Azoles

GENERAL PRINCIPLES

Azoles are fungistatic agents that inhibit ergosterol synthesis, a key component of fungal cell membranes.

TREATMENT

• Fluconazole (100-800 mg PO/IV q24h) is the drug of choice for many Candida infections, such as UTIs, thrush, vaginal candidiasis (150-mg single dose), esophagitis, peritonitis, hepatosplenic infection, and severe disseminated candidal infections (e.g., candidemia).

• Itraconazole (200 mg q8h ? 3 d, then 200-400 mg PO q24h or super-bioavailable [SUBA] 130 mg po q8h ? 3 d, then 130 mg PO q24h) is a triazole with broad-spectrum antifungal activity. It is primarily used to treat dimorphic mold infections, including the endemic mycoses (coccidioidomycosis, histoplasmosis, and blastomycosis) and sporotrichosis. It is an alternative therapy for Aspergillus and can also be used to treat infections caused by dermatophytes, including onychomycosis of the toenails and fingernails.

° The traditional capsules require adequate gastric acidity for absorption and, therefore, should be taken with food or carbonated beverage. The liquid formulation is preferred as it is not significantly affected by gastric acidity and is better absorbed on an empty stomach. SUBA-itraconazole is a new highly bioavailable capsule that can be administered without regard to meals.

î All formulations of itraconazole exhibit negative ionotropic effects and can cause or exacerbate congestive heart failure. Use should be avoid in individuals with preexisting heart failure.

î Therapeutic drug monitoring is indicated with itraconazole. Doses should be titrated to achieve a steady-state trough gt;1 #956;g#8725;mL (sum of itraconazole and its hydroxy metabolite).

• Posaconazole (delayed-release [DR] tablet and IV doses are 300 mg PO/IV q12h on day 1, followed by 300 mg PO/IV q24h; oral suspension dose is 200 mg PO q8h for prophylaxis and 100-400 mg PO q12-24h for oropharyngeal candidiasis treatment) is an oral azole agent that is used for prophylaxis of invasive aspergillosis and candidiasis in hematopoietic stem cell transplant patients with graft-versus- host disease or in patients with hematologic malignancies experiencing prolonged neutropenia from chemotherapy as well as treatment of oropharyngeal candidiasis. It has also been used for treatment of mucormycosis, although it is not FDA-approved for this use.

î Each suspension dose should be administered with a full meal, liquid supplement, or acidic carbonated beverage (e.g., ginger ale). Acid-suppressive therapy may reduce absorption of the oral suspension, but not the DR tablets.

î Rifabutin, phenytoin, and cimetidine reduce posaconazole concentrations and should not be used concomitantly.

î Posaconazole increases bioavailability of cyclosporine, tacrolimus, and midazolam, necessitating dosage reductions of these agents. Dosage reduction of vinca alkaloids, statins, and calcium channel blockers should also be considered.

î Terfenadine, astemizole, pimozide, cisapride, quinidine, and ergot alkaloids are contraindicated with posaconazole.

î Therapeutic drug monitoring is recommended when using posaconazole at treatment doses. Doses should be adjusted to obtain a target trough of gt;1.25 #956;g#8725;mL when used for active treatment.

• Voriconazole (loading dose of 6 mg/kg IV [two doses 12 h apart], followed by a maintenance dose of 4 mg/kg IV q12h or 200 mg PO q12h [100 mg PO q12h if lt;40 kg]) is a triazole antifungal with a wide range of activity against pathogenic fungi.

î It is the treatment of choice for most forms of invasive aspergillosis, for which it demonstrates response rates of 40%-50% and superiority over conventional amphotericin B.

î Vbriconazole is extensively metabolized via the CYP enzyme system, including enzymes 2C19, 2C9, and 3A4, resulting in several clinically significant drug interactions that must be considered. In particular, rifampin, rifabutin, and carbamazepine (reduced drug levels), and sirolimus (increased drug levels) are contraindicated with voriconazole. Concomitantly administered cyclosporine, tacrolimus, and warfarin can be coadministered but require more careful monitoring.

î Owing to extensive drug interactions and genetic variations in CYP2C19 metabolism, therapeutic drug monitoring is required to ensure safe and efficacious use of voriconazole. Doses should be titrated to achieve a steady-state trough of 1-5.5 #956;g#8725;mL.

• Isavuconazonium sulfate, the prodrug of isavuconazole (372 mg isavuconazonium sulfate [equivalent to 200 mg isavuconazole] PO/IV q8h for 48 h, then 372 mg isavuconazonium sulfate [equivalent to 200 mg isavuconazole] PO/IV q24h), is an azole with broad-spectrum antifungal activity that is FDA- approved for treatment of invasive aspergillosis and invasive mucormycosis.

o The oral formulation has a 98% oral bioavailability that is unaffected by food.

î Unlike all other azoles, isavuconazole is not associated with QTc prolongation, but rather QTc shortening.

î Rifampin, carbamazepine, long-acting barbiturates, and St. John's wort significantly reduce isavuconazole concentrations and are contraindicated.

î High-dose ritonavir and ketoconazole can significantly increase isavuconazole concentrations and are contraindicated.

SPECIAL CONSIDERATIONS

Adverse effects of all azoles include nausea, diarrhea, and rash. Hepatitis is a rare but serious complication. LFTs should be monitored regularly with chronic use and especially with compromised liver function. Azoles can prolong the QTc interval (excluding isavuconazole) and should be avoided with concomitant QTc prolonging agents. The IV formulations of voriconazole and posaconazole should be used with caution in patients with a CrCl lt;50 mL/min due to theoretical risk cyclodextrin vehicle accumulation. Voriconazole can commonly cause transient visual disturbances and hallucinations with high trough concentration, as well as phototoxicity. This class of antibiotics has major drug interactions.