Call for concern over the use of the new agricultural fungicide, ipflufenoquin, in Australia.
The Australia and New Zealand Mycoses Interest Group (ANZMIG), of the Australasian Society for Infectious Diseases (ASID), is advocating for a One Health approach to address significant concerns regarding the use of the new agricultural fungicide compound – ipflufenoquin - in Australia.
To this end, it seeks dialogue with the Australian Pesticides and Veterinary Medicines Authority (APVMA).
1. Use of ipflufenoquin in Australia
• ANZMIG notes the APVMA’s approval and recent, restricted, registration of the fungicide, ipflufenoquin, to protect strawberry crops against fungal diseases.
• In particular, ipflufenoquin is designed to target Botrytis cinerea, a plant fungal pathogen that causes plant rot in crops including grapes, strawberries, and tomatoes. B. cinerea is notable for its propensity to develop resistance by multiple mechanisms upon exposure to fungicides.
“Ipflufenoquin has a similar structure and mode of action to the novel antifungal drug, olorofim, a new medication specifically developed for human use. Olorofim is a critical addition to the antifungal armamentarium because in 2024, there are no other effective antifungal treatments for a number of highly resistant fungal infections. In this context, the demonstration of ipflufenoquin-induced cross-resistance to olorofim in fungal pathogens is very concerning.”
2. What is the evidence for concern over the use of ipflufenoquin?
As noted In the APVMA evaluation summary for ipflufenoquin, concerns for ipflufenoquin use include:
• long duration of persistence of the agent in the natural environment.
• selection pressure that is likely to drive fungicide resistance over time with an acknowledgement of potential impacts for agricultural crop losses (see ref 1)
• The human health risk assessment of theoretical toxicity risks (footnote 1 and ref 2) makes no reference to an assessment of the additional and potentially high risk of inducing antifungal drug resistance. Note ref 3.
In human and veterinary practice ipflufenoquin-induced drug resistance is worrying because:
• Many human and animal fungal pathogens reside in soil/agricultural environments and when exposed to ipflufenoquin during crop spraying are likely to develop ipflufenoquin resistance.
• Humans and animals will subsequently become infected by these drug-resistant fungi.
• Recent research has documented that exposure to ipflufenoquin in Aspergillus fungi spurs the rapid evolution of resistance to olorofim (ref 1), the new antifungal expected to be a frontline treatment for otherwise untreatable human infections (ref 4)
• It Is highly likely that similar induction of cross-resistance will occur on ipflufenoquin exposure of additional human fungal pathogens present in soil/agricultural environments, such as Lomentospora prolificans and Scedosporium.
• Globally, Australians suffer a disproportionately high number of infections due to the highly resistant L. prolificans and related fungi, which are deadly and have no other effective treatment options. The mortality in persons with cancer, transplantation and other types of immunosuppression approaches 100% (ref 5)
• Olorofim is currently effective against these fungal pathogens (ref 4).
ASID’s mycology experts are concerned that cross resistance to olorofim induced by ipflufenoquine use poses a critical danger to the deployment of olorofim as a lifesaving medicine in both human and veterinary health - noting in particular that this fungicide persists in the environment for a relatively long duration, increasing the likelihood of inadvertently inducing resistance in off-target pathogens.
To this end, ANZMIG is calling for immediate cessation of the use of ipflufenoquin to preserve the efficacy of olorofim, the first member of a new antifungal drug class, for the treatment of life-threatening human invasive fungal infections.
Specifically, ANZMIG requests policymakers and regulators to:
• Pause the approval of ipflufenoquin for agricultural use until the risks of cross-resistance are further understood.
• Develop a risk management framework that evaluates the likelihood of cross-resistance emerging between new agricultural antimicrobials and existing clinical agents that is protected under legislation.
References
1. van Rhijn N, Storer ISR, Birch M, Oliver JD, Bottery MJ, Bromley MJ. Aspergillus fumigatus strains that evolve resistance to the agrochemical fungicide ipflufenoquin in vitro are also resistant to olorofim. Nat Microbiol. 2024 Jan;9(1):29-34. doi: 10.1038/s41564-023-01542-4. Epub 2023 Dec 27. PMID: 38151646; PMCID: PMC10769868.
2. Australian Pesticides and Veterinary Medicines Authority 2023. Public Release Summary on the evaluation of ipflufenoquin in the product MIGIWA Fungicide APVMA product number 91333. Available from: https://www.apvma.gov.au/sites/default/files/publication/108271-public_release_summary_on_the_evaluation_of_ipflufenoquin_in_the_product_migiwa_fungicide.pdf
Footnote 1 The only mitigation actions advised in reference to the development of fungicide resistance is a disclaimer of liability for crop loss from the manufacturer of ipflufenoquin.
3. Australian Government Department of Health / Department of Agriculture Water and the Environment, 2019. Australia’s National Antimicrobial Resistance Strategy – 2020 and Beyond. Available from: Available from: https://www.amr.gov.au/sites/default/files/2022-11/ ustralia-s-national-antimicrobial-resistance-strategy-2020-and-beyond_0.pdf
4. Hoenigl M, Arastehfar A, Arendrup MC, Brüggemann R, Carvalho A, Chiller T, Chen S, Egger M, Feys S, Gangneux J, Gold JAW, Groll AH, Heylen J, Jenks JD, Krause R, Lagrou K, Lamoth F, Prattes J, Sedik S, Wauters J, Wiederhold NP, Thompson GR. Novel antifungals and treatment approaches to tackle resistance and improve outcomes of invasive fungal disease. Clin Microbiol Rev 0:e00074-23. https://doi.org/10.1128/cmr.00074-23
5. Neoh CF, Chen SCA, Crowe A, Hamilton K, Nguyen QA, Marriott D, Trubiano JA, Spelman T, Kong DCM, Slavin MA. Invasive Scedosporium and Lomentospora prolificans Infections in Australia: A Multicenter Retrospective Cohort Study. Open Forum Infect Dis. 2023 Feb 8;10(2):ofad059. doi: 10.1093/ofid/ofad059. PMID: 36861090; PMCID: PMC9970007.
Media Contact: Alison Sweeney alison@asid.com.au or 0425 221 155.