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Introduction1
As the use of antimicrobials in agriculture has become a globally widespread and standard practice, the impacts on human, animal, and ecosystem health have become more pronounced. Antimicrobial resistance (AMR) is now one of the most pressing global health threats as microbes affecting humans, animals, and plants become less responsive to standard treatments (WHO, 2021). The use of fungicides that belong to the same chemical class as antifungal medicines in crop production is an area of concern that has garnered the attention of global health entities such as the World Health Organization (WHO) and U.S. Department of Health and Human Services (HHS, 2021; WHO, 2021). Use of these fungicides in agriculture may promote the development of resistant fungi in the environment that could have implications for human health. However, several questions remain as to the practices that promote resistance, the effects of resistant fungi in the environment, and how this phenomenon might affect human health.
For decades, antimicrobials have been the cornerstone of control and treatment of many diseases in humans, animals, and plants alike. Fungal plant pathogens rarely infect animals and humans; however, some have been known to cause disease in immune-compromised people or animals, and several plant pathogenic fungi produce toxins that are harmful to humans
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1 The planning committee’s role was limited to planning the workshop, and the Proceedings of a Workshop has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, and are not necessarily endorsed or verified by the National Academies of Sciences, Engineering, and Medicine, and they should not be construed as reflecting any group consensus.
and animals (WHO, 2018). Furthermore, these plant pathogens share the same environment with saprotrophic fungi that can also cause opportunistic infections in susceptible individuals. Antimicrobials are widely used in crop agriculture to protect plants from yield- or quality-limiting diseases. Recent estimates indicate that 20–40 percent of global crop production is lost to pre- and post-harvest diseases and pests, with climate change predicted to worsen this destruction (FAO, 2021a; Savary et al., 2019). Fungi and oomycetes cause the majority of plant diseases, and fungicide use is common in commercial crop production and landscaping, as well as in home gardening. While limiting the use of antimicrobials is foundational to mitigating AMR, steps to address this issue must be balanced with the need to address diseases and infections that threaten agricultural production. Food production, human health, and environmental stability depend on sustainable solutions for mitigating diseases that affect crops while reducing risk of AMR (FAO, 2016).
Although fungi can cause a spectrum of human infections, systemic antifungal therapies available for use in human and veterinary medicine are limited. Of the three drug classes currently used to treat systemic infections, azoles are the most diverse class of antifungals. Several different azole compounds and formulations are also used to control fungal diseases in plants. Widespread and long-term use of azoles on crops has resulted in the selection of fungal phytopathogens and saprophytes (i.e., environmental isolates) that are resistant to these fungicides. Although the same agents are not employed for medical purposes, structural similarities of these compounds that belong to the same chemical class give rise to concerns that the use of these fungicides could result in cross-resistance with azoles reserved for use in human medicine. Aspergillus fumigatus (A. fumigatus), an environmental fungus that can cause aspergillosis (a lung infection) in humans, is primarily treated with azole antifungal drugs. Azole-resistant A. fumigatus is much more difficult to treat and results in higher chances of patient death (CDC, 2021a). Although more research is required, this example demonstrates how human health can be affected by AMR that may have arisen through agricultural practices.
In the United States and other high-income countries, the sale and use of fungicides is regulated based on efficacy evaluation and risk assessments for human health and the environment (EPA, 2022). U.S. statistics on pesticide use are generated from self-reporting by farmers responding to surveys or specific census requests.2 In contrast, regulations for pesticide use in low- and middle-income countries (LMIC) may be less stringent or not fully enforced due to lack of capacity. Additional surveillance is required to
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2 U.S. Department of Agriculture survey data and reports are available at https://www.nass.usda.gov (accessed August 31, 2022).
gain a better understanding of how pesticides are used globally, how their use influences AMR, and how human and plant pathogens interact to affect various aspects of health.
Various strategies have been developed to prevent or mitigate AMR development in agriculture to limit its deleterious effects on crop production. “Integrated pest management” (IPM) is an approach to reduce the use of antimicrobials in conventional plant production systems and maintain their effectiveness. A systems approach, IPM is designed to minimize economic losses to crops, as well as risks to people, animals, and the environment. The main components of IPM for plant diseases are (1) accurate diagnosis and monitoring, which can also include disease modeling and predictive systems to guide the timing of pesticide applications, (2) use of disease-resistant crop varieties, (3) exclusionary practices that prevent the introduction of pathogens into a crop, (4) site selection and soil improvement to maximize plant health and minimize environmental factors that favor pathogens, (5) crop rotation and other cultural practices to prevent pathogen buildup, (6) use of biological and biorational products, and (7) judicious use of pesticides, including both antibiotics and fungicides.
While promising, the successful implementation of IPM and other approaches to counter the spread of AMR from agricultural practices hinges on closing several critical knowledge gaps. These include accurate measurements of antimicrobial use and their regulatory guidance in different contexts (e.g., high-income countries vs LMICs), understanding of AMR mechanisms in the environmental microbiota that may be consequential for human health, and data on the effectiveness of current surveillance tools and systems. This public workshop series will provide an opportunity for researchers and policy makers working at the intersection of plant, animal, and human health to share the latest knowledge, advance the ongoing discussions, and explore ideas that can improve the mitigation strategies to contain the spread of AMR.
In opening remarks, Paige Waterman, interim chair of medicine and vice chair for clinical research at the F. Edward Herbert School of Medicine at the Uniformed Services University of the Health Sciences, Bethesda, emphasized that the workshop represents a collaboration of experts across the spectrum of infectious diseases in humans, plants, animals, and microbiomes. Antimicrobials have both beneficial and harmful effects on humans, animals, and environment. As the global population continues to adjust to the ramifications of SARS-CoV-2, AMR poses a pressing global health threat, according to WHO and other expert entities. She remarked that antimicrobials, including antifungals, play a critical role in the control and treatment of human and animal diseases and in preventing diseases in plants. Although fungi cause a majority of plant diseases, antifungal stewardship in limiting or moderating the use of antifungals is needed to
limit further resistance in humans, animals, and plants. This workshop provided an opportunity to bridge gaps in combined knowledge about antifungal resistance and identify connections between the environment, plant agriculture, and human health in mitigation approaches.
WORKSHOP OBJECTIVES
On June 21, 22, and 27, 2022, the Forum on Microbial Threats at the National Academies of Sciences, Engineering, and Medicine held a 3-part public workshop series titled The Role of Plant Agricultural Practices on Development of Antimicrobial Resistant Fungi Affecting Human Health. The first two parts were virtual meetings, and the third was a hybrid meeting held in Washington, DC. The aims of the workshop were to consider (1) the magnitude of environmentally induced/selected AMR in agricultural practices worldwide, with a focus on plant crop production, (2) the practices that contribute to AMR in human pathogens, (3) surveillance strategies, and (4) mitigation strategies. The workshop featured invited presentations and discussions to explore the following questions:3
- What is the magnitude of antifungal use in crop production in high-, middle-, and low-income countries? How are such uses regulated?
- What are the mechanisms of AMR in plant pathogens and non-target environmental microbiota? How might this influence AMR in human pathogens?
- Which practices promote, prevent, or reduce the development of AMR in plant production environments, specifically in fungal pathogens? How does this affect risk of produce contamination with AMR pathogens?
- Are sampling and testing technologies for AMR surveillance in plant production systems adequate? What further evidence is needed to inform the use of antimicrobials worldwide? What further evidence is needed to understand the presence and effects of environmental AMR on human health?
ORGANIZATION OF THE PROCEEDINGS OF THE WORKSHOP
In accordance with the policies of the National Academies, the workshop did not attempt to establish any conclusions or recommendations about needs and future directions, focusing instead on information
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3 The full Statement of Task is available in Appendix A. The workshop agenda is provided in Appendix B.
presented, questions raised, and improvements suggested by individual workshop participants. Chapter 2 focuses on fungal disease, antifungal drugs, fungicide use in agriculture, and efforts to address AMR. Chapter 3 features an overview of fungal disease in humans, the emergence of antifungal-resistant infections, and implications and challenges in effectively treating these diseases. Chapter 4 explores the development of resistance in response to the agricultural use of fungicides. Chapter 5 discusses the role of fungicides in producing an adequate and safe food supply. Chapter 6 highlights efforts to assess the extent and causes of fungal drug resistance and the role of regulatory bodies in addressing it. Chapter 7 explores nontraditional approaches to AMR research, including community science, simulation modeling, and network modeling. Chapter 8 focuses on research investigating the association between the use of agricultural fungicides and the emergence of antifungal-resistant infections, the factors contributing to the risk of cross-resistance, and mitigation efforts. Chapter 9 discusses the role of resistance in driving a continued need for new antifungal drugs, particularly those featuring novel modes of action, and the challenges inherent in antifungal discovery and development. Chapter 10 highlights agricultural technologies and strategies to mitigate the threat of resistance by reducing the use of fungicides and addressing conditions that foster development of resistant fungi.
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