Azoles for Use in Animals

Imidazoles alter the cell membrane permeability of susceptible yeasts and fungi by blocking the synthesis of ergosterol, the primary fungal cell sterol, via inhibition of the demethylation of lanosterol. The enzyme targeted is a fungal cytochrome P450 (CYP450). 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. This lag time may be further prolonged by the long half-life of these drugs.

Clinical isolates of Candida and Aspergillus organisms have been demonstrating increased resistance to azoles via a variety of mechanisms. Upregulation of the ABC transporters CDR1 and CDR2 leads to increased drug efflux. Mutations in the ERG11 gene that codes for the lanosterol demethylase causes alteration in the ability of an azole drug binding to its target site. Increased expression of major facilitator transporters results in a reduction in the intracellular accumulation of azoles. Itraconazole and fluconazole have been demonstrated to have resistance developing in strains isolated from equine uterine cultures. Fluconazole resistance has been noted in clinical isolates of C neoformans. Currently, there is no evidence of azole resistance for Aspergillus fumigatus isolates from dogs and cats; however, itraconazole and voriconazole resistance has been reported for avian A fumigatus strains in Europe.

The antifungal azoles also have some antibacterial action but are rarely administered for this purpose. Miconazole has a wide antifungal spectrum against most fungi and yeasts of veterinary interest. Sensitive organisms include B dermatitidis, P brasiliensis, H capsulatum, Candida spp, C immitis, C neoformans, and A 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. However, fluconazole is less efficacious against Aspergillus species. Clotrimazole and econazole are administered for superficial mycoses (dermatophytosis and candidiasis); econazole also has been used for oculomycosis. Thiabendazole is effective against Aspergillus and Penicillium spp; however, its use has largely been replaced by the more effective imidazoles.

Voriconazole and posaconazole are considered newer-generation azoles that posses a wide range of activity and are more effective against Candida and Aspergillus compared to classic triazoles. Voriconazole is approved for human use in treatment of Aspergillus but is effective against many other fungal organisms.Posaconazole may be more effective than itraconazole or fluconazole but may be associated with more adverse effects.

Ketoconazole was the first antifungal approved for systemic use in humans in the United States; however, despite this approval there are several drawbacks to its use. Ketoconazole is poorly absorbed after oral administration in small animals, and it is not absorbed in horses. No parenteral formulations have been developed. Finally, ketoconazole is less pharmaceutically active in immunosuppressed patients, mostly due to its fungistatic nature. These deficiencies spurred the development of the triazoles.

The triazoles are rapidly but sometimes erratically absorbed from the GI tract with plasma levels peaking within 2 hours after oral administration. Fluconazole is an exception, being close to 100% bioavailable after oral administration. In humans, oral formulations of voriconazole are recommended to be taken on an empty stomach. Chickens have been noted to have poor voriconazole bioavailability (<20%) compared to other avian species, which precludes the achievement of clinically effective plasma concentrations. Posaconazole, on the other hand, should be administered with a high-fat meal due to saturable absorption mechanisms. An acidic environment is required for dissolution of the triazoles, except for fluconazole, and a decrease in gastric acidity can decrease bioavailability after oral administration. Therefore, the use of antacids, proton pump inhibitors, or H2 antagonists may significantly decrease the drug's bioavailability and therefore its therapeutic effect.

The rate of absorption appears to be increased when itraconazole is administered with meals, but reports are conflicting. Itraconazole is available as a capsule or an oral solution. The capsules must be delivered intact (i.e. not crushed), because crushing decreases bioavailability. Because oral bioavailability can be very poor with noncommercial azole products, caution is recommended with compounded products, and monitoring is recommended if a compounded preparation is administered.

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 azoles (except fluconazole) are highly protein-bound in the circulation (>95%), most to albumin. The highest concentrations of azoles are found in the liver, adrenal glands, lungs, and kidneys.

Metabolism of ketoconazole and most other imidazoles by oxidative pathways is extensive. Itraconazole is metabolized to an active metabolite, hydroxy-itraconazole, which may contribute significantly to antimicrobial activity. The biliary route is the major excretory pathway for itraconazole (>80%); ~20% of the metabolites are eliminated in the urine. In contrast, 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 hours, then a slower decline over the next 6–9 hours. Ketoconazole is usually administered every 12 hours. The half-life of itraconazole is longer (up to 48 hours in cats), thus allowing treatment once to twice daily. Because of the long half-life and mechanism of action (impaired synthesis of the fungal cell membrane), time to efficacy may be longer than drugs that have more rapid actions (such as amphotericin B). Voriconazole has been noted to demonstrate nonlinear pharmacokinetics due to saturation of hepatic metabolic mechanisms. Therefore, therapeutic drug monitoring is recommended due to the narrow therapeutic window for voriconazole, which requires minimum trough concentrations of at least 1 mg/L, and maximum peak concentrations of less than 5.5 mg/L.

The azoles administered orally result in few adverse effects, but nausea, vomiting, and hepatic dysfunction can develop. Ketoconazole in particular is associated with hepatotoxicity, especially in cats. Because azoles also inhibit CYP450 associated with steroid synthesis, metabolism of sex steroids, including testosterone and adrenal steroid (cortisol), is inhibited. Reproductive disorders related to ketoconazole administration may be seen in dogs. Adrenal responsiveness to adrenocorticotropic hormone (ACTH) will be decreased, particularly with ketoconazole.

Due to its myriad of adverse effects and lower success rate compared to itraconazole and fluconazole, ketoconazole is more often administered topically than systemically in humans. Voriconazole is associated with a number of adverse effects in people, including vision disturbances, phototoxicity, alopecia, and periostitis. Itraconazole carries a black box warning in humans due to its negative inotropic effect. In patients with impaired ventricular function, the use of itraconazole may result in congestive heart failure.

African grey parrots have been reported to be more sensitive to itraconazole, and therefore dose reduction or avoidance of this drug is recommended. Neuronal phospholipidosis has been observed in dogs after the use of posaconazole. Posaconazole is metabolized via glucuronidation and therefore should be administered with caution in cats. Due to their teratogenic potential, fluconazole and ketoconazole should be avoided in pregnant animals where safety studies have not been conducted.

Azoles, in general, inhibit the metabolism of many drugs. Although ketoconazole has the broadest inhibitory effects, fluconazole followed by itraconazole also inhibits metabolism. Concurrent administration of these drugs with other drugs that are metabolized by the liver and potentially toxic should be done only with extreme caution.

Azoles also are substrates for P-glycoprotein transport protein and may compete with other substrates, causing higher concentrations. Many of the substrates for P-glycoprotein are also substrates for CYP450. Rifampin, which is a P-glycoprotein substrate, decreases serum ketoconazole because of microsomal enzyme induction. Absorption of the imidazoles, except for fluconazole, is inhibited by concurrent administration of cimetidine, ranitidine, anticholinergic agents, or gastric antacids. The risk of hepatotoxicity is increased if ketoconazole and griseofulvin are administered together. Azoles might be used concurrently with other antifungals to facilitate synergistic efficacy.

Treatment with imidazoles increases AST, ALT, plasma bilirubin, and plasma cholesterol. Adrenal responsiveness is altered.