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Drugs for systemic antifungal treatment include amphotericin B (and its lipid formulations), various azole derivatives, echinocandins, and flucytosine (see Table 1: Fungi: Some Drugs for Systemic Fungal Infections ). 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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Table 1
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| Some Drugs for Systemic Fungal Infections |
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Drug
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Uses
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Dose
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Some Adverse Effects
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Amphotericin B
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Most fungal infections
(Not for Pseudallescheria sp)
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Conventional formulation: 0.5–1.5 mg/kg IV once/day
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Conventional formulation: Acute infusion reactions, cardiac arrest, encephalopathy, neuropathy, GI upset, renal damage, liver failure, bone marrow injury, thrombophlebitis, hearing loss, visual impairment, rash
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Various lipid formulations: 3–15 mg/kg IV once/day
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Lipid formulations: Infusion reactions (uncommon), renal failure (rare)
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Anidulafungin
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Candidiasis, including candidemia
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200 mg IV on day 1, then 100 mg IV once/day
For esophageal candidiasis, half of this dose
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Hepatitis, diarrhea, hypokalemia, infusion reaction
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Caspofungin
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Aspergillosis
Candidiasis, including candidemia
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70 mg IV on day 1, then 50 mg IV once/day
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Phlebitis, headache, GI upset, rash, bone marrow injury, myalgia, edema, fever
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Fluconazole
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Mucosal and systemic candidiasis
Cryptococcal meningitis
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3–12 mg/kg po or IV once/day
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GI upset, dizziness, hepatitis, angioedema, anaphylaxis, seizures, exfoliative dermatitis, QT prolongation
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Flucytosine
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Candidiasis (systemic)
Cryptococcosis
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12.5–37.5 mg/kg po qid
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Pancytopenia due to bone marrow toxicity, myocardial toxicity, psychosis, neuropathy, nausea, vomiting, hepatic and renal injury, colitis, respiratory arrest
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Itraconazole
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Dermatomycosis
Multiple systemic mycoses
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100 mg po once/day to 200 mg po bid
or
200 mg IV bid
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Hepatitis, GI upset, rash, headache, dizziness, bone marrow suppression, hemolysis, hypokalemia, hypertension, edema, hepatitis, hallucinations, QT prolongation
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Ketoconazole
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Multiple systemic mycoses
Severe, recalcitrant dermatomycosis
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200 mg po once/day
or
3.3–6.6 mg/kg po once/day (for patients > 2 yr)
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GI upset, hepatitis, depression, itching, headache, dizziness, bone marrow suppression, hemolysis, QT prolongation
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Micafungin
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Candidiasis, including candidemia
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100 mg IV once/day (dose 150 mg for esophageal candidiasis)
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Phlebitis, hepatitis, acute renal failure, rash, headache, nausea, leukopenia
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Nystatin
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Nonesophageal membrane GI candidiasis
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500,000–1,000,000 units suspension swish and swallow tid
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GI upset
Systemic effects unlikely because suspension is not absorbed through oral or GI mucosa
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Posaconazole
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Prophylaxis for invasive aspergillosis and candidiasis
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200 mg po tid
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Hepatitis, GI upset, rash, QT prolongation
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Oral candidiasis
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100 mg po bid on day 1, then 100 mg once/day for 13 days
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Oral candidiasis refractory to itraconazole
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400 mg po bid
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Voriconazole
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Invasive aspergillosis
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200 mg po bid
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3 to 6 mg/kg IV q 12 h
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GI upset, transient visual disturbances, peripheral edema, rash, hepatitis, QT prolongation
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 Clinical Calculator
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Amphotericin B
Amphotericin B has been the mainstay of antifungal therapy for invasive and serious mycoses, but other antifungals (eg, voriconazole, posaconazole, the echinocandins) are now considered first-line drugs for many of these infections.
For chronic mycoses, conventional amphotericin B is usually started at ≥ 0.3 mg/kg IV once/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. If patients tolerate the target dose, twice that dose can be given on a more convenient alternate-day schedule. Extended treatment courses may be even less frequent (eg, 3 times/wk).
For acute, life-threatening mycoses, amphotericin B is started at 0.6 to 1.0 mg/kg IV once/day. For certain rapidly progressive opportunistic mycoses (eg, invasive aspergillosis), daily doses as high as 1.5 mg/kg have been used, usually divided into 2 or 3 infusions. These doses must be decreased to about 0.5 mg/kg/day as nephrotoxicity develops.
For chronic meningitis, intrathecal amphotericin B injections can be used but are now rarely needed because potent triazoles (eg, voriconazole, posaconazole) are an effective alternative. Administration is usually via direct intracisternal injection or through a subcutaneous Ommaya-type reservoir connected to an intraventricular catheter. Headache, nausea, and vomiting may occur, but adding dexamethasone to each intrathecal injection may lessen these effects. Amphotericin B can also be given as lumbar intrathecal injections. At the time of injection, ≥ 10 mL of CSF is withdrawn into a syringe containing amphotericin B diluted in 5% D/W to 0.2 mg/mL. Doses of 0.05 to 0.5 mg are then injected over 2 min or more. Doses are gradually increased as tolerated, peaking with a regimen of 0.5 mg 3 times/wk.
Formulations
There are 2 formulations of amphotericin:
The standard formulation, colloidal 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 h, although more rapid infusions over 20 to 60 min can be used in selected patients. However, more rapid infusions usually have no advantage. Many patients experience 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. Pretreatment with acetaminophen or NSAIDs 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). Three preparations are available:
The first 2 lipid formulations are preferred over conventional amphotericin B because they cause fewer infusion-related symptoms and less nephrotoxicity. Amphotericin B cholesteryl sulfate does not provide any advantages over conventional amphotericin B.
Adverse effects
The main adverse effects are
Renal impairment is the major toxic risk of amphotericin B therapy. Serum creatinine and BUN should be monitored before treatment and at regular intervals during treatment: several times/wk for the first 2 to 3 wk, then 1 to 4 times/mo 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 if serum creatinine rises to > 3.0 to 3.5 mg/dL (> 265 to 309 μmol/L) or BUN rises to > 50 mg/dL (> 18 mmol urea/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 largely been supplanted by more effective, less toxic triazole derivatives, such as fluconazole, itraconazole, posaconazole, and voriconazole. Drug interactions can occur with all azoles but are less likely with fluconazole.
Fluconazole
This water-soluble drug is absorbed almost completely after an oral dose. It is excreted largely unchanged in urine and has a half-life of > 24 h, allowing single daily doses. It has high penetration into CSF (≥ 70% of serum levels) and has been especially useful in treating cryptococcal and coccidioidal meningitis. It is also one of the first-line drugs for treatment of candidemia in non-neutropenic patients. Doses range from 200 to 400 mg po once/day to as high as 160 mg once/day in some seriously ill patients and in patients infected with Candida glabrata or other Candida sp (not C. albicans); daily doses of ≥ 1000 mg have been given and had acceptable toxicity.
Adverse effects that occur most commonly are GI discomfort and skin rash. More severe toxicity is unusual, but the following have occurred: hepatic necrosis, Stevens-Johnson syndrome, anaphylaxis, alopecia, and, when taken after 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 cyclosporine, rifabutin, phenytoin, tacrolimus, warfarin-type oral anticoagulants, sulfonylurea drugs (eg, tolbutamide), and zidovudine. Rifampin may lower fluconazole blood levels.
Itraconazole
This drug 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. Itraconazole can clear 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 is likely to decline as use of voriconazole and posaconazole increases.
Adverse effects 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.
Drug and food interactions can be significant. Acidic drinks (eg, cola, acidic fruit juices) or food (especially high-fat foods) improves absorption from the GI tract. However, absorption may be reduced if itraconazole is taken with prescription or OTC 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 digoxin, tacrolimus, oral anticoagulants, or sulfonylureas may increase when these drugs are used with itraconazole.
Posaconazole
The triazole posaconazole is an oral suspension; it is not available in tablet or IV formulations. 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 sp). Posaconazole is also being evaluated as prophylaxis in neutropenic patients with various cancers.
Adverse effects for posaconazole, as for other triazoles, include a prolonged QT interval and interaction with many drugs, including rifampin, statins, various immunosuppressants, and barbiturates.
Voriconazole
This broad-spectrum triazole can be used as first-line therapy for serious Aspergillus infections; most clinical mycologists consider it the treatment of choice for Aspergillus infections 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 other candidal infections; it has activity against a broader spectrum of Candida sp than does fluconazole.
Adverse effects that must be monitored for include hepatotoxicity, visual disturbances, hallucinations, and dermatologic reactions. This drug can prolong the QT interval. Also, there are numerous drug-drug interactions, notably with certain immunosuppressants used after organ transplantation.
Echinocandins
Echinocandins are water-soluble lipopeptides that inhibit glucan synthase. 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. 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 can be used to treat various forms of candidiasis, aspergillosis, and other mycoses.
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 plus amphotericin B is used primarily to treat cryptococcosis but is also valuable for some cases of disseminated candidiasis, other yeast infections, and severe invasive aspergillosis. Flucytosine plus antifungal azoles may be beneficial in treating cryptococcosis and some other mycoses.
The usual dose (12.5 to 37.5 mg/kg po qid) leads to high drug levels in serum, urine, and CSF. Major adverse effects are bone marrow suppression (thrombocytopenia and leukopenia), hepatotoxicity, and enterocolitis; only 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 μg/mL. CBC and renal and liver function tests should be done twice/wk. If blood levels are unavailable, therapy is begun at 25 mg/kg qid, and dosage is decreased if renal function deteriorates.
Last full review/revision April 2009 by Alan M. Sugar, MD
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