Ionophores are lipid-soluble molecules that transport ions across lipid cell membranes. After ion transport, ionophores subsequently disrupt the ion concentration gradient for calcium, potassium, hydrogen, and sodium ions in microorganisms. This prevents the microorganism from maintaining appropriate metabolism, leading to antimicrobial effects. Ionophores used in veterinary medicine include monensin, lasalocid, salinomycin, narasin, maduramicin, semduramicin, and laidlomycin propionate. Monensin is a the prototypical ionophore antimicrobial and is derived from Streptomyces.
Monensin forms complexes with monovalent cations, including sodium and potassium. The complexes are then transported in a nonpolar manner across the bacterial cell membrane. As such, monensin acts as an Na+/H+ antiporter. It blocks intracellular protein transport, resulting in antibacterial and antimalarial effects.
Monensin is used extensively in the beef and dairy industries in feed to prevent coccidiosis and improve feed efficiency. Feed efficiency is improved due to selecting against gram-positive bacteria and protozoa in the rumen. This allows for an increased efficiency of the remaining beneficial bacteria via increases in propionic acid and decreases in acetic acid and lactic acid production.
Resistance to ionophores is likely adaptive in nature and is less likely via mutation or gene acquisition. Monensin is primarily metabolized and excreted by the liver and is rapidly eliminated in the feces.
The ionophores are approved only as medicated feed additives in the US. Monensin is approved in cattle, chickens, goats, and turkeys. Lasalocid is approved in cattle, sheep, chickens, rabbits, turkeys, chickens, and partridges. Salinomycin is approved in chickens and quail. Narasin is approved in swine and chickens. Maduramicin and semduramicin are approved in chickens. Laidlomycin propionate is approved in cattle. In the US, extra-label use of medicated feeds is prohibited in major food-producing animal species (ie, chickens, turkeys, cattle, and swine).
Extralabel use of medicated feeds is permissible in minor species provided stipulations are met. For more information on this topic, the FDA has provided a compliance policy guide. Withdrawal times can vary between products, even for the same drug. Therefore, when using products according to label recommendations, it is imperative to follow the label meat and milk withdrawal times for the particular product. For instances of extralabel drug use (ELDU), it is recommended to contact a country-specific advisory program to obtain evidence-based withdrawal recommendations extrapolated from known species pharmacokinetics. In the US, veterinarians may contact the Food Animal Residue Avoidance Databank (FARAD, www.farad.org) for withdrawal recommendations.
While ionophores are safe and effective in target species receiving recommended doses, toxicity in off-target species can be fatal. There is species-specific variability in the median lethal dose for ionophores, and horses, birds, sheep, pigs, dogs, cats, and rats are particularly sensitive to ionophore toxicity. For example, the median lethal dose for monensin in horses is 2–3 mg/kg, 20 mg/kg in dogs, and 20–80 mg/kg in cattle. Lasolacid appears to be marginally safer than monensin. Ionophore toxicity typically occurs due to accidental overdose, misuse in a nontarget species, feed mill mixing errors, and accidental ingestion. Ionophore toxicity is directly due to their mechanism action—disruption of normal ionic gradients. This perturbation of intracellular ionic gradients leads to destabilization of biological membranes.
The heart is the primary organ affected in monensin toxicosis; however, lesions also occur in skeletal muscle, smooth muscle, and nervous system. Monensin toxicosis causes an excessive increase in intracellular calcium ions in myocardial muscles, leading to tachycardia, tachyarrhythmias, increased contractility, premature ventricular complexes, and atrial fibrillation. Acute, high-dose monensin toxicosis in horses results in weakness, anorexia, colic, profuse sweating, tachyarrhythmias, recumbency, and sudden death. Chronic or low-dose monensin toxicosis in horses results in cardiac failure, poor performance, weakness, and muscle stiffness.
In dogs, clinical signs of monensin toxicosis include weakness, ataxia, bilateral mydriasis, cardiomyopathies, myoglobinuria, polyneuromyopathy, and respiratory distress. Delayed neurotoxicity after lasalocid intoxication has been reported in horses. There are no specific treatments or antidotes for ionophore toxicosis.