Azoles

Azoles is a topic covered in the Washington Manual of Medical Therapeutics.

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General Principles

Azoles are fungistatic agents that inhibit ergosterol synthesis.

  • 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 can also be used for severe disseminated candidal infections (e.g., candidemia). It is the treatment of choice for consolidation therapy of cryptococcal meningitis following an initial 14-day course of an amphotericin B product or as a second-line agent for primary treatment of cryptococcal meningitis (400–800 mg PO q24h for 8 weeks, followed by 200 mg PO q24h thereafter for chronic maintenance treatment).

Fluconazole does not have activity against Aspergillus spp. or Candida krusei. Candida glabrata also has intrinsically low susceptibility to fluconazole.

  • Itraconazole (200–400 mg PO q24h) is a triazole with broad-spectrum antifungal activity.
    • It is used to treat endemic mycoses such as coccidioidomycosis, histoplasmosis, 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 (200 mg PO q24h for 12 weeks) and fingernails (200 mg PO q12h for 1 week, with a 3-week interruption, and then a second course of 200 mg PO q12h for 1 week).
    • The 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.
  • Posaconazole (delayed-release 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.
    • 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 delayed-release tablets.
    • Rifabutin, phenytoin, and cimetidine reduce posaconazole concentrations and should not be used concomitantly.
    • 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.
    • Terfenadine, astemizole, pimozide, cisapride, quinidine, and ergot alkaloids are contraindicated with posaconazole.
  • Voriconazole (loading dose of 6 mg/kg IV [two doses 12 hours apart], followed by a maintenance dose of 4 mg/kg IV q12h or 200 mg PO q12h [100 mg PO q12h if <40 kg]) is a triazole antifungal with a wide range of activity against pathogenic fungi. It is active against all clinically important species of Aspergillus, as well as Candida (including most non-albicans), Scedosporium apiospermum, and Fusarium spp.
    • 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. It is also effective in treating candidemia, esophageal candidiasis, and Scedosporium and Fusarium infections.
    • An advantage of voriconazole is the easy transition from IV to PO therapy because of excellent bioavailability. For refractory fungal infections, a dose increase of 50% may be useful. The maintenance dose is reduced by 50% for patients with moderate hepatic failure.
    • Because of its metabolism through the cytochrome P450 system (enzymes 2C19, 2C9, and 3A4), there are several clinically significant drug interactions that must be considered. Rifampin, rifabutin, carbamazepine (markedly reduced voriconazole levels), sirolimus (increased drug concentrations), and astemizole (prolonged QTc) are contraindicated with voriconazole. Concomitantly administered cyclosporine, tacrolimus, and warfarin require more careful monitoring.
  • Isavuconazonium sulfate, the prodrug of isavuconazole (372 mg isavuconazonium sulfate [equivalent to 200 mg isavuconazole] PO/IV q8h for 48 hours, 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.
    • The oral formulation has a 98% oral bioavailability that is unaffected by food.
    • The IV formulation does not contain a cyclodextrin-based solubilizing vehicle and can be safely used in patients with CrCl ≤50 mL/min.
    • It is not associated with QTc prolongation, but rather a minor QTc shortening.
    • Rifampin, carbamazepine, long-acting barbiturates, and St. John’s wort significantly reduce isavuconazole concentrations and are contraindicated.
    • High-dose ritonavir and ketoconazole can significantly increase isavuconazole concentrations and are contraindicated.

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