Antifungal Medications

ByPaschalis Vergidis, MD, MSc, Mayo Clinic College of Medicine & Science
Reviewed/Revised Sept 2023
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Medications for systemic antifungal treatment include the following (see also table Medications for Systemic Fungal Infections):

(See also Overview of Fungal Infections.)

Table
Table
Clinical Calculators

Amphotericin B

amphotericin B does not have good cerebrospinal fluid penetration, it is still effective for certain mycoses such as cryptococcal meningitis.

Formulations

There are 2 formulations of amphotericin B:

  • Deoxycholate (standard)

  • Lipid-based

The standard formulation,

Many patients have chills, fever, nausea, vomiting, anorexia, headache, and, occasionally, hypotension during and for several hours after an infusion. Amphotericin Bhydrocortisone

Several lipid vehicles

  • Amphotericin B lipid complex

  • Liposomal amphotericin B

Lipid formulations are preferred over conventional amphotericin B because they cause fewer infusion-related symptoms and less nephrotoxicity.

Adverse effects

The main adverse effects of amphotericin B are

  • Nephrotoxicity (most common)

  • Hypokalemia

  • Hypomagnesemia

  • Bone marrow suppression

Renal impairment is the major toxic risk of amphotericin B

Amphotericin B is unique among nephrotoxic antimicrobials because it is not eliminated appreciably via the kidneys and does not accumulate as renal failure worsens. Nevertheless, dosages should be lowered or a lipid formulation should be used instead if serum creatinine rises to > 2.0 to 2.5 mg/dL (> 177 to 221 micromol/L) or BUN rises to > 50 mg/dL (> 18 millimole/L). Acute nephrotoxicity can be reduced by aggressive IV hydration with saline before amphotericin B infusion; at least 1 L of normal saline should be given before amphotericin B infusion.

Mild to moderate renal function abnormalities induced by amphotericin B usually resolve gradually after therapy is completed. Permanent damage occurs primarily after prolonged treatment; after > 4 g total dose, approximately 75% of patients have persistent renal insufficiency.

Amphotericin B also may blunt the erythropoietin response and cause anemia. Hepatotoxicity or other untoward effects are unusual.

Azole Antifungals

Drug interactions can occur with all azoles but are less likely with fluconazole. The drug interactions mentioned below are not intended as a complete listing; clinicians should refer to a specific drug interaction reference before using azole antifungals (see also the Antifungal Drug Interactions Database).

Pearls & Pitfalls

  • Drug interactions are common with azole antifungals; review all concurrent medications before prescribing them.

Fluconazole

> 24 hours, allowing single daily doses. It has high penetration into cerebrospinal fluid (CSF) ( 70% of serum levels) and has been especially useful in treating cryptococcal meningitis and coccidioidal meningitis. It is also one of the first-line drugs for treatment of candidemia in nonneutropenic patients.

Candida glabrata infection and coccidioidal meningitis. Daily doses of 1000 mg have been given and have acceptable toxicity. Of note, Pichia kudriavzevii (Candida krusei) is inherently resistant to fluconazole.

Adverse effects that occur most commonly with fluconazole are gastrointestinal (GI) discomfort and rash. More severe toxicity is unusual, but the following have occurred: hepatic necrosis, Stevens-Johnson syndrome, anaphylaxis, alopecia, and, when taken for long periods of time during the first trimester of pregnancy, congenital fetal anomalies.

Drug interactions occur less often with fluconazole than with other azoles. However, fluconazolefluconazole blood levels.

Itraconazole

sporotrichosis as well as for mild or moderately severe histoplasmosis, blastomycosis, and paracoccidioidomycosis. It is also effective for chronic pulmonary aspergillosis, coccidioidomycosis, and certain types of chromoblastomycosis. Despite poor CSF penetration, itraconazole can be used to treat some types of fungal meningitis, but it is not the drug of choice. Because of its high lipid solubility and protein binding, itraconazole blood levels tend to be low, but tissue levels are typically high. Drug levels are negligible in urine and CSF. Use of itraconazole

Adverse effects of itraconazole with doses of up to 400 mg/day most commonly are GI, but a few men have reported erectile dysfunction, and higher doses may cause hypokalemia, hypertension, and peripheral edema. Other reported adverse effects include allergic rash, hepatitis, and hallucinations. A U.S. Food and Drug Administration boxed warning for heart failure has been issued.

Drug and food interactions can be significant. When the capsule form is used, acidic drinks (eg, cola, acidic fruit juices) or foods (especially high-fat foods) improve absorption of itraconazole

itraconazoleItraconazoleitraconazole.

A new formulation of itraconazole (SUBA-itraconazole, for SUper BioAvailable) has improved bioavailability without the need for an acidic environment in the stomach. SUBA-itraconazole is taken with food and can be used to treat histoplasmosis, blastomycosis, and aspergillosis. Its dosage is different from other forms of itraconazole.

Voriconazole

This broad-spectrum triazole is available as a tablet and an IV formulation. It is considered the treatment of choice for Aspergillus infections (aspergillosisScedosporium apiospermum and Fusarium infections. Additionally, this medication is effective in candidal esophagitis and invasive candidiasis, although it is not usually considered a first-line treatment; it has activity against a broader spectrum of Candida

Adverse effects that must be monitored for include hepatotoxicity, visual disturbances (common), hallucinations, and dermatologic reactions (eg, photosensitivity). Voriconazole can prolong the QT interval.

Drug interactions are numerous, notably with certain immunosuppressants used after organ transplantation.

Posaconazole

Cladophialophora species). It is effective against many of the species that cause mucormycosis. Posaconazole can also be used as antifungal prophylaxis in patients with neutropenia with hematologic malignancies and in bone marrow transplant recipients.

Adverse effects of posaconazole, as for other triazoles, include a prolonged QT interval and hepatitis.

Drug interactions

Isavuconazonium

aspergillosis and mucormycosis. It is available as an IV formulation as well as an oral capsule. No drug level monitoring is required.

Adverse effects of isavuconazonium include GI upset and hepatitis; the QT interval may decrease.

Drug interactions occur with many medications.

Oteseconazole

is an oral, novel azole antifungal that is used for the treatment of recurrent vulvovaginal candidiasis.

Adverse effects of oteseconazole include headache and nausea.

Drug interactions

Echinocandins

Echinocandins are water-soluble lipopeptides that inhibit glucan synthase. They are available only in an IV formulation. Their mechanism of action is unique among antifungals; echinocandins target the fungal cell wall, making them attractive because they lack cross-resistance with other drugs and their target is fungal and has no mammalian counterpart. Drug levels in urine and CSF are not significant.

anidulafungin appears to interact with fewer medications than the others.

The dose of caspofungin needs to be adjusted in patients with severe hepatic insufficiency.

Anidulafungin is not metabolized by the liver but is eliminated by slow, spontaneous degradation. Dose adjustment for hepatic insufficiency is not required for anidulafungin.

These drugs are potently fungicidal against most clinically important Candida species (see treatment of invasive candidiasis) but are considered fungistatic against Aspergillus.

Adverse effects of echinocandins include hepatitis and rash.

Flucytosine

Flucytosine plus amphotericin B is used primarily to treat cryptococcosis but is also valuable for some cases of disseminated candidiasis (including endocarditis). Flucytosine plus antifungal azoles may be beneficial in treating cryptococcal meningitis and some other mycoses.

Major adverse effects of flucytosine are bone marrow suppression (thrombocytopenia and leukopenia), hepatotoxicity, and enterocolitis; the degree of bone marrow suppression is proportional to serum levels.

amphotericin B, particularly when amphotericin B is used in doses > 0.4 mg/kg/day. Flucytosine serum levels should be monitored, and the dosage should be adjusted to keep levels between 40 and 90 mcg/mL. Complete blood count and renal and liver tests should be done twice/week. If blood levels are unavailable, therapy is begun at 25 mg/kg 4 times a day, and dosage is decreased if renal function deteriorates.

Drugs Mentioned In This Article
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