Treatment Guidelines from The Medical Letter® Published by The Medical Letter, Inc. • 1000 Main Street, New Rochelle, NY 10801 • A Nonprofit Publication IN THIS ISSUE (starts on next page) Antifungal Drugs...................................................................p 61 Important Copyright Message The Medical Letter® publications are protected by US and international copyright laws. Forwarding, copying or any distribution of this material is prohibited. Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited. By accessing and reading the attached content I agree to comply with US and international copyright laws and these terms and conditions of The Medical Letter, Inc. For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769 FORWARDING OR COPYING IS A VIOLATION OF US AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter publications are protected by US and international copyright laws. Forwarding, copying or any other distribution of this material is strictly prohibited. For further information call: 800-211-2769 Treatment Guidelines from The Medical Letter® Published by The Medical Letter, Inc. • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication Volume 10 (Issue 120) August 2012 www.medicalletter.org Tables 1. Treatment of Fungal Infections Pages 62-63 Take CME exams 2. Amphotericin B Formulations Page 66 3. Treatment of Onychomycosis and Tinea Page 67 Pedis Antifungal Drugs The drugs of choice for treatment of fungal infections ties, including brachycephaly, cleft palate and congen- are listed in the table that begins on page 62. Some of ital heart disease, have been reported in infants the indications and dosages recommended here have exposed in utero to high doses (400-800 mg/day) of not been approved by the FDA. More detailed guide- fluconazole during most or all of the first trimester.2 lines for some of these infections are available online from the Infectious Diseases Society of America Drug Interactions – Fluconazole is a strong inhibitor (www.idsociety.org). of CYP2C9 and 2C19 and a moderate inhibitor of CYP3A4; it can increase serum concentrations of AZOLES drugs metabolized by these pathways. Concurrent use of fluconazole with other drugs known to prolong the Azole antifungal agents inhibit synthesis of ergosterol, an QT interval, particularly those metabolized by essential component of the fungal cell membrane. They CYP2C9, 2C19 or 3A4, may increase the risk of QT vary in their spectrum of activity, oral bioavailability, prolongation and torsades de pointes.3 Taking flucona- adverse effects and potential for drug-drug interactions. zole with the potent CYP enzyme inducer rifampin can reduce fluconazole serum concentrations, possibly FLUCONAZOLE — Fluconazole (Diflucan, and to subtherapeutic levels. others) is active against most Candida species other than C. krusei, which is intrinsically resistant, and ITRACONAZOLE — Itraconazole (Sporanox, and many strains of C. glabrata, which are variably others) has a broader spectrum of activity than resistant. It has good activity against Coccidioides fluconazole. It is active against a wide variety of fungi spp. and Cryptococcus neoformans and some activity 1 including C. neoformans, Aspergillus spp., Blastomyces against Histoplasma capsulatum. The drug has no dermatitidis, Coccidioides spp., H. capsulatum, clinically significant activity against most molds, Paracoccidioides brasiliensis, Sporothrix spp., and der- including Aspergillus spp., Fusarium spp., and the matophytes. It is also active against most species of Mucorales (formerly called Zygomycetes), such as Candida. Itraconazole has no clinically significant Mucor spp. and Rhizopus spp.. activity against Fusarium spp. or the Mucorales and has variable activity against Scedosporium spp.. Adverse Effects – Fluconazole is generally well tol- erated. Headache, gastrointestinal distress, facial Itraconazole is available in capsules and as an oral edema, rash and pruritus can occur. Stevens-Johnson solution; an IV formulation is no longer available in syndrome, anaphylaxis, hepatic toxicity, leukopenia the US. The oral solution is more bioavailable than the and hypokalemia have been reported. QT prolongation capsules. The capsules should be taken with food, and torsades de pointes have also been reported. while the solution is absorbed best without food. Pregnancy – Fluconazole is teratogenic in animals. It Adverse Effects – The most common adverse effects of is classified as pregnancy category C (risk cannot be oral itraconazole are nausea, diarrhea, vomiting and ruled out) when used in a low dose (single dose of 150 rash. Stevens-Johnson syndrome and serious hepatic mg) for vaginal candidiasis. It is classified as preg- toxicity can occur. Negative inotropic effects, peripher- nancy category D (positive evidence of risk) when al and pulmonary edema, and congestive heart failure used for any other indication. Congenital abnormali- have been reported; itraconazole should not be used in Federal copyright law prohibits unauthorized reproduction by any means and imposes severe fines. 61 Antifungal Drugs Table 1. Treatment of Fungal Infections Infection Drug of Choice1 Some Alternatives1 Aspergillosis Voriconazole 6 mg/kg IV q12h x 2 doses, A lipid formulation of amphotericin B2 IV then 4 mg/kg IV q12h3 or 200 mg4 PO bid Posaconazole 200 mg PO qid, then 400 mg bid until resolved Caspofungin 70 mg IV x 1, then 50 mg IV 1x/d Micafungin 100-150 mg IV 1x/d Blastomycosis5 Mild to moderate Itraconazole 200 mg PO tid x 3 d, then bid Fluconazole 400-800 mg PO 1x/d6-8 x 6-12 mo Moderately severe Amphotericin B2 0.7-1 mg/kg/d IV x 1-2 wks, to severe then itraconazole 200 mg PO tid x 3 d, then 200 mg bid x 6-12 mos9 Candidiasis Vulvovaginal10 Intravaginal butoconazole, clotrimazole, miconazole, nystatin, tioconazole, terconazole 1x/d x 1-14 d11 or Fluconazole 150 mg PO once12 Itraconazole 200 mg PO bid x 1d Recurrent Topical or oral azole x 10-14 d, Clotrimazole 200 mg 2x/wk topically then fluconazole 150 mg PO 1x/wk x 6 mos or 500 mg 1x/wk intravaginally Urinary13 Fluconazole 200 mg (3 mg/kg)8,14 IV or PO Amphotericin B2 0.3-0.6 mg/kg/d14 IV x 1-7 d 1x/d x 2 wks Oropharyngeal15-19 Fluconazole 100-200 mg (3 mg/kg)8 PO Itraconazole20 200 mg PO 1x/d x 7-14 d Posaconazole 400 mg PO bid x 3 d, then 400 mg 1x/d Voriconazole 200 mg3,4 PO bid Amphotericin B oral susp 100 mg/mL qid An echinocandin: Micafungin 150 mg IV 1x/d Caspofungin 50 mg IV 1x/d Anidulafungin 200 mg IV 1x/d Amphotericin B 0.3 mg/kg/d IV Esophageal17,18,21 Fluconazole 200-400 mg (3-6 mg/kg)8 PO Itraconazole20 200 mg PO 1x/d or 400 mg IV 1x/d Posaconazole 400 mg PO bid Voriconazole 200 mg3,4 PO or IV bid Amphotericin B2 0.3-0.7 mg/kg/d IV An echinocandin: Micafungin 150 mg IV 1x/d Caspofungin 50 mg IV 1x/d Anidulafungin 200 mg IV 1x/d Candidemia and Fluconazole23 400 mg (6 mg/kg)6,8 IV 1x/d Amphotericin B2 0.5-1 mg/kg/d IV Invasive Candidiasis17,22 or An echinocandin24 Caspofungin 70 mg x 1, then 50 mg IV 1x/d Micafungin 100 mg IV 1x/d Anidulafungin 200 mg x 1, then 100 mg IV 1x/d 1. Usual adult dosage. Some drugs may need dosage adjustment for renal or hepatic dysfunction or when used with interacting drugs. The optimal duration of treatment with antifungal drugs is often unclear. Depending on the disease and its severity, they may be continued for weeks or months or, particularly in immunocompromised patients, indefinitely. Some of these indications and dosages have not been approved by the FDA. 2. Lipid-based formulations are often preferred, especially in patients at risk for nephrotoxicity or who are expected to receive a long course of therapy. Usual doses of lipid-based formulations for treatment of invasive fungal infection are: amphotericin B lipid complex (Abelcet) 5 mg/kg/d; liposomal amphotericin B (AmBisome) 3-5 mg/kg/d; amphotericin B cholesteryl sulfate (Amphotec) 3-4 mg/kg/d. For treatment of mucormycosis or fusariosis, the lipid formulation dosage is >5 mg/kg/d. For treatment of cryptococcal meningitis in HIV patients, the dosage of AmBisome is 4-6 mg/kg/d. The usual dosage of amphotericin B deoxycholate for treatment of systemic fungal infections is 0.7-1 mg/kg/d. 3. Children may need higher doses. According to the manufacturer, serum concentrations in children with doses of 4 mg/kg are similar to those in adults given 3 mg/kg. In the European Union, where voriconazole is licensed for use in children 2-11 years old, the recommended maintenance dosage is 8 mg/kg IV bid or 200 mg PO bid (LE Friberg et al, Antimicrob Agents Chemother 2012; 56:3032). 4. Some Medical Letter reviewers recommend a weight-based dose of oral voriconazole (4 mg/kg PO bid) rather than the FDA-approved dose of 200 mg PO bid because of the potential for subtherapeutic serum concentrations. According to the manufacturer, adults who weigh <40 kg should receive half the oral maintenance dose. 5. Patients with severe illness or CNS involvement should receive a lipid formulation of amphotericin B for 4-6 weeks, followed by an azole for at least 1 year. 6. In general, a loading dose of twice the daily dose is recommended on the first day of therapy. 7. For use in patients who cannot tolerate itraconazole or amphotericin B. 8. Children need higher doses of fluconazole than adults do. According to the manufacturer, an adult dose of 100 mg is equivalent to a pediatric dose of 3 mg/kg. 9. For disseminated extrapulmonary or osteoarticular disease, treat for at least 12 months.