EPA publishes interagency framework on antifungal and antibiotic resistance from pesticides

Background: FIFRA and antimicrobial pesticides

• Under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), the EPA is responsible for the regulation of pesticides in the United States. Under FIFRA, a pesticide must be registered with the EPA before it can be sold or distributed in the U.S., and during that process, the EPA determines whether the pesticide will cause unreasonable adverse effects on people or the environment.
• Antimicrobial pesticides are covered by FIFRA. The EPA defines an “ antimicrobial pesticide” as a substance “intended to disinfect, sanitize, reduce, or mitigate growth or development of microbiological organisms or protect inanimate objects, industrial processes or systems, surfaces, water, or other chemical substances from contamination, fouling, or deterioration caused by bacteria, viruses, fungi, protozoa, algae, or slime.” This ends up covering many products, including those not necessarily immediately thought of as “pesticides,” such as disinfectants or industrial microbiocide products.
• In addition to traditional pesticide registration requirements, antimicrobial pesticides also have a diverse set of additional requirements before the pesticide can be used or sold in the U.S. A registrant who wants to add a label claim that the product is effective against a specific microorganism must submit specific efficacy testing that demonstrates the effectiveness of the product. The EPA may also condition a registration on receipt of product samples for testing as well as documentation of any pre-submission consultations with the agency.
• A growing U.S. and global concern is antimicrobial resistance (AMR), which occurs when pathogenic bacteria, viruses, fungi and parasites acquire adaptations that confer resistance against commonly used medicines to treat infections caused by these pathogens. Although AMR can occur over time with genetic change, a main driver of AMR currently is misuse and overuse of antimicrobials, according to the World Health Organization. As pathogens become resistant to common, safe, inexpensive medicines, the armamentarium of effective therapies narrows, particularly in lower-resource areas.
• More than 3 million occur annually in the U.S., resulting in more than 35,000 deaths. The EPA is concerned about the usage of antibacterial and antifungal pesticides that are used in agriculture and other settings and how that may impact the effectiveness of antimicrobial drugs used on humans or animals, since animal-hosted AMR pathogens can drive AMR in human pathogens. Other federal agencies, including the Food and Drug Administration (FDA), are involved in AMR efforts through the “One Health” initiative, that approaches public health by addressing human, animal, and environmental health holistically. The National Antimicrobial Resistance Monitoring System, a collaborative public health surveillance system, uses a One Health approach to AMR monitoring.
• On September 26, 2023, the EPA announced a new concept for developing a proposed framework to improve assessments of potential risks to human and animal health when the usage of certain pesticides could compromise the effectiveness of antimicrobial drugs. The agency requested feedback on how the agency could better assess the potential risks to human and animal health from AMR that could be caused by exposure to antimicrobial or antifungal pesticides.

Draft framework

• On July 2, 2024, the EPA published a Federal Register notice announcing the draft framework’s availability and soliciting comment on the proposal. In the notice, the agency stated that it was issuing the framework for pesticide applicants, growers, the public health community, and the public to explain how it plans to consider resistance issues and what future regulations may take into account during the drafting process. However, the framework is not binding EPA policy, and the agency is therefore free to depart from it when it decides to.
• The framework begins by discussing its purpose and applicability, focusing on the potential adverse impacts of pesticides on AMR and the efficacy of human and animal drugs. The EPA explains that it has “significant unknowns” on the AMR risk front associated with the use of pesticides in the environment. The agency further explained that it had coordinated the framework with HHS, the USDA, and the White House Executive Office of the President.
• The framework also reviews the impetus for its publication, focusing on the costs and widespread proliferation of AMR infections each year in the U.S. The EPA notes that it is unable to quantify the percentage of U.S.-based fungal infections that come from antimicrobial resistant fungi. The EPA stated that for fungal pathogens, current research indicates that some antifungal pesticides may lead to resistant organisms that pose a threat to human and animal health.
• The EPA also proposed a process for future interagency collaborations on AMR topics. The agency plans to establish an Interagency Drug and Pesticide Resistance and Efficacy Workgroup (IDPREW), chaired by the EPA with participation from other agencies including the CDC, FDA, and USDA.
• The IDPREW workgroup would be convened whenever the EPA determines that a pesticide undergoing registration or reregistration may impact the efficacy of a human or animal antibacterial or antifungal drug. The EPA would then consult with IDPREW during the risk assessment process to determine what risks are posed to human antibacterial or antifungal drugs, and what application methods or restrictions could mitigate the risk to those drugs. The agency also floated the option of actions involving other types of pesticides that could trigger IDPREW review; for example, the group could convene to assess an herbicide that has a similar mode of action with an antibacterial or antifungal drug that could possibly cause co-resistance.
• EPA also noted that bacteria and fungi each present differing evaluation challenges, both biologically and behaviorally. Although the agency has developed processes for assessing the resistance risks associated with the use of antibacterial pesticides, the agency does not have the same level of knowledge, nor is the current process easily adaptable, to determining resistance risks posed by the use of antifungal pesticides. When feasible, the EPA plans to apply a weight-of-evidence approach to assess the potential risk posed by use of an antifungal pesticide.
• Overall, the framework represents only the first step for the agency in developing a better approach to determine the potential risks of antibacterial and antifungal pesticides. The EPA stated that it intends to incorporate future research and understanding on the mechanisms of resistance to better assess the potential for risk from antibacterial or antifungal pesticides.

Next steps

• The EPA has issued a research agenda to better prioritize understanding for resistance in risk assessments for antifungal or antibacterial pesticides, which will likely influence the agency’s science team as well as grant recipients for future studies. The agenda includes information on the scope and scale of antifungal product use in the environment, as well as learning more about resistant fungi.
• The agency also requested comment on the proposal, stating that it will consider feedback in its finalized framework. The agency plans to release the framework by “ the end of 2024.”

To contact the author of this analysis, please email Walker Livingston ( wlivingston@agencyiq.com).

To contact the editor of this analysis, please email Kari Oakes ( koakes@agencyiq.com).

Key Documents and Dates

• Pesticides; White Paper: Framework for Interagency Collaboration To Review Potential Antibacterial and Antifungal Resistance Risks Associated With Pesticide Use; Notice of Availability and Request for Comment (July 2, 2024) (AgencyIQ link)
• Framework for Interagency Collaboration to Review Potential Antibacterial and Antifungal Resistance Risks Associated with Pesticide Use (July 2, 2024)
• Pesticides; Concept for a Framework To Assess the Risk to the Effectiveness of Human and Animal Drugs Posed by Certain Antibacterial or Antifungal Pesticides; Notice of Availability and Request for Comment (September 26, 2023)