Pennsylvania, 2010. Following stem cell transplantation for sickle cell anemia, a woman developed graft-versus-host disease and respiratory failure. Resistant A. fumigatus was isolated from sputum. Despite therapy with voriconazole and caspofungin, her respiratory status worsened, and therapy was switched to amphotericin B and caspofungin. She deteriorated further and died of multisystem organ failure 6 months after isolate collection.

Pennsylvania, 2014. A man with A. fumigatus colonization following lung transplantation initially was treated with long-term voriconazole followed by itraconazole. He was hospitalized with bacterial and viral pneumonia, developed clinical invasive pulmonary aspergillosis, and was treated with itraconazole and caspofungin, followed by posaconazole and caspofungin, then inhaled amphotericin B. Resistant A. fumigatus was isolated from a bronchoalveolar lavage. With worsening clinical status and persistently positive A. fumigatus cultures, therapy was switched to liposomal amphotericin B and caspofungin; however, bronchoscopy indicated ongoing fungal infection. He died from multisystem organ failure approximately 2 months after isolate collection.

Pennsylvania, 2016. A woman with sarcoidosis and invasive pulmonary aspergillosis was treated with low-dose voriconazole because of vision-associated side effects at higher doses. Respiratory symptoms had worsened at the time of sputum collection, and when the resistant A. fumigatus isolate was identified, therapy was changed to caspofungin for 12 months. Following therapy, the patient was clinically stable with no radiographic evidence of progression to chronic cavitary pulmonary aspergillosis or aspergilloma.

Pennsylvania, 2017. A resistant A. fumigatus isolate was collected by bronchoalveolar lavage from a woman with chronic obstructive pulmonary disease, interstitial pulmonary fibrosis, and hypersensitivity pneumonitis, while she was hospitalized for hydropneumothorax and bacterial pneumonia secondary to trauma; no antifungal treatment was given. The patient died of complications of her hydropneumothorax thought to be unrelated to A. fumigatus.

Virginia, 2016, case 1. A man who visited Virginia from Guatemala was hospitalized for acute bronchitis 3 weeks after his arrival. Resistant A. fumigatus was isolated from sputum during this hospitalization. No antifungals were administered, and the patient was discharged to primary care.

Virginia, 2016, case 2. A woman with cystic fibrosis had resistant A. fumigatus isolated from sputum at an outpatient visit 2 days before hospital admission for a cystic fibrosis exacerbation. While hospitalized, she received steroids and antibiotics but not antifungals. She was later discharged with oral antibiotics.

California 2017. A woman with a history of chronic obstructive pulmonary disease requiring inhaled corticosteroids, chronic heart failure, and chronic kidney disease was evaluated as an outpatient for a productive cough. Sputum cultures grew A. fumigatus, and IgG antibody to A. fumigatus was twice the normal value. She was not started on antibiotics or antifungals.

A. fumigatus strains with mutations conferring resistance to mold-active triazole agents have been found in clinical and environmental specimens in the United States. In total, 10 U.S. clinical isolates with these genotypes (seven TR₃₄/L98H and three TR₄₆/Y121F/T289A) have been reported (5,10). Together, these reports likely underrepresent the number of U.S. isolates because aspergillosis and A. fumigatus colonization are not reportable in any state and few laboratories perform susceptibility testing for Aspergillus species. Four of the seven patients with TR₃₄/L98H were not treated with antifungal therapy following culture; these four isolates, all from sputum or bronchoalveolar lavage, likely reflected A. fumigatus colonization rather than infection. However, the presence of highly resistant A. fumigatus strains in patient isolates suggests that U.S. clinicians need to be aware of the risk for triazole-resistant aspergillosis. Notably, four patients had no known exposure to antifungal medications before culture of the resistant isolate, supporting possible environmentally acquired resistance.

The five isolates identified at CDC during 2016–2017 were collected from patients who did not share health care facilities, procedures, or county of residence, arguing against shared health care acquisition. Given that A. fumigatus can undergo selection for antifungal resistance during triazole fungicide exposure in the environment, and spores of resistant strains might be transmitted through the air and inhaled, further exploration of triazole fungicide use and presence of triazole-resistant A. fumigatus in these areas is warranted.

The findings in this report are subject to at least two limitations. First, among the seven A. fumigatus isolates with the TR₃₄/L98H mutations identified in the United States to date, four were collected in Pennsylvania, two in Virginia, and one in California. These three states contributed only 28% of all CDC A. fumigatus isolates collected during 2015–2017, raising the possibility of geographic localization. Second, because isolates were collected through passive monitoring and not systematic surveillance, caution must be exercised when interpreting these findings.

With environmentally derived TR₃₄/L98H triazole-resistant A. fumigatus detected in the United States, systematic surveillance, detailed geographic data, and data on triazole fungicide use could be important for assessing the scope of the problem and trends in resistance. Exploration of risk factors for patient acquisition might provide opportunities to prevent exposure and mitigate risk for invasive infection in susceptible populations. Clinicians and microbiologists need to be aware of the possibility of triazole-resistant A. fumigatus infections, even in triazole-naïve patients. Expanded capacity to test for antifungal susceptibility in A. fumigatus could help inform clinical and public health decisions.