Use of Clotrimazole in Finfish Aquaculture: Mechanistic Insights, Limitations, and Future Directions for Antifungal Therapy

ABSTRACT Fungal infections, including saprolegniasis and opportunistic mycoses, pose persistent challenges in aquaculture, driving the search for effective and safe antifungal agents. Clotrimazole (CLO), a clinically established imidazole, exhibits broad‐spectrum antifungal activity by inhibiting sterol 14α‐demethylase, disrupting ergosterol biosynthesis, and compromising fungal cell membrane integrity. This review synthesizes current knowledge on CLO's potential role in fungal disease, particularly saprolegniasis management, highlighting mechanistic plausibility alongside significant limitations largely based on in vitro and mechanistic data. Key challenges include the paucity of replicated in vivo efficacy and toxicokinetic data in representative aquaculture species, unresolved residue and food‐safety considerations, regulatory constraints, and potential environmental impacts, including selection for antifungal resistance. This review examines pharmacokinetic and pharmacodynamic considerations, environmental fate, and ecotoxicological risks, emphasizing the need for closed‐system testing and targeted delivery to mitigate off‐target exposure. Future research directions focus on species‐specific in vivo trials, good laboratory practice‐compliant residue and tissue distribution studies, advanced formulation strategies such as mucoadhesive carriers and nanoparticle delivery, and integrated One Health‐oriented stewardship frameworks, including resistance monitoring. By framing CLO as a conditional candidate for controlled aquaculture use, this review provides a comprehensive blueprint for rational evaluation, highlighting the balance between therapeutic promise and precautionary risk management in aquatic veterinary pharmacology, and offers a scientific basis for future research priorities and informed policy decisions.