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Published in final edited form as: Drug Resist Updat. 2022 Oct 20;65:100885. doi: 10.1016/j.drup.2022.100885

Dual use of antifungals in medicine and agriculture: How do we help prevent resistance developing in human pathogens?

Paul E Verweij a,b,*, Maiken C Arendrup c,d,h, Ana Alastruey-Izquierdo e, Jeremy AW Gold f, Shawn R Lockhart f, Tom Chiller f, PLewis White g
PMCID: PMC10693676  NIHMSID: NIHMS1943354  PMID: 36283187

Abstract

Azole resistance in Aspergillus fumigatus is a One Health resistance threat, where azole fungicide exposure compromises the efficacy of medical azoles. The use of the recently authorized fungicide ipflufenoquin, which shares its mode-of-action with a new antifungal olorofim, underscores the need for risk assessment for dual use of antifungals.

Keywords: Aspergillus fumigatus, DHODH inhibitor, One Health, triazole resistance, olorofim

Considering the interconnectedness of humans, animals, and the environment can foster our health and continued existence. Antimicrobial resistance (AMR) is a complex challenge that could benefit from a One Health perspective. In recent decades, AMR policies have focused on bacterial resistance and animal-environment-human interface, with limited attention to fungal resistance. However, the emerging threat of fungal resistance is increasingly recognized by public health institutes. The U.S. Centers for Disease Control 2019 Antibiotic Resistance Threats Report and the World Health Organization (WHO) Fungal Priority Pathogen List include Candida auris as an urgent public health threat (CDC, www.cdc.gov) and recently added azole-resistant Aspergillus fumigatus to the pathogen watchlist (WHO, www.who.int).

The dual use of azoles in the environment and in the clinic has been shown to be an important driver for azole-resistant A. fumigatus infections in humans (Snelders et al. 2012; Fisher et al., 2022). Recent surveillance studies show resistance rates varying between 1.4 % and 11.4 % in clinical A. fumigatus isolates, which predominantly (72 %, 95 % CI: 69–74) involve resistance mutations associated with environmental resistance selection (Table 1). Triazole fungicides and medical azoles share structural characteristics and therefore, mutations in the cyp51A target gene confer cross-resistance (Snelders et al., 2012). Although not a plant pathogen, A. fumigatus is environmentally ubiquitous and inevitably exposed to azole fungicides used for crop protection (Verweij et al., 2009). A. fumigatus thrives on decaying plant material and becomes resistant in the presence of azole fungicide residues (Schoustra et al., 2019). In addition to agricultural practices, substantial contamination of residential gardens with tebuconazole-resistant A. fumigatus was recently shown in a U.K.-wide study (Shelton et al., 2022). Migration of resistance through horticultural products and dispersal of Aspergillus conidia with air currents has facilitated global spread and make control difficult (Dunne et al., 2017; Fisher et al., 2022). Adaptation to azole stress may also drive other adaptations potentially leading to increased virulence in host infection (Fisher et al., 2022). Current clinical implications of azole resistance are significant with 25 % day-90 excess mortality in patients with voriconazole-resistant invasive aspergillosis who were treated with voriconazole (Lestrade et al., 2019). Azoles are the first-line treatment and currently the only oral option for A. fumigatus infections, and few alternative treatment options exist for azole-resistant aspergillosis (Ostrosky-Zeichner et al., 2010; Verweij et al., 2015).

Table 1.

Azole resistance rates in clinical A. fumigatus isolates in recent surveillance studies.

Continent Country;
Years		 Prevalencea Characteristicsb Reference
Europe Denmark; 2018–2020 6.1 % (66/1083) National surveillance TR34 (39/66; 59 %) Risum et al., 2022
Belgium; 2016–2020 7.1 % (85/1192) Single center TR34 (74/78; 95 %) Resendiz-Sharpe et al., 2021
Netherlands; 2018–2021 9.2 % (567/6134) Multicenter (10 centers) TR34 (392/660; 59 %); TR46 (132/660; 20 %) https://swab.nl/nl/nethmap
Turkey; 2018–2019 3.3 % (13/392) Multicenter (21 centers) TR34 (9/19; 47 %) Ener et al., 2022
France; 2017 2.1 % (4/195) Single center No TR resistance mechanisms Simon et al., 2021
Switzerland; 2018–2019 1.4 % (3/365) Multicenter (7 centers) TR34 (3/3; 100 %) Ragozzino et al., 2021
Italy; 2016–2018 6.6 % (19/286) Multicenter, isolate denominator TR34 (12/19; 63 %) Prigitano et al., 2021
Spain; 2019 4.7 % (34/725) Multicenter TR34 (19/34; 56 %); TR46 (1/34; 3 %) Escribano et al., 2021
Americas USA; 2015–2020 3.5 % (73/2072) Multicenter, isolate denominator TR34 (7/73; 10 %); TR46 (7/73; 10 %) Badali et al., 2022
Martinique; 2014–2018 11.4 % (4/35) Single center, isolate denominator TR34 (1/4; 25 %) Monpierre et al., 2021
Asia China; 2019–2020 4.1 % (3/73) Single center, patients with IA. TR46 (2/3; 67 %) Wang et al., 2022
China; 2009–2019 4.3 % (19/445) Single center TR34 (4/19; 21 %); TR46 (3/19; 16 %) Yang et al., 2021
China; 2016–2018 7.0 % (4/57) Two hospitals TR46 (1/4; 25 %) Xu et al., 2020
Taiwan; 2015–2020 1.8 % (2/113) Single center TR34/L98H (2/2; 100 %) Hsu et al., 2022
Open in a new tab
a

Number of patients with a positive A. fumigatus is used as denominator, unless stated otherwise.

b

TR34 and TR46 refer to the genetic background of the resistance mutations. IA, invasive aspergillosis.

Developing antifungal drugs is challenging because of the homology of drug targets between fungal and human eukaryotic cells (Ostrosky-Zeichner et al., 2010). However, researchers have recently discovered the orotomide class, which targets the biosynthesis of pyrimidines by inhibiting the key enzyme dihydroorotate dehydrogenase (DHODH) (Oliver et al., 2016). Olorofim, an orally available drug currently undergoing clinical evaluation, is the first member of its class to show promising in vitro and in vivo activity against azole-resistant A. fumigatus and other difficult-to-treat mold infections (Jørgensen et al., 2018; Hoenigl et al., 2021). The U.S. Food and Drug Administration granted breakthrough drug therapy designation and orphan drug designation to olorofim for the treatment of invasive aspergillosis (FDA, www.fda.gov), reflecting the potential improvement the drug may offer over existing therapies.

We can learn from the One Health azole-resistant A. fumigatus challenge to preserve the clinical efficacy of new modes of action (MoA). Evaluating the use of similar compounds in medical and non-medical applications and incorporating an assessment of risk to human and animal health during the authorization process could prevent an environmental route of resistance selection for novel classes. Of concern is the use of the recently authorized fungicide ipflufenoquin (EPA, www.epa.gov). The Fungicide Resistance Action Committee (FRAC) has classified ipflufenoquin as a DHODH inhibitor, meaning ipflufenoquin shares its MoA with olorofim (FRAC, www.frac.info). Furthermore, the risk of resistance selection by ipflufenoquin is considered moderate to high, suggesting a potential human health concern.

Preliminary in vitro susceptibility testing of 21 Aspergillus isolates indicated that olorofim and ipflufenoquin display in vitro activity against all but four and five Aspergillus spp. isolates, respectively (Table 2). With all four isolates in Section Aspergillus demonstrating high MIC values to olorofim and 3/4 of these isolates also potentially resistant to ipflufenoquin which also appeared to be ineffective against A. niger at both 50 % and 100 % growth inhibition endpoints (Table 2)(Materials and methods are shown in supplementary material). In general, a good correlation was observed between the in vitro activity against Aspergillus spp., with A. sydowii, A. flavus and A. terreus species complex (sc) being most susceptible and A. nidulans sc, A. niger sc, A. calidoustus, Section Aspergillus being the least susceptible species. This was not the case comparing MICs against 16 other mold spp. with the exception of both agents being inactive against the Rhizopus microsporus, in agreement with the DHODH drug target being absent in Mucorales (Table S1).

Table 2.

Comparison of the in vitro activity of two DHODH inhibitors, olorofim and ipflufenoquin against Aspergillus species determined according to the EUCAST E.Def 9.4 with a complete inhibition endpoint and by applying a partial (50%) growth inhibition endpoint.

Inhibition endpoint criteria and species (n) Olorofim MIC (mg/L)
 Ipflufenoquin MIC (mg/L)
0.002 0.004 0.008 0.016 0.03 0.06 0.125 0.25 0.5 1 2 > 4 0.06 0.125 0.25 0.5 1 2 4 8 16 32 > 32
Visual complete inhibition
A. sydowii (2) 1 1 2
A. flavus SC (2) 1 1 1 1
A. terreus SC (2) 2 1 1
A. fumigatus SC* (5) 1 1 3 1** 1** 1 2
A. nidulans SC (2) 2 2
A. niger SC (2) 1 1 2
A. calidoustus (2) 2 2
Section Aspergillus# (4) 4 1 3
Spec. 50% inhibition
A. sydowii (2) 1 1 1 1
A. flavus SC (2) 1 1 2
A. terreus SC (2) 1 1 1 1
A. fumigatus SC * (5) 1 4 4 1
A. nidulans SC (2) 2 1 1
A. niger SC (2) 1 1 2
A. calidoustus (2) 1 1 1 1
Section Aspergillus# (4) 4 1## 3
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#

One A. montevidensis, one A. chevalieri, two A. intermedius.

##

one A. chevalieri.

*

Two A. fumigatus Cyp51A wild-type, one A. fumigatus Cyp51A TR34/L98H, and two A. hiratsukae.

**

Two A. hiratsukae.

On the basis of drug concentration (mg/L), olorofim was more potent against Aspergillus (MIC50 0.016/0.06 mg/L with 50 % and complete inhibition endpoints, respectively) than ipflufenoquin (MIC50 2/4 mg/L). With the difference slightly larger for A. fumigatus sensu stricto (MIC50 0.016/0.06 mg/L for olorofim versus MIC50 2/16–32 mg/L for ipflufenoquin). Our data suggest an overall similarity between the medical DHODH inhibitor olorofim and the agricultural pesticide ipflufenoquin against Aspergillus spp., supporting the concern that ipflufenoquin use may cause cross-resistance to olorofim in Aspergillus. However, the ability of ipflufenoquin to select for olorofim resistance and associated mutations in the target PyrE-gene would need to be demonstrated. If confirmed, environmental monitoring programs are needed to determine if resistance selection in A. fumigatus occurs in the field.

In addition to orotomides, other new MoA’s are in clinical development, including fosmanogepix, an inhibitor of fungal protein Gwt1. Pyridine fungicides that target this same enzyme, such as aminopyrifen, are in development with a potential risk for cross resistance emerging in human fungal pathogens (Hatamoto et al., 2019).

Increased emphasis and inclusion of antifungal resistance by research and surveillance programs could help inform policymakers about the risks and benefits of antifungal applications. For example, global action plans involving the quadripartite WHO, Food and Agriculture Organization of the United Nations, World Organization for Animal Health, and the UN Environment Progamme, could address risk assessment strategies for new MoA in relation to the development of cross-resistance in medically relevant (non-target) fungi. International surveillance programs could detect and monitor trends in AMR, especially those taking a combined One Health approach, but need to incorporate antifungal resistance. The incorporation of fungi in the Strategic Research and Innovation Agenda of the Joint Programming Initiative on AMR (JPIAMR) represents a first step to address urgent questions related to fungal AMR (Fisher et al., 2022). Leading international mycology societies, including the European Confederation for Medical Mycology (ECMM), the International Society for Human and Animal Mycology (ISHAM), the Mycoses Study Group Education and Research Consortium (MSGERC), and the ESCMID Fungal Infection Study Group (EFISG), have endorsed the need to prioritize One Health antifungal resistance research and policies that protect antifungal drugs developed for treatment of fungal diseases and to incorporate these into the early steps of fungicide development. Furthermore, fungicide producers are also stakeholders that need to take responsibility for safeguarding crop protection without unintended effects for human health. In order to complete our understanding of the One Health perspective, it is imperative that they are involved in future discussions on managing this critical issue. Together, these actions may help to curb fungal AMR on a global scale.

Supplementary Material

supplemental materials

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Footnotes

Disclaimer

The findings and conclusions of this paper are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention (CDC).

Declaration of Competing Interest

Paul E Verweij declares grants from F2G and Gilead Sciences and payments for lectures and advisory boards by F2G, Gilead Sciences, Pfizer and Mundipharma. All payments to institute. Maiken C Arendrup, Ana Alastruey-Izquierdo, Jeremy A W Gold, Shawn R Lockhart, and Tom Chiller declare no competing interests. P Lewis White declares grants from F2G, CERBA, IHMA, payments for lectures and advisory boards by F2G, Gilead Sciences, and Pfizer, and support for travel from OLM.

Appendix A. Supporting information

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.drup.2022.100885.

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