Systemic Antifungal Agents

Mechanisms of Action

The azole ring confers antifungal activity on a variety of synthetic organic compounds. N -substitution of imidazoles has created a family of drugs called triazoles that have the same mechanism of action as imidazoles, a similar or broader spectrum of activity, and less effect on human sterol synthesis. Both imidazoles and triazoles inhibit C-14α demethylation of lanosterol in fungi; this leads to reduced concentrations of ergosterol, which is essential for a normal fungal cytoplasmic membrane. The principal pharmacodynamic driver for the response of Candida spp to the triazole antifungal agents has been the ratio of total drug exposure (area under the curve) to the minimum inhibitory concentration. For Aspergillus spp, the critical driver has been the amount of time that the drug is above a critical inhibitory threshold. Because of their interaction with the cytochrome P-450 (CYP) system and, in some cases, the P-glycoprotein pumps, the azoles as a class have a large number of drug-drug interactions, about 10% of which cause important clinical events. Careful attention must be paid to these potential interactions whenever azoles are prescribed (see https://www.aspergillus.org.uk/antifungal-drug-interactions/ ).

Newer triazoles have properties that make them preferable to ketoconazole. These properties include not only less hormonal inhibition but also better distribution into body fluids, the availability of both parenteral and oral formulations, less hepatotoxicity, and a broader spectrum. Resistance to azoles is emerging in previously susceptible species, and new resistant species, such as Candida auris , have spread globally. Resistance mechanisms include increased drug efflux, as well as altered or increased C-14α demethylase. Some of the common resistance mutations seen in Aspergillus isolates from certain geographic areas may have arisen owing to the widespread agricultural use of azole fungicides. All agents in this class have the potential for embryotoxicity and teratogenicity, so they generally should be avoided during pregnancy, particularly during the first trimester.

Formulations and Pharmacology

Itraconazole is marketed as a capsule, as a new super bioavailable (SUBA)-itraconazole capsule with better bioavailability, and as an oral and intravenous suspension in cyclodextrin (an oligosaccharide ring). The ring entraps the hydrophobic, water-insoluble drug, thereby making it soluble. Oral absorption of the capsule is significantly enhanced by food, whereas absorption of the oral solution is best on an empty stomach. By comparison, absorption of SUBA-itraconazole does not vary with food. Peak levels with oral preparations are achieved 4 to 6 hours after a dose. Steady state is achieved only after 13 to 15 days, at which time the β-elimination half-life is approximately 19 to 22 hours. Absorption of the capsule is markedly depressed in patients who have graft-versus-host mucositis and in patients who have enteritis caused by acquired immunodeficiency syndrome (AIDS), but this problem can be alleviated by using the solution or SUBA-itraconazole.

Bioassays of itraconazole yield much higher concentrations than by direct measurement because of the hydroxyitraconazole metabolite. Hydroxyitraconazole, which appears in the blood in amounts roughly twice that of the parent drug, has antifungal activity and pharmacokinetics similar to those of the parent compound. Concentrations of itraconazole in tissue, pus, and bronchial secretions are generally higher than those in plasma. Ocular levels are low. Saliva concentrations persist for 8 hours after administration of the solution and may be beneficial in treating oral disease or eradicating oral colonization. The drug is metabolized in the liver (so its half-life is prolonged in patients with cirrhosis) and excreted in feces as metabolites. No useful amount of bioactive itraconazole appears in urine. Plasma concentrations do not increase in patients with renal insufficiency or decrease with hemodialysis.

Indications and Dosage

Itraconazole is useful for the treatment of invasive aspergillosis ( Chapter 311 ), allergic bronchopulmonary aspergillosis, chronic pulmonary aspergillosis, blastomycosis ( Chapter 308 ), histoplasmosis ( Chapter 308 ), meningeal and nonmeningeal coccidioidomycosis ( Chapter 308 ), paracoccidioidomycosis ( Chapter 308 ), sporotrichosis ( Chapter 308 ), talaromycosis, phaeohyphomycosis ( Chapter 314 ), mucosal candidiasis ( Chapter 310 ), ringworm (including terbinafine-resistant infections), and tinea versicolor ( Chapter 405 ). Itraconazole is also useful for the prevention of relapse of disseminated histoplasmosis in patients with AIDS. SUBA-itraconazole or oral solution can be used for antifungal prophylaxis in immunosuppressed and neutropenic patients, and intravenous itraconazole can be used as empiric therapy for episodes of febrile neutropenia ( Chapter 260 ).

For deep mycoses, an initial oral itraconazole dose of 200 mg three times daily is recommended for the first 3 days to achieve high serum and tissue levels quickly ( Table 307-1 ). SUBA-itraconazole requires only 100 mg twice daily. For intravenous use, a 200 mg loading dose four times daily is then followed by 200 mg twice daily.

Drug Interactions

Drugs that decrease gastric acidity reduce the absorption of capsules, except for SUBA-itraconazole. Some of the most notable drug interactions are rifampin, rifabutin, isoniazid, phenytoin, and carbamazepine, all of which decrease itraconazole blood levels. Itraconazole decreases rifampin blood levels and increases blood levels of some antihistamines and ivabradine, thereby potentially causing ventricular tachycardia. It also increases blood levels of warfarin, benzodiazepines, statins, dihydropyridine calcium-channel blockers, digoxin, quinidine, cyclosporine, tacrolimus, methylprednisolone, human immunodeficiency virus (HIV) protease inhibitors (e.g., ritonavir, indinavir, elvitegravir/cobicistat), and vinca alkaloids.

Adverse Effects

The most common adverse effect is dose-related nausea and abdominal discomfort, but symptoms rarely necessitate stopping therapy. Dividing the dose and administering the drug twice daily can improve tolerance and raise blood levels. Hypokalemia and edema may occur at doses of 400 mg/day or higher. Allergic rash is seen occasionally. Itraconazole is rarely hepatotoxic. Diarrhea, nausea, and other gastrointestinal complaints are more frequent with the oral solution. A negative inotropic effect, which is manifested as subacute onset of heart failure, is rarely seen. Longer-term use can result in peripheral neuropathy. Itraconazole during pregnancy is associated with increased fetal loss.

Formulations and Pharmacology

Fluconazole is currently available in oral and vaginal tablets, as a powder for oral suspension, and as an intravenous formulation. Fluconazole is well absorbed from the gastrointestinal tract. Of the oral dose, 60 to 75% appears unchanged in the urine. Fluconazole penetrates into the brain, cerebrospinal fluid (CSF), saliva, sputum, and urine.

Fluconazole’s half-life increases with diminished renal function. Although the dose may be reduced in such circumstances, the drug’s toxicity is minimal even at high exposures, so the tendency to reduce the dose must be weighed against the risk of undertreatment. The dose should be doubled in patients who are receiving hemofiltration because of rapid clearance. Patients receiving hemodialysis should have one daily dose after each session.

Indications and Dosage

Drug Interactions

Among other drug interactions, fluconazole can cause significant increases in the blood level of phenytoin, glipizide, glyburide, tolbutamide, warfarin, rifabutin, cisapride, quinidine, bosentan, and cyclosporine. Rifampin lowers fluconazole blood levels by approximately 25%.

Adverse Effects

Adverse effects are uncommon. Even with chronic therapy, including doses exceeding 400 mg/day, headache, usually reversible alopecia, and anorexia are the most common symptoms; about 10% of patients develop elevated aspartate aminotransferase levels. Toxicity is, however, increased with doses over 1200 mg/day. Fluconazole use during pregnancy increases cardiac defects at birth by about three-fold.

Formulations and Pharmacology

Voriconazole is marketed as tablets, an oral solution, topical eye drops, and a solution in sulfobutyl ether β-cyclodextrin for intravenous administration. Voriconazole is cleared by hepatic metabolism, with less than 2% of the dose excreted unchanged in the urine. Voriconazole exhibits nonlinear pharmacokinetics in adults, owing to saturation of the clearance pathways at higher doses, but linear kinetics in children, who usually clear the drug rapidly. The principal enzymes involved in clearance are hepatic CYP2C19 and CYP3A4. Despite significant genetic polymorphisms that affect the drug’s metabolism, achieved plasma levels overlap, and an initial dose adjustment based on genotype or racial group is not necessary. Therapeutic drug monitoring with dose adjustments as necessary is recommended because favorable outcomes correlate with serum concentrations greater than 1 to 2 µg/mL, but neurologic/psychiatric, hepatic, or cardiac side effects occur with levels greater than 5 µg/mL.

Standard loading doses followed by maintenance doses that are 50% of normal are recommended for patients who are older than 75 years or have mild-to-moderate hepatic cirrhosis. Dosage adjustments are not required for renal dysfunction, and voriconazole is not significantly cleared by hemodialysis.

Indications and Dosage

The standard dosing of voriconazole in adults is 6 mg/kg intravenously and 200 to 300 mg orally, both twice daily, preceded by loading doses for 1 day in severely ill patients (see Table 307-1 ). Doses should be adjusted by therapeutic drug monitoring, and lower doses such as 150 mg twice daily are preferred in older (age >75 years) and low weight (<50 kg) patients. Treatment is given for weeks or months.

Drug Interactions

Voriconazole has many drug interactions. Rifampin, carbamazepine, long-acting barbiturates, glucocorticoids, and ritonavir induce the hepatic enzymes responsible for the clearance of voriconazole and thereby reduce voriconazole levels. Sirolimus levels are increased dramatically. Prolonged sedation is likely if voriconazole is coadministered with methadone, hydrocodone, alfentanil, fentanyl, or other short-acting opiates. Reduction in the clearance of pimozide, quinidine, ivabradine, and some antihistamines increases the risk for QT prolongation. Coadministration should be avoided with naloxegol, everolimus, St. John’s wort, and venetoclax. Cyclosporine, tacrolimus, warfarin, statins, benzodiazepines, calcium-channel blockers, sulfonylureas, and vinca alkaloids can be coadministered, but the dosages of these drugs may need to be reduced, and clinical or laboratory monitoring is suggested. Coadministration of voriconazole with omeprazole or elvitegravir-cobicistat elevates the levels of both drugs. Voriconazole with rifabutin, phenytoin, or efavirenz results in lower voriconazole levels and elevated levels of the other drug. Numerous other interactions have been documented, and any cytochrome P-450 inhibitors, blockers, or inducers could have an interaction with voriconazole.

Adverse Effects

Transient, reversible visual disturbance beginning approximately 30 minutes after a dose is common. Hallucinations, unsteadiness, confusion, and liver enzyme abnormalities also have been associated with higher blood levels. Photosensitivity can be severe and has been associated with skin cancers in rare instances. Prolongation of the QT interval and tachyarrhythmias have been noted in patients with pro-arrhythmic risk factors, such as electrolyte abnormalities. Periostitis has been noted after prolonged therapy, apparently related to the fluoride atoms in the molecule. Leukoencephalopathy has been rarely reported.