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Antifungal Drugs


Sanjay G. Revankar

, MD, Wayne State University School of Medicine

Last full review/revision Apr 2021| Content last modified Apr 2021
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Drugs for systemic antifungal treatment include the following (see Table: Some Drugs for Systemic Fungal Infections):

  • Amphotericin B (and its lipid formulations)

  • Various azole derivatives (fluconazole, isavuconazole, itraconazole, posaconazole, and voriconazole)

  • Echinocandins (anidulafungin, caspofungin, and micafungin)

  • Flucytosine

Amphotericin B, an effective but relatively toxic drug, has long been the mainstay of antifungal therapy for invasive and serious mycoses. However, newer potent and less toxic triazoles and echinocandins are now often recommended as first-line drugs for many invasive fungal infections. These drugs have markedly changed the approach to antifungal therapy, sometimes even allowing oral treatment of chronic mycoses.


Some Drugs for Systemic Fungal Infections




Some Adverse Effects

Amphotericin B

Most fungal infections

(Not for Pseudallescheria species)

Conventional (deoxycholate) formulation: 0.5–1.0 mg/kg IV once a day

Conventional formulation: Acute infusion reactions, neuropathy, gastrointestinal (GI) upset, renal failure, anemia, thrombophlebitis, hearing loss, rash, hypokalemia, hypomagnesemia

Various lipid formulations: 3–5 mg/kg IV once a day

Lipid formulations: Infusion reactions*, renal failure*


Candidiasis, including candidemia

200 mg IV on day 1, then 100 mg IV once a day

For esophageal candidiasis, half of this dose

Hepatitis, diarrhea, hypokalemia, infusion reactions


Candidiasis, including candidemia

70 mg IV on day 1, then 50 mg IV once a day

Phlebitis, headache, GI upset, rash


Mucosal and systemic candidiasis

Coccidioidal meningitis

100–1200 mg orally or IV once a day (loading dose may be given)

Children: 3–12 mg/kg orally or IV once a day

GI upset, rash, hepatitis, QT prolongation


Candidiasis (systemic)

12.5–37.5 mg/kg orally 4 times a day

Pancytopenia due to bone marrow toxicity, neuropathy, nausea, vomiting, hepatic and renal injury, colitis


372 mg orally or IV every 8 hours (6 doses) initially, then 372 mg orally or IV once a day for maintenance

Nausea, vomiting, hepatitis, QT shortening with no evidence of cardiac risk, infusion-related reactions



100 mg orally once a day to 200 mg orally 2 times a day (give oral solution with empty stomach and capsule after meals)

Hepatitis, GI upset, rash, headache, dizziness, hypokalemia, hypertension, edema, QT prolongation, heart failure

SUBA-itraconazole (SUper-BioAvailable-itraconazole)

130 mg orally once a day to 130 mg 2 times a day

Hepatitis, GI upset, rash, headache, dizziness, hypokalemia, hypertension, edema, QT prolongation, heart failure


Candidiasis, including candidemia

100 mg IV once a day (dose 150 mg for esophageal candidiasis)

Phlebitis, hepatitis, rash, headache, nausea, acute intravascular hemolysis


Prophylaxis for invasive aspergillosis and candidiasis

200 mg orally 3 times a day

Hepatitis, GI upset, rash, QT prolongation

Oral candidiasis

100 mg orally 2 times a day on day 1, then 100 mg once a day for 13 days

Oral candidiasis refractory to itraconazole

400 mg orally 2 times a day


Invasive aspergillosis



6 mg/kg IV for 2 loading doses, then 200 mg orally every 12 hours


3 to 6 mg/kg IV every 12 hours

GI upset, transient visual disturbances, peripheral edema, rash, hepatitis, QT prolongation

* This adverse effect is less common with lipid formulations than with the conventional formulation.

† Amphotericin B is used with flucytosine for serious Candida and cryptococcal infections.

‡ Isavuconazole is given as the prodrug isavuconazonium; 372 mg of isavuconazonium is equivalent to 200 mg of isavuconazole.

Amphotericin B

Amphotericin B has been the mainstay of antifungal therapy for invasive and serious mycoses, but other antifungals (eg, fluconazole, voriconazole, posaconazole, the echinocandins) are now considered first-line drugs for many of these infections. Although amphotericin B does not have good cerebrospinal fluid penetration, it is still effective for certain mycoses such as cryptococcal meningitis.

For chronic mycoses, amphotericin B deoxycholate is usually started at 0.3 mg/kg IV once a day, increased as tolerated to the desired dose (0.4 to 1.0 mg/kg; generally not > 50 mg/day); many patients tolerate the target dose on the first day.

For acute, life-threatening mycoses, amphotericin B deoxycholate may be started at 0.6 to 1.0 mg/kg IV once a day.


There are 2 formulations of amphotericin:

  • Deoxycholate (standard)

  • Lipid-based

The standard formulation, amphotericin B deoxycholate, must always be given in 5% D/W because salts can precipitate the drug. It is usually given over 2 to 3 hours, although more rapid infusions over 20 to 60 minutes can be used in selected patients. However, more rapid infusions usually have no advantage. Many patients have chills, fever, nausea, vomiting, anorexia, headache, and, occasionally, hypotension during and for several hours after an infusion. Amphotericin B may also cause chemical thrombophlebitis when given via peripheral veins; a central venous catheter may be preferable. Pretreatment with acetaminophen or nonsteroidal anti-inflammatory drugs is often used; if these drugs are ineffective, hydrocortisone 25 to 50 mg or diphenhydramine 25 mg is sometimes added to the infusion or given as a separate IV bolus. Often, hydrocortisone can be tapered and omitted during extended therapy. Severe chills and rigors can be relieved or prevented by meperidine 50 to 75 mg IV.

Several lipid vehicles reduce the toxicity of amphotericin B (particularly nephrotoxicity and infusion-related symptoms). Two preparations are available:

  • 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 therapy. Serum creatinine and blood urea nitrogen (BUN) should be monitored before treatment and at regular intervals during treatment: several times/week for the first 2 to 3 weeks, then 1 to 4 times/month as clinically indicated. Amphotericin B is unique among nephrotoxic antimicrobial drugs 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 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, about 75% of patients have persistent renal insufficiency.

Amphotericin B also frequently suppresses bone marrow function, manifested primarily by anemia. Hepatotoxicity or other untoward effects are unusual.

Azole Antifungals

Azoles block the synthesis of ergosterol, an important component of the fungal cell membrane. They can be given orally to treat chronic mycoses. The first such oral drug, ketoconazole, has been supplanted by more effective, less toxic triazole derivatives, such as fluconazole, isavuconazole, itraconazole, posaconazole, and voriconazole.

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 antifungal drugs.

Pearls & Pitfalls

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


This water-soluble drug is absorbed almost completely after an oral dose. Fluconazole is excreted largely unchanged in urine and has a half-life of > 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.

Doses range from 200 to 400 mg orally once a day to as high as 800 mg once a day in some seriously ill patients and in patients infected with Candida glabrata or other Candida species (not C. albicans or C. krusei); daily doses of 1000 mg have been given and had acceptable toxicity.

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 1st trimester of pregnancy, congenital fetal anomalies.

Drug interactions occur less often with fluconazole than with other azoles. However, fluconazole sometimes elevates serum levels of calcium channel blockers, cyclosporine, rifabutin, phenytoin, tacrolimus, warfarin-type oral anticoagulants, sulfonylurea drugs (eg, tolbutamide), and zidovudine. Rifampin may lower fluconazole blood levels.


Isavuconazole is a broad-spectrum triazole for the treatment of 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 isavuconazole include GI upset and hepatitis; the QT interval may decrease.

Drug interactions occur with many drugs.


Itraconazole has become the standard treatment for lymphocutaneous sporotrichosis as well as for mild or moderately severe histoplasmosis, blastomycosis, and paracoccidioidomycosis. It is also effective in mild cases of invasive aspergillosis, some cases of 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 has declined as use of voriconazole and posaconazole has increased.

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 edema. Other reported adverse effects include allergic rash, hepatitis, and hallucinations. A U.S. Food and Drug Administration black box warning for heart failure has been issued, particularly with a total daily dose of 400 mg.

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 from the GI tract. However, absorption may be reduced if itraconazole is taken with prescription or over-the-counter drugs used to lower gastric acidity. Several drugs, including rifampin, rifabutin, didanosine, phenytoin, and carbamazepine, may decrease serum itraconazole levels. Itraconazole also inhibits metabolic degradation of other drugs, elevating blood levels with potentially serious consequences. Serious, even fatal cardiac arrhythmias may occur if itraconazole is used with cisapride (not available in the US) or some antihistamines (eg, terfenadine, astemizole, perhaps loratadine). Rhabdomyolysis has been associated with itraconazole-induced elevations in blood levels of cyclosporine or statins. Blood levels of some drugs (eg, digoxin, tacrolimus, oral anticoagulants, sulfonylureas) may increase when these drugs are used with itraconazole.

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 is approved for histoplasmosis, blastomycosis, and aspergillosis. Its dosage is different from other forms of itraconazole (see Table: Some Drugs for Systemic Fungal Infections).


The triazole posaconazole is available as an oral suspension, a tablet, and an IV formulation. This drug is highly active against yeasts and molds and effectively treats various opportunistic mold infections, such as those due to dematiaceous (dark-walled) fungi (eg, Cladophialophora species). It is effective against many of the species that cause mucormycosis. Posaconazole can also be used as fungal prophylaxis in neutropenic patients with various cancers and in bone marrow transplant recipients.

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

Drug interactions occur with many drugs, including rifabutin, rifampin, statins, various immunosuppressants, and barbiturates.


This broad-spectrum triazole is available as a tablet and an IV formulation. It is considered the treatment of choice for Aspergillus infections (aspergillosis) in immunocompetent and immunocompromised hosts. Voriconazole can also be used to treat Scedosporium apiospermum and Fusarium infections. Additionally, the drug 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 species than does fluconazole.

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

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


Echinocandins are water-soluble lipopeptides that inhibit glucan synthase. They are available only in an IV formulation. Their mechanism of action is unique among antifungal drugs; 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.

Echinocandins available in the US are anidulafungin, caspofungin, and micafungin. There is little evidence to suggest that one is better than the other, but anidulafungin appears to interact with fewer drugs than the other two.

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, a nucleic acid analog, is water soluble and well-absorbed after oral administration. Preexisting or emerging resistance is common, so it is almost always used with another antifungal, usually amphotericin B. Flucytosine plus amphotericin B is used primarily to treat cryptococcosis but is also valuable for some cases of disseminated candidiasis (including endocarditis), other yeast infections, and severe invasive aspergillosis. Flucytosine plus antifungal azoles may be beneficial in treating cryptococcal meningitis and some other mycoses.

The usual dose (12.5 to 37.5 mg/kg orally 4 times a day) leads to high drug levels in serum, urine, and CSF.

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.

Because flucytosine is cleared primarily by the kidneys, blood levels rise if nephrotoxicity develops during concomitant use with 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

Drug Name Select Trade
No US trade name
No US brand name
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