THE MERCK VETERINARY MANUAL
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Imidazoles

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Imidazoles may have antibacterial, antifungal, antiprotozoal, and anthelmintic activity. Several distinct phenylimidazoles are therapeutically useful antifungal agents with wide spectra against yeasts and filamentous fungi responsible for either superficial or systemic infections. The anthelmintic thiabendazole is also an imidazole with antifungal properties. Clotrimazole, miconazole, econazole, ketoconazole, itraconazole, and fluconazole are the most clinically important members of this group.

Imidazoles generally are poorly soluble in water but can be dissolved in organic solvents such as chloroform, propylene glycol, and polyethoxylated castor oil (preparation for IV use but dangerous in dogs). An exception is fluconazole. Imidazoles are weak dibasic agents. Alterations in side-chain structure determine antifungal activity as well as the degree of toxicity.

Antifungal Activity

Imidazoles alter the cell membrane permeability of susceptible yeasts and fungi by blocking the synthesis of ergosterol (demethylation of lanosterol is inhibited), the primary cell sterol of fungi. Other enzyme systems are also impaired, such as those required for fatty acid synthesis. Because of the drug-induced changes of oxidative and peroxidative enzyme activities, toxic concentrations of hydrogen peroxide develop intracellularly. The overall effect is cell membrane and internal organelle disruption and cell death. The cholesterol in host cells is not affected by the imidazoles, although some drugs impair synthesis of selected steroids and drug-metabolizing enzymes in the host. Because imidazoles impair synthesis, a lag time to efficacy occurs.

Sensitivity to the imidazoles varies greatly between various strains of yeasts and fungi, but neither natural nor acquired resistance appears to be prevalent.

The antifungal imidazoles also have some antibacterial action but are rarely used for this purpose. Miconazole has a wide antifungal spectrum against most fungi and yeasts of veterinary interest. Sensitive organisms include Blastomyces dermatitidis, Paracoccidioides brasiliensis, Histoplasma capsulatum, Candida spp, Coccidioides immitis, Cryptococcus neoformans, and Aspergillus fumigatus. Some Aspergillus and Madurella spp are only marginally sensitive.

Ketoconazole has an antifungal spectrum similar to that of miconazole, but it is more effective against C immitis and some other yeasts and fungi. Itraconazole and fluconazole are the most active of the antifungal imidazoles. Their spectrum includes dimorphic fungal organisms and dermatophytes. They are also effective against some cases of aspergillosis (60–70%) and cutaneous sporotrichosis. Clotrimazole and econazole are used for superficial mycoses (dermatophytosis and candidiasis); econazole also has been used for oculomycosis. Thiabendazole is effective against Aspergillus and Penicillium spp, but its use has largely been replaced by the more effective imidazoles. Voriconazole is approved for human use in the treatment of Aspergillus, but is effective against many other fungal organisms.

Pharmacokinetic Features

The imidazoles are rapidly but sometimes erratically absorbed from the GI tract; plasma levels peak within 2 hr after administration PO. Fluconazole is an exception, being close to 100% bioavailable after administration PO. Except for fluconazole, an acidic environment is required for the dissolution of the imidazoles, and a decrease in gastric acidity can reduce the bioavailability after administration PO. The rate of absorption appears to be increased when the drug is given with meals, but reports are conflicting.

Imidazoles appear to be widely distributed in the body with detectable concentrations in saliva, milk, and cerumen. CSF penetration is poor except for fluconazole, which reaches 50–90% of plasma concentrations. Most imidazoles (except fluconazole) are highly protein bound in the circulation (>95%), most to albumin. The highest concentrations of imidazoles are found in the liver, adrenal glands, lungs, and kidneys.

Hepatic metabolism is the primary route of elimination. Metabolism of ketoconazole and most other imidazoles by oxidative pathways is extensive. Only ∼2–4% of a dose administered PO appears unchanged in the urine. Itraconazole is metabolized to an active metabolite that may contribute significantly to antimicrobial activity. The biliary route is the major excretory pathway (>80%); ∼20% of the metabolites are eliminated in the urine. Fluconazole (in people) is eliminated (≥90%) unchanged in the urine. The kinetics of voriconazole have not yet been evaluated in animals.

The rate of elimination of ketoconazole appears to be dose dependent—the greater the dose, the longer the elimination half-life. There is also a biphasic elimination pattern with rapid elimination in the first 1–2 hr, then a slower decline over the next 6–9 hr. Ketoconazole is usually administered bid. The half-life of itraconazole is longer (up to 48 hr in cats), thus allowing treatment sid-bid. Because of the long half-life and mechanism of action (impaired synthesis of the fungal cell membrane), time to efficacy may take longer than drugs that have more rapid actions (such as amphotericin B).

Therapeutic Indications and Dose Rates

The imidazoles are used to treat systemic fungal diseases, dermatomycoses that have not responded to griseofulvin or topical therapy, Malassezia infection in dogs, aspergillosis, and sporotrichosis in animals that cannot tolerate or do not respond to sodium iodide. For serious infections, combination with amphotericin B is strongly recommended. Among the imidazoles, fluconazole is most indicated for tissues that are tough to penetrate. Both itraconazole and fluconazole are generally preferred to other imidazoles for treatment of systemic fungal infections, including aspergillosis and sporotrichosis. Topically applied imidazoles (clotrimazole, miconazole, econazole) are used for local dermatophytosis. Thiabendazole is included in some otic preparations for treatment of yeast infections.

Enilconazole is an imidazole that can be applied topically for the treatment of dermatophytosis and aspergillosis. It has been used safely in cats, dogs, cattle, horses, and chickens and is prepared as a 0.2% solution for the treatment of fungal skin infections. When infused into the nasal turbinates of dogs with aspergillosis, enilconazole treated and prevented the recurrence of fungal disease. When applied topically to dog and cat hairs, enilconazole inhibits fungal growth in 2 rather than 4–8 treatments, as is necessary with other topically administered antifungal agents.

General dosages for the antifungal imidazoles are listed in see Table 2: Dosages of ImidazolesTables. The dose rate and frequency should be adjusted as needed for the individual animal.

Table 2

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Special Clinical Concerns

The imidazoles given PO result in few adverse effects, but nausea, vomiting, and hepatic dysfunction can develop, particularly with ketoconazole. Altered testosterone and cortisol metabolism, as well as blunted adrenal responsiveness to ACTH, have been reported, particularly with ketoconazole. Reproductive disorders related to ketoconazole administration may be seen in dogs. Voriconazole is associated with a number of adverse effects in humans, including vision disturbances.

The imidazoles may be used concurrently with amphotericin B or 5-flucytosine to potentiate its antifungal activity. The absorption of the imidazoles, except for that of fluconazole, is inhibited by concurrent administration of cimetidine, ranitidine, anticholinergic agents, or gastric antacids. Rifampin decreases the serum levels of active ketoconazole because of microsomal enzyme induction. The risk of hepatotoxicity is increased if ketoconazole and griseofulvin are administered together. Imidazoles in general, and ketoconazole in particular, inhibit the metabolism of some drugs and, if administered concurrently, their concentrations may be higher than anticipated. Imidazoles are substrates for p-glycoprotein transport protein and may compete with other substrates, causing higher concentrations.

AST, ALT, plasma bilirubin, and plasma cholesterol increase. Adrenal responsiveness is altered.

Last full review/revision March 2012 by Dawn Merton Boothe, DVM, PhD, DACVIM, DACVCP

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