Chemotherapy (Antifungals): Antifungal Drugs

Introduction / Overview

Fungal infections pose a significant therapeutic challenge, particularly in immunocompromised populations such as hematopoietic stem cell transplant recipients, patients with advanced malignancies, and individuals with prolonged neutropenia. Antifungal chemotherapy constitutes a critical component of modern infectious disease management, offering targeted eradication of pathogenic fungi while attempting to minimize host toxicity. Contemporary practice requires a nuanced understanding of each drug’s pharmacologic profile, including its spectrum of activity, mechanism of action, pharmacokinetics, and potential for adverse events and drug interactions. This chapter aims to consolidate current evidence regarding antifungal agents, facilitating informed decision-making in clinical scenarios.

Learning objectives:

• Identify the major classes of antifungal drugs and their chemical classifications.
• Describe the pharmacodynamic mechanisms by which antifungal agents inhibit fungal growth.
• Summarize the pharmacokinetic properties influencing dosing regimens.
• Recognize approved therapeutic indications and common off‑label applications.
• Appreciate the spectrum of adverse effects, drug interactions, and special population considerations.

Classification

Major Drug Classes

Antifungal chemotherapy is traditionally organized into five principal classes based on structural and mechanistic attributes:

• Azoles – triazoles (e.g., fluconazole, voriconazole, posaconazole) and imidazoles (e.g., clotrimazole, miconazole).
• Polyenes – amphotericin B and its lipid formulations (liposomal amphotericin B, amphotericin B lipid complex).
• Echinocandins – caspofungin, micafungin, anidulafungin.
• Allylamines – terbinafine.
• Pyrimidine analogs – flucytosine.

Additional agents such as isavuconazole and olorofim are emerging and may be considered in specific contexts.

Chemical Classification

Azoles are divided into two subgroups based on ring heteroatom composition: imidazoles possess a 1,3‑diazole ring, whereas triazoles incorporate a 1,2,4‑triazole moiety. Polyenes are characterized by a linear conjugated system of alternating double bonds, conferring the ability to bind ergosterol. Echinocandins are cyclic lipopeptides containing a β‑hydroxy‑α‑amino acid core linked to a lipid side chain. Allylamines contain a 2,4‑alkenyl side chain that interferes with squalene epoxidase. Pyrimidine analogs are structurally similar to 5-fluorouracil, enabling inhibition of nucleic acid synthesis.

Mechanism of Action

Azoles

Azoles exert fungistatic effects primarily by inhibiting the cytochrome P450‑dependent enzyme lanosterol 14‑α‑demethylase (CYP51). This inhibition blocks the conversion of lanosterol to ergosterol, a key component of fungal cell membranes. Reduced ergosterol incorporation destabilizes membrane integrity and impairs membrane protein function, leading to increased permeability and cellular dysfunction. Some triazoles, particularly voriconazole and posaconazole, also exhibit activity against demethylation of 14‑α‑lanosterol, contributing to broad spectrum efficacy.

Polyenes

Polyenes act by binding with high affinity to ergosterol, forming transmembrane pores that create ion channels. The resulting pore formation causes efflux of essential ions and molecules, culminating in cell death. The fungicidal activity of amphotericin B is dose‑dependent and is correlated with the degree of ergosterol binding. Lipid formulations mitigate nephrotoxicity by altering distribution profiles.

Echinocandins

Echinocandins inhibit β‑1,3‑D‑glucan synthase, an enzyme complex essential for the synthesis of β‑1,3‑D‑glucan, a fundamental component of the fungal cell wall. Disruption of the cell wall compromises structural integrity, leading to lysis of the organism. The inhibition is fungicidal for most Candida species and fungistatic for Aspergillus species.

Allylamines

Allylamines block squalene epoxidase, the enzyme responsible for the epoxidation of squalene to lanosterol within the ergosterol biosynthetic pathway. Accumulation of squalene and depletion of downstream intermediates culminate in impaired membrane synthesis and fungal growth inhibition.

Pyrimidine Analogs

Flucytosine is converted intracellularly by cytosine deaminase to 5‑fluorouracil, which subsequently integrates into RNA and DNA, disrupting gene expression and DNA replication. Additionally, 5‑fluorouracil inhibits thymidylate synthase, further impairing DNA synthesis. The drug is fungicidal against Cryptococcus neoformans and Coccidioides spp. when used in combination with amphotericin B.

Pharmacokinetics

Absorption

Oral absorption varies markedly among classes. Fluconazole demonstrates >90 % bioavailability, whereas itraconazole requires acidic gastric pH and is formulated as a delayed‑release capsule to enhance absorption. Voriconazole possesses high oral bioavailability (~96 %) but shows significant inter‑individual variability due to CYP2C19 polymorphisms. Liposomal amphotericin B and other lipid formulations are administered intravenously, bypassing gastrointestinal absorption.

Distribution

Azoles are lipophilic and achieve appreciable tissue penetration, including the central nervous system (CNS) for fluconazole and voriconazole. Amphotericin B displays extensive tissue distribution but limited CNS penetration in its conventional form; however, liposomal preparations improve CNS bioavailability. Echinocandins exhibit high protein binding (~70–90 %) and distribution into interstitial spaces, though CNS penetration remains limited. Terbinafine penetrates skin and nails effectively, aligning with its dermatological indications.

Metabolism

CYP450 enzymes mediate metabolism for many azoles, rendering them susceptible to drug–drug interactions. Voriconazole is metabolized predominantly by CYP2C19, with secondary contributions from CYP3A4 and CYP2C9. Posaconazole is primarily metabolized via glucuronidation. Amphotericin B is not extensively metabolized, reducing interaction potential. Echinocandins undergo limited hepatic metabolism via limited glucuronidation and hydrolysis, with excretion largely unchanged.

Excretion

Fluconazole is excreted unchanged via glomerular filtration and tubular secretion. Voriconazole and posaconazole undergo hepatic metabolism and biliary excretion. Amphotericin B is eliminated via the reticuloendothelial system, with minimal renal excretion. Echinocandins are eliminated by biliary excretion and fecal routes, with negligible renal clearance. Terbinafine is metabolized hepatically and excreted in feces.

Half‑Life and Dosing Considerations

The half‑life of fluconazole ranges from 6 to 10 h in healthy adults, permitting once‑daily dosing. Voriconazole has a half‑life of approximately 6 h, necessitating twice‑daily administration. Posaconazole half‑life extends to 30 h, allowing once‑daily dosing after a loading dose. Amphotericin B’s half‑life is 24–48 h, though dosing is typically based on weight and adjusted for renal function. Echinocandins possess half‑lives of 12–16 h, with once‑daily dosing. Terbinafine’s half‑life is 5–7 days, supporting once‑daily dosing for dermatological infections. Dose adjustments are imperative in renal or hepatic impairment, with therapeutic drug monitoring recommended for agents exhibiting significant variability (e.g., voriconazole).

Therapeutic Uses / Clinical Applications

Approved Indications

Azoles are indicated for a broad spectrum of candidiasis (oropharyngeal, esophageal, esophageal candidiasis), invasive aspergillosis (voriconazole, posaconazole), cryptococcal meningitis (fluconazole, voriconazole), and prophylaxis in neutropenic patients (fluconazole, posaconazole). Polyenes, particularly amphotericin B, are reserved for life‑threatening infections such as disseminated histoplasmosis, blastomycosis, and mucormycosis. Echinocandins are first‑line agents for candidemia and invasive candidiasis, while terbinafine is employed for dermatophyte infections of nails and skin. Flucytosine is utilized in combination therapy for cryptococcal meningitis and coccidioidomycosis.

Off‑Label Uses

Voriconazole is frequently applied off‑label for mucormycosis and aspergillosis in patients with severe disease unresponsive to standard therapy. Posaconazole serves as secondary prophylaxis in patients intolerant to fluconazole. Liposomal amphotericin B is employed in patients with renal dysfunction or in combination protocols for severe fungal infections. Echinocandins are sometimes used empirically in candidemia pending species identification. Terbinafine is occasionally prescribed for onychomycosis caused by yeasts, despite limited evidence.

Adverse Effects

Common Side Effects

• Azoles: gastrointestinal upset, hepatotoxicity (elevated transaminases), QT interval prolongation (voriconazole, posaconazole), and photosensitivity (fluconazole).
• Polyenes: infusion‑related reactions (fever, chills), nephrotoxicity, hypokalemia, and anemia.
• Echinocandins: infusion reactions, mild hepatotoxicity, and gastrointestinal disturbances.
• Allylamines: hepatotoxicity, photosensitivity, and rash.
• Pyrimidine analogs: bone marrow suppression, gastrointestinal intolerance, and increased risk of secondary infections.

Serious / Rare Adverse Reactions

Azole hepatotoxicity may progress to fulminant hepatic failure, especially in patients with pre‑existing liver disease. Voriconazole can precipitate visual disturbances, neurotoxicity, and severe skin reactions (Stevens–Johnson syndrome). Amphotericin B is associated with cumulative nephrotoxicity, electrolyte derangements, and infusion‑related pulmonary complications. Echinocandins may rarely provoke serious hypersensitivity reactions and hepatotoxicity. Flucytosine monotherapy induces bone marrow suppression; when combined with amphotericin B, risk of toxicity escalates. Terbinafine may cause hepatotoxicity and, in rare cases, neuropsychiatric manifestations.

Black Box Warnings

Flucytosine carries a black box warning due to the potential for severe bone marrow suppression and secondary infections. Liposomal amphotericin B has a boxed warning for nephrotoxicity, and monitoring of serum creatinine is advised. Voriconazole’s boxed warning highlights the risk of serious skin reactions and hepatotoxicity. Terbinafine’s boxed warning addresses hepatotoxicity and the need for liver function monitoring.

Drug Interactions

Major Drug–Drug Interactions

Azoles act as potent inhibitors of CYP3A4 and other CYP450 enzymes, leading to elevated serum concentrations of statins, benzodiazepines, anticoagulants (warfarin), and certain antiretrovirals. Voriconazole, in particular, can augment the plasma levels of drugs metabolized by CYP2C19 and CYP2C9. Posaconazole’s extensive inhibition of CYP3A4 can potentiate the effects of oral hypoglycemics and antipsychotics. Echinocandins exhibit fewer interactions due to limited metabolism, yet caspofungin may inhibit CYP3A4 to a modest degree. Terbinafine induces CYP2D6, potentially reducing the efficacy of beta‑blockers and oral contraceptives. Flucytosine has minimal interaction potential but requires careful monitoring when combined with other myelosuppressive agents.

Contraindications

Concomitant use of azoles with drugs having narrow therapeutic indices is contraindicated unless dose adjustments and monitoring are feasible. Amphotericin B is contraindicated in patients with severe renal impairment unless a lipid formulation is employed. Terbinafine should be avoided in patients with significant hepatic dysfunction. Flucytosine is contraindicated in patients with myelosuppression or severe hepatic dysfunction, given the risk of exacerbated cytopenias and hepatotoxicity.

Special Considerations

Pregnancy / Lactation

Azoles are classified as pregnancy category C; evidence suggests potential fetal harm, particularly with prolonged exposure. Fluconazole at therapeutic doses carries a low risk; however, high doses (>400 mg/day) are discouraged. Voriconazole and posaconazole have limited human data and are generally avoided. Liposomal amphotericin B is category B and preferred in pregnancy due to lower fetal toxicity. Echinocandins are category C, with limited safety data. Terbinafine’s teratogenic potential is uncertain, but caution is advised. Lactation: most azoles are excreted into breast milk; fluconazole is considered relatively safe, whereas voriconazole and posaconazole should be avoided. Amphotericin B is not significantly excreted into milk. Echinocandins and terbinafine have minimal excretion into milk but are generally avoided unless benefits outweigh risks. Flucytosine is excreted into milk and should be avoided.

Pediatric / Geriatric Considerations

Pediatric dosing often relies on body weight and age‑specific pharmacokinetic data. Fluconazole is well tolerated in infants and children, with dosing adjustments for renal function. Voriconazole’s metabolism is variable in neonates; therapeutic drug monitoring is essential. Echinocandins have limited pediatric data but are used in neonates with invasive candidiasis. Terbinafine dosing in children is weight‑based. Geriatric patients frequently exhibit reduced hepatic and renal clearance; dose reductions and monitoring are recommended, particularly for azoles and amphotericin B.

Renal / Hepatic Impairment

Renal impairment necessitates dose adjustments for fluconazole, posaconazole, and voriconazole, as renal clearance contributes substantially to elimination. Liposomal amphotericin B dosing may be reduced in patients with creatinine clearance <30 mL/min, and continuous monitoring of renal function is advised. Echinocandins are primarily eliminated hepatically; hepatic impairment warrants dose modification. Terbinafine dosing should be carefully considered in hepatic disease due to potential hepatotoxicity. Flucytosine is contraindicated in severe renal dysfunction (eGFR <30 mL/min) due to accumulation and increased toxicity risk.

Summary / Key Points

• Antifungal chemotherapy encompasses azoles, polyenes, echinocandins, allylamines, and pyrimidine analogs, each with distinct mechanisms targeting ergosterol synthesis, cell membrane integrity, or cell wall formation.
• Pharmacokinetic variability, particularly for azoles, necessitates therapeutic drug monitoring and consideration of CYP450 interactions.
• Clinical indications span mucocutaneous, systemic, and invasive infections; prophylactic use is common in high‑risk immunocompromised patients.
• Adverse effect profiles range from mild gastrointestinal upset to severe hepatotoxicity and nephrotoxicity; black box warnings underscore the need for vigilant monitoring.
• Drug interactions are frequent, especially with azoles; dose adjustments and monitoring are essential when concurrent medications with narrow therapeutic windows are present.
• Special populations—pregnancy, lactation, pediatrics, geriatrics, and organ dysfunction—require tailored dosing strategies and careful risk–benefit assessment.
• Therapeutic decision‑making should incorporate drug spectrum, patient comorbidities, potential interactions, and pharmacokinetic considerations to optimize efficacy while minimizing toxicity.

By integrating these pharmacologic principles, clinicians and pharmacists can refine antifungal therapy, thereby improving outcomes for patients afflicted with fungal infections.

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