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Azole-resistant (azole-R)  Aspergillus  is an increasing challenge worldwide. Patients with cystic fibrosis (CF) are at risk of  Aspergillus  colonization and disease due to a favorable lung environment for microorganisms. We performed a nationwide study in 2018 of azole-non-susceptible  Aspergillus  in CF patients and compared with data from two prior studies. All airway samples with mold isolates from patients monitored at the two CF centers in Denmark (RH, Jan–Sept and AUH, Jan–Jun) were included. Classical species identification (morphology and thermo-tolerance) was performed and MALDI-TOF/β-tubulin sequencing was performed if needed. Susceptibility was determined using EUCAST E.Def 10.1, and E.Def 9.3.2.  cyp51A  sequencing and STR Af  genotyping were performed for azole-non-susceptible isolates and relevant sequential isolates. In total, 340 mold isolates from 159 CF patients were obtained. The most frequent species were  Aspergillus fumigatus  (266/340, 78.2%) and  Aspergillus terreus  (26/340, 7.6%). Azole-R  A. fumigatus  was cultured from 7.3% (10/137) of patients, including 9.5% (9/95) of patients at RH and 2.4% at AUH (1/42), respectively. In a 10-year perspective, azole-non-susceptibility increased numerically among patients at RH (10.5% in 2018 vs 4.5% in 2007–2009). Cyp51A resistance mechanisms were found in nine azole-R  A. fumigatus  from eight CF patients. Five were of environmental origin (TR 34 /L98H), three were human medicine-driven (two M220K and one M220R), and one was novel (TR 34  3 /L98H) and found in a patient who also harbored a TR 34 /L98H isolate. STR Af  genotyping identified 27 unique genotypes among 45 isolates and ≥2 genotypes in 8 of 12 patients. This included one patient carrying two unique TR 34 /L98H isolates, a rare phenomenon. Genotyping of sequential TR 34  3 /L98H and TR 34 /L98H isolates from the same patient showed only minor differences in 1/9 markers. Finally, azole-R  A. terreus  was found in three patients including two with Cyp51A alterations (M217I and G51A, respectively). Azole-R  A. fumigatus  is increasing among CF patients in Denmark with the environmentally associated resistance TR 34 /L98H mechanism being dominant. Mixed infections (wildtype/non-wildtype and several non-wildtypes) and a case of potential additional tandem repeat acquisition  in vivo  were found. However, similar genotypes were identified from another patient (and outside this study), potentially suggesting a predominant TR 34 /L98H clone in DK. These findings suggest an increasing prevalence and complexity of azole resistance in  A. fumigatus .

Azole-Resistant Aspergillus fumigatus Among Danish Cystic Fibrosis Patients: Increasing Prevalence and Dominance of TR34/L98H