Pharmacology of Antifungal Drugs

Introduction/Overview

The management of fungal infections represents a significant and growing challenge in clinical medicine. The increasing prevalence of invasive mycoses is driven by several factors, including a rise in the number of immunocompromised patients due to chemotherapy, organ transplantation, and the human immunodeficiency virus (HIV) epidemic, as well as the widespread use of broad-spectrum antibacterial agents and invasive medical devices. Fungal pathogens can cause a spectrum of diseases, from superficial mucosal infections to life-threatening systemic dissemination. The pharmacology of antifungal drugs is therefore a critical area of study, as these agents form the cornerstone of treatment for these conditions. The therapeutic arsenal is characterized by drugs with distinct mechanisms of action, pharmacokinetic profiles, and toxicity spectra, necessitating a nuanced understanding for optimal clinical application.

The clinical relevance of antifungal pharmacology is underscored by the high morbidity and mortality associated with invasive fungal infections, particularly in vulnerable patient populations. Successful treatment outcomes depend not only on accurate diagnosis but also on the appropriate selection of antifungal therapy based on the suspected or proven pathogen, the site of infection, host factors, and the pharmacodynamic and pharmacokinetic properties of the available drugs. The evolution of antifungal resistance, notably among Candida and Aspergillus species, further complicates therapeutic decisions and highlights the importance of rational drug use.

The learning objectives for this chapter are as follows:

• To classify the major antifungal drug classes based on their chemical structure and primary mechanism of action.
• To describe in detail the molecular and cellular pharmacodynamics of each antifungal class, including their interactions with fungal cellular targets.
• To analyze the pharmacokinetic principles of absorption, distribution, metabolism, and excretion for systemic antifungal agents and their implications for dosing.
• To evaluate the approved clinical indications, common adverse effects, and significant drug interactions for each major antifungal drug.
• To apply knowledge of antifungal pharmacology to special clinical situations, including organ impairment, pediatric and geriatric use, and pregnancy.

Classification

Antifungal drugs are systematically classified according to their chemical structure and primary mechanism of action. This classification provides a framework for understanding their spectra of activity, resistance patterns, and clinical utility.

Chemical and Mechanistic Classification

The major classes of systemic antifungal agents include:

• Polyenes: This class is characterized by large macrocyclic lactone rings with both hydrophilic and lipophilic regions. The prototype drug is amphotericin B, which exists in conventional deoxycholate and various lipid-based formulations (e.g., liposomal amphotericin B, amphotericin B lipid complex). Nystatin is another polyene used primarily for topical and mucosal applications.
• Azoles: These synthetic agents contain a five-membered azole ring (imidazole or triazole) as their core structure. The triazoles, which have largely superseded the older imidazoles for systemic use, are further subdivided.
  • First-generation triazoles: Fluconazole, itraconazole.
  • Second-generation triazoles: Voriconazole, posaconazole, isavuconazonium sulfate (the prodrug of isavuconazole).
• Echinocandins: These are semisynthetic lipopeptides derived from fungal fermentation products. The class includes caspofungin, micafungin, and anidulafungin.
• Pyrimidine Analogs: Flucytosine (5-fluorocytosine) is the sole representative in this class used for systemic antifungal therapy.
• Allylamines: Terbinafine is the principal systemic agent, although it is used almost exclusively for dermatophyte infections (onychomycosis).
• Other Agents: Griseofulvin, an older antifungal used for dermatophytosis, and various topical agents like ciclopirox, tolnaftate, and undecylenic acid.

Spectrum-Based Classification

Antifungals can also be categorized by their spectrum of activity against common pathogenic fungi:

• Broad-spectrum agents: Amphotericin B, voriconazole, posaconazole, isavuconazole, and the echinocandins exhibit activity against a wide range of yeasts and molds.
• Narrow-spectrum agents: Fluconazole (primarily active against Candida species and cryptococci), flucytosine (used in combination for specific yeasts), and terbinafine (active against dermatophytes).

Mechanism of Action

The pharmacodynamic actions of antifungal drugs target structures or biosynthetic pathways that are unique or more essential to fungal cells compared to human host cells, providing a basis for selective toxicity.

Polyenes: Membrane Disruption

Amphotericin B and other polyenes exert their fungicidal effect by binding irreversibly to ergosterol, the principal sterol component of the fungal cell membrane. The amphipathic nature of the polyene molecule allows it to intercalate into the membrane, with the hydrophobic polyene region associating with ergosterol and the hydrophilic hydroxylated region facing the exterior. This binding leads to the formation of transmembrane pores or channels. These channels permit the uncontrolled leakage of monovalent ions (K⁺, Na⁺, H⁺, Cl^–) and small molecules from the fungal cell, disrupting electrochemical gradients and leading to cell death. A secondary effect involves the induction of oxidative damage to the fungal cell. The drug’s affinity for ergosterol is significantly greater than for cholesterol, the major mammalian membrane sterol, though this difference is not absolute and accounts for its human toxicity.

Azoles: Sterol Biosynthesis Inhibition

Azole antifungals act by inhibiting the cytochrome P450-dependent enzyme lanosterol 14α-demethylase. This enzyme is crucial in the ergosterol biosynthesis pathway, catalyzing the conversion of lanosterol to ergosterol. Inhibition leads to the accumulation of toxic 14α-methylated sterols (e.g., lanosterol) and a depletion of ergosterol within the fungal membrane. The resultant membrane becomes structurally and functionally impaired, leading to increased permeability, inhibition of cell growth, and ultimately fungistatic activity. The triazole ring coordinates with the heme iron in the active site of the fungal cytochrome P450 enzyme, blocking the binding of molecular oxygen and the demethylation reaction. The relative potency and spectrum of different azoles are influenced by their specific binding affinity for the fungal enzyme versus homologous human cytochrome P450 enzymes.

Echinocandins: Cell Wall Synthesis Inhibition

The echinocandins are non-competitive inhibitors of the enzyme β-(1,3)-D-glucan synthase. This enzyme complex, located in the fungal cell membrane, is responsible for the synthesis of β-(1,3)-D-glucan, a critical polysaccharide component of the fungal cell wall that provides structural integrity. Inhibition of glucan synthase leads to reduced glucan incorporation into the cell wall, resulting in a weakened, osmotically unstable cell wall. This defect manifests as abnormal hyphal tip growth, distorted septation, and ultimately osmotic lysis of the fungal cell. Echinocandins are considered fungicidal against most Candida species and fungistatic against Aspergillus species. The target is absent in mammalian cells, contributing to the class’s favorable safety profile.

Flucytosine: RNA and DNA Metabolism Disruption

Flucytosine (5-FC) is a prodrug that requires uptake by fungal-specific cytosine permease and intracellular conversion to its active metabolites. Inside the fungal cell, it is deaminated to 5-fluorouracil (5-FU) by cytosine deaminase, an enzyme not present in human cells. 5-FU is then metabolized along two pathways: first, to 5-fluorouridine triphosphate (5-FUTP), which is incorporated into fungal RNA, disrupting protein synthesis; and second, to 5-fluoro-2′-deoxyuridine-5′-monophosphate (5-FdUMP), which inhibits thymidylate synthase, thereby impairing DNA synthesis. The dual mechanism leads to unbalanced growth and cell death. The requirement for fungal-specific enzymes for activation provides selectivity, but resistance emerges rapidly if flucytosine is used as monotherapy.

Allylamines and Others

Terbinafine, an allylamine, inhibits the enzyme squalene epoxidase early in the ergosterol biosynthesis pathway. This leads to squalene accumulation, which is toxic to the fungal cell, and ergosterol depletion. Griseofulvin disrupts fungal mitosis by binding to microtubular proteins, interfering with spindle formation and arresting metaphase.

Pharmacokinetics

The pharmacokinetic properties of antifungal drugs vary widely between classes and individual agents, profoundly influencing their route of administration, dosing regimens, and penetration to sites of infection.

Absorption

Oral bioavailability differs significantly among systemic antifungals. Fluconazole exhibits high bioavailability (>90%) that is unaffected by food or gastric pH. In contrast, the absorption of itraconazole capsules is enhanced by food and a low gastric pH, necessitating administration with an acidic beverage, while the oral solution achieves higher bioavailability under fasting conditions. Voriconazole has high bioavailability (96%), but its absorption can be reduced by high-fat meals. Posaconazole delayed-release tablets demonstrate consistent absorption, whereas the oral suspension requires administration with a high-fat meal or nutritional supplement to maximize absorption. Isavuconazonium sulfate, as a prodrug, is rapidly hydrolyzed to isavuconazole with high bioavailability (98%) unaffected by food. The echinocandins and conventional amphotericin B are not absorbed orally and must be administered intravenously. Flucytosine is well absorbed orally (78-90%).

Distribution

Volume of distribution and tissue penetration are critical for efficacy. Fluconazole has a low molecular weight and is minimally protein-bound, leading to excellent distribution into body fluids, including cerebrospinal fluid (CSF), where concentrations may reach 50-90% of simultaneous plasma levels. The distribution of voriconazole and posaconazole is more extensive, with good penetration into the CNS, lungs, and eyes. Itraconazole, highly protein-bound, achieves high concentrations in tissues like skin and nails but has negligible penetration into CSF. Amphotericin B, particularly its lipid formulations, is extensively distributed to tissues rich in the reticuloendothelial system (liver, spleen) but achieves lower concentrations in sites like the kidneys, which may account for reduced nephrotoxicity. Echinocandins are highly protein-bound and distribute well into visceral tissues but achieve only low concentrations in CSF, urine, and ocular fluids.

Metabolism

Metabolic pathways are a major source of drug interactions for antifungal agents. The azoles are primarily metabolized by hepatic cytochrome P450 (CYP) enzymes. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4. Itraconazole and its active metabolite hydroxy-itraconazole are potent inhibitors of CYP3A4. Voriconazole is metabolized by CYP2C19, CYP2C9, and CYP3A4 and is subject to significant genetic polymorphism, particularly in CYP2C19 poor metabolizers. It is also a potent inhibitor of CYP2C19, CYP2C9, and CYP3A4. Posaconazole and isavuconazole are substrates and inhibitors of CYP3A4 and are also substrates of P-glycoprotein. Flucytosine is minimally metabolized. Echinocandins undergo varying degrees of hepatic metabolism: caspofungin undergoes peptide hydrolysis and N-acetylation, micafungin is metabolized by catechol-O-methyltransferase and hydroxylation, and anidulafungin undergoes slow chemical degradation in plasma without hepatic metabolism.

Excretion

Renal excretion plays a key role for some antifungals. Approximately 80% of a fluconazole dose is excreted unchanged in the urine, necessitating dose adjustment in renal impairment. Flucytosine is also excreted largely unchanged by the kidneys. In contrast, itraconazole, voriconazole, posaconazole, and isavuconazole undergo primarily hepatic metabolism with fecal excretion of metabolites; renal excretion of unchanged drug is negligible. Amphotericin B is excreted very slowly via both renal and biliary pathways, with detectable levels in urine for weeks after discontinuation. The elimination of echinocandins is primarily non-renal: caspofungin excretion is roughly equal between feces and urine (as metabolites), micafungin is predominantly fecal, and anidulafungin is eliminated in the feces as degraded product.

Half-life and Dosing Considerations

Elimination half-life (t_1/2) dictates dosing frequency. Fluconazole has a long t_1/2 of approximately 30 hours, allowing for once-daily dosing. Itraconazole capsules have a t_1/2 of 21 hours, but this increases with repeated dosing due to saturation of its metabolism. Voriconazole has a non-linear pharmacokinetic profile and a t_1/2 of about 6 hours, typically requiring twice-daily dosing after a loading dose. Posaconazole and isavuconazole have long half-lives (26-31 hours and 130 hours, respectively), supporting once-daily maintenance dosing. The echinocandins have half-lives ranging from 10-15 hours (caspofungin, micafungin) to 24-26 hours (anidulafungin), all dosed once daily. Amphotericin B deoxycholate has a biphasic elimination with a terminal t_1/2 of about 15 days, but its pharmacodynamic activity supports once-daily infusion.

Therapeutic Uses/Clinical Applications

The selection of an antifungal agent is guided by the infecting organism, site and severity of infection, host immune status, and local resistance patterns.

Polyenes

Amphotericin B deoxycholate remains a broad-spectrum agent for the treatment of severe, life-threatening invasive fungal infections, including invasive candidiasis, cryptococcal meningitis, invasive aspergillosis, mucormycosis, and disseminated histoplasmosis. Its use is often limited by toxicity, leading to preferential use of lipid formulations (e.g., liposomal amphotericin B) in patients with or at high risk for nephrotoxicity, or for specific indications like cryptococcal meningitis or empirical therapy in febrile neutropenia. Nystatin is used topically for oropharyngeal and cutaneous candidiasis.

Azoles

• Fluconazole: First-line therapy for uncomplicated candidemia in non-neutropenic patients, oropharyngeal and esophageal candidiasis, and urinary tract candidiasis. It is also used for consolidation and maintenance therapy in cryptococcal meningitis and for prophylaxis in high-risk settings (e.g., stem cell transplant). Its lack of activity against molds limits its use.
• Itraconazole: Used for the treatment of blastomycosis, histoplasmosis, sporotrichosis, and certain forms of aspergillosis. It is also effective for dermatophyte infections like onychomycosis.
• Voriconazole: The drug of choice for invasive aspergillosis. It is also indicated for invasive candidiasis (including cases refractory to fluconazole), candidemia in non-neutropenics, and serious infections caused by Scedosporium and Fusarium species.
• Posaconazole: Used for prophylaxis of invasive aspergillosis and candidiasis in high-risk immunocompromised patients. It is also indicated for the treatment of oropharyngeal candidiasis and as salvage therapy for invasive fungal infections like aspergillosis, fusariosis, and chromoblastomycosis.
• Isavuconazole: Approved for the treatment of invasive aspergillosis and invasive mucormycosis.

Echinocandins

Echinocandins are considered first-line agents for candidemia and invasive candidiasis in many clinical scenarios, particularly in critically ill patients, those with recent azole exposure, or where Candida glabrata or Candida krusei are suspected. They are also indicated as salvage therapy for invasive aspergillosis and for empirical therapy in persistent febrile neutropenia.

Flucytosine

Flucytosine is never used as monotherapy due to rapid resistance development. Its primary use is in combination with amphotericin B for the induction treatment of cryptococcal meningitis, where it demonstrates synergistic activity. It may also be used in combination for severe invasive candidiasis.

Terbinafine

Terbinafine is the oral drug of choice for dermatophyte onychomycosis due to its fungicidal activity and excellent nail penetration. It is also used for extensive tinea corporis, cruris, and capitis.

Adverse Effects

The toxicity profiles of antifungal drugs are class-specific and often dictate their use in clinical practice.

Polyenes

The administration of amphotericin B deoxycholate is nearly universally associated with acute infusion-related reactions, including fever, chills, rigors, nausea, vomiting, and headache. These effects are mediated by prostaglandin release and can be mitigated by premedication with antipyretics, antihistamines, or corticosteroids. The most significant dose-limiting toxicity is nephrotoxicity, characterized by decreased glomerular filtration rate, renal tubular acidosis, and electrolyte disturbances (notably hypokalemia and hypomagnesemia). Nephrotoxicity is related to renal vasoconstriction and direct tubular cell injury. Lipid formulations significantly reduce the incidence and severity of nephrotoxicity and infusion reactions. Anemia due to suppressed erythropoietin production may also occur.

Azoles

Adverse effects vary among azoles. Hepatotoxicity, manifesting as asymptomatic elevation of transaminases or, rarely, clinical hepatitis, is a class effect. Fluconazole is generally well-tolerated but can cause gastrointestinal upset and headache. Itraconazole can cause nausea, vomiting, hypokalemia, hypertension, and peripheral edema, and is associated with negative inotropy that may exacerbate congestive heart failure. Voriconazole is associated with transient, dose-related visual disturbances (photopsia, blurred vision), hallucinations, and hepatotoxicity. A significant long-term adverse effect is photosensitivity and an increased risk of cutaneous malignancies. Posaconazole commonly causes gastrointestinal disturbances and headache. Isavuconazole may cause gastrointestinal events, elevated liver enzymes, and, uniquely among azoles, can shorten the QTc interval.

Echinocandins

The echinocandins are generally the best-tolerated class of systemic antifungals. The most common adverse effects are related to intravenous infusion (phlebitis, histamine-mediated reactions like flushing, pruritus, and rash). Mild elevations in liver transaminases may occur. Caspofungin has been associated with rare histamine-mediated reactions when infused too rapidly.

Flucytosine

The major dose-dependent toxicities of flucytosine are bone marrow suppression (leukopenia, thrombocytopenia) and hepatotoxicity. Gastrointestinal disturbances are also common. Toxicity is more likely when serum levels exceed 100 mg/L, emphasizing the need for therapeutic drug monitoring, especially in renal impairment.

Black Box Warnings

Amphotericin B deoxycholate carries a black box warning for its nearly universal potential to cause nephrotoxicity. Voriconazole has a black box warning regarding the potential for visual disturbances, hepatotoxicity, and serious dermatologic reactions. Isavuconazonium sulfate carries a warning for hepatotoxicity and infusion-related reactions.

Drug Interactions

Drug interactions are a major clinical consideration, particularly for the azole class due to their potent inhibition of cytochrome P450 enzymes.

Major Drug-Drug Interactions

• Azoles (especially itraconazole, voriconazole, posaconazole): As strong CYP3A4 inhibitors, they can significantly increase plasma concentrations of co-administered substrates, potentially leading to toxicity. Key interactions include:
  • Calcineurin inhibitors: Cyclosporine and tacrolimus levels are markedly increased, requiring close monitoring and dose reduction.
  • Sirolimus: Contraindicated with voriconazole and posaconazole due to dramatic increases in sirolimus exposure.
  • Statins: Increased risk of myopathy/rhabdomyolysis with simvastatin and lovastatin.
  • Benzodiazepines, calcium channel blockers, warfarin, vinca alkaloids, and many others.
• Enzyme Inducers: Drugs like rifampin, rifabutin, phenytoin, and carbamazepine can dramatically reduce azole concentrations, risking therapeutic failure. Voriconazole, conversely, increases rifabutin levels, increasing toxicity risk.
• QTc Prolonging Agents: Voriconazole and fluconazole can prolong the QTc interval; co-administration with other QTc-prolonging drugs (e.g., certain antiarrhythmics, macrolides) may increase the risk of torsades de pointes.
• Amphotericin B and Nephrotoxic Agents: Concurrent use with aminoglycosides, cyclosporine, or cisplatin can potentiate nephrotoxicity.
• Flucytosine and Cytotoxic Agents: May exacerbate bone marrow suppression.

Contraindications

Absolute contraindications are relatively few but critical. Coadministration of terfenadine, astemizole, cisapride, or pimozide with itraconazole or voriconazole is contraindicated due to the high risk of fatal cardiac arrhythmias from QTc prolongation. Sirolimus is contraindicated with voriconazole and posaconazole. Voriconazole is contraindicated with rifampin, rifabutin, ritonavir (high dose), carbamazepine, and long-acting barbiturates due to profound reductions in voriconazole levels. Isavuconazonium sulfate is contraindicated with strong CYP3A4 inducers like rifampin.

Special Considerations

Pregnancy and Lactation

The use of systemic antifungals in pregnancy requires careful risk-benefit assessment. Fluconazole, in single low doses for vaginal candidiasis, is considered low risk. However, high-dose or prolonged use during the first trimester is associated with a specific pattern of congenital abnormalities (Antley-Bixler syndrome) and is contraindicated. Itraconazole is teratogenic in animal studies and is contraindicated in pregnancy. Voriconazole is teratogenic and embryotoxic in animals and should be avoided. Amphotericin B is generally considered the drug of choice for life-threatening systemic fungal infections in pregnancy due to its lack of teratogenicity, despite its maternal toxicity. Echinocandins have limited data; use may be considered if amphotericin B is not suitable. Most antifungals are excreted in breast milk in low concentrations; consultation with a specialist is recommended during lactation.

Pediatric Considerations

Pharmacokinetics can differ in children. Voriconazole requires higher weight-based dosing in children to achieve exposures comparable to adults due to increased clearance. Fluconazole clearance is more rapid in young children, also necessitating higher mg/kg dosing. Liposomal amphotericin B is commonly used in pediatric patients. Safety profiles are generally similar, though monitoring for growth and development with long-term azole use is prudent.

Geriatric Considerations

Age-related declines in renal and hepatic function may alter drug disposition. Dose adjustments for fluconazole and flucytosine based on renal function are essential. Increased susceptibility to drug interactions due to polypharmacy is a significant concern, particularly with azoles. Careful monitoring for adverse effects like hepatotoxicity, QTc prolongation, and peripheral edema is warranted.

Renal Impairment

Dose adjustment is critical for renally excreted drugs. Fluconazole requires dose reduction when the creatinine clearance falls below 50 mL/min. Flucytosine dosing must be guided by therapeutic drug monitoring and significant dose reduction in renal failure to avoid bone marrow toxicity. Amphotericin B nephrotoxicity is exacerbated in pre-existing renal impairment; lipid formulations are preferred. The intravenous vehicle of voriconazole (sulfobutyl ether beta-cyclodextrin) accumulates in severe renal impairment (CrCl < 50 mL/min); the oral formulation is preferred in such cases. Echinocandins and most azoles (except fluconazole) do not require renal dose adjustment.

Hepatic Impairment

For hepatically metabolized drugs, caution and potential dose reduction are advised. Voriconazole requires a loading dose maintenance dose reduction in mild to moderate hepatic impairment (Child-Pugh A and B) and is not recommended in severe impairment. Itraconazole should be avoided in patients with evidence of ventricular dysfunction or a history of heart failure. Monitoring of liver function tests is mandatory during therapy with all azoles, voriconazole in particular.

Summary/Key Points

• Antifungal drugs are classified into polyenes, azoles, echinocandins, pyrimidine analogs, and allylamines based on chemical structure and mechanism of action.
• The primary mechanisms involve disruption of the fungal cell membrane (polyenes, azoles), inhibition of cell wall synthesis (echinocandins), or interference with nucleic acid synthesis (flucytosine).
• Pharmacokinetic properties vary widely: fluconazole has excellent oral bioavailability and CSF penetration; azoles are metabolized by CYP450 enzymes leading to numerous drug interactions; echinocandins are IV-only with minimal drug interactions; amphotericin B exhibits significant nephrotoxicity.
• Clinical applications are guided by spectrum: echinocandins or fluconazole for invasive candidiasis; voriconazole for invasive aspergillosis; amphotericin B for mucormycosis and severe disseminated infections; fluconazole for mucosal candidiasis.
• Major toxicities include nephrotoxicity (amphotericin B), hepatotoxicity (azoles), bone marrow suppression (flucytosine), and infusion reactions (polyenes, echinocandins).
• Azoles, particularly itraconazole, voriconazole, and posaconazole, are potent inhibitors of CYP3A4 and have extensive, clinically significant drug interaction profiles.
• Special population considerations are paramount: amphotericin B is often preferred in pregnancy; pediatric dosing differs for voriconazole; renal dose adjustment is essential for fluconazole and flucytosine.

Clinical Pearls: The choice of antifungal therapy should be based on a specific diagnosis or a well-reasoned empirical strategy considering local epidemiology. For critically ill patients with candidemia, an echinocandin is often the initial agent of choice. Therapeutic drug monitoring is recommended for voriconazole, posaconazole suspension, itraconazole, and flucytosine to optimize efficacy and minimize toxicity. The management of invasive fungal infections frequently requires a multidisciplinary approach involving infectious diseases specialists, pharmacists, and microbiologists.

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