128/AAC.00514-12 PMID:22751542 DOI: https://doi.org/10.1128/AAC.00514-12

Chowdhary A, Sharma C, van den Boom M, et al. Multi-azole-resistant Aspergillus fumigatus in the environment in Tanzania. J Antimicrob Chemother. 2014;69(11):2979-2983. https://doi.org/10.1093/jac/dku259 PMID:25006238 DOI: https://doi.org/10.1093/jac/dku259

Rajendran R, Mowat E, McCulloch E, et al. Azole resistance of Aspergillus fumigatus biofilms is partly associated with efflux pump activity. Antimicrob Agents Chemother. 2011;55(5):2092-2097. https://doi.org/10.1128/AAC.01189-10 PMID:21321135 DOI: https://doi.org/10.1128/AAC.01189-10

Tekaia F, Latgé JP. Aspergillus fumigatus: saprophyte or pathogen? Curr Opin Microbiol. 2005;8(4):385-392. https://doi.org/10.1016/j.mib.2005.06.017 PMID:16019255 DOI: https://doi.org/10.1016/j.mib.2005.06.017

Wesenberg D, Kyriakides I, Agathos SN. White-rot fungi and their enzymes for the treatment of industrial dye effluents. Biotechnol Adv. 2003;22(1-2):161-187. https://doi.org/10.1016/j.biotechadv.2003.08.011 PMID:14623049 DOI: https://doi.org/10.1016/j.biotechadv.2003.08.011

Dagenais TR, Keller NP. Pathogenesis of Aspergillus fumigatus in invasive aspergillosis. Clin Microbiol Rev. 2009;22(3):447-465. https://doi.org/10.1128/CMR.00055-08 PMID:19597008 DOI: https://doi.org/10.1128/CMR.00055-08

Godeau C, Reboux G, Scherer E, et al. Azole-resistant Aspergillus fumigatus in the hospital: surveillance from flower beds to corridors. Am J Infect Control. 2020;48(6):702-704. https://doi.org/10.1016/j.ajic.2019.10.003 PMID:31753549 DOI: https://doi.org/10.1016/j.ajic.2019.10.003

Gonzalez-Jimenez I, Lucio J, Menéndez-Fraga MD, Mellado E, Peláez T. Hospital environment as a source of azole-resistant Aspergillus fumigatus strains with TR34/L98H and G448S Cyp51A mutations. J Fungi (Basel). 2021;7(1):22. https://doi.org/10.3390/jof7010022PMID:33401764 DOI: https://doi.org/10.3390/jof7010022

Bowyer P, Moore CB, Rautemaa R, Denning DW, Richardson MD. Azole antifungal resistance today: focus on Aspergillus. Curr Infect Dis Rep. 2011;13(6):485-491. https://doi.org/10.1007/s11908-011-0218-4 PMID:21931980 DOI: https://doi.org/10.1007/s11908-011-0218-4

Mitchell KF, Zarnowski R, Andes DR. The extracellular matrix of fungal biofilms. Adv Exp Med Biol. 2016;931:21-35. https://doi.org/10.1007/5584_2016_6 PMID:27271680 DOI: https://doi.org/10.1007/5584_2016_6

Subroto E, van Neer J, Valdes I, de Cock H. Growth of Aspergillus fumigatus in biofilms in comparison to Candida albicans. J Fungi (Basel). 2022;8(1):48. https://doi.org/10.3390/jof8010048 PMID:35049988 DOI: https://doi.org/10.3390/jof8010048

Kaur S, Singh S. Biofilm formation by Aspergillus fumigatus. Med Mycol. 2014;52(1):2-9. PMID:23962172 DOI: https://doi.org/10.3109/13693786.2013.819592

Blankenship JR, Mitchell AP. How to build a biofilm: a fungal perspective. Curr Opin Microbiol. 2006;9(6):588-594. https://doi.org/10.1016/j.mib.2006.10.003 PMID:17055772 DOI: https://doi.org/10.1016/j.mib.2006.10.003

Mowat E, Butcher J, Lang S, Williams C, Ramage G. Development of a simple model for studying the effects of antifungal agents on multicellular communities of Aspergillus fumigatus. J Med Microbiol. 2007;56(Pt 9):1205-1212. https://doi.org/10.1099/jmm.0.47247-0PMID:17761484 DOI: https://doi.org/10.1099/jmm.0.47247-0

Liu M, Zheng H, Zeng R, Liang G, Zheng N, Liu W. Effects of itraconazole and micafungin on Aspergillus fumigatus biofilms. Mycopathologia. 2021;186(3):387-397. https://doi.org/10.1007/s11046-021-00534-4 PMID:33956291 DOI: https://doi.org/10.1007/s11046-021-00534-4

Morelli KA, Kerkaert JD, Cramer RA. Aspergillus fumigatus biofilms: toward understanding how growth as a multicellular network increases antifungal resistance and disease progression. PLoS Pathog. 2021;17(8):e1009794. https://doi.org/10.1371/journal.ppat.1009794PMID:34437655 DOI: https://doi.org/10.1371/journal.ppat.1009794



How to Cite

Sen P, Vijay M, Singh S, Hameed S, Vijayaraghvan P. Understanding the environmental drivers of clinical azole resistance in Aspergillus species. dti [Internet]. 2022 Nov. 22 [cited 2023 Sep. 23];16(1):25-3. Available from: https://journals.aboutscience.eu/index.php/dti/article/view/2476



Focus on Antimicrobial Resistance (AMR)


Received 2022-07-27
Accepted 2022-10-24
Published 2022-11-22