Medications for systemic antifungal treatment include the following (see also table Medications for Systemic Fungal Infections):
Amphotericin B (and its lipid formulations)
Various azole derivatives (fluconazole, isavuconazonium [also referred to as isavuconazole], itraconazole, posaconazole, and voriconazole)
Echinocandins (anidulafungin, caspofungin, and micafungin)
Flucytosine
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 drugs have markedly changed the approach to antifungal therapy, sometimes even allowing oral treatment of chronic mycoses.
(See also Overview of Fungal Infections.)
Лікарські препарати для лікування системних грибкових інфекцій
Medication | Uses | Potential Adverse Effects |
|---|---|---|
Amphotericin 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* | ||
Anidulafungin | Candidiasis, including candidemia | Hepatitis, diarrhea, hypokalemia, infusion reactions |
Caspofungin | Candidiasis, including candidemia | Phlebitis, headache, GI upset, rash |
Fluconazole | Mucosal and systemic candidiasis Coccidioidal meningitis | GI upset, rash, hepatitis, QT prolongation |
Flucytosine† | Candidiasis (systemic) | Pancytopenia due to bone marrow toxicity, neuropathy, nausea, vomiting, hepatic and renal injury, colitis |
Isavuconazonium (isavuconazole)‡ | Nausea, vomiting, hepatitis, QT shortening with no evidence of cardiac risk, infusion-related reactions | |
Itraconazole | Dermatomycosis Histoplasmosis, blastomycosis, coccidioidomycosis, sporotrichosis, aspergillosis | Hepatitis, GI upset, rash, headache, dizziness, hypokalemia, hypertension, edema, QT prolongation, heart failure |
Micafungin | Candidiasis, including candidemia | Phlebitis, hepatitis, rash, headache, nausea, acute intravascular hemolysis |
Posaconazole§ | Prophylaxis for invasive fungal infection Oral candidiasis refractory to fluconazole | Hepatitis, GI upset, rash, QT prolongation |
Rezafungin | Candidemia | Photosensitivity, abnormal liver tests, infusion-related reactions (flushing, sensation of warmth, urticaria, nausea, chest tightness) |
Voriconazole | Fusariosis Scedosporiosis | 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. | ||
§ The delayed-release tablets, delayed-release oral suspension, and immediate-release oral suspension of posaconazole are NOT interchangeable because of differences in dosing. | ||
Амфотерицин В
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.
Рецептури
There are 2 formulations of amphotericin B:
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 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. 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.
Побічні ефекти
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 antimicrobials 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 B 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, approximately 75% of patients have persistent renal insufficiency.
Amphotericin B also may blunt the erythropoietin response and cause anemia. Hepatotoxicity or other untoward effects are unusual.
Протигрибкові препарати Азоле
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 medication, ketoconazole, has been supplanted by more effective, less toxic triazole derivatives, such as fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazonium.
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 antifungals (see also the Antifungal Drug Interactions Database).
Цінні поради та підводні камені
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Флуконазол
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 of fluconazole range from 200 to 400 mg orally once a day to as high as 800 mg once a day for Candida glabrata infection and coccidioidal meningitis. Daily doses of ≥ 1000 mg have been given and have acceptable toxicity. Of note, Pichia kudriavzevii (Candida krusei) is inherently resistant to fluconazole.
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 first 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, and warfarin-type oral anticoagulants. Rifampin may lower fluconazole blood levels.
Ітраконазол
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 for chronic pulmonary aspergillosis, 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 peripheral edema. Other reported adverse effects include allergic rash, hepatitis, and hallucinations. A U.S. Food and Drug Administration boxed warning for heart failure has been issued.
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 medications used to lower gastric acidity.
Several medications, including rifampin, rifabutin, didanosine, phenytoin, and carbamazepine, may decrease serum itraconazole levels.
Itraconazole also inhibits metabolic degradation of other medications, elevating blood levels with potentially serious consequences. Serious, even fatal cardiac arrhythmias may occur if itraconazole is used with cisapride (not available in the United States) or some antihistamines (eg, terfenadine, astemizole, perhaps loratadine). Rhabdomyolysis has been associated with itraconazole-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.
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 can be used to treat histoplasmosis, blastomycosis, and aspergillosis. Its dosage is different from other forms of itraconazole.
Вориконазол
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, 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.
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.
Позаконазол
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 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 antifungal prophylaxis in patients with neutropenia with hematologic malignancies 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 medications, including rifabutin, rifampin, statins, and various immunosuppressants.
Ізавуконазоній
Isavuconazonium 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 isavuconazonium include GI upset and hepatitis; the QT interval may decrease.
Drug interactions occur with many medications.
Отезеконазол
Oteseconazole is an oral, novel azole antifungal that is used for the treatment of recurrent vulvovaginal candidiasis.
Adverse effects of oteseconazole include headache and nausea.
Drug interactions occur with rosuvastatin.
Ехінокандини
Echinocandins are water-soluble lipopeptides that inhibit glucan synthase. They are available only in an IV formulation. Their mechanism of action is unique among antifungals; 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 United States are anidulafungin, caspofungin micafungin, and rezafungin. There is little evidence to suggest that one is better than the other, but anidulafungin appears to interact with fewer medications than the others.
The dose of caspofungin needs to be adjusted in patients with severe hepatic insufficiency.
Anidulafungin is not metabolized by the liver but is eliminated by slow, spontaneous degradation. Dose adjustment for hepatic insufficiency is not required for anidulafungin.
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.
Флуцитозин
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). Flucytosine plus antifungal azoles 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 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.
