Medications for systemic antifungal treatment include the following (see also table Medications for Systemic Fungal Infections):
Amphotericin B (and its lipid formulations)Amphotericin B (and its lipid formulations)
Triazoles (fluconazole, itraconazole, voriconazole, posaconazole, oteseconazole, and isavuconazonium)Triazoles (fluconazole, itraconazole, voriconazole, posaconazole, oteseconazole, and isavuconazonium)
Echinocandins (anidulafungin, caspofungin, micafungin, and rezafungin)Echinocandins (anidulafungin, caspofungin, micafungin, and rezafungin)
FlucytosineFlucytosine
Amphotericin B, an effective but relatively toxic medication, 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 medications have markedly changed the approach to antifungal therapy, sometimes even allowing for oral treatment of chronic mycoses.
(See also Overview of Fungal Infections.)
Medications for Systemic Fungal Infections
Medication | Uses | Potential Adverse Effects |
|---|---|---|
Amphotericin BAmphotericin B | Most fungal infections | Conventional formulation: Acute infusion reactions, neuropathy, gastrointestinal (GI) upset, renal failure, anemia, thrombophlebitis, hearing loss, rash, hypokalemia, hypomagnesemia |
Lipid formulations: Infusion reactions*, renal failure* | ||
AnidulafunginAnidulafungin | Invasive candidiasis, including candidemia | Hepatitis, diarrhea, hypokalemia, infusion reactions |
CaspofunginCaspofungin | Invasive candidiasis, including candidemia | Phlebitis, headache, GI upset, rash |
FluconazoleFluconazole | Mucosal and systemic candidiasis Coccidioidal meningitis | GI upset, rash, hepatitis, QT prolongation |
Flucytosine†Flucytosine† | Candidiasis (systemic) | Pancytopenia due to bone marrow toxicity, neuropathy, nausea, vomiting, hepatic and renal injury, colitis |
Isavuconazonium sulfate (isavuconazole)‡ Isavuconazonium sulfate (isavuconazole)‡ | Nausea, vomiting, hepatitis, QT shortening with no evidence of cardiac risk, infusion-related reactions | |
ItraconazoleItraconazole | Dermatomycosis Histoplasmosis, blastomycosis, coccidioidomycosis, paracoccidioidomycosis, sporotrichosis, aspergillosis, chromoblastomycosis | Hepatitis, GI upset, rash, headache, dizziness, hallucinations, hypokalemia, hypertension, edema, QT prolongation, heart failure |
MicafunginMicafungin | Invasive candidiasis, including candidemia | Phlebitis, hepatitis, rash, headache, nausea, acute intravascular hemolysis |
Osteoconazole | Vulvovaginal candidiasis | Headache, nausea, indigestion, hot flushes, painful urination, heavy menstrual periods, vaginal irritation |
Posaconazole§Posaconazole§ | Prophylaxis for invasive fungal infection Histoplasmosis | Hepatitis, GI upset, rash, QT prolongation |
RezafunginRezafungin | Invasive candidiasis, including candidemia | Photosensitivity, abnormal liver tests, infusion-related reactions (flushing, sensation of warmth, urticaria, nausea, chest tightness) |
VoriconazoleVoriconazole | Candidiasis, including candidemia Fusariosis Scedosporiosis | GI upset, transient visual disturbances, peripheral edema, rash, hepatotoxicity, hallucinations, QT prolongation |
* These adverse effects are less common with lipid formulations than with the conventional formulation. | ||
† Amphotericin B is used with flucytosine for serious † Amphotericin B is used with flucytosine for seriousCandida and cryptococcal infections. | ||
‡ Isavuconazole is given as the prodrug isavuconazonium sulfate; 372 mg of ‡ Isavuconazole is given as the prodrug isavuconazonium sulfate; 372 mg ofisavuconazonium sulfate is equivalent to 200 mg of isavuconazole. | ||
§ The delayed-release tablets, delayed-release oral suspension, and immediate-release oral suspension of posaconazole are NOT interchangeable because of differences in dosing.§ The delayed-release tablets, delayed-release oral suspension, and immediate-release oral suspension of posaconazole are NOT interchangeable because of differences in dosing. | ||
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. 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.
Despite limited cerebrospinal fluid penetration, amphotericin B remains effective for central nervous system fungal infections such as cryptococcal meningitis.
Formulations
There are 2 formulations of amphotericin B:
Deoxycholate (conventional)
Lipid-based
Lipid formulations are generally preferred over conventional amphotericin B because they cause fewer infusion-related symptoms and less nephrotoxicity.
The deoxycholate formulation of amphotericin B must be diluted in 5% D/W because the presence of salts can cause precipitation. It is typically infused over 2 to 3 hours, but shorter infusion times of 20 to 60 minutes may be used in select patients. Rapid infusions generally offer no clinical advantage.of amphotericin B must be diluted in 5% D/W because the presence of salts can cause precipitation. It is typically infused over 2 to 3 hours, but shorter infusion times of 20 to 60 minutes may be used in select patients. Rapid infusions generally offer no clinical advantage.
Lipid vehicles reduce the toxicity of amphotericin B (particularly nephrotoxicity and infusion-related symptoms); this includes liposomal reduce the toxicity of amphotericin B (particularly nephrotoxicity and infusion-related symptoms); this includes liposomalamphotericin B.
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, particularly with the deoxycholate formulation. Serum creatinine and blood urea nitrogen (BUN) should be monitored before treatment and at regular intervals during treatment.
Amphotericin B-induced nephrotoxicity is primarily caused by direct tubular cell toxicity and renal vasoconstriction. Amphotericin B is unique among nephrotoxic antimicrobials because it is not eliminated appreciably via the kidneys and does not accumulate as renal failure worsens. Acute nephrotoxicity can be reduced by aggressive IV hydration with saline before amphotericin B infusion; 500 cc of normal saline should be given before and after amphotericin B infusion.
Mild to moderate renal function abnormalities induced by amphotericin B usually resolve gradually after therapy is completed. Permanent damage may occur after prolonged treatment with a dose > 4 g (1).
Patients may develop chills, fever, nausea, vomiting, anorexia, headache, and, occasionally, hypotension during and for several hours after an infusion. Amphotericin B deoxycholate 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 medications 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, deoxycholate 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 medications 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.
Amphotericin B may blunt the erythropoietin response and cause anemia. Hepatotoxicity or other untoward effects are unusual.
Amphotericin B reference
1. Givens M, Caldera J, Rouhollah P: Antibacterial and Antifungal Agents. In Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose, ed. 4, edited by Shannon MW, Borron SW, Burns MJ. W.B. Saunders, 2007, pp. 877–887.
Azole Antifungals
Triazoles, a subclass of azoles that also includes imidazoles and tetrazoles, block the synthesis of ergosterol, an important component of the fungal cell membrane. They can be administered in oral or IV formulations.
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 triazoles (1).
Systemic azole therapy should be avoided during the first trimester of pregnancy because of the risk of congenital anomalies.
Pearls & Pitfalls
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Fluconazole
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 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 dosing. 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.
Pichia kudriavzevii (Candida krusei) is inherently resistant to fluconazole.
Adverse effects that occur most commonly with fluconazole are gastrointestinal (GI) discomfort, hepatitis, QT prolongation, and rash. More severe toxicity is unusual, but the following have occurred: hepatic necrosis, Stevens-Johnson syndrome, anaphylaxis, alopecia.
Drug interactions occur less often with fluconazole than with other triazoles. However, fluconazole sometimes elevates serum levels of calcium channel blockers, cyclosporine, rifabutin, phenytoin, tacrolimus, and warfarin-type oral anticoagulants. Rifampin may lower fluconazole blood levels.
Itraconazole
Itraconazole is the treatment of choice for mild or moderately severe Itraconazole is the treatment of choice for mild or moderately severehistoplasmosis, 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 certain types of fungal meningitis, but it is not the drug of choice. Because itraconazole has high lipid solubility and strong protein binding, it exhibits low plasma concentrations but achieves high tissue levels. Drug levels are negligible in urine and CSF.
The most common adverse effects of itraconazole are gastrointestinal. High doses may lead to hypokalemia, hypertension, QT prolongation, and peripheral edema. Other reported adverse effects include allergic rash, hepatitis, and hallucinations. Rarely, some men have reported erectile dysfunction. The U.S. Food and Drug Administration has issued a boxed warning for the risk of heart failure.
Drug and food interactions can be significant. When the capsule formulation is taken, 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 medications that lower gastric acidity (eg, hismatine-2 receptor antagonists, proton pump inhibitors).
Several medications, including rifampin, rifabutin, didanosine, phenytoin, and carbamazepine, may decrease the serum concentration of itraconazole.
Itraconazole also inhibits metabolic degradation of other medications, elevating blood levels with potentially serious consequences. Rhabdomyolysis has been associated with Itraconazole also inhibits metabolic degradation of other medications, elevating blood levels with potentially serious consequences. Rhabdomyolysis has been associated withitraconazole-induced elevations in blood levels of cyclosporine or statins. Itraconazole may increase the serum concentration of certain medications (eg, tacrolimus, warfarin, digoxin), and therapeutic drug monitoring is recommended when these medications are used with itraconazole.
Another formulation of itraconazole (SUBA-itraconazole, for SUper BioAvailable) has improved bioavailability without the need for an acidic gastric environment. SUBA-(SUBA-itraconazole, for SUper BioAvailable) has improved bioavailability without the need for an acidic gastric environment. SUBA-itraconazole is dosed differently and taken with food. It can be used to treat histoplasmosis, blastomycosis, and aspergillosis.
Voriconazole
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 ) in immunocompetent and immunocompromised hosts. Voriconazole can also be used to treatScedosporium 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 species than does fluconazole.
Because of variable pharmacokinetics, serum voriconazole concentrations should be monitored. The recommended target trough concentration is > 1 mcg/mL and < 5.5 mcg/mL.
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
The triazole posaconazole is available as an oral suspension, a tablet, and an IV formulation. Delayed-release tablets are the preferred formulation because of improved oral bioavailability. This drug is highly active against yeasts and molds and effectively treats aspergillosis, histoplasmosis, and various opportunistic mold infections, such as those caused by dematiaceous (dark-walled) fungi (eg, The triazole posaconazole is available as an oral suspension, a tablet, and an IV formulation. Delayed-release tablets are the preferred formulation because of improved oral bioavailability. This drug is highly active against yeasts and molds and effectively treats aspergillosis, histoplasmosis, and various opportunistic mold infections, such as those caused by dematiaceous (dark-walled) fungi (eg,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 and in bone marrow transplant recipients.
The recommended target trough concentration is ≥ 0.7 mcg/mL for prophylaxis and ≥ 1.0 mcg/mL for the treatment of invasive fungal infections. Although specific toxicity thresholds have not been clearly established, concentrations exceeding 2.0 mcg/mL may be associated with an increased risk of adverse effects.
Adverse effects of posaconazole, as for other triazoles, include a prolonged QT interval and hepatitis.
Drug interactions occur with many medications, including rifabutin, rifampin, statins, and various immunosuppressants.
Isavuconazonium sulfate (isavuconazole)
Isavuconazonium sulfate (sometimes called isavuconazonium, or by its active drug name isavuconazole) is a broad-spectrum triazole for the treatment of Isavuconazonium sulfate (sometimes called isavuconazonium, or by its active drug name isavuconazole) is a broad-spectrum triazole for the treatment ofaspergillosis and mucormycosis. It is available as an IV formulation as well as an oral capsule. Therapeutic drug monitoring is usually not required for this medication. Isavuconazonium sulfate is the water-soluble prodrug that is prescribed, which is rapidly converted to the active form of the antifungal agent isavuconazole. . It is available as an IV formulation as well as an oral capsule. Therapeutic drug monitoring is usually not required for this medication. Isavuconazonium sulfate is the water-soluble prodrug that is prescribed, which is rapidly converted to the active form of the antifungal agent isavuconazole.
Adverse effects of isavuconazonium include GI upset and hepatitis; the QT interval may decrease.
Drug interactions occur with many medications. Isavuconazole generally has weaker drug interactions compared to itraconazole, voriconazole, and posaconazole.
Oteseconazole
Oteseconazole is an oral, novel tetrazole that is used for the treatment of recurrent vulvovaginal candidiasis.Oteseconazole is an oral, novel tetrazole that is used for the treatment of recurrent vulvovaginal candidiasis.
Adverse effects of oteseconazole include headache, nausea, indigestion, and hot flushes. Less common adverse effects can include painful urination, heavy menstrual periods, or vaginal irritation.
Drug interactions occur with rosuvastatin.
Azole antifungals reference
1. Life Worldwide. Antifungal Drug Interactions Database. Accessed July 15, 2025.
Echinocandins
Echinocandins are water-soluble lipopeptides that inhibit glucan synthase. They are available only in an IV formulation.
Echinocandins target the fungal cell wall, a structure that is absent in mammalian cells. Because they target the cell wall, they exhibit minimal cross-resistance with other antifungal classes. However, their penetration into the CSF and urine is low.
These drugs are potently fungicidal against most clinically important Candida species (see treatment of invasive candidiasis) but are considered fungistatic against Aspergillus. Anidulafungin, caspofungin, micafungin, and rezafungin have similar efficacy against candidemia and invasive candidiasis.. Anidulafungin, caspofungin, micafungin, and rezafungin have similar efficacy against candidemia and invasive candidiasis.
Available echinocandins include anidulafungin, caspofungin, micafungin, and rezafungin. Available echinocandins include anidulafungin, caspofungin, micafungin, and rezafungin.
The dose of caspofungin requires adjustment in patients with severe hepatic insufficiency.
Anidulafungin is not metabolized by the liver and is eliminated by slow, spontaneous degradation. Dose adjustment for hepatic insufficiency is not required for anidulafungin.
Adverse effects of echinocandins include hepatitis and rash.
Drug interactions occur less often with anidulafungin than with other echinocandins.
Flucytosine
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, 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 can also be used to treat disseminated candidiasis (including endocarditis). Flucytosine plus triazoles 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.
Because flucytosine is cleared primarily by the kidneys, blood levels rise if nephrotoxicity develops during concomitant use with Because flucytosine is cleared primarily by the kidneys, blood levels rise if nephrotoxicity develops during concomitant use withamphotericin B. Flucytosine serum levels should be monitored, and the dosage should be adjusted to keep a peak (2-hour post-dose) concentration between 40 and 80 mcg/mL. Complete blood count and renal and liver tests should be obtained twice/week.
Drugs Mentioned In This Article
