- An extremely common type of fungus found indoors and outdoors could harm the lungs of immunocompromised individuals.
- These molds are becoming increasingly drug-resistant, making infections harder to treat.
- Genetic analysis of a new study finds that the widespread presence of agricultural antifungals in the environment is the cause of this growing drug resistance.
The fungus Aspergillus fumigatus is everywhere. The mold is so common both indoors and outdoors that most people inhale and exhale some of it on a daily basis to no ill effect.
For about 10 to 20 million people globally who have compromised immune systems, however, its spores remain in the lungs, and if it progresses into aspergillosis, these spores can cause lung infections, allergic reactions, and infections in other organs.
The preferred treatment of aspergillosis is the administration of azole antifungal drugs. However, in recent years, the fungus has become progressively more resistant to these medications.
A new study led by researchers at Imperial College London has found that azole antifungals left in the environment from long-time agricultural use could be the cause of drug-resistant Aspergillus fumigatus.
Imperial’s Dr. Johanna Rhodes, who was the lead author of the study, tells Imperial College London News, “Increasingly, the cases of aspergillosis seen in the clinic are resistant to first-line azole drugs.”
“Understanding the environmental hotspots and genetic basis of evolving fungal drug resistance needs urgent attention because resistance is compromising our ability to prevent and treat this disease,” notes the study’s senior author Professor Matthew Fisher.
“The prevalence of drug-resistant aspergillosis has grown from negligible levels before 1999 to up to 3-40% of cases now across Europe.”
— Prof. Matthew Fisher
Adding to the sense of urgency is a growing number of vulnerable people, particularly since the pandemic.
“At the same time, more and more people might be susceptible to Aspergillus fumigatus infection because of growing numbers of people receiving stem cell or solid organ transplants, being on immunosuppressive therapy, or having lung conditions or severe viral respiratory infections,” adds Prof. Fisher. Among these respiratory infections is COVID-19.
The study is published in the journal Nature Microbiology.
Azole antifungals are 14-alpha demethylase inhibitors. There are more than 25 different varieties of azoles, with which farmers have been protecting crops from fungal diseases for decades.
Dr. Takahiro Takazono, assistant professor at the University of Nagasaki in Japan, who was not involved in the study, told Medical News Today:
“There are other classes of antifungals for filamentous fungi… However, the route of administration of these antifungals is only intravenous. Azoles are [the] only oral antifungal so far.”
He also noted that there may be a new alternative to azoles currently under clinical trial.
Identifying drug resistance
Researchers collected 218 Aspergillus fumigatus isolates from 2005 to 2017 across England, Wales, and Scotland. Roughly 7 in 10 of the molds, or 153 samples, came from 143 patients in five hospitals. The remaining 65 samples came directly from the environment.
Nearly half, 48% or 104 samples, proved resistant to itraconazole, the most commonly used azole antifungal.
The remaining drug-resistant samples included 64, or 29%, that were resistant to voriconazole, with 21% resistant to posaconazole, two other azole antifungals.
Over 10%, or 23 environmental samples and 3 from patients, were resistant to two or more azole medications.
To establish possible connections between the two sets of samples, the researchers extracted and sequenced DNA from the molds.
Genetic comparison of the samples revealed that six Aspergillus strains found in the environment had infected six patients.
The study describes their patient and environmental samples as “genetically very highly related.”
The mechanism of developing resistance
“The spores of Aspergillus are floating in the air everywhere,” said Dr. Takazono.
“[Aspergillus fumigatus spores] can be easily spread by the wind. Another possibility is that the spores (within the soil) attach to agricultural products and can be spread to the daily life of an immunocompromised host.”
— Dr. Takahiro Takazono
“We’ve not been sure how patients are acquiring these infections, whether they develop in the lungs during treatment for the infection, or whether the mold spores that infect them are drug-resistant in the first place,” says Dr. Rhodes.
“Our study finds that both routes of infection are possible and confirms concerns that pre-resistant mold spores in the environment are able to enter and infect people’s lungs, causing harder-to-treat disease,” he adds.
According to the study, the findings demonstrate that “at-risk patients were infected by isolates that have pre-acquired their resistance to azoles in the environment” since research so far has not shown patients transmitting their Aspergillus fumigatus to the environment.
A new type of resistance
Genetic analysis divided the samples into two distinct groups or “clades.” Clade A contained 123 isolates, and Clade B 95. About 80% of Clade A samples were drug-resistant, while 87% of Clade B’s samples were not.
Separate as the two clades were, however, the researchers found indications that they could swap genetic material, allowing for novel drug-resistant genetic combinations.
“These findings point to the existence of new resistance mechanisms with an underlying polygenic basis and show that further understanding [of] the role of accessory genes in generating drug-resistant phenotypes is needed,” the authors write.
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