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Drugs for systemic antifungal treatment include amphotericin B (and its lipid formulations), various azole derivatives, echinocandins, and flucytosine (see Table: 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.
Some Drugs for Systemic Fungal 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. Although amphotericin B does not have good CSF 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/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/day.
There are 2 formulations of amphotericin:
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 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; a central venous catheter may be preferable. 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). Two preparations are available:
Lipid formulations are preferred over conventional amphotericin B because they cause fewer infusion-related symptoms and less nephrotoxicity.
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, or a lipid formulation should be used instead if serum creatinine rises to > 2.0 to 2.5 mg/dL (> 177 to 221 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.
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, 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.
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 nonneutropenic patients. Doses range from 200 to 400 mg po once/day to as high as 800 mg once/day in some seriously ill patients and in patients infected with Candida glabrata or other Candida sp (not C. albicans or C. krusei); daily doses of ≥ 1000 mg have been given and had acceptable toxicity.
Adverse effects that occur most commonly are 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 Ca channel blockers, cyclosporine, rifabutin, phenytoin, tacrolimus, warfarin-type oral anticoagulants, sulfonylurea drugs (eg, tolbutamide), and zidovudine. Rifampin may lower fluconazole blood levels.
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. 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 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. An FDA 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 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 some drugs (eg, digoxin, tacrolimus, oral anticoagulants, sulfonylureas) may increase when these drugs are used with itraconazole.
The triazole posaconazole is available as an oral suspension and a tablet. An IV formulation will probably be available soon. 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). It is the only oral azole 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 for 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 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 sp than does fluconazole.
Adverse effects that must be monitored for include hepatotoxicity, visual disturbances (common), hallucinations, and dermatologic reactions. This drug 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 for IV administration. 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 sp but are considered fungistatic against Aspergillus.
Adverse effects 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 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.
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