Use of Epidemiological Cutoff Values To Examine 9-Year Trends in Susceptibility of Aspergillus Species to the Triazoles
Open accessAbstract
In the absence of clinical breakpoints, epidemiological cutoff values (ECVs) have been established to distinguish wild-type (WT) isolates of Aspergillus spp. from those that may harbor resistance mutations. Recently, the CLSI has developed ECVs for triazoles (itraconazole, posaconazole, and voriconazole) and common Aspergillus species. We applied the triazole ECVs to 1,789 Aspergillus isolates collected from 63 centers worldwide from 2001 to 2009 to determine the frequency of non-WT strains of each species. Temporal trends were evaluated for Aspergillus fumigatus and Aspergillus flavus over the 9-year period for each drug. The collection included 1,312 isolates of A. fumigatus , 235 of A. flavus , 162 of Aspergillus niger , 64 of Aspergillus terreus , and 15 of Aspergillus versicolor . Using the ECVs, the percentages of non-WT isolates for itraconazole, posaconazole, and voriconazole, respectively, were as follows: A. fumigatus (2.0%, 3.5%, and 1.4%), A. flavus (0.8%, 5.1%, and 1.7%), A. niger (17.3%, 3.7%, and 0.6%), A. terreus (0.0%, 1.6%, and 3.2%), and A. versicolor (6.3%, 0.0%, and 0.0%). Among 49 Aspergillus isolates for which itraconazole MICs were >2 μg/ml, the posaconazole and voriconazole MICs were greater than the ECVs for 14 and 12 isolates, respectively. The percentages of isolates for which MICs were greater than the ECVs ranged from 1.1 to 5.7% for posaconazole, 0.0 to 1.6% for voriconazole, and 0.7 to 4.0% for itraconazole. There was no consistent trend toward decreased susceptibility for any triazole and A. fumigatus or A. flavus over time. Decreased susceptibility among Aspergillus spp. was observed for each of the extended-spectrum triazoles and varied by species over the 9-year study period.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the US, fluconazole resistance rates in C. parapsilosis range between 4-10%.
“In the US, fluconazole resistance rates range between 4–10%; rates are much higher in other parts of the world including Japan, Western Europe, and Latin America.”
From Epidemiology of Invasive Candidiasis (2024) · cites this paper as [120]
The Results and Discussion passages report susceptibility of Aspergillus species to itraconazole, posaconazole, and voriconazole; page numbers are unavailable in our copy. Searches for fluconazole, C. parapsilosis, and the stated geographic comparison found no passage reporting the claimed US resistance rate. (LLM, conf=0.78)
Experimental — accuracy not yet measuredResistance to the echinocandins in C. parapsilosis has remained relatively infrequent (0-3%).
“Resistance to the echinocandins has remained relatively infrequent (0–3%) despite a higher baseline susceptible MIC cutoff value compared to the other Candida spp. due to a naturally occurring polymorphism in FKS1.62,103,112,120”
From Epidemiology of Invasive Candidiasis (2024) · cites this paper as [120]
The Results and Discussion section (page unavailable) examines triazole susceptibility in Aspergillus species, not echinocandin resistance in C. parapsilosis. Searches for C. parapsilosis, echinocandins, the 0–3% figure, and FKS1 found no passage addressing the claim. (LLM, conf=0.78)
Experimental — accuracy not yet measuredFluconazole resistance rates in C. parapsilosis are much higher in Japan, Western Europe, and Latin America than in the US.
“In the US, fluconazole resistance rates range between 4–10%; rates are much higher in other parts of the world including Japan, Western Europe, and Latin America.”
From Epidemiology of Invasive Candidiasis (2024) · cites this paper as [120]
The Results and Discussion passages report susceptibility of Aspergillus species to itraconazole, posaconazole, and voriconazole; no page numbers are provided. Searches for C. parapsilosis, fluconazole, and the claimed regional resistance rates found no passage addressing that comparison. (LLM, conf=0.78)
Experimental — accuracy not yet measuredC. parapsilosis has a higher baseline susceptible MIC cutoff value compared to other Candida spp. due to a naturally occurring polymorphism in FKS1.
“Resistance to the echinocandins has remained relatively infrequent (0–3%) despite a higher baseline susceptible MIC cutoff value compared to the other Candida spp. due to a naturally occurring polymorphism in FKS1.62,103,112,120”
From Epidemiology of Invasive Candidiasis (2024) · cites this paper as [120]
The Materials and Methods mention C. parapsilosis only as a quality-control strain, while the Results and Discussion concern Aspergillus susceptibility to triazoles (page numbers unavailable). Searches for FKS1 polymorphisms, echinocandin MIC cutoffs, and the 0–3% resistance figure found no passage addressing the claim. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
Hussain, H. M. (2007) · New England Journal of Medicine · doi:10.1056/nejmc076105 · Cited by 36 · see citing works
RetractedWalsh, T. J., Anaissie, E. J., Denning, D. W., Herbrecht, R., Kontoyiannis, D. P., Marr, K. A., Morrison, V. A., Segal, B. H., Steinbach, W. J., Stevens, D. A., et al. (2008) · Clinical Infectious Diseases · doi:10.1086/525258 · Cited by 2,685 · see citing works
Howard, S. J., Cerar, D., Anderson, M. J., Albarrag, A., Fisher, M. C., Pasqualotto, A. C., Laverdiere, M., Arendrup, M. C., Perlin, D. S., & Denning, D. W. (2009) · Emerging Infectious Diseases · doi:10.3201/eid1507.090043 · Cited by 750 · see citing works
Emergence of Azole Resistance in Aspergillus fumigatus and Spread of a Single Resistance Mechanism
Snelders, E., van der Lee, H. A. L., Kuijpers, J., Rijs, A. J. M. M., Varga, J., Samson, R. A., Mellado, E., Donders, A. R. T., Melchers, W. J. G., & Verweij, P. E. (2008) · PLoS Medicine · doi:10.1371/journal.pmed.0050219 · Cited by 726 · see citing works
Efflux-Mediated Antifungal Drug Resistance
Cannon, R. D., Lamping, E., Holmes, A. R., Niimi, K., Baret, P. V., Keniya, M. V., Tanabe, K., Niimi, M., Goffeau, A., & Monk, B. C. (2009) · Clinical Microbiology Reviews · doi:10.1128/cmr.00051-08 · Cited by 608 · see citing works
Azole resistance in Aspergillus fumigatus: a side-effect of environmental fungicide use?
Verweij, P. E., Snelders, E., Kema, G. H., Mellado, E., & Melchers, W. J. (2009) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(09)70265-8 · Cited by 604 · see citing works
Setting and Revising Antibacterial Susceptibility Breakpoints
Turnidge, J. D., & Paterson, D. L. (2007) · Clinical Microbiology Reviews · doi:10.1128/cmr.00047-06 · Cited by 580 · see citing works
Mellado, E., Garcia-Effron, G., Alcázar-Fuoli, L., Melchers, W. J. G., Verweij, P. E., Cuenca-Estrella, M., & Rodríguez-Tudela, J. L. (2007) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01092-06 · Cited by 490 · see citing works
European harmonization of MIC breakpoints for antimicrobial susceptibility testing of bacteria
Kahlmeter, G. (2003) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkg312 · Cited by 404 · see citing works
Turnidge, J. D., Kahlmeter, G., & Kronvall, G. (2006) · Clinical Microbiology and Infection · doi:10.1111/j.1469-0691.2006.01377.x · Cited by 399 · see citing works
Multiple-Triazole–Resistant Aspergillosis
Verweij, P. E., Mellado, E., & Melchers, W. J. G. (2007) · New England Journal of Medicine · doi:10.1056/nejmc061720 · Cited by 380 · see citing works
Azole antifungal resistance in Aspergillus fumigatus: 2008 and 2009
Bueid, A. S., Howard, S. J., Moore, C. B., Richardson, M. D., Harrison, E., Bowyer, P., & Denning, D. W. (2010) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkq279 · Cited by 333 · see citing works
Diaz-Guerra, T. M., Mellado, E., Cuenca-Estrella, M., & Rodriguez-Tudela, J. L. (2003) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.47.3.1120-1124.2003 · Cited by 281 · see citing works
Azole-resistance in Aspergillus: Proposed nomenclature and breakpoints
Verweij, P. E., Howard, S. J., Melchers, W. J. G., & Denning, D. W. (2009) · Drug Resistance Updates · doi:10.1016/j.drup.2009.09.002 · Cited by 258 · see citing works
do Nascimento, A. M., Goldman, G. H., Park, S., Marras, S. A. E., Delmas, G., Oza, U., Lolans, K., Dudley, M. N., Mann, P. A., & Perlin, D. S. (2003) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.47.5.1719-1726.2003 · Cited by 256 · see citing works
Espinel-Ingroff, A. V., Diekema, D. J., Fothergill, A. W., Johnson, E. M., Peláez, T., Pfaller, M. A., Rinaldi, M. G., Cantón, R., & Turnidge, J. D. (2010) · Journal of Clinical Microbiology · doi:10.1128/jcm.00536-10 · Cited by 240 · see citing works
Self-citationMortensen, K. L., Mellado, E., Lass‐Flörl, C., Rodrı́guez-Tudela, J. L., Johansen, H. K., & Arendrup, M. C. (2010) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00692-10 · Cited by 238 · see citing works
Mellado, E., Garcia-Effron, G., Alcazar-Fuoli, L., Cuenca-Estrella, M., & Rodriguez-Tudela, J. L. (2004) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.48.7.2747-2750.2004 · Cited by 210 · see citing works
Epidemiological Cutoffs and Cross-Resistance to Azole Drugs in Aspergillus fumigatus
Rodrı́guez-Tudela, J. L., Alcázar‐Fuoli, L., Mellado, E., Alastruey‐Izquierdo, A., Monzón, A., & Cuenca‐Estrella, M. (2008) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00156-08 · Cited by 209 · see citing works
Slaven, J. W., Anderson, M. J., Sanglard, D., Dixon, G. K., Bille, J., Roberts, I. S., & Denning, D. W. (2002) · Fungal Genetics and Biology · doi:10.1016/s1087-1845(02)00016-6 · Cited by 202 · see citing works
Multi-azole resistance in Aspergillus fumigatus
Howard, S. J., Webster, I., Moore, C. B., Gardiner, R. E., Park, S., Perlin, D. S., & Denning, D. W. (2006) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2006.08.017 · Cited by 202 · see citing works
Acquired antifungal drug resistance inAspergillus fumigatus:epidemiology and detection
Howard, S. J., & Arendrup, M. C. (2010) · Medical Mycology · doi:10.3109/13693786.2010.508469 · Cited by 199 · see citing works
Chen, J., Li, H., Li, R., Bu, D., & Wan, Z. (2004) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkh507 · Cited by 196 · see citing works
Mann, P. A., Parmegiani, R. M., Wei, S.-Q., Mendrick, C. A., Li, X., Loebenberg, D., DiDomenico, B., Hare, R. S., Walker, S. S., & McNicholas, P. M. (2003) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.47.2.577-581.2003 · Cited by 188 · see citing works
Arendrup, M. C., Mavridou, E., Mortensen, K. L., Snelders, E., Møller, J. K., Khan, H., Melchers, W. J. G., & Verweij, P. E. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010080 · Cited by 175 · see citing works
Pfaller, M. A., Diekema, D. J., Ghannoum, M. A., Rex, J. H., Alexander, B. D., Andes, D. R., Brown, S. D., Chaturvedi, V. P., Espinel‐Ingroff, A., Fowler, C. L., et al. (2009) · Journal of Clinical Microbiology · doi:10.1128/jcm.00940-09 · Cited by 139 · see citing works
Self-citationMellado, E., García‐Effrón, G., Buitrago, M. J., Alcázar‐Fuoli, L., Cuenca‐Estrella, M., & Rodríguez-Tudela, J. L. (2005) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.49.6.2536-2538.2005 · Cited by 129 · see citing works
Pfaller, M. A., Messer, S. A., Boyken, L. B., Rice, C., Tendolkar, S., Hollis, R. J., & Diekema, D. J. (2008) · Journal of Clinical Microbiology · doi:10.1128/jcm.00535-08 · Cited by 119 · see citing works
Self-citationAzole‐Resistant Central Nervous System Aspergillosis
van der Linden, J. W. M., Jansen, R. R., Bresters, D., Visser, C. E., Geerlings, S. E., Kuijper, E. J., Melchers, W. J. G., & Verweij, P. E. (2009) · Clinical Infectious Diseases · doi:10.1086/597465 · Cited by 84 · see citing works
Balashov, S. V., Gardiner, R. E., Park, S., & Perlin, D. S. (2005) · Journal of Clinical Microbiology · doi:10.1128/jcm.43.1.214-222.2005 · Cited by 73 · see citing works
Etienne, K. A., Gade, L., Lockhart, S. R., et al. (2009) · Journal of Clinical Microbiology · doi:10.1128/jcm.01415-09 · Cited by 20 · see citing works
Azole resistance in aspergillosis: The next threat?
Lass‐Flörl, C. (2009) · Current Fungal Infection Reports · doi:10.1007/s12281-009-0033-7 · Cited by 8 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [6]6. CLSI 2008. Reference method for broth dilution antifungal susceptibility testing of filamentous fungi, 2nd ed Approved standard M38-A2. Clinical and Laboratory Standards Institute, Wayne, PA [Google Scholar]
Cited by
Sorted by citations
Patterson, T. F., Thompson, G. R., Denning, D. W., Fishman, J. A., Hadley, S., Herbrecht, R., Kontoyiannis, D. P., Marr, K. A., Morrison, V. A., Nguyen, M. H., et al. (2016) · Clinical Infectious Diseases · doi:10.1093/cid/ciw326 · Cited by 2,926 · see citing works
van der Linden, J. W. M., Camps, S. M. T., Kampinga, G. A., Arends, J. P. A., Debets-Ossenkopp, Y. J., Haas, P. J. A., Rijnders, B. J. A., Kuijper, E. J., van Tiel, F. H., Varga, J., et al. (2013) · Clinical Infectious Diseases · doi:10.1093/cid/cit320 · Cited by 342 · see citing works
Zhang, J., Snelders, E., Zwaan, B. J., Schoustra, S. E., Meis, J. F., van Dijk, K., Hagen, F., van der Beek, M. T., Kampinga, G. A., Zoll, J., et al. (2017) · mBio · doi:10.1128/mbio.00791-17 · Cited by 129 · see citing works
Epidemiology of Invasive Candidiasis
Bays, D., Jenkins, E., Lyman, M., Chiller, T., Strong, N., Ostrosky-Zeichner, L., Hoenigl, M., Pappas, P., & Thompson, G. (2024) · Clinical Epidemiology · doi:10.2147/clep.s459600 · Cited by 109 · see citing works
“62,103,112,120 C. krusei is considered inherently resistant to fluconazole yet demonstrates variable susceptibility to both voriconazole and posaconazole.”
Background
- Authors
- Pfaller, M., Boyken, L., Hollis, R., Kroeger, J., Messer, S., Tendolkar, S., & Diekema, D.
- Affiliations
- University of Iowa (US)
- Venue
- Journal of Clinical Microbiology
- Publisher
- American Society for Microbiology
- Published
- 2011-02
- Volume
- 49
- Issue
- 2
- Pages
- 586-590
- ISSN
- 0095-1137 (ISSN-L)
- 1098-660X
- PMC
- PMC3043512
- OpenAlex
- W2098654234
- Cited by
- 91
- References
- 32
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 5 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 5 · 2018: 6 · 2017: 6 · 2016: 7 · 2015: 12 · 2014: 9 · 2013: 10 · 2012: 9
- FWCI
- 5.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Microbiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pfizer
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- Aspergillus, triazole antifungals, epidemiological cut-off values, antifungal susceptibility, itraconazole, posaconazole, voriconazole, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Aspergillus versicolor, resistance mutations, temporal trends
- MeSH terms
- Antifungal Agents, Aspergillosis, Aspergillus, Humans, Microbial Sensitivity Tests, Triazoles, Drug Resistance, Fungal
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
