Treatment Guidelines from The Medical Letter
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88
Antifungal Drugs
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Treat Guidel Med Lett. 2009 Dec;7(88):95-102
 Select a term to see related articles  ABCD   Abelcet   ABLC   Absidia spp.   AmBisome   Amphotec   Amphotericin B cholesteryl sulfate complex   Amphotericin B deoxycholate   Amphotericin B lipid complex   Ancobon   anidulafungin   Antifungal drugs   Aspergillosis   Aspergillus spp.   Aspergillus terreus   Blastomyces dermatitidis   Blastomycosis   C. glabrata   C. Krusei   Cancidas   Candida Glabrata   Candida Krusei   Candida lusitaniae   candidemia   candidiasis   Carbamazepine   Caspofungin   Coccidioides   Coccidioidomycosis   Cryptococcosis   Cryptococcus spp.   CYP2C19   CYP2C9   CYP3A4   December 2009   Dermatophytes   Dexamethasone   Diflucan   Echinocandins   Efavirenz   eraxis   Esophageal candidiasis   Fluconazole   Flucytosine   Fungal infections   Fusariosis   Fusarium spp.   H. capsulatum   Histoplasma capsulatum   Histoplasmosis   Invasive mycoses   Issue 88   Itraconazole   Ketoconazole   L-AmB   Lamisil   Liposomal amphotericin B   Micafungin   Mucor spp.   Mycamine   Nevirapine   Nizoral   noxafil   Onychomycosis   Oropharnygeal candidiasis   P-glycoprotein   P-gp   Paracoccidioides brasiliensis   Phenytoin   posaconazole   Rifampin   Scedosporiosis   Scedosporium apiospermum   Scedosporium spp.   Scopulariopsis spp.   Sporanox   Sporothrix spp.   Sporotrichosis   Terbinafine   Tinea pedis   treatment guidelines   Trichosporon spp.   Vfend   Volume 7   Voriconazole   zygomycetes   zygomycosis 

The drugs of choice for treatment of some fungal infections are listed in the table that begins on page 96. Some of the indications and dosages recommended here have not been approved by the FDA. More detailed guidelines are available online from the Infectious Diseases Society of America (www.idsociety.org).

AZOLES

Azole antifungal agents inhibit synthesis of ergosterol, an essential component of the fungal cell membrane.

FLUCONAZOLE — Fluconazole (Diflucan, and others) is active against most Candida species other than C. krusei, which is intrinsically resistant, and many strains of C. glabrata, which are increasingly resistant. Fluconazole has good activity against Coccidioides and Cryptococcus spp.; higher doses may be needed against Histoplasma capsulatum. The drug has no clinically significant activity against most molds, including Aspergillus spp., Fusarium spp. and Zygomycetes, such as Mucor spp.

Adverse Effects – Fluconazole is generally well tolerated. Headache, gastrointestinal distress, facial edema, rash and pruritus can occur. Stevens-Johnson syndrome, anaphylaxis, hepatic toxicity, leukopenia and hypokalemia have been reported. Some post-marketing cases of QT prolongation and torsades de pointes have also been reported. Fluconazole is teratogenic in animals (pregnancy category C).

Drug Interactions – Fluconazole is a strong inhibitor of CYP2C9 and 2C19 (in vitro) and a moderate inhibitor of CYP3A4; it may increase serum concentrations of drugs metabolized by these enzymes.1 Concomitant administration of rifampin can lower serum concentrations of fluconazole. Concurrent use of fluconazole with other drugs known to prolong the QT interval, particularly those metabolized by CYP2C9, 2C19 or 3A4, may increase the risk of QT prolongation and torsades de pointes.1,2

ITRACONAZOLE — Itraconazole (Sporanox, and others) has a broader spectrum of activity than fluconazole. It is active against a wide variety of fungi including Cryptococcus neoformans, Aspergillus spp., Blastomyces dermatitidis, Coccidioides spp., H. capsulatum, Paracoccidioides brasiliensis, Sporothrix spp. and dermatophytes. It is also active against most species of Candida. Itraconazole has no clinically significant activity against Scedosporium spp., Fusarium spp., Scopulariopsis spp. or Zygomycetes.

Itraconazole is available orally in both capsules and solution; an IV formulation is no longer being produced in the US. Absorption after oral dosing is variable. The solution is more bioavailable than the capsules. The capsules should be taken with food, while the solution is absorbed best without food.

Adverse Effects – The most common adverse effects of itraconazole are nausea, vomiting and rash. Stevens-Johnson syndrome and serious hepatic toxicity can occur. The drug can cause hypokalemia, edema and hypertension. Negative inotropic effects and congestive heart failure have been reported; itraconazole should not be used in patients with a history of heart failure or ventricular dysfunction. Peripheral neuropathy, visual disturbances, hearing loss and tinnitus have also been reported. Itraconazole is teratogenic in rats (pregnancy category C).

Drug Interactions – The absorption of itraconazole from capsules is reduced by drugs that decrease gastric acidity, such as antacids, H2-receptor blockers or proton pump inhibitors.

Itraconazole is a substrate of CYP3A4 and P-glycoprotein (P-gp); its metabolism may be affected by both inducers and inhibitors of these pathways.1

Itraconazole is a strong inhibitor of CYP3A4 and may significantly increase serum concentrations of drugs metabolized by this enzyme.3 It is contraindicated for use with some drugs that are metabolized by CYP3A4, particularly those known to prolong the QT interval.2 Itraconazole may increase the serum concentrations and negative inotropic effects of calcium channel blockers. It is also a P-gp inhibitor and can increase serum concentrations of P-gp substrates.1

VORICONAZOLE — Voriconazole (Vfend) has a spectrum of activity similar to that of itraconazole but appears to be more active against Aspergillus spp. and most species of Candida, including C. glabrata and C. krusei. Unlike itraconazole, voriconazole is active against Fusarium spp. and Scedosporium spp. It is not active against Sporothrix spp. or Zygomycetes; infection with these organisms has developed during treatment with voriconazole. In a randomized trial of initial treatment of invasive aspergillosis, voriconazole improved survival compared to amphotericin B and caused fewer severe adverse effects.4

Patients with mild to moderate hepatic insufficiency should receive a normal loading dose of voriconazole, but half the maintenance dose. Serum concentrations of voriconazole may need monitoring; they vary from patient to patient and with the formulation used (lower with capsules and higher with the solution).5,6 Children need a higher per-kg dose than adults because they clear the drug more rapidly.7

Adverse Effects – Transient visual disturbances including blurred vision, photophobia and altered perception of color or image have occurred in about 20% of patients treated with voriconazole. Rash (including Stevens-Johnson syndrome), photosensitivity, increased transaminase levels, confusion and hallucinations have also occurred. In patients with creatinine clearance <50 mL/min, the oral formulation is preferred because the solubilizing agent in the IV formulation (sulfobutyl ether beta-cyclodextrin) can accumulate and cause toxicity. Anaphylactoid infusion reactions have occurred. Voriconazole is teratogenic in animals (pregnancy category D).

Drug Interactions – Voriconazole is a substrate of CYP2C19, 2C9, 3A4 and P-gp. Drugs that inhibit or induce one or more of these clearance pathways may significantly alter serum concentrations of voriconazole. 1 Patients deficient in CYP2C19 (about 3-5% of Caucasians and African-Americans and about 15% of Asians do not express it) may have 2- to 4-fold higher serum concentrations of voriconazole.

Voriconazole is an inhibitor (in vitro) of CYP2C9, 3A4 and, to a lesser extent, 2C19; it may significantly increase serum concentrations of drugs metabolized by these enzymes. Concurrent use of voriconazole with other drugs that prolong the QT interval, particularly those metabolized by CYP2C9, 2C19 or 3A4, may increase the risk of QT prolongation and torsades de pointes.1,2

POSACONAZOLE — Posaconazole (Noxafil), the newest triazole,8 has an antifungal spectrum similar to that of itraconazole, but its in vitro activity is about twice as great; it can be used to treat Fusarium spp. and Scedosporium spp. and has up to 4-fold greater activity against many species of Mucor, such as Absidia spp. Posaconazole is only available for oral use and must be taken with meals for optimal absorption.

Clinical Studies – A randomized, open-label clinical trial of posaconazole for prophylaxis against fungal infections found that 602 adults who were neutropenic as a result of induction chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) had fewer invasive mycoses (including aspergillosis) and lower mortality rates when taking posaconazole (200 mg t.i.d.) compared to those taking fluconazole (400 mg once/day) or itraconazole (200 mg b.i.d.).9 A double-blind randomized trial in 600 adults with graft-versus-host disease following allogeneic hematopoietic stem cell transplantation (HSCT) found posaconazole similar to fluconazole in preventing invasive mycoses and superior in preventing invasive aspergillosis and death.10

HIV-infected patients with oropharyngeal or esophageal candidiasis refractory to treatment with fluconazole or itraconazole have responded to posaconazole; in one study, 75% of these patients achieved cure or improvement after 28 days of treatment. 11 Posaconazole is not approved in the US for salvage therapy of invasive mycoses, but it has been used successfully for this indication in patients with invasive aspergillosis. It has also been used off-label to treat coccidioidomycosis and zygomycosis.12-15

Adverse Effects – Posaconazole has a safety profile comparable to that of fluconazole; dry mouth, rash, headache, diarrhea, fatigue, nausea, vomiting, QT prolongation and abnormal liver function have been reported, but infrequently lead to drug discontinuation. Arrhythmias, toxic epidermal necrolysis, angioedema and anaphylaxis have been rare. Posaconazole causes skeletal malformations in rats (pregnancy category C).

Drug Interactions – Posaconazole is primarily metabolized through UDP glucuronidation and is also a substrate of P-gp.1 Any drug that inhibits or induces these clearance pathways may alter serum concentrations of posaconazole. Drugs that increase gastric pH, such as proton pump inhibitors, H2-receptor blockers or antacids, may decrease the absorption of posaconazole. Posaconazole is a strong inhibitor of CYP3A4 and may increase serum concentrations of drugs that are metabolized by this enzyme.3 Posaconazole is contraindicated for use with sirolimus, ergot alkaloids, and CYP3A4 substrates that also prolong the QT interval. It should be used with caution with other drugs known to prolong the QT interval.2

KETOCONAZOLE — Ketoconazole (Nizoral, and others) is seldom used now. Other azoles are preferred because they have fewer adverse effects.

Adverse Effects – Anorexia, nausea and vomiting are common with higher doses (>400 mg/day) of ketoconazole. Pruritus, rash, dizziness and photophobia may occur. Ketoconazole can decrease plasma testosterone concentrations and cause gynecomastia, decreased libido and erectile dysfunction in men and menstrual irregularities in women. High doses may inhibit adrenal steroidogenesis and decrease plasma cortisol concentrations. Hepatic toxicity, including fatal hepatic necrosis, can occur. Ketoconazole is teratogenic in animals (pregnancy category C).

Drug Interactions – Ketoconazole is a strong inhibitor of CYP3A4 and other metabolic pathways; it can significantly increase serum concentrations of many other drugs.3 The absorption of ketoconazole is significantly reduced by drugs that increase gastric pH, such as proton pump inhibitors, H2-receptor blockers and antacids

ECHINOCANDINS

Echinocandins inhibit synthesis of ß (1, 3)-D-glucan, an essential component of the fungal cell wall. Their potential for adverse effects in humans is low due to the absence in mammalian cells of enzymes involved in glucan synthesis. Caspofungin, anidulafungin and micafungin all have activity against most Candida species, including those resistant to azoles. Their activity against molds appears to be confined to Aspergillus. All 3 echinocandins are given intravenously once daily, do not require dose adjustment for renal failure, do not significantly interact with other drugs, and appear to be similar to each other in efficacy and safety.16

CASPOFUNGIN — Caspofungin (Cancidas) is FDAapproved for treatment of esophageal candidiasis, candidemia, intra-abdominal abscesses, peritonitis, and pleural space infections due to Candida. It is also approved for empiric treatment of presumed fungal infections in febrile, neutropenic patients and for treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies. Data on its use for primary treatment of aspergillosis are lacking.

Adverse Effects – Although generally well tolerated, caspofungin occasionally causes rash, fever, nausea, vomiting, headache, hypokalemia and mild hepatic toxicity. Stevens-Johnson syndrome and exfoliative dermatitis have been reported. Anaphylaxis has occurred. Dosage should be reduced in patients with moderate hepatic dysfunction. Caspofungin is embryo-toxic in animals (pregnancy category C).

Drug Interactions – Rifampin, carbamazepine, dexamethasone, efavirenz, nevirapine and phenytoin may increase the clearance of caspofungin. An increase in caspofungin dosage to 70 mg daily (70 mg/m2/day in children, max 70 mg) should be considered when it is co-administered with these drugs. Caspofungin can decrease serum concentrations of tacrolimus.

MICAFUNGIN — Micafungin (Mycamine) is FDA-approved for treatment of esophageal candidiasis and prevention of invasive candidiasis in autologous or allogeneic stem cell transplant recipients. It is also approved for treatment of candidemia and deeply invasive candidiasis. Approval was based on showing noninferiority in 2 large randomized clinical trials in patients with invasive candidiasis, one comparing micafungin to liposomal amphotericin B and the other comparing it to caspofungin.17,18 In an open-label, noncomparative trial, micafungin appeared to be efficacious in 12 patients with untreated and 24 patients with partially treated aspergillosis.19

Adverse Effects – Micafungin is well tolerated. Adverse effects have included rash, pruritus and facial swelling. Anaphylaxis has been rare. Fever, hepatic function abnormalities, hypokalemia, thrombocytopenia, renal dysfunction, headache, nausea, vomiting and diarrhea have been reported, but rarely limit therapy. Micafungin is teratogenic in animals (pregnancy category C).

ANIDULAFUNGIN — Anidulafungin (Eraxis)20 is FDA-approved for treatment of esophageal candidiasis. It is also approved for treatment of candidemia and deeply invasive candidiasis based on a randomized, double-blind trial demonstrating noninferiority to fluconazole. 21

Adverse Effects – Anidulafungin has a low incidence of adverse effects similar to those of caspofungin and micafungin. Unlike micafungin and caspofungin, hepatic failure does not appear to increase anidulafungin serum concentrations. Its safety in pregnancy has not been established (pregnancy category C).

AMPHOTERICIN B

Amphotericin B binds to ergosterol in the fungal cell membrane, leading to loss of membrane integrity and leakage of cell contents. Conventional amphotericin B and the newer lipid-based formulations have the same spectrum of activity and are active against most pathogenic fungi and some protozoa. They are not active against most strains of Aspergillus terreus, Scedosporium apiospermum, Trichosporon spp., Fusarium spp. and Candida lusitaniae. Amphotericin B is the preferred treatment for deep fungal infections during pregnancy because of experience with its use and apparent safety.

Conventional Amphotericin B – Amphotericin B deoxycholate, the non-lipid formulation of amphotericin, is the least expensive but also the most toxic, particularly to the kidney. The development of better tolerated lipid-based formulations has led to a decrease in its use. Intravenous infusion of amphotericin B deoxycholate frequently causes fever and chills, and sometimes headache, nausea, vomiting, hypotension and tachypnea, usually beginning 1-3 hours after starting the infusion and lasting about 1 hour. The intensity of these infusion-related acute reactions tends to decrease after the first few doses. Pretreatment with acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID) such as ibuprofen, diphenhydramine 25 mg IV and/or hydrocortisone 25 mg IV can decrease the severity of the reaction. Treatment with meperidine 25-50 mg IV can shorten the duration of rigors.

Nephrotoxicity is the major dose-limiting toxicity of amphotericin B deoxycholate; sodium loading with normal saline may prevent or ameliorate it and is generally recommended for patients who can tolerate a fluid load. The nephrotoxicity of amphotericin B may add to the nephrotoxicity of other drugs including cyclosporine, tacrolimus and aminoglycoside antibiotics such as gentamicin. Hypokalemia and hypomagnesemia are common and are usually due to a mild renal tubular acidosis. Weight loss, malaise, anemia, thrombocytopenia and mild leukopenia can occur. Cardiac toxicity and myopathy have been reported.

Lipid Formulations – The 3 lipid formulations of amphotericin B marketed in the US appear to be as effective as amphotericin B deoxycholate. Compared to conventional amphotericin B, acute infusion-related reactions are more severe with Amphotec, less severe with Abelcet, and least severe with AmBisome. Acute, severe pain in the chest, back or abdomen has occurred during the first infusion of liposomal amphotericin B.22 The cause of the pain is unknown. Some patients have tolerated subsequent, slower infusions of the drug when pretreated with diphenhydramine. Nephrotoxicity is less common with lipidbased products than with amphotericin B deoxycholate and, when it occurs, less severe. Liver toxicity, which is generally not associated with amphotericin B deoxycholate, has occurred rarely with the lipid formulations.

Cost comparisons with amphotericin B lipid formulations should take into account the fact that conventional amphotericin B deoxycholate may cause renal failure, which can increase the length of hospital stays, healthcare costs and mortality rates.23

OTHER DRUGS

FLUCYTOSINE – Potentially lethal, dose-related bone marrow toxicity and rapid development of resistance have occured with flucytosine (Ancobon) monotherapy; it is mainly used in combination with amphotericin B for treatment of cryptococcal meningitis or systemic candidiasis. Keeping serum concentrations below 100 mcg/mL decreases toxicity, but delays in obtaining assay results often limit their utility. Flucytosine is only available for oral use in the US. Doses must be adjusted for renal dysfunction. It is classified as category C for use in pregnancy.

TERBINAFINE – Terbinafine (Lamisil, and others) is a synthetic allylamine approved by the FDA for treatment of onychomycosis of the toenail or fingernail due to dermatophytes. It acts by inhibiting squalene epoxidase and blocking ergosterol synthesis.

The most common adverse effects of oral terbinafine have been headache, gastrointestinal symptoms including diarrhea, dyspepsia and abdominal pain, and occasionally a taste disturbance that may persist for weeks after the drug is stopped. Rash, pruritus and urticaria, usually mild and transient, have occurred. Toxic epidermal necrolysis and erythema multiforme have been reported. Increased aminotransferase levels and serious hepatic injury have occurred. Liver function should be assessed before starting and periodically during treatment with terbinafine. Anaphylaxis, pancytopenia and severe neutropenia have also been reported. Terbinafine is classified as category B for use in pregnancy.

Drug Interactions – Terbinafine is an inhibitor of CYP2D6 and may increase serum concentrations of drugs metabolized by this enzyme.1 Cimetidine may reduce the clearance of terbinafine. Enzyme inducers such as rifampin may increase terbinafine clearance.

COMBINATION THERAPY

Use of combination therapy for treatment of immunosuppressed patients with invasive aspergillosis, which has a high rate of morbidity and mortality despite current treatments, is controversial. In vitro studies and animal data suggest a potential benefit of combining an echinocandin with either an azole or amphotericin B, but clinical studies are lacking.

NEUTROPENIA

PROPHYLAXIS — High-risk neutropenic patients, such as those undergoing allogeneic and certain autologous stem cell transplants, and those with hematologic malignancy who are expected to have prolonged profound neutropenia, may require prophylactic treatment with antifungal drugs. Fluconazole (400 mg PO or IV once daily) has been used, but because of the high risk of invasive aspergillosis in these patients, some clinicians now use voriconazole (6 mg/kg every 12 hours x 2 doses, then 4-5 mg/kg every 12 hours) or posaconazole (200 mg t.i.d.) instead. Itraconazole solution, 200 mg twice daily, is an alternative but may not be well tolerated. In a prospective, randomized trial for prevention of invasive fungal infections in neutropenic patients with acute myelogenous leukemia or myelodysplastic syndrome undergoing chemotherapy, posaconazole was superior to fluconazole or itraconazole and improved survival.9 Micafungin 50 mg/day has been recommended for prophylactic use in patients with neutropenia.24

FEVER AND NEUTROPENIA — For neutropenic patients with fever that persists despite treatment with antibacterial drugs, empiric addition of an antifungal drug is common practice.25 Caspofungin and voriconazole appear to be as effective as liposomal amphotericin B.26,27 Fluconazole and itraconazole have also been used for this indication.

1. Drug interactions. Med Lett Drugs Ther 2003; 45:46.

2. Arizona Center for Education and Research on Therapeutics. Drugs that prolong the QT interval and/or induce torsades de pointes ventricular arrhythmia. Available at www.azcert.org. Accessed November 18, 2009.

3. CYP3A and drug interactions. Med Lett Drugs Ther 2005; 47:54.

4. R Herbrecht et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 347:408.

5. J Smith et al. Voriconazole therapeutic drug monitoring. Antimicrob Agents Chemother 2006; 50:1570.

6. A Pascaul et al. Voriconazole therapeutic drug monitoring in patients with mycoses improves efficacy and safety outcomes. Clin Infect Dis 2008; 46:201.

7. MO Karlsson et al. Population pharmacokinetic analysis of voriconazole plasma concentration data from pediatric studies. Antimicrob Agents Chemother 2009; 53:935.

8. Posaconazole (Noxafil) for invasive fungal infections. Med Lett Drugs Ther 2006; 48:93.

9. OA Cornely et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007; 356:348.

10. AJ Ullmann et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007; 356:335.

11. DJ Skiest et al. Posaconazole for the treatment of azole-refractoryoropharyngeal and esophageal candidiasis in subjects with HIV infection. Clin Infect Dis 2007; 44:607.

12. TJ Walsh et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therpy: an externally controlled trial. Clin Infect Dis 2007; 44:2.

13. A Cantanzaro et al. Safety, tolerance, and efficacy of posaconazole therapy in patients with nonmeningeal disseminated or chronic pulmonary coccidioidomycosis. Clin Infect Dis 2007; 45:562.

14. DA Stevens et al. Posaconazole therapy for chronic refractory coccidioidomycosis. Chest 2007; 132:952.

15. JA Van Burik et al. Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases. Clin Infect Dis 2006; 42:e61.

16. C Wagner et al. The echinocandins: comparison of their pharmacokinetics, pharmacodynamics and clinical applications. Pharmacology 2006; 78:161.

17. ER Kuse et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised doubleblind trial. Lancet 2007; 369:1519.

18. PG Pappas et al. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis 2007; 45:883.

19. DW Denning. Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis. J Infect 2006; 53:337.

20. Anidulafungin (Eraxis) for Candida infections. Med Lett Drugs Ther 2006; 48:43.

21. AC Reboli et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007; 356:2472.

22. MM Roden. Triad of acute infusion-related reactions associated with liposomal amphotericin B: analysis of clinical and epidemiological characteristics. Clin Infect Dis 2003; 36:1213.

23. AJ Ullmann et al. Prospective study of amphotericin B formulations in immunocompromised patients in 4 European countries. Clin Infect Dis 2006; 43:e29.

24. PG Pappas et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Disease Society of America. Clin Infect Dis 2009; 48:503.

25. WT Hughes et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002; 34:730.

26. TJ Walsh et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med 2004; 351:1391.

27. TJ Walsh et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002; 346:225.

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