Antifungal Antibiotics

Polyene antifungals (e.g., 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.[30]

Azole (e.g., miconazole)antifungal compounds are non-competitive inhibitors of the fungal enzyme lanosterol 14-alpha-demethylase, which is a rate-limiting enzyme in the fungal biosynthetic pathway of ergosterol. This action destabilizes the fungal cell membrane, causing cell content leakage, lysis, and eventual death.[31]

Allylamines (e.g., terbinafine) inhibit the rate-limiting enzyme squalene epoxidase, 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.[32]

Echinocandins (e.g., caspofungin) inhibit the fungal beta-(1,3)-D-glucan synthase, which is the enzyme responsible for synthesizing beta-(1,3)-D-glucan, a key component of fungal cell walls. Losing this cell wall component leads to osmotic instability and cell death.[5]

Griseofulvin is a mitotic inhibitor, which binds to polymerized fungal microtubules, thereby inhibiting the de-polymerization and leading to the failure of the fungal cell replication.[33]

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.[34]

Ciclopirox has a poorly understood mechanism of action but is believed to interfere with the structural integrity of the fungal cell membrane.[35]

Quinoline antifungal (e.g., clioquinol) compound derivatives also have a poorly understood mechanism of action.

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 via the action of myeloperoxidase. Iodine inhibits fungal germination and reduces structural integrity through the intracytosolic destruction of structural components.[36]

Zinc Pyrithione has a poorly understood antifungal mechanism of action. Still, leading theories suggest this agent modifies fungal cellular membrane transport, leading to decreased concentrations of critical metabolic substrates, inhibiting protein synthesis, and limiting ATP production.[37] These metabolic changes are likely due to increased intracellular copper and iron-sulfur clusters, which lead to protein damage.[38]

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 are 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.

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

Terbinafine, from the allylamine class of antifungals, can be administered topically or orally, which is dependent on the fungal infection being local or systemic, respectively. 

Caspofungin, anidulafungin, and micafungin, the three main drugs in the echinocandin class, are all given intravenously as a reconstituted solution. 

Griseofulvin is only given orally as a tablet or suspension, which should be taken with a fatty meal to aid absorption. 

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

Ciclopirox is approved for topical use only but not for intracavitary or ophthalmic applications. For these purposes, it is available as a compounded gel, cream, lacquer, shampoo, and suspension. 

The 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 as a non-shampoo liquid.

The systemic polyene antifungal amphotericin B (formulated as AMB-d, L-AMB, ABLC, and ABCD) has potentially 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.[39] 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, hyponatremia), hyperglycemia, abnormal liver function tests. ABLC also carries a risk of nephrotoxicity, leading to increased serum creatinine, fever related to infusion, rigors, and chills, but these risks are less than treatment regimens, including AMB-d.

Nystatin is approved only for topical and oral "swish-and-swallow" applications because of severe systemic side effects. Adverse events related to topical nystatin include mild contact dermatitis, with the most severe side 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 has associations with orthostatic hypotension, thrombocytopenia, pruritis, rash, myalgias, and a rare suppression of glucocorticoid production in the adrenal glands. Of note, ketoconazole also correlates with a significant amount more gastrointestinal distress than other azoles.
• Fluconazole has been shown to cause mild headaches, dizziness, and alopecia in high doses.[40]
• 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 of all the side 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.[41]
• Isavuconazole has more severe gastrointestinal side 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 but commonly causes contact dermatitis, burning/stinging, and pruritis at the application site.
• Clotrimazole has no severe adverse reactions but commonly causes irritation, burning/stinging, pruritis, urticaria, and possible blistering at the application site.

Terbinafine, an allylamine, most commonly results in central nervous system side effects, with a headache being the most frequently reported symptom. Other manifestations of adverse events include but are not limited to rashes, diarrhea, dyspepsia, and upper respiratory inflammation or infection.

Echinocandins, like many other antifungal drugs, can result in 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.

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 reported serious adverse reactions, but common benign reactions include skin irritation/burning, contact dermatitis, and pruritis.

Quinolines (clioquinol and iodoquinol) most commonly have associations with dry skin, contact dermatitis, allergic reaction, rapid hair growth in areas 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 serious 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. 

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

• AMB-d carries two 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 but require caution in renal impairment.

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

All azoles should be avoided in patients with hypersensitivities to azole drugs or dosage form components and used with caution in patients with renal impairment/failure and or hepatic impairment/failure. 

• Fluconazole requires cautious administration in patients with electrolyte abnormalities, torsades de pointes, and or medical history, family history, and 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 the elderly.
• Ketoconazole carries several FDA boxed warnings:

1. This agent should be used only when another effective antifungal, including azoles, cannot be tolerated or is not available
2. 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.
3. Ketoconazole has several contraindicated drug interactions that may cause QTc prolongation by increasing concentrations of cisapride, disopyramide, dofetilide, dronedarone, methadone, quinidine, or ranolazine. Ketoconazole is a cytochrome P450 inhibitor.

• Voriconazole is contraindicated in galactose malabsorption/intolerance, Lapp 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 medical history/family history/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 hypersensitivities to any of the echinocandin drugs or dosage form components. Caspofungin should be used with caution in hepatic impairment.

Treatment with griseofulvin should include considerations for potential adverse events in susceptible patients and those with existing disease states; particularly patients with a hypersensitivity to griseofulvin, a hypersensitivity to penicillins (there is a possible cross-reaction between penicillins and griseofulvin), hepatic failure, patients with known porphyrias, and patients that are pregnant or nursing.

Flucytosine carries an FDA boxed warning that this agent should be used with extreme caution in renal impairment and that hematologic, hepatic, and renal function should have close monitoring. 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, which are utilized only as topical agents, including ciclopirox, potassium iodide, and zinc pyrithione, should be avoided in patients with hypersensitivities to these agents.

Polyenes have no supporting evidence or indication at this time to support the utilization of therapeutic drug level monitoring (TDM) in patients treated with AMB-d, L-AMB, and ABLC.[42] All patients receiving any formulations of amphotericin B should have BUN and creatinine assessed at baseline then frequently after; additionally, CBC, electrolytes, and LFTs require monitoring. Nystatin does not have supporting evidence for TDM or routine laboratory monitoring.

Azole antifungals that are generally indicated for therapeutic drug concentration monitoring (TDM) all come from the triazole sub-class: itraconazole, voriconazole, posaconazole.[42] Laboratory monitoring is necessary for the use of fluconazole, isavuconazonium sulfate, and ketoconazole; there is no current monitoring indication for clotrimazole or miconazole.

• Patients receiving itraconazole should receive TDM. Therapeutic drug concentrations are between 0.5 to 1 mcg/mL. Trough concentrations should be assessed after the first administration around the time of steady-state (approximately 5 to 7 days) and then re-assessed just before each consecutive dose. There is an increased likelihood of adverse reactions if concentrations are greater than 5 mcg/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 have a recommended trough between 1 to 1.5 mcg/mL; this requires assessment at the time to steady-state (variable, about 4 to 7 days) and before subsequent administrations. Toxic concentrations are concentrations greater than 5 mcg/mL, at which CNS toxicity tends to occur. Monitoring includes LFTs, creatinine, and electrolytes (including magnesium and calcium) at baseline and frequently after that (every one week for LFTs for four weeks, then every four weeks subsequently). Lipase should undergo assessment if a patient has a risk of pancreatitis. Finally, an ophthalmic exam is necessary for patients receiving voriconazole for greater than 28 days. 
• Posaconazole has therapeutic drug concentrations of greater than 0.7 mcg/mL in prophylaxis and greater than 1.0 mcg/mL in salvage therapy. Trough serum concentration should get measured on day seven and before doses or following dose adjustments. Creatinine, electrolytes (including magnesium and calcium), and LFTs should be checked at baseline, then frequently during treatment.
• Monitoring parameters for fluconazole entail checking creatinine at baseline and monitoring LFTs.
• The use of isavuconazonium sulfate requires checking LFTs at baseline, then periodically during treatment.
• Monitoring of ketoconazole-containing regimens should include LFTs at baseline and during therapy, with ALT being checked weekly. The adrenal function requires monitoring if the patient is at risk of adrenal insufficiency. 

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, an indication at baseline. Immunodeficient patients receiving terbinafine for greater than six weeks should have a CBC checked.

Griseofulvin does not currently 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 hepatic aminotransferases (AST, ALT), with the additional consideration of alkaline phosphatase. There is currently no supporting evidence for TDM. Micafungin regimens should include BUN and creatinine in routine laboratory monitoring.

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 to 40 mcg/L (some sources state 50 to 100 mcg/mL). Toxic concentrations occur when serum drug concentrations exceed 100 mcg/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.[42]

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 three. 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, combinatorial strategies, utilization of antifungal adjuvants, and continued antifungal drug discovery/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 watch 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 essential to preserve the effectiveness of current antifungal agents.[43] [Level 5]

Combination therapy comprises treatment regimens that include 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.[44] [Level 5] 

Antifungal adjuvants can enhance and 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.[45] [Level 4]

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 add to the existing collection of antifungals. The increasing prevalence of drug-resistant fungal diseases presents a unique challenge to antifungal drug discovery. Yet, there are several promising new drug/class pipelines, theoretical fungal vaccines, and the opportunity to generate compounds to inhibit resistance.[46][47][48] [Level 5]

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.[49] This cycle, unfortunately, leads to the need for ancillary and interim solutions, which include judicious prescribing to limit resistance, combinatorial therapy, and antifungal adjuvant therapies.