e1-23: Antifungal Medications

Empiric antifungal therapy is rarely instituted except for immunocompromised (eg, febrile neutropenia) and other high-risk patients. Therapy generally is reserved for situations in which yeast or mold is seen on KOH preparation or when isolated organisms are thought to be pathogenic. Antifungal standardized susceptibility testing is available for Candida spp and predicts clinical outcome. In contrast, susceptibility testing for most other fungi is only available at certain centers; in vitro results for these pathogens are less predictive of patient outcomes due to limited clinical experience.

Amphotericin B in vitro inhibits several organisms producing systemic mycotic disease in humans, including Aspergillus, Histoplasma, Cryptococcus, Coccidioides, Candida, Blastomyces, Sporothrix, and others. This medication can be used for treatment of these systemic fungal infections. Pseudallescheria boydii and Fusarium are often resistant to amphotericin B.

The nephrotoxicity of conventional amphotericin has resulted in the development of lipid-based amphotericin B products. The most commonly used agent is liposomal amphotericin B (L-AmB; AmBisome). Liposomal amphotericin B 10 mg/kg/day is no better, but more nephrotoxic, than 3 mg/kg/day in the treatment of invasive mold infection. Liposomal amphotericin B is effective in the treatment of visceral leishmaniasis. Short courses (5–10 days) with low doses (2–4 mg/kg/day depending on which preparation is used) are very effective in eradicating the parasite, probably because of distribution of the medication to the reticuloendothelial system, the major site of parasite invasion.

Liposomal amphotericin B is associated with less nephrotoxicity and infusion reactions when compared with conventional amphotericin B.

The availability of lipid-based amphotericin, echinocandins, and triazoles has resulted in a greatly reduced role for conventional amphotericin for the prevention and treatment of fungal infection. If conventional amphotericin B is used, the daily dose for most fungal infections varies from 0.3 mg/kg to 0.7 mg/kg, though infections caused by Aspergillus and Mucor are often treated with 1–1.5 mg/kg daily.

Electrolyte disturbances (hypokalemia, hypomagnesemia, distal renal tubular acidosis) also commonly occur. Kidney injury can be reduced with sodium supplementation and intravenous hydration.

Nystatin has a wide spectrum of antifungal activity but is used almost exclusively to treat superficial candidal infections. It is too toxic for systemic administration, and the medication is not absorbed from mucous membranes or the gastrointestinal tract. Several preparations are available, including oral suspension (100,000 units/mL) and ointments, gels, and creams (100,000 units/g). For oral candidiasis, 500,000 units of suspension are used as a “swish and swallow” and repeated four times a day for at least 2 days after resolution of the infection. Infections of skin are treated with cream or ointment with 100,000 units applied to the affected area twice daily until resolution of the infection.

Flucytosine inhibits some strains of Candida, Cryptococcus, and other fungi. Dosages of 3–8 g daily (75–150 mg/kg/day) orally produce therapeutic levels in serum, urine, and cerebrospinal fluid. When used as monotherapy, development of resistance is common; thus, flucytosine is not used as a single medication therapy except in candiduria. In kidney disease, flucytosine may accumulate to toxic levels, and dosage adjustment is needed. Because patients with HIV infection and normal kidney function do not tolerate the previously used doses of flucytosine (150 mg/kg/day in four divided doses), 75–100 mg/kg/day is recommended. The medication is effectively removed by hemodialysis. Toxic effects include bone marrow depression, abnormal liver function, and nausea. Bone marrow suppression is caused by conversion of flucytosine to fluorouracil. Combination amphotericin and flucytosine is associated with improved survival in patients with cryptococcal meningitis.

Natamycin is a polyene antifungal medication effective against many different fungi in vitro. When it is combined with appropriate surgical measures, topical application of 5% ophthalmic suspension may be beneficial in the treatment of keratitis caused by Fusarium, Acremonium (cephalosporium), or other fungi. The toxicity after topical application appears to be low.

Terbinafine, an allylamine, inhibits fungal cell membrane function by blocking ergosterol synthesis. Terbinafine is available topically as well as in 250-mg tablets for oral administration. It is superior to itraconazole at a recommended dosage of 250 mg daily for 12 weeks for toenail infections and 250 mg daily for 6 weeks for fingernail infections. Pulse therapy (1 week on and 3 weeks off) is as effective as continuous therapy for 6–12 weeks. The medication also is active against many strains of Candida and Aspergillus organisms and has been used in combination with other antifungals to treat severe infections with these pathogens. Most adverse effects are minor (diarrhea, dyspepsia) or transient (taste disturbance). Rare cases of severe hepatic injury have occurred.

These antifungal medications inhibit synthesis of ergosterol, resulting in inhibition of membrane-associated enzyme activity, cell wall growth, and replication.

Clotrimazole, taken orally in the form of 10-mg troches five times daily, can prevent and treat oral candidiasis. Vaginal azole tablets inserted daily for 1–7 days are effective for vaginal candidiasis. Topical preparations for treatment of cutaneous dermatophytes are also available.

Fluconazole, a bis-triazole with activity similar to that of ketoconazole, is water-soluble and can be given both orally and intravenously. Absorption of the medication after oral administration is not pH-dependent. It penetrates well into the cerebrospinal fluid and eye. The medication is effective primarily in the treatment of Candida, Cryptococcus, and Blastomyces infections. C albicans, C tropicalis, and C parapsilosis are usually sensitive to fluconazole, but many other species of Candida (C krusei, C glabrata, etc) are often resistant. Fluconazole-resistant strains of C albicans are primarily observed in patients receiving long-term fluconazole therapy. Candida auris, closely related to C krusei and C lusitaniae, is commonly fluconazole resistant. C auris has emerged as a global health threat due to its propensity to cause nosocomial outbreaks. Additionally, multidrug resistance (voriconazole, amphotericin B, echinocandins) has been reported with C auris. Since echinocandin resistance is less common overall, these medications are typically recommended for the treatment of C auris infections. The medication is inactive against Aspergillus, Mucor, and Pseudallescheria. Fluconazole is effective in oropharyngeal candidiasis and candidal esophagitis. A single oral dose of 150 mg is as effective or more effective than vaginal creams and suppositories in vaginal candidiasis. Fluconazole, 400 mg intravenously and orally daily, is as effective as amphotericin B, 0.5–0.6 mg/kg/day, for candidemia in both neutropenic and nonneutropenic patients. Fluconazole (200 mg/day) is effective as long-term suppressive therapy of cryptococcal meningitis in patients with HIV/AIDS. In the treatment of cryptococcal meningitis, response rates and overall mortality rates are the same in patients treated with oral fluconazole and with amphotericin B. However, the mortality rate in the first 2 weeks is higher with fluconazole, and sterilization of cerebrospinal fluid is slower with fluconazole. Consequently, cryptococcal meningitis induction therapy generally takes place with amphotericin B (in combination with flucytosine) for 2 weeks, followed by oral fluconazole. A dosage of 400 mg of fluconazole daily is effective therapy for coccidioidal meningitis (80% response), but improvement is slow, taking as long as 4–8 months. Increased doses (800–1200 mg/day) have been used in the treatment of coccidiomycosis; however, they have not been found to be superior to usual doses. Fluconazole, 400 mg daily, is effective prophylaxis against superficial and invasive fungal infections in bone marrow and liver transplant recipients, but this practice results in superinfection with resistant organisms (C krusei, C glabrata). Increased doses of fluconazole may be necessary to achieve adequate drug exposure in critically ill pediatric cancer patients. Fluconazole is also effective for the therapy of cutaneous leishmaniasis due to Leishmania major in a dose of 200 mg/day for 6 weeks.

Fluconazole is well absorbed after oral administration (greater than 90% bioavailability), and serum levels approach those seen after administering the same dose intravenously. Thus, unless the patient cannot take medication by mouth or is hemodynamically unstable, the preferred route of administration is by mouth. While generally well tolerated, fluconazole is associated with dose-dependent nausea and vomiting. Altered liver biochemical tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) and clinical hepatitis have been reported. While less potent than other azoles (itraconazole, ketoconazole, posaconazole, voriconazole), fluconazole inhibits cytochrome P450, resulting in reduced elimination of certain agents. Rifampin and phenytoin increase metabolism of fluconazole, necessitating increased fluconazole dosage.

Itraconazole is an oral triazole with variable bioavailability. It is moderately well absorbed from the gastrointestinal tract (food increases absorption from 30% to 60%; antacids, proton pump inhibitors, and H₂-receptor antagonists decrease absorption). While the tablet formulation should be administered with food, the solution is best absorbed on an empty stomach. A SUBA-itraconazole (super bioavailability itraconazole) formulation was developed to improve oral bioavailability and increase the gastrointestinal tolerability of itraconazole. Itraconazole is widely distributed in tissues with the notable exception of the central nervous system, where levels in cerebrospinal fluid are undetectable. Itraconazole solution is more predictably absorbed than the tablets. The medication is metabolized by the liver, and no dosage adjustment is needed in kidney disease. Itraconazole is very active against most strains of Histoplasma capsulatum, Blastomyces dermatitidis, Cryptococcus neoformans, Sporotrichum schenkii, and various dermatophytes. It is also active against Aspergillus species but inactive against Fusarium and Zygomycetes. Itraconazole in doses of 200–400 mg/day is effective and approved therapy for localized or disseminated histoplasmosis. It is also effective in sporotrichosis, dermatophytic infections (including those of the nails), and oral and esophageal candidiasis. Itraconazole is at least as effective as fluconazole in the treatment of nonmeningeal coccidioidomycosis and may be superior in the management of skeletal disease. At doses of 200 mg twice daily, itraconazole increases exercise tolerance and decreases corticosteroid requirements in patients with allergic bronchopulmonary aspergillosis. Itraconazole pulse therapy with 200 mg twice daily for 1 week each month, repeated for 4 consecutive months, is effective in the treatment of onychomycosis.

Adverse effects are similar to those of fluconazole, with anorexia, nausea, vomiting, and abdominal pain occurring most commonly. Skin rash has been reported in up to 8% of patients. Hepatitis and hypokalemia occur uncommonly. Medications that increase hepatic cytochrome P450 (rifampin, phenytoin, phenobarbital) may increase itraconazole metabolism, and increased doses may be needed when these medications are administered concurrently with itraconazole. Itraconazole decreases the metabolism of cyclosporine, digoxin, and warfarin.

The usual dosage varies depending on the formulation and indication.

Voriconazole is a triazole antifungal with broad in vitro activity against most species of Candida and molds (eg, Aspergillus, Fusarium, Pseudallescheria, and others). It is as efficacious as liposomal amphotericin in the therapy of documented and suspected fungal infections in febrile neutropenic patients and superior to liposomal amphotericin in preventing breakthrough fungemia in this patient population. Voriconazole is superior to conventional amphotericin in the treatment of disseminated aspergillosis. Animal data also suggest voriconazole to be the most effective agent against Aspergillus, particularly in combination with caspofungin or another echinocandin. Voriconazole is the medication of choice in the treatment of Fusarium and Scedosporium infections. Voriconazole is widely used in the treatment of neutropenic patients with suspected or documented fungal infection. Voriconazole has limited activity against zygomycete pathogens, and some centers have reported increased rates of infection due to Rhizopus and Mucor in stem cell transplantation patients receiving voriconazole. Similar to fluconazole, oral administration leads to predictable absorption.

The primary early toxicity associated with voriconazole is infusion-related, transient visual disturbances, particularly during the first week of therapy. Of all the azole antifungal agents, voriconazole is associated with the most frequent elevation in liver biochemical tests and frank hepatitis. Long-term therapy may be associated with a multistep phototoxic process, followed by actinic keratosis, then squamous cell carcinoma. It has been recommended that discontinuation of voriconazole take place in patients experiencing chronic photosensitivity. The trifluorinated molecular structure of voriconazole has been associated with increased fluoride levels and periostitis in patients receiving voriconazole for long-term therapy. Also, when voriconazole is administered intravenously, it must be delivered in a cyclodextrin solution. In mice and rat animal models, the cyclodextrin (unlike the voriconazole) accumulates in kidney disease and has been associated with kidney toxicity. However, in human patients with kidney dysfunction, administration of voriconazole in cyclodextrin has not been associated with worsening kidney function. Similar to itraconazole, voriconazole is associated with numerous drug interactions. Enzyme inducers can decrease voriconazole plasma levels with potential for reduction in efficacy. Pharmacogenomic differences in cytochrome P450 2C19 can result in large differences in voriconazole clearance; therapeutic trough levels should be 1–5 mcg/mL. Voriconazole is also an inhibitor of cytochrome P450 activity, reducing the clearance of numerous substrates including cyclosporine and tacrolimus.

Posaconazole is an antifungal derivative of itraconazole with similar spectrum of activity as voriconazole, including yeast and Aspergillus spp. Unique from voriconazole, posaconazole has activity against the zygomycete fungi approaching that of amphotericin. Salvage treatment studies demonstrate efficacy in the treatment of these pathogens. Posaconazole is superior to fluconazole as fungal prophylaxis of neutropenia. Oral posaconazole should always be administered with food to ensure adequate oral bioavailability; the oral delayed-release product is associated with improved oral bioavailability when compared to the oral solution. Intravenous posaconazole should be used in patients unable to tolerate oral therapy or at risk for malabsorption from the gastrointestinal tract. Similar to voriconazole, posaconazole is primarily eliminated via nonrenal mechanisms. As with the other azole agents, posaconazole has primarily upper gastrointestinal adverse events and occasional liver biochemical test abnormalities. While not as problematic as voriconazole, posaconazole is also an inhibitor of cytochrome P450. Higher concentrations of posaconazole have been associated with pseudohyperaldosteronism.

Isavuconazole, the most recently approved azole, demonstrates excellent in vitro activity against both yeast and molds, including Aspergillus and the Mucorales. The medication is administered as the prodrug, isavuconazonium, which is available both as a highly absorbed oral preparation and a cyclodextrin-free intravenous formulation. Isavuconazole is at least as effective as voriconazole in the treatment of invasive mold infection due to Aspergillus and other filamentous fungi and much better tolerated. However, isavuconazole is less effective than caspofungin in the treatment of patients with invasive candidiasis. The rate of hepatobiliary, ocular, and skin disorders is significantly less with isavuconazole than with voriconazole. Isavuconazole is both a sensitive substrate and a mild to moderate inhibitor of CYP 3A4. Medications that alter gastric pH do not alter the oral bioavailability of the drug, and the oral preparation does not have dietary requirements.

Ketoconazole, the first orally bioavailable azole, previously was used in the treatment of a variety of fungal infections. However, the improved spectrum of activity, reduced toxicity, and superior pharmacokinetics of newer azoles have reduced ketoconazole to a secondary role.

The echinocandins (anidulafungin, caspofungin, micafungin) act by inhibiting fungal cell wall synthesis. They are active against Candida, including nonalbicans species, as well as Aspergillus species. They are not active against Cryptococcus or Fusarium. While appreciable in vitro activity against Mucorales is lacking, clinical data suggest echinocandins are beneficial in combination with mold-active agents such as amphotericin B. Their long pharmacologic half-life confers the advantage of once-daily dosing. No change in dose is necessary in patients with kidney disease; however, moderate to severe hepatic disease necessitates a reduction in dosage for caspofungin. Because dexamethasone, rifampin, and phenytoin significantly increase the metabolism of caspofungin, increased doses of the antifungal are necessary when these agents are given concomitantly. Animal data suggest that caspofungin is inferior to voriconazole in the treatment of Aspergillus; however, the addition of caspofungin to voriconazole has been associated with in vitro and in vivo additive or synergistic effects. Caspofungin is superior to conventional amphotericin B in the treatment of candidemia, primarily on the basis of greater patient tolerability. The echinocandins should be considered the medications of choice in the treatment of infections due to C glabrata and C krusei and probably C auris. While these agents are generally active against C glabrata, the rate of resistance associated with echinocandins has increased over the past several years, now averaging 5–10%. Consequently, all bloodstream infection isolates should be checked for echinocandin susceptibility. Risk factors for echinocandin nonsusceptibility include prior echinocandin exposure, previous candidemia exposure, recent hospitalization, and fluconazole resistance. Micafungin is as effective as and less toxic than liposomal amphotericin in the treatment of candidemia and invasive candidiasis. Anidulafungin is at least as effective as fluconazole in the treatment of invasive candidiasis. Empiric micafungin treatment in nonneutropenic critically ill patients does not increase fungal infection-free survival.

These agents are associated with minimal toxicity or adverse effects. Histamine release is common with basic polypeptide compounds, such as the echinocandins; thus infusion-related reactions have been reported.