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Video:Antifungal-resistant aspergillosis

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Description

Antifungal-resistant aspergillosis is a serious and growing health problem, involving the mold Aspergillus fumigatus developing resistance to first-line antifungal drugs, the azoles(voriconazole). This resistance is driven by long-term azole therapy, as well as, widespread use of chemically similar azole fungicides in agriculture, which exposes the environmental mold to selection pressure, leading to the creation of resistant strains that can be inhaled by humans. Individuals with weakened immune systems or chronic lung diseases are at high risk for these difficult-to-treat infections, which can cause significantly higher mortality rates. Treatment for resistant cases requires susceptibility testing and often involves switching to alternative drug classes, or using combination therapy.[1][2][3]

Presentation

In terms of the presentation we find that antifungal-resistant aspergillosis mirror those of invasive aspergillosis(but persistent): [4][5] fever, cough with blood, chest pain and shortness of breath.

Cause

In terms of the etiology of Antifungal-resistant aspergillosis we find these are the causes and contributing factors:[1][2] prolonged azole therapy, immunocompromised status, azole fungicide exposure and underlying lung disease.

Mechanism

As to the pathophysiology of antifungal-resistant aspergillosis the main mechanism involves alterations in the gene cyp51A which encodes the drugs target enzyme, lanosterol 14-alpha-demethylase. This resistance develops through two main alterations, point mutations in the gene that change the enzymes structure and reduce the drugs binding affinity, and a tandem repeat insertion in the cyp51A promoter region that causes overexpression of the target enzyme. The most common and globally disseminated forms, such as TR34(L98H) combine both a tandem repeat and a point mutation, leading to high-level cross-resistance to multiple medical azoles. A secondary, but important mechanism is the overexpression of drug efflux pumps, which actively transport the antifungal agent out of the fungal cell preventing it from reaching inhibitory concentrations. [6][7][2][8]

Diagnosis

In terms of diagnosing antifungal-resistant aspergillosis involves two steps: [9][10][5] first identify by assessing symptoms, CT scan findings , and fungal markers(Galactomannan or Beta-D-glucan) and second, confirm resistance to first-line azoles using culture-based susceptibility testing to determine the Minimum inhibitory concentration or rapid molecular assays to detect resistance mutations.

Treatment

As to treatment we find that when azole resistance occurs, the primary approach is to discontinue the azole and switch to Liposomal Amphotericin B being the preferred alternative . Echinocandins may be used for salvage therapy or in combination regimens with another agent. Treatment must be guided by antifungal susceptibility testing of the isolate and involves TDM to ensure adequate drug exposure for any triazoles used.[7][11][5]

Prognosis

Individuals with azole-resistant Aspergillus fumigatus infections face a 33 percent higher risk of mortality compared to those with strains that are susceptible.[1]

Epidemiology

In terms of incidence and global distribution, we find that the prevalence of azole-resistant A. fumigatus varies widely by geographical region but has generally been increasing worldwide over the last two decades.The prevalence ranges from less than 1 percent( Austria) to 11 percent(the Netherlands). Studies have shown significantly lower susceptibility to voriconazole in some regions like the Netherlands compared to other countries.[12][13][14]

History

In terms of history we find that the first documented case of azole-resistant Aspergillus fumigatus was reported in the Netherlands during the late 1980s.[15]

Research

A 2025 article details how Next-generation sequencing (NGS) is being explored for comprehensive resistance profiling, especially in refractory or disseminated cases of Antifungal-resistant aspergillosis.[16]

References

  1. ↑ 1.0 1.1 1.2 "Antimicrobial-Resistant Aspergillus". Aspergillosis. 11 October 2024. Retrieved 26 October 2025.
  2. ↑ 2.0 2.1 2.2 Dladla, Mthokozisi; Gyzenhout, Marieka; Marias, Gert; Ghosh, Soumya (15 June 2024). "Azole resistance in Aspergillus fumigatus- comprehensive review". Archives of Microbiology. 206 (7): 305. doi:10.1007/s00203-024-04026-z. ISSN 1432-072X.
  3. ↑ "Antimicrobial-Resistant Fungal Infections with Aspergillus fumigatus" (PDF). cdc. Archived (PDF) from the original on 5 July 2025. Retrieved 3 October 2025.
  4. ↑ "Aspergillosis". cdc. 14 May 2024. Archived from the original on 28 August 2025. Retrieved 10 October 2025.
  5. ↑ 5.0 5.1 5.2 Patterson, Thomas F.; Thompson, George R.; Denning, David W.; Fishman, Jay A.; Hadley, Susan; Herbrecht, Raoul; Kontoyiannis, Dimitrios P.; Marr, Kieren A.; Morrison, Vicki A.; Nguyen, M. Hong; Segal, Brahm H.; Steinbach, William J.; Stevens, David A.; Walsh, Thomas J.; Wingard, John R.; Young, Jo-Anne H.; Bennett, John E. (15 August 2016). "Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America". Clinical Infectious Diseases. 63 (4): e1 – e60. doi:10.1093/cid/ciw326. PMC 4967602. PMID 27365388. Archived from the original on 29 September 2025. Retrieved 19 October 2025.
  6. ↑ Wang, Caroline; Miller, Natalie; Vines, Douglas; Severns, Paul M.; Momany, Michelle; Brewer, Marin T. (23 April 2024). "Azole resistance mechanisms and population structure of the human pathogen Aspergillus fumigatus on retail plant products". Applied and Environmental Microbiology. 90 (5): e02056–23. Bibcode:2024ApEnM..90E2056W. doi:10.1128/aem.02056-23. PMID 38651929. Archived from the original on 6 December 2024. Retrieved 11 October 2025.
  7. ↑ 7.0 7.1 Chowdhary, Anuradha; Sharma, Cheshta; Meis, Jacques F (15 August 2017). "Azole-Resistant Aspergillosis: Epidemiology, Molecular Mechanisms, and Treatment". The Journal of Infectious Diseases. 216 (suppl_3): S436 – S444. doi:10.1093/infdis/jix210. PMID 28911045.
  8. ↑ Hagiwara, Daisuke; Watanabe, Akira; Kamei, Katsuhiko; Goldman, Gustavo H. (2016). "Epidemiological and Genomic Landscape of Azole Resistance Mechanisms in Aspergillus Fungi". Frontiers in Microbiology. 7: 1382. doi:10.3389/fmicb.2016.01382. ISSN 1664-302X. PMC 5030247. PMID 27708619.
  9. ↑ "Laboratory Azole-Resistant Aspergillus fumigatus Screening". Aspergillosis. 16 May 2024. Archived from the original on 28 August 2025. Retrieved 9 October 2025.
  10. ↑ Lamoth, Frederic; Calandra, Thierry (29 November 2022). "Pulmonary aspergillosis: diagnosis and treatment". European Respiratory Review. 31 (166). doi:10.1183/16000617.0114-2022. ISSN 0905-9180. PMC 9724826. PMID 36450372.
  11. ↑ Aigner, Maria; Lass-Flörl, Cornelia (13 October 2015). "Treatment of drug-resistant Aspergillus infection". Expert Opinion on Pharmacotherapy. 16 (15): 2267–2270. doi:10.1517/14656566.2015.1083976. ISSN 1465-6566. Archived from the original on 24 December 2023. Retrieved 9 October 2025.
  12. ↑ Lestrade, Pieter P. A.; Buil, Jochem B.; van der Beek, Martha T.; Kuijper, Ed J.; van Dijk, Karin; Kampinga, Greetje A.; Rijnders, Bart J. A.; Vonk, Alieke G.; de Greeff, Sabine C.; Schoffelen, Annelot F.; van Dissel, Jaap; Meis, Jacques F.; Melchers, Willem J. G.; Verweij, Paul E. (July 2020). "Paradoxal Trends in Azole-Resistant Aspergillus fumigatus in a National Multicenter Surveillance Program, the Netherlands, 2013-2018". Emerging Infectious Diseases. 26 (7): 1447–1455. doi:10.3201/eid2607.200088. ISSN 1080-6059. PMC 7323544. PMID 32568033.
  13. ↑ Morrissey, C. Orla; Kim, Hannah Y.; Duong, Tra-My N.; Moran, Eric; Alastruey-Izquierdo, Ana; Denning, David W.; Perfect, John R.; Nucci, Marcio; Chakrabarti, Arunaloke; Rickerts, Volker; Chiller, Tom M.; Wahyuningsih, Retno; Hamers, Raph L.; Cassini, Alessandro; Gigante, Valeria; Sati, Hatim; Alffenaar, Jan-Willem; Beardsley, Justin (27 June 2024). "Aspergillus fumigatus-a systematic review to inform the World Health Organization priority list of fungal pathogens". Medical Mycology. 62 (6): myad129. doi:10.1093/mmy/myad129. ISSN 1460-2709. PMC 11210617. PMID 38935907.
  14. ↑ Wiederhold, Nathan P. (1 September 2023). "Epidemiology and Prevalence of Azole-Resistant Aspergillus fumigatus: What Is Our Understanding of the Situation?". Current Fungal Infection Reports. 17 (3): 177–187. doi:10.1007/s12281-023-00469-x. ISSN 1936-377X. Retrieved 19 October 2025.
  15. ↑ Bosetti, Davide; Neofytos, Dionysios (18 March 2023). "Invasive Aspergillosis and the Impact of Azole-resistance". Current Fungal Infection Reports. 17 (2): 77–86. doi:10.1007/s12281-023-00459-z. ISSN 1936-3761. PMC 10024029. PMID 37360857.
  16. ↑ Chaudhary, Renu; Thakur, Zoozeal (3 June 2025). "From detection to action: new diagnostic insights into antifungal resistance". Expert Review of Molecular Diagnostics. 25 (6): 203–208. doi:10.1080/14737159.2025.2477027. ISSN 1473-7159. PMID 40052616.
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