Aspergillus on a tomato. Image: Multimotyl/Wikimedia Commons, CC BY-SA 3.0
- Several fungal species of the genus Aspergillus can cause respiratory infections. These infections have a high mortality rate, around 50-80%.
- Patients are treated with appropriate antifungal drugs – although only a limited number are available. Triazoles among them are the first choice.
- But scientists have been able to isolare azole-resistant Aspergillus strains from patients who have never been exposed to these drugs before.
- The implication is that azole-resistant Aspergillus strains are emerging in the environment and infecting the general population.
- The most feasible explanation of this baffling phenomenon is exposure to azole fungicides used to protect crops and produce from fungal diseases.
Respiratory fungal infections were considered rare until the mid-20th century. Usually, these infections were known to occur in patients with a compromised immune system. But the incidence of such infections has been increasing worldwide, and of late more rapidly.
One of the major reasons is a concomitant increase in the number of immunocompromised individuals. People suffering from fatal conditions like liver failure or cancer are treated with medicines that impair the immune system. Organ transplants, chemotherapy and radiation therapy also compromise the system of patients for brief or extended periods. People with HIV/AIDS are also immunocompromised.
Several fungal species of the genus Aspergillus can cause respiratory infections, including chronic pulmonary aspergillosis, invasive aspergillosis, bronchitis, allergic bronchopulmonary aspergillosis and severe asthma. Aspergillosis infections have a high mortality rate, around 50–80%.
Patients can however be treated with the appropriate antifungal drugs – although only a limited number of these drugs are available.
Triazoles among them are the first choice to treat Aspergillus infections in humans. They have been widely used since the 1970s. But there is a problem: the number of instances of Aspergillus infections resisting treatment by triazoles has been increasing worldwide. This resistance is often conferred by the presence of mutations in a key gene (cyp51), which is involved in synthesising the fungal cell wall.
In clinical settings, microorganisms become resistant to drugs after prolonged exposure. Such exposure happens when people overuse or misuse antibiotics. Antibiotic resistance in bacterial pathogens will definitely be the next pandemic to afflict the human population. So it makes sense when azole-resistant Aspergillus strains are isolated from patients who are undergoing chronic azole therapy. This mode of development of resistance is called the ‘patient route’.
But there appears to be a more surprising alternative route: the isolation of azole-resistant Aspergillus strains from patients who have never been exposed to these drugs before. Such individuals are called ‘azole-naïve’. The implication is that azole-resistant Aspergillus strains are emerging in the environment and infecting the general population.
The global prevalence of environmental azole-resistant Aspergillus strains is a major concern for everyone – but the worst-affected group is immunocompromised individuals.
Why are fungi present in the environment, such as Aspergillus, are becoming resistant to a drug that is used in clinical settings?
The most feasible explanation of this baffling phenomenon is that azole fungicides are used to protect crops and produce from fungal diseases. Their unregulated use, especially to increase yields, is thus jeopardising public health in an unexpected manner.
Of the 38 registered fungicides in India, 14 are azoles. Five of them have a molecular structure that resembles that of their medical counterparts. The mechanism of action of these drugs is also similar in human and plant pathogens. Azoles are also highly stable compounds that can persist in the environment because they resist biodegradation.
So when fungal pathogens are exposed to high concentrations of azoles in the environment, they become resistant to the life-saving drugs. (The unregulated use of antifungals also exerts a selection pressure that encourages pathogens to evolve new mechanisms of resistance.) When these strains infect susceptible individuals, the resulting disease is untreatable with existing azole drugs. The result is greater mortality as well as clinicians being compelled to choose other antifungals, many of which are more toxic and have serious side effects.
The idea that Aspergillus species were becoming azole-resistant due to agricultural fungicides first emerged out of studies in the Netherlands. Thereafter, varying rates of azole-resistant Aspergillus have been documented across the world. In India, 64-71% of multi-triazole resistant strains have been isolated from patients suffering from Aspergillus infections who were never exposed to triazole treatments.
The risk for patients from multi-azole-resistant strains from the environment could seriously affect the management of life-threatening invasive fungal infections. We need wider monitoring of azole resistance; environmental surveillance studies of azole resistance (to understand the prevalence of resistant strains); studies to understand the way to mitigate exposure to azole fungicides; and good agricultural management practices.
Maansi Vermani Sarin, PhD is a biotechnology educator and researcher. She is a freelance scientific writer and editor from New Delhi.