Antifungal Agents

Mechanism of Action

Polyene antifungals (eg, amphotericin B) bind to ergosterol, a steroid-alcohol unique to fungi. The polyene-ergosterol complex creates pores in the fungal cell membrane, ultimately leading to electrolyte leakage, cell lysis, and cell death.[37]

Azole (eg, miconazole) antifungal compounds are non-competitive inhibitors of the fungal enzyme lanosterol 14-α-demethylase, a rate-limiting enzyme in the fungal biosynthetic ergosterol pathway. This action destabilizes the fungal cell membrane, leading to leakage of cell content, lysis, and ultimately, cell death.[38]

Allylamines (eg, terbinafine) inhibit the rate-limiting enzyme squalene epoxidase, which is responsible for synthesizing precursors to ergosterol. This type of drug is another antifungal compound whose mechanism of action is the loss of cell membrane integrity.[39]

Echinocandins (eg, caspofungin) inhibit the fungal β-(1,3)-D-glucan synthase, which is the enzyme responsible for synthesizing β-(1,3)-D-glucan, a key component of fungal cell walls. Losing this cell wall component leads to osmotic instability and cell death.[7]

Griseofulvin is a mitotic inhibitor that binds to polymerized fungal microtubules, thereby inhibiting depolymerization and leading to the failure of fungal cell replication.[40]

Flucytosine is an antimetabolite compound absorbed into fungal cells via cytosine permease. Within the fungal cell, flucytosine gets converted to 5-fluorouracil, which interferes with fungal RNA biosynthesis.[41]

Ciclopirox has a poorly understood mechanism of action but is believed to interfere with the structural integrity of the fungal cell membrane.[42]

Quinoline antifungal (eg, clioquinol) compound derivatives also have a mechanism of action that is poorly understood.

Potassium iodide exerts its effects directly on Sporothrix spp, yet the exact mechanism of action remains unproven. Leading theories suggest that human polymorphonuclear cells convert potassium iodide to iodine through the action of myeloperoxidase. Iodine inhibits fungal germination and reduces structural integrity through the intracytosolic destruction of structural components.[43]

Zinc pyrithione has a poorly understood mechanism of action against fungi. Still, leading theories suggest that this agent modifies fungal cellular membrane transport, decreasing the concentrations of critical metabolic substrates, inhibiting protein synthesis, and limiting ATP production.[44] These metabolic changes are likely due to increased intracellular copper and iron-sulfur cluster formation, which leads to protein damage.[45]

Administration

Amphotericin B has several formulations, including amphotericin B deoxycholate (d-AMB, or AMB-d), liposomal amphotericin B (L-AMB), amphotericin B lipid complex (ABLC), and amphotericin B colloidal dispersion (ABCD; not available in the United States). All approved indications require intravenous administration. Off-label administration of AMB-d is also given intraventricularly and as an irrigation solution.

Nystatin, the other polyene drug, is only approved for topical and oral "swish-and-swallow' applications. Nystatin is available as a powder, cream, and oral solution.

Azole preparations for systemic azole antifungals include tablets, capsules, oral, and IV solutions. Azole drugs for local or topical use include powders, creams, ointments, gels, shampoos, and lozenges.

Terbinafine, a member of the allylamine class of antifungals, can be administered topically or orally, depending on whether the fungal infection is local or systemic. 

Caspofungin, anidulafungin, and micafungin, the 3 primary echinocandin medications, are all given intravenously as a reconstituted solution. 

Griseofulvin is administered orally as a tablet or suspension and should be taken with a fatty meal to enhance absorption. 

Flucytosine, also commonly known as 5-fluorocytosine, is almost always administered intravenously as a combination therapy with amphotericin B to treat mycoses.

Ciclopirox is approved for topical use only, not intracavitary or ophthalmic applications. This drug is available as a compounded gel, cream, lacquer, shampoo, and suspension. 

Quinolines, iodoquinol, and clioquinol had approval for topical administration. Clioquinol is combined with hydrocortisone in a compounded cream.

Potassium iodide is most commonly administered topically as a saturated solution of potassium iodide (SSKI).

Zinc pyrithione, a compound used to treat topical fungal infections, is applied topically as a shampoo, a solid soap-like bar, or a non-shampoo liquid.

Adverse Effects

The systemic polyene antifungal amphotericin B (formulated as AMB-d, L-AMB, ABLC, and ABCD) has the potential for severe adverse reactions. AMB-d therapy carries the risk of hypotension, chills, headache, hypokalemia, hypomagnesemia, anemia, renal insufficiency, renal function abnormalities, injection site pain, nausea, vomiting, rigors, and fever.[46] L-AMB therapy has decreased the incidence of renal function abnormalities when compared to AMB-d, yet it still carries a risk of nephrotoxicity. The most common adverse events caused by L-AMB therapy include hypertension, hypotension, tachycardia, localized phlebitis, chills, headache, skin rash, electrolyte abnormalities (hypokalemia, hypomagnesemia, hyponatremia), hyperglycemia, and abnormal liver function tests. ABLC also carries a risk of nephrotoxicity, leading to increased serum creatinine, fever related to infusion, rigors, and chills; however, these risks are less than those associated with treatment regimens, including AMB-d.

Nystatin is approved only for topical and oral "swish-and-swallow" applications due to the potential for severe systemic adverse effects. Adverse events related to topical nystatin include mild contact dermatitis, with the most severe adverse effect being Stevens-Johnson syndrome. Oral "swish-and-swallow" nystatin carries a lower risk of hypersensitivity reactions than topical formulations; there are also reports of diarrhea, nausea, vomiting, and abdominal pain. 

Azoles, while typically well-tolerated, frequently cause nausea, vomiting, diarrhea, and abdominal pain. Hepatotoxicity (elevated liver function tests, hepatitis, cholestasis, and or fulminant liver failure) is a common adverse reaction associated with all azoles. Each of the azole drugs has unique adverse events as well:

• Ketoconazole is associated with orthostatic hypotension, thrombocytopenia, pruritis, rash, myalgias, and a rare suppression of glucocorticoid production in the adrenal glands. Of note, ketoconazole also correlates with significantly more gastrointestinal distress than other azoles.
• Fluconazole has been shown to cause mild headaches, dizziness, and alopecia in high doses.[47]
• Itraconazole has a triad of heart failure-like symptoms, hypertension, peripheral edema, and hypokalemia. There are reports of an increased risk of herpes zoster activation or reactivation, headache, dizziness, and fatigue.
• Voriconazole has the most numerous and unique adverse effects in the azole class. These include vision changes, auditory and/or visual hallucinations, neurotoxicity, photosensitivity rash, photophobia, periostitis, cardiotoxicity, and alopecia.
• Posaconazole most commonly causes thrombophlebitis secondary to peripheral intravenous catheters, hypertension, hypotension, headache, rash, hypokalemia, and thrombocytopenia. Another reported adverse event is a rare prolongation of the QTc interval.[48]
• Isavuconazole has more severe gastrointestinal adverse effects than most of the other azoles. Other reported adverse events include a headache, hypokalemia, dyspnea, cough, and peripheral edema.
• Miconazole has no reported serious adverse events; however, it commonly causes contact dermatitis, burning, stinging, and pruritus at the application site.
• Clotrimazole has no severe adverse reactions but commonly causes irritation, burning, or stinging, pruritus, urticaria, and possible blistering at the application site.

Terbinafine, an allylamine, most commonly results in central nervous system adverse effects, with a headache being the most frequently reported symptom. Other manifestations of adverse events include rashes, diarrhea, dyspepsia, and upper respiratory inflammation or infection.

Echinocandins, like many other antifungal agents, can cause hepatotoxicity. 

• Anidulafungin is associated with hypotension, peripheral edema, insomnia, hypokalemia, hypomagnesemia, increased risk of urinary tract infections, dyspnea, and fever.
• Caspofungin can cause hypotension, peripheral edema, tachycardia, chills, headache, rash, anemia, localized phlebitis, respiratory failure, and infusion-related reactions.
• Micafungin can cause phlebitis, anemia, transaminitis, hyperbilirubinemia, renal failure, and fever.
• Rezafungin can cause hypomagnesemia, vomiting, hypokalemia, diarrhea, pyrexia, abdominal pain, constipation, anemia, hypophosphatemia, and hepatotoxicity.[49]

Griseofulvin has numerous potential adverse events, with the most commonly reported adverse events being rash and urticaria. More severe complications can occur and include an erythema multiforme-like drug reaction, skin photosensitivity, leukopenia (rare), granulocytopenia, and hepatotoxicity.

Flucytosine can cause adverse reactions to all body systems but is most commonly associated with the following: cardiovascular (cardiotoxicity, chest pain), central and peripheral nervous systems (confusion, headache hallucination, parkinsonian-like syndrome, peripheral neuropathy), dermatologic (pruritis, urticaria, rash), gastrointestinal (abdominal pain, nausea, vomiting, GI hemorrhage), hematologic (agranulocytosis, aplastic anemia, pancytopenia, eosinophilia), hepatic (acute hepatic injury/insufficiency/necrosis), and renal (acute kidney injury, renal failure).

Ciclopirox has no significant associated severe adverse reactions; however, common benign reactions include skin irritation, burning, contact dermatitis, and pruritus.

Quinolines (clioquinol and iodoquinol) are most commonly associated with dry skin, contact dermatitis, allergic reactions, rapid hair growth in areas where the agent is applied, and folliculitis.

Potassium iodide (as a saturated solution of potassium iodide) has several reported severe adverse reactions, including arrhythmias, GI bleeding, angioedema, parotitis, thyroid adenoma, and goiter. More frequent and less severe reactions include a possible metallic taste, urticaria, acne, cutaneous hemorrhage, numbness, and paresthesias.

Zinc pyrithione has no reported serious adverse reactions and most commonly can cause mild skin irritation.

Contraindications

Amphotericin B: All formulations (AMB-d, L-AMB, ABLC, and ABCD) are contraindicated for patients with a known or likely hypersensitivity to amphotericin B or any components of the L-AMB, ABLC, or ABCD formulations.

• AMB-d carries 2 FDA boxed warnings: 1) amphotericin B deoxycholate should be used for invasive, potentially life-threatening mycoses and avoided in non-invasive fungal infections (oral thrush, esophageal candidiasis, and vaginal candidiasis in patients with neutrophil counts within normal limits); 2) risk of accidental overdose. The use of this agent should also exercise extreme caution in patients with renal impairment and or electrolyte abnormalities.
• L-AMB, ABLC, and ABCD do not carry FDA boxed warnings; however, they require caution when administered to patients with renal impairment.

Nystatin is contraindicated for patients with hypersensitivity to the drug or any additional components in the dosage formulation.

Azoles: All should be avoided in patients with hypersensitivity to azole drugs or components of the dosage form, and used with caution in patients with renal impairment or failure, or hepatic impairment or failure.

• Fluconazole requires cautious administration in patients with electrolyte abnormalities, torsades de pointes, and or medical history, family history, or current QTc prolongation.
• Itraconazole has an FDA boxed warning against the use in treating onychomycosis in patients with CHF. Itraconazole is contraindicated in pregnancy, left ventricular dysfunction, and current or active congestive heart failure. This drug should be used cautiously in patients with cystic fibrosis, cardiovascular disease, pulmonary disease, and older adults.
• Ketoconazole carries several FDA boxed warnings:
  • This agent should be used only when another effective antifungal, such as azoles, cannot be tolerated or is unavailable.
  • This agent carries a significant risk of hepatotoxicity, even in patients without predisposing factors, and thus, any treatment with ketoconazole should include close liver function monitoring.
  • Ketoconazole is a cytochrome P450 inhibitor. It has several contraindications for coadministration with drugs that result in QTc prolongation, as it causes increasing concentrations of cisapride, disopyramide, dofetilide, dronedarone, methadone, quinidine, or ranolazine.
• Voriconazole oral formulation is contraindicated in galactose malabsorption/intolerance, lactase deficiency, glucose malabsorption, uncorrected electrolyte abnormalities, and pregnancy. Clinicians should use this agent with caution in patients with a medical or family history of QTc prolongation, history of torsades de pointes, and or hematologic malignancy. 
• Isavuconazole is contraindicated in patients with familial short QTc syndrome and should be used with caution in patients with hematologic malignancies. 
• Posaconazole is contraindicated in pregnancy. Caution is advisable in patients with electrolyte abnormalities; renal insufficiency; cardiomyopathy; torsades de pointes; or a medical history, family history, or congenital prolonged QTc interval. 

Terbinafine should be utilized with caution or avoided in patients with hypersensitivity reactions, depression, gastrointestinal issues, liver failure, and immune suppression secondary to hematologic effects.

All echinocandins are contraindicated in patients with a history of hypersensitivity to any echinocandin drug or its components. Caspofungin should be used with caution in hepatic impairment.

Treatment with griseofulvin should include consideration of potential adverse events in susceptible patients and those with existing disease states, particularly patients with a history of hypersensitivity to griseofulvin, hypersensitivity to penicillins (due to a possible cross-reaction between penicillins and griseofulvin), hepatic failure, known porphyrias, and pregnant or nursing patients.

Flucytosine carries an FDA boxed warning that it should be used with extreme caution in patients with renal impairment, and hematologic, hepatic, and renal function should be closely monitored. This agent is contraindicated in patients with hypersensitivity to this drug or its components, first-trimester pregnancies, and breastfeeding women. Caution is advisable with this agent in patients with renal impairment, hepatic impairment, bone marrow depression, and pregnant patients in their second or third trimester.

The quinolines iodoquinol and clioquinol are contraindicated in patients with hypersensitivities to the drugs or their components.

Antifungals, including ciclopirox, potassium iodide, and zinc pyrithione, are used only as topical agents and should be avoided in patients with hypersensitivities to them.

Monitoring

Polyenes lack supporting evidence or indications to justify the use of therapeutic drug level monitoring (TDM) in patients treated with AMB-d, L-AMB, and ABLC.[50] All patients receiving amphotericin B formulations should have their BUN and creatinine levels assessed at baseline and then monitored frequently; additionally, CBC, electrolytes, and LFTs should be monitored regularly. Nystatin does not have supporting evidence for TDM or routine laboratory monitoring.

Azole antifungals, which are generally indicated for therapeutic drug concentration monitoring (TDM), all belong to the triazole subclass. These include itraconazole, voriconazole, and posaconazole.[50] Laboratory monitoring is necessary for the use of fluconazole, isavuconazonium sulfate, and ketoconazole; however, there is no current indication for monitoring with clotrimazole or miconazole.

• Patients receiving itraconazole should receive TDM. Therapeutic drug concentrations range from 0.5 to 1 μg/mL. Trough concentrations should be assessed after the first administration, around the steady-state time (approximately 5 to 7 days), and reassessed before each consecutive dose. Adverse reactions are more likely to occur if concentrations exceed 5 μg/mL. Additionally, LFTs should undergo an assessment at baseline and be periodically evaluated in patients with hepatic impairment or treatment regimens lasting longer than one month.
• Therapeutic drug concentrations in voriconazole-containing regimens are recommended to be between 1 and 1.5 μg/mL; this requires assessment at the time of steady-state (which varies, approximately 4 to 7 days) and before subsequent administrations. Toxic concentrations are concentrations greater than 5 μg/mL, at which CNS toxicity tends to occur. Monitoring includes LFTs, creatinine, and electrolytes (including magnesium and calcium) at baseline, and LFT levels are frequently checked after that (every week for 4 weeks, then once every 4 weeks thereafter). Lipase should be assessed if a patient is at risk of pancreatitis. Finally, an ophthalmic examination is necessary for patients receiving voriconazole for more than 28 days.
• Posaconazole is administered to achieve therapeutic drug concentrations of greater than 0.7 μg/mL in prophylaxis and greater than 1.0 μg/mL in salvage therapy. Trough serum concentration should be measured on day 7 and before doses or after dose adjustments. Creatinine, electrolytes (including magnesium and calcium), and LFTs should be checked at baseline and then frequently during treatment.
• Monitoring parameters for fluconazole entail checking creatinine at baseline and monitoring LFTs.
• Administering isavuconazonium sulfate requires checking LFTs and baseline, then periodically during treatment.
• Monitoring of ketoconazole-containing regimens should include LFTs at baseline and during therapy, with ALT checked weekly. If the patient is at risk of adrenal insufficiency, their adrenal function should be monitored.

Terbinafine has no supporting evidence to suggest that TDM is necessary for its utilization in prophylaxis, treatment, or toxicity. Monitoring creatinine and LFTs is, however, a baseline indication. Immunodeficient patients receiving terbinafine for longer than 6 weeks should have a CBC checked.

Griseofulvin does not have supporting evidence for TDM, but laboratory monitoring includes BUN, creatinine, CBC, and LFTs.

Patients on echinocandin therapy should be regularly monitored for hepatotoxicity via measurement of hepatic aminotransferases (AST, ALT), with consideration also given to alkaline phosphatase. There is currently no supporting evidence for TDM. Micafungin regimens should include routine laboratory monitoring of BUN and creatinine.

Patients receiving flucytosine-containing combination therapy require TDM. Patients should have serum concentration measured 2 to 4 hours after each dose; the trough concentration should be between 20 and 40 μg/L (some sources state 50 to 100 μg/mL). Toxic concentrations occur when serum drug concentrations exceed 100 μg/mL. Other indications for TDM in flucytosine therapy include when a drug with a known drug interaction is started or stopped, when adherence for oral therapy is uncertain, or when manifestations of toxicity occur.[50]

Enhancing Healthcare Team Outcomes

Pragmatic management of mycoses is dependent on the interprofessional healthcare team characterizing the fungal infection as discussed in the introduction, then selecting the most effective antifungal treatment regimen; this requires a strong understanding of public health/epidemiology, medical microbiology/mycology, clinical pharmacology, and healthcare infrastructure which dictates the application of the first 3. There is currently a diverse and effective arsenal of antifungal agents. Still, the alarming global rise in drug-resistant fungi warrants judicious antifungal prescribing by clinicians, the development of combinatorial strategies, the utilization of antifungal adjuvants, and continued antifungal drug discovery and development.

Judicious prescribing begins with the healthcare team selecting the proper regimen based on culture and sensitivity data, patient history, and socioeconomic factors. Providers should work closely with pharmacists and, when appropriate, public health officials to provide therapy that appropriately treats infections. Nurses can also assess patient adherence, help administer the drug in the inpatient setting, answer patient questions, and monitor for adverse drug reactions. The ultimate goal is to provide antifungal therapy without unnecessarily creating drug-resistant organisms, limiting adverse events, and reducing drug-drug interactions. Antifungal stewardship is crucial for preserving the effectiveness of current antifungal agents.[51]

Combination therapy comprises treatment regimens that incorporate multiple antifungals from different classes and antifungal agents combined with non-antifungal agents. Non-antifungal drug targets include heat shock proteins, calcineurin, lysine acetyltransferase, lysine deacetylase, protein kinase C, and fungal sphingolipids.[52]

Antifungal adjuvants can enhance or extend the efficacy of existing antifungal regimens and limit resistance. Some of these encouraging adjuvants could eventually be the standard of care in antifungal-adjuvant combination therapy. The potential adjuvants include drugs with widely variable mechanisms of action, like cyclosporin A, deferasirox, FK506, tamoxifen, and sertraline.[53]

Antifungal drug discovery has been bolstered by the Orphan Drug Act (1983) and, more recently, the Generating Antibiotic Incentives Now (GAIN) Act (2012). These policies incentivize pharmaceutical companies and researchers to pursue new leads and expand the existing collection of antifungals. The increasing prevalence of drug-resistant fungal diseases presents a significant challenge to the discovery of antifungal drugs. Yet, there are several promising new drugs and class pipelines, theoretical fungal vaccines, and opportunities to generate compounds that inhibit resistance.[54][55][56]

The caveat to all of these potentially promising leads in new drugs and drug classes is the time it takes from discovery to dispensing a new medication, estimated to be roughly 12 years.[57] Unfortunately, this cycle leads to the need for ancillary and interim solutions, which include judicious prescribing to limit resistance, combinatorial therapy, and antifungal adjuvant therapies.