Semin Respir Crit Care Med 2024; 45(01): 032-040
DOI: 10.1055/s-0043-1776997
Review Article

Antifungal Resistance in Pulmonary Aspergillosis

Paul E. Verweij
1   Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands
2   Radboudumc-CWZ Center of Expertise for Mycology, Nijmegen, the Netherlands
3   Center for Infectious Disease Research, Diagnostics and Laboratory Surveillance, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands
,
Yinggai Song
1   Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands
4   Department of Dermatology and Venerology, Peking University First Hospital, 8 Xishiku Street, Xicheng District, Beijing, China
5   National Clinical Research Center For Skin and Immune Diseases, Beijing, China
6   Research Center for Medical Mycology, Peking University, Beijing, China
,
Jochem B. Buil
1   Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands
2   Radboudumc-CWZ Center of Expertise for Mycology, Nijmegen, the Netherlands
,
Jianhua Zhang
3   Center for Infectious Disease Research, Diagnostics and Laboratory Surveillance, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands
,
Willem J.G. Melchers
1   Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands
2   Radboudumc-CWZ Center of Expertise for Mycology, Nijmegen, the Netherlands
› Author Affiliations

Abstract

Aspergilli may cause various pulmonary diseases in humans, including allergic bronchopulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis (CPA), and acute invasive pulmonary aspergillosis (IPA). In addition, chronic colonization may occur in cystic fibrosis (CF). Aspergillus fumigatus represents the main pathogen, which may employ different morphotypes, for example, conidia, hyphal growth, and asexual sporulation, in the various Aspergillus diseases. These morphotypes determine the ease by which A. fumigatus can adapt to stress by antifungal drug exposure, usually resulting in one or more resistance mutations. Key factors that enable the emergence of resistance include genetic variation and selection. The ability to create genetic variation depends on the reproduction mode, including, sexual, parasexual, and asexual, and the population size. These reproduction cycles may take place in the host and/or in the environment, usually when specific conditions are present. Environmental resistance is commonly characterized by tandem repeat (TR)-mediated mutations, while in-host resistance selection results in single-resistance mutations. Reported cases from the literature indicate that environmental resistance mutations are almost exclusively present in patients with IA indicating that the risk for in-host resistance selection is very low. In aspergilloma, single-point mutations are the dominant resistance genotype, while in other chronic Aspergillus diseases, for example, ABPA, CPA, and CF, both TR-mediated and single-resistance mutations are reported. Insights into the pathogenesis of resistance selection in various Aspergillus diseases may help to improve diagnostic and therapeutic strategies.



Publication History

Article published online:
09 January 2024

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  • References

  • 1 Houbraken J, Kocsubé S, Visagie CM. et al. Classification of Aspergillus, Penicillium, Talaromyces and related genera (Eurotiales): an overview of families, genera, subgenera, sections, series and species. Stud Mycol 2020; 95: 5-169
  • 2 Latgé JP, Chamilos G. Aspergillus fumigatus and Aspergillosis in 2019. Clin Microbiol Rev 2019; 33 (01) e00140-e18
  • 3 Verweij PE, Rijnders BJA, Brüggemann RJM. et al. Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion. Intensive Care Med 2020; 46 (08) 1524-1535
  • 4 Hoenigl M, Seidel D, Sprute R. et al. COVID-19-associated fungal infections. Nat Microbiol 2022; 7 (08) 1127-1140
  • 5 Gregg KS, Kauffman CA. Invasive aspergillosis: epidemiology, clinical aspects, and treatment. Semin Respir Crit Care Med 2015; 36 (05) 662-672
  • 6 Ullmann AJ, Aguado JM, Arikan-Akdagli S. et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect 2018; 24 (Suppl. 01) e1-e38
  • 7 Nywening AV, Rybak JM, Rogers PD, Fortwendel JR. Mechanisms of triazole resistance in Aspergillus fumigatus . Environ Microbiol 2020; 22 (12) 4934-4952
  • 8 Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi. Wayne, PA: Clinical and Laboratory Standards Institute;; 2017
  • 9 Arendrup MC, Friberg N, Mares M, Kahlmeter G, Meletiadis J, Guinea J. Subcommittee on Antifungal Susceptibility Testing (AFST) of the ESCMID European Committee for Antimicrobial Susceptibility Testing (EUCAST). How to interpret MICs of antifungal compounds according to the revised clinical breakpoints v. 10.0 European committee on antimicrobial susceptibility testing (EUCAST). Clin Microbiol Infect 2020; 26 (11) 1464-1472
  • 10 Kahlmeter G, Turnidge J. How to: ECOFFs—the why, the how, and the don'ts of EUCAST epidemiological cutoff values. Clin Microbiol Infect 2022; 28 (07) 952-954
  • 11 Kashyap VH, Mishra A, Bordoloi S, Varma A, Joshi NC. Exploring the intersection of Aspergillus fumigatus biofilms, infections, immune response and antifungal resistance. Mycoses 2023; 66 (09) 737-754
  • 12 Liu S, Le Mauff F, Sheppard DC, Zhang S. Filamentous fungal biofilms: Conserved and unique aspects of extracellular matrix composition, mechanisms of drug resistance and regulatory networks in Aspergillus fumigatus. NPJ Biofilms Microbiomes 2022; 8 (01) 83
  • 13 Ferreira JA, Penner JC, Moss RB. et al. Inhibition of Aspergillus fumigatus and its biofilm by Pseudomonas aeruginosa is dependent on the source, phenotype and growth conditions of the bacterium. PLoS One 2015; 10 (08) e0134692
  • 14 Garcia-Sherman MC, Lundberg T, Sobonya RE, Lipke PN, Klotz SA. A unique biofilm in human deep mycoses: fungal amyloid is bound by host serum amyloid P component. NPJ Biofilms Microbiomes 2015; 1: 15009
  • 15 Seidler MJ, Salvenmoser S, Müller FM. Aspergillus fumigatus forms biofilms with reduced antifungal drug susceptibility on bronchial epithelial cells. Antimicrob Agents Chemother 2008; 52 (11) 4130-4136
  • 16 Kowalski CH, Kerkaert JD, Liu KW. et al. Fungal biofilm morphology impacts hypoxia fitness and disease progression. Nat Microbiol 2019; 4 (12) 2430-2441
  • 17 Gow NAR, Johnson C, Berman J. et al. The importance of antimicrobial resistance in medical mycology. Nat Commun 2022; 13 (01) 5352
  • 18 O'Gorman CM, Fuller H, Dyer PS. Discovery of a sexual cycle in the opportunistic fungal pathogen Aspergillus fumigatus. Nature 2009; 457 (7228) 471-474
  • 19 Auxier B, Debets AJM, Stanford FA. et al. The human fungal pathogen Aspergillus fumigatus can produce the highest known number of meiotic crossovers. PLoS Biol 2023; 21 (09) e3002278
  • 20 Engel T, Verweij PE, van den Heuvel J. et al. Parasexual recombination enables Aspergillus fumigatus to persist in cystic fibrosis. ERJ Open Res 2020; 6 (04) 00020-02020
  • 21 Baptista F, Machado MFPS, Castro-Prado MAA. Alternative reproduction pathway in Aspergillus nidulans. Folia Microbiol (Praha) 2003; 48 (05) 597-604
  • 22 Zhang J, Debets AJ, Verweij PE, Melchers WJ, Zwaan BJ, Schoustra SE. Asexual sporulation facilitates adaptation: the emergence of azole resistance in Aspergillus fumigatus. Evolution 2015; 69 (10) 2573-2586
  • 23 Zhang J, Debets AJM, Verweij PE, Snelders E. Azole-resistance development; How the Aspergillus fumigatus lifecycle defines the potential for adaptation. J Fungi (Basel) 2021; 7 (08) 599
  • 24 Zhang J, Snelders EE, Zwaan BJ. et al. Relevance of heterokaryosis for adaptation and azole-resistance development in Aspergillus fumigatus. Proc Biol Sci 2019; 286 (1896) 20182886
  • 25 Verweij PE, Zhang J, Debets AJM. et al. In-host adaptation and acquired triazole resistance in Aspergillus fumigatus: a dilemma for clinical management. Lancet Infect Dis 2016; 16 (11) e251-e260
  • 26 Schoustra SE, Debets AJM, Rijs AJMM. et al. Environmental hotspots for azole resistance selection of Aspergillus fumigatus, the Netherlands. Emerg Infect Dis 2019; 25 (07) 1347-1353
  • 27 Zhang J, Lopez Jimenez L, Snelders E. et al. Dynamics of Aspergillus fumigatus in azole fungicide-containing plant waste in the Netherlands (2016–2017). Appl Environ Microbiol 2021; 87 (02) e02295-e20
  • 28 Verweij PE, Chowdhary A, Melchers WJ, Meis JF. Azole resistance in Aspergillus fumigatus: can we retain the clinical use of mold-active antifungal azoles?. Clin Infect Dis 2016; 62 (03) 362-368
  • 29 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 (06) 2425-2430
  • 30 Camps SM, van der Linden JW, Li Y. et al. Rapid induction of multiple resistance mechanisms in Aspergillus fumigatus during azole therapy: a case study and review of the literature. Antimicrob Agents Chemother 2012; 56 (01) 10-16
  • 31 Henry B, Guenette A, Cheema F. et al. CYP51A polymorphisms of Aspergillus fumigatus in lung transplant recipients: prevalence, correlation with phenotype, and impact on outcomes. Med Mycol 2021; 59 (07) 728-733
  • 32 Snelders E, van der Lee HA, Kuijpers J. et al. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLoS Med 2008; 5 (11) e219
  • 33 van der Linden JW, Camps SM, Kampinga GA. et al. Aspergillosis due to voriconazole highly resistant Aspergillus fumigatus and recovery of genetically related resistant isolates from domiciles. Clin Infect Dis 2013; 57 (04) 513-520
  • 34 Snelders E, Camps SM, Karawajczyk A. et al. Triazole fungicides can induce cross-resistance to medical triazoles in Aspergillus fumigatus . PLoS One 2012; 7 (03) e31801
  • 35 Buil JB, Hare RK, Zwaan BJ, Arendrup MC, Melchers WJG, Verweij PE. The fading boundaries between patient and environmental routes of triazole resistance selection in Aspergillus fumigatus . PLoS Pathog 2019; 15 (08) e1007858
  • 36 Pelaez T, Gijón P, Bunsow E. et al. Resistance to voriconazole due to a G448S substitution in Aspergillus fumigatus in a patient with cerebral aspergillosis. J Clin Microbiol 2012; 50 (07) 2531-2534
  • 37 Fraaije B, Atkins S, Hanley S, Macdonald A, Lucas J. The multi-fungicide resistance status of Aspergillus fumigatus populations in arable soils and the wider European environment. Front Microbiol 2020; 11: 599233
  • 38 Hare RK, Gertsen JB, Astvad KMT. et al. In vivo selection of a unique tandem repeat mediated azole resistance mechanism (TR120) in Aspergillus fumigatus cyp51A, Denmark. Emerg Infect Dis 2019; 25 (03) 577-580
  • 39 Lestrade PP, Bentvelsen RG, Schauwvlieghe AFAD. et al. Voriconazole resistance and mortality in invasive aspergillosis: a multicenter retrospective cohort study. Clin Infect Dis 2019; 68 (09) 1463-1471
  • 40 Resendiz-Sharpe A, Mercier T, Lestrade PPA. et al. Prevalence of voriconazole-resistant invasive aspergillosis and its impact on mortality in haematology patients. J Antimicrob Chemother 2019; 74 (09) 2759-2766
  • 41 Steinmann J, Hamprecht A, Vehreschild MJ. et al. Emergence of azole-resistant invasive aspergillosis in HSCT recipients in Germany. J Antimicrob Chemother 2015; 70 (05) 1522-1526
  • 42 Vermeulen E, Maertens J, De Bel A. et al. Nationwide surveillance of azole resistance in Aspergillus diseases. Antimicrob Agents Chemother 2015; 59 (08) 4569-4576
  • 43 Howard SJ, Pasqualotto AC, Anderson MJ. et al. Major variations in Aspergillus fumigatus arising within aspergillomas in chronic pulmonary aspergillosis. Mycoses 2013; 56 (04) 434-441
  • 44 Singh A, Sharma B, Mahto KK, Meis JF, Chowdhary A. High-frequency direct detection of triazole resistance in Aspergillus fumigatus from patients with chronic pulmonary fungal diseases in India. J Fungi (Basel) 2020; 6 (02) 67
  • 45 Denning DW, Park S, Lass-Florl C. et al. High-frequency triazole resistance found In nonculturable Aspergillus fumigatus from lungs of patients with chronic fungal disease. Clin Infect Dis 2011; 52 (09) 1123-1129
  • 46 Seufert R, Sedlacek L, Kahl B. et al. Prevalence and characterization of azole-resistant Aspergillus fumigatus in patients with cystic fibrosis: a prospective multicentre study in Germany. J Antimicrob Chemother 2018; 73 (08) 2047-2053
  • 47 Burgel PR, Baixench MT, Amsellem M. et al. High prevalence of azole-resistant Aspergillus fumigatus in adults with cystic fibrosis exposed to itraconazole. Antimicrob Agents Chemother 2012; 56 (02) 869-874
  • 48 Morio F, Aubin GG, Danner-Boucher I. et al. High prevalence of triazole resistance in Aspergillus fumigatus, especially mediated by TR/L98H, in a French cohort of patients with cystic fibrosis. J Antimicrob Chemother 2012; 67 (08) 1870-1873
  • 49 Risum M, Hare RK, Gertsen JB. et al. Azole-resistant Aspergillus fumigatus among Danish cystic fibrosis patients: increasing prevalence and dominance of TR34/L98H. Front Microbiol 2020; 11: 1850
  • 50 Kolwijck E, van der Hoeven H, de Sévaux RG. et al. Voriconazole-susceptible and voriconazole-resistant Aspergillus fumigatus coinfection. Am J Respir Crit Care Med 2016; 193 (08) 927-929
  • 51 Wu CJ, Cia CT, Wang HC. et al. Clinical and microbiological characteristics of culture-positive, influenza-associated pulmonary aspergillosis: a single-center study in southern Taiwan, 2016–2019. J Fungi (Basel) 2022; 8 (01) 49
  • 52 Meijer EFJ, Dofferhoff ASM, Hoiting O, Meis JF. COVID-19-associated pulmonary aspergillosis: a prospective single-center dual case series. Mycoses 2021; 64 (04) 457-464
  • 53 Bongomin F, Harris C, Hayes G, Kosmidis C, Denning DW. Twelve-month clinical outcomes of 206 patients with chronic pulmonary aspergillosis. PLoS One 2018; 13 (04) e0193732
  • 54 Fisher MC, Alastruey-Izquierdo A, Berman J. et al. Tackling the emerging threat of antifungal resistance to human health. Nat Rev Microbiol 2022; 20 (09) 557-571
  • 55 Salmanton-García J, Hoenigl M, Gangneux JP. et al. The current state of laboratory mycology and access to antifungal treatment in Europe: a European Confederation of Medical Mycology survey. Lancet Microbe 2023; 4 (01) e47-e56
  • 56 Buil JB, Zoll J, Verweij PE, Melchers WJG. Molecular detection of azole-resistant Aspergillus fumigatus in clinical samples. Front Microbiol 2018; 9: 515
  • 57 Verweij PE, Ananda-Rajah M, Andes D. et al. International expert opinion on the management of infection caused by azole-resistant Aspergillus fumigatus . Drug Resist Updat 2015; 21-22: 30-40
  • 58 Anderson JB. Evolution of antifungal-drug resistance: mechanisms and pathogen fitness. Nat Rev Microbiol 2005; 3 (07) 547-556
  • 59 Jjingo CJ, Bala S, Waack U. et al. FDA public workshop summary-addressing challenges in inhaled antifungal drug development. Clin Infect Dis 2023; (e-pub ahead of print). DOI: 10.1093/cid/ciad607.