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Antifungal Drugs

By

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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Topic Resources
  • 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.

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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 Cryptococcal meningitis Subacute meningitis develops over days to a few weeks. Chronic meningitis lasts ≥ 4 weeks. Possible causes include fungi, Mycobacterium tuberculosis, rickettsiae, spirochetes, Toxoplasma gondii... read more 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.

Formulations

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.

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 > 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 Cryptococcal meningitis Subacute meningitis develops over days to a few weeks. Chronic meningitis lasts ≥ 4 weeks. Possible causes include fungi, Mycobacterium tuberculosis, rickettsiae, spirochetes, Toxoplasma gondii... read more 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

Itraconazole

Itraconazole has become the standard treatment for lymphocutaneous sporotrichosis Sporotrichosis Sporotrichosis is a cutaneous infection caused by the saprophytic mold Sporothrix schenckii. Pulmonary and hematogenous involvement is uncommon. Symptoms are cutaneous nodules that spread via... read more Sporotrichosis as well as for mild or moderately severe histoplasmosis Histoplasmosis Histoplasmosis is a pulmonary and hematogenous disease caused by Histoplasma capsulatum; it is often chronic and usually follows an asymptomatic primary infection. Symptoms are those of pneumonia... read more Histoplasmosis , blastomycosis Blastomycosis Blastomycosis is a pulmonary disease caused by inhaling spores of the dimorphic fungus Blastomyces dermatitidis. Occasionally, the fungi spread hematogenously, causing extrapulmonary disease... read more Blastomycosis , and paracoccidioidomycosis Paracoccidioidomycosis Paracoccidioidomycosis is progressive mycosis of the lungs, skin, mucous membranes, lymph nodes, and internal organs caused by Paracoccidioides brasiliensis. Symptoms are skin ulcers, adenitis... read more Paracoccidioidomycosis . It is also effective in mild cases of invasive aspergillosis Aspergillosis Aspergillosis is an opportunistic infection that usually affects the lower respiratory tract and is caused by inhaling spores of the filamentous fungus Aspergillus, commonly present in the environment... read more Aspergillosis , some cases of coccidioidomycosis Coccidioidomycosis Coccidioidomycosis is a pulmonary or hematogenously spread disseminated disease caused by the fungi Coccidioides immitis and C. posadasii; it usually occurs as an acute benign asymptomatic or... read more Coccidioidomycosis , and certain types of chromoblastomycosis Chromoblastomycosis Chromoblastomycosis is a specific type of cutaneous infection caused by one of several species of dematiaceous (pigmented) fungi. Symptoms are ulcerating nodules on exposed body parts. Diagnosis... read more 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 Some Drugs for Systemic Fungal Infections 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... read more ).

Posaconazole

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 Mucormycosis Mucormycosis refers to infection caused by diverse fungal organisms in the order Mucorales, including those in the genera Rhizopus, Rhizomucor, and Mucor. Symptoms most frequently result from... read more 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.

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 Aspergillosis Aspergillosis is an opportunistic infection that usually affects the lower respiratory tract and is caused by inhaling spores of the filamentous fungus Aspergillus, commonly present in the environment... read more 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 Candidiasis (Invasive) Candidiasis is infection by Candida species (most often C. albicans), manifested by mucocutaneous lesions, fungemia, and sometimes focal infection of multiple sites. Symptoms depend on the site... read more Candidiasis (Invasive) , 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

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.

Adverse effects of echinocandins include hepatitis and rash.

Flucytosine

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.

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