Triazole-Resistant Aspergillus Fumigatus Cases Caused by Exposure to Fungicides

In patients with high-risk conditions that can escalate or complicate invasive aspergillosis, mortality currently exceeds 50%. The use of triazole antifungals have been a key weapon used by clinicians to improve survival chances in these patients.

However, triazole-resistant Aspergillus fumigatus has become more common and has led to increased treatment failure and mortality. Active triazole antifungals, including voriconazole, posaconazole, and itraconazole have improved clinical outcomes and are associated with fewer adverse events than amphotericin B.

In a new report published in the US Centers for Disease Control and Prevention’s (CDC) Morbidity and Mortality Weekly Report, the authors have determined that infections with triazole-resistant A fumigatus can occur in patients who did not have previous exposure to a medical triazole.

Triazoles with a similar structure are commonly used as fungicides in agriculture and other settings, where A fumigatus is commonly found in soil and material of decaying plants. If the fungicide is exposed to A fumigatus, resistance strains can emerge as a result and can put patients at risk.

In Europe, studies have identified 2 resistant A fumigatus genotypes associated with environmental triazole exposure—TR₃₄/L98H and TR₄₆/Y121F/T289A—which confer resistance to triazoles by altering the drug target, Cyp51A, which is involved in fungal cell wall synthesis.

“Importantly, TR₃₄/L98H confers resistance to all mold-active medical triazoles without incurring a fitness cost or survival disadvantage to the fungus,” the authors write about the European findings. “A fumigatus strains of this genotype have been isolated from the environment (e.g. compost, seeds, soil, commercial plant bulbs, and patient households).”

In 2011, the CDC initiated passive monitoring for triazole-resistant A fumigatus isolates in the United States by reaching out to clinical laboratories across the nation. This surveillance system identified 7 isolates of the TR₃₄/L98H markers that occurred between 2010 and 2017.

A total of 7 isolates were collected from 3 states: 4 from Pennsylvania, 2 from Virginia, 1 from California. Three of the isolates were collected from patients with invasive pulmonary aspergillosis and 4 patients had no known previous exposure to triazoles, suggesting the resistance was acquired through exposure to a resistant strain in the environment.

This is a critical point because it demonstrates that triazole-resistant strains have emerged in the United States in both patients and the environment. Additionally, the data in this article likely underrepresent the actual case count in the United States because aspergillosis and A. fumigatus colonization are not required to be reported to state health officials and few laboratories perform susceptibility testing.

Four of the 7 patients were not treated with antifungal therapy; therefore, those isolates likely reflect A fumigatus colonization rather than infection, however the presence of highly resistant strains suggests that US clinicians need to be aware of the risk for triazole-resistant aspergillosis.

The isolates identified in this report represent only 28% of all CDC A fumigatus isolates and were collected from patients who did not share health care facilities, procedures, or country of residence, arguing against shared health care acquisition.

One limitation of this report is that these data were collected through passive monitoring and we not part of active systematic surveillance, according to the authors; therefore, caution must be exercised when interpreting the findings.

The implications of these findings are that US clinicians and public health personnel should be aware that infections with triazole-resistant A fumigatus can occur in patients who have not previously been exposed to this form of medicine.

Future research is needed to understand the prevalence of these isolates to guide decision-making for clinicians treating immunocompromised patients.