] belongs to a drug class known as polyene antibiotics, so named because their structures contain a series of conjugated double bonds. Nystatin, another antifungal drug, is in the same family.
Amphotericin B is active against a broad spectrum of pathogenic fungi and is a drug of choice for most systemic mycoses. Unfortunately, amphotericin B is highly toxic: infusion reactions and renal damage occur in many patients. Because of its potential for harm, amphotericin B should be employed only against infections that are progressive and potentially fatal.
Amphotericin B is available in four formulations: a conventional formulation (amphotericin B deoxycholate) and three lipid-based formulations. The lipid-based formulations are as effective as the conventional formulation and cause less toxicity—but are much more expensive. For treatment of systemic mycoses, all formulations are administered by intravenous (IV) infusion. Infusions are given daily or every other day for several months.
Mechanism of Action
Amphotericin B binds to components of the fungal cell membrane, increasing permeability. The resultant leakage of intracellular cations (especially potassium) reduces viability. Depending on the concentration of amphotericin B and the susceptibility of the fungus, the drug may be fungistatic or fungicidal.
The component of the fungal membrane to which amphotericin B binds is ergosterol, a member of the sterol family of compounds. Hence, for a cell to be susceptible, its cytoplasmic membrane must contain sterols. Because bacterial membranes lack sterols, bacteria are not affected.
Much of the toxicity of amphotericin is attributable to the presence of sterols (principally cholesterol) in mammalian cell membranes. When amphotericin binds with cholesterol in mammalian membranes, the effect is similar to that seen in fungi. However, there is some degree of selectivity: amphotericin binds more strongly to ergosterol than it does to cholesterol, so fungi are affected more than we are.
Microbial Susceptibility and Resistance
Amphotericin B is active against a broad spectrum of fungi. Some protozoa (e.g., Leishmania braziliensis) are also susceptible. As noted, bacteria are resistant.
Emergence of resistant fungi is extremely rare and occurs only with long-term amphotericin use. In all cases of resistance, the fungal membranes had reduced amounts of ergosterol or none at all.
Therapeutic Uses
Amphotericin B is a drug of choice for most systemic mycoses. Before this drug became available, systemic fungal infections usually proved fatal. Treatment is prolonged; 6 to 8 weeks is common. In some cases, treatment may last for 3 or 4 months. In addition to its antifungal applications, amphotericin B is a drug of choice for leishmaniasis.
Pharmacokinetics
Absorption and Distribution
Amphotericin is poorly absorbed from the gastrointestinal (GI) tract, and hence oral therapy cannot be used for systemic infection. Rather, amphotericin must be administered intravenously. When the drug leaves the vascular system, it undergoes extensive binding to sterol-containing membranes of tissues. Levels about half those in plasma are achieved in aqueous humor and in peritoneal, pleural, and joint fluids. Amphotericin B does not readily penetrate to the cerebrospinal fluid (CSF).
Metabolism and Excretion
Little is known about the elimination of amphotericin B. We do not know if the drug is metabolized or if it is ultimately removed from the body. Renal excretion of unchanged amphotericin is minimal. However, dose or frequency reduction may be considered in patients with preexisting renal impairment. Complete elimination of amphotericin takes a long time; the drug has been detected in tissues more than a year after cessation of treatment.
Adverse Effects
Amphotericin can cause a variety of serious adverse effects. Patients should be under close supervision, preferably in a hospital.
Black Box Warning: Amphotericin Toxicity
Because of its toxicity, amphotericin should be used only in the setting of a potentially life-threatening infection.
Infusion Reactions
Intravenous amphotericin frequently produces fever, chills, rigors, nausea, and headache. These reactions are caused by release of proinflammatory cytokines (tumor necrosis factor, interleukin-1, interleukin-6) from monocytes and macrophages. Symptoms begin 1 to 3 hours after starting the infusion and persist about an hour. Mild reactions can be reduced by pretreatment with diphenhydramine plus acetaminophen. Aspirin can also help, but it may increase kidney damage (see later). Intravenous meperidine or dantrolene can be given if rigors occur. If other measures fail, hydrocortisone can be used to decrease fever and chills. However, because glucocorticoids can reduce the patient’s ability to fight infection, routine use of hydrocortisone should be avoided. Infusion reactions are less intense with lipid-based amphotericin formulations than with the conventional formulation.
Amphotericin infusion produces a high incidence of phlebitis. This can be minimized by changing peripheral venous sites often, administering amphotericin through a large central vein, and pretreatment with heparin.
Nephrotoxicity
Amphotericin is toxic to cells of the kidneys. Renal impairment occurs in practically all patients. The extent of kidney damage is related to the total dose administered over the full course of treatment. In most cases, renal function normalizes after amphotericin use stops. However, if the total dose exceeds 4 g, residual impairment is likely. Kidney damage can be minimized by infusing 1 L of saline on the days amphotericin is given. Other nephrotoxic drugs (e.g., aminoglycosides, cyclosporine, nonsteroidal antiinflammatory drugs [NSAIDs]) should be avoided. To evaluate renal injury, tests of kidney function should be performed every 3 to 4 days, and intake and output should be monitored. If plasma creatinine content rises above 3.5 mg/dL, amphotericin dosage should be reduced. As noted, the degree of renal damage is less with lipid-based amphotericin than with the conventional formulation.
Hypokalemia
Damage to the kidneys often causes hypokalemia. Potassium supplements may be needed to correct the problem. Potassium levels and serum creatinine should be monitored often.
Hematologic Effects
Amphotericin can cause bone marrow suppression, resulting in normocytic, normochromic anemia. Hematocrit determinations should be conducted to monitor red blood cell status.
Effects Associated With Intrathecal Injection
Intrathecal administration may cause nausea, vomiting, headache, and pain in the back, legs, and abdomen. Rare reactions include visual disturbances, impairment of hearing, and paresthesias (tingling, numbness, or pain in the hands and feet).
Drug Interactions
Nephrotoxic Drugs
Use of amphotericin with other nephrotoxic drugs (e.g., aminoglycosides, cyclosporine, NSAIDs) increases the risk for kidney damage. Accordingly, these combinations should be avoided if possible.
Flucytosine
Amphotericin potentiates the antifungal actions of flucytosine, apparently by enhancing flucytosine entry into fungi. Thanks to this interaction, combining flucytosine with low-dose amphotericin can produce antifungal effects equivalent to those of high-dose amphotericin alone. By allowing a reduction in amphotericin dosage, the combination can reduce the risk for amphotericin-induced toxicity.
Preparations, Dosage, and Administration
Preparations
Amphotericin B is available in a conventional formulation—amphotericin B deoxycholate [Fungizone 
]—and three lipid-based formulations: liposomal amphotericin B [AmBisome], amphotericin B cholesteryl sulfate complex [Amphotec], and amphotericin B lipid complex [Abelcet]. The lipid-based formulations cause less nephrotoxicity and fewer infusion reactions than the conventional formulation.
Routes
For treatment of systemic mycoses, amphotericin B is almost always administered intravenously. Infusions should be performed slowly (over 2–4 hours) to minimize phlebitis and cardiovascular reactions. Alternate-day dosing can reduce adverse effects. For most patients, several months of therapy are required. Because amphotericin B does not readily enter the CSF, intrathecal injection is used for fungal meningitis.
Intravenous Dosage and Administration
Fungal Infections.
Dosage is individualized and based on disease severity and the patient’s ability to tolerate treatment. Optimal dosage has not been established. A small test dose is often infused to assess patient reaction. After this, therapy is initiated with a dosage of 0.25 mg/kg/day. Maintenance dosages range from 1.5 to 6 mg/kg/day, depending on the severity of the infection and the form of amphotericin used. Dosage should be reduced in patients with renal impairment.
Leishmaniasis.
Leishmaniasis can be treated with amphotericin B deoxycholate or liposomal amphotericin B [AmBisome]. For conventional amphotericin B deoxycholate, the dosage is 0.25 to 1 mg/kg daily for up to 8 weeks. For AmBisome, the dose in immunocompetent individuals is 3 mg/kg on days 1, 2, 3, 4, 5, 14, and 21. However, a single infusion of 10 mg/kg may be just as effective.
Azoles
Like amphotericin B, the azoles are broad-spectrum antifungal drugs. As a result, azoles represent an alternative to amphotericin B for most systemic fungal infections. In contrast to amphotericin, which is highly toxic and must be given intravenously, the azoles have lower toxicity and can be given by mouth. However, azoles do have one disadvantage: they inhibit hepatic cytochrome P450 drug-metabolizing enzymes and can increase the levels of many other drugs. Of the azoles in current use, only six—itraconazole, ketoconazole, fluconazole, voriconazole, posaconazole, and isavuconazonium—are indicated for systemic mycoses. Azoles used for superficial mycoses are discussed separately later.
Itraconazole
Itraconazole [Sporanox] is an alternative to amphotericin B for several systemic mycoses and will serve as our prototype for the azole family. The drug is safer than amphotericin B and has the added advantage of oral dosing. Principal adverse effects are cardiosuppression and liver injury. Like other azoles, itraconazole can inhibit drug-metabolizing enzymes and raise levels of other drugs.
Mechanism of Action
Itraconazole inhibits the synthesis of ergosterol, an essential component of the fungal cytoplasmic membrane. The result is increased membrane permeability and leakage of cellular components. Accumulation of ergosterol precursors may also contribute to antifungal actions. Itraconazole suppresses ergosterol synthesis by inhibiting fungal cytochrome P450–dependent enzymes.
Therapeutic Use
Itraconazole is active against a broad spectrum of fungal pathogens. At this time, it is a drug of choice for blastomycosis, histoplasmosis, paracoccidioidomycosis, and sporotrichosis and is an alternative to amphotericin B for aspergillosis, candidiasis, and coccidioidomycosis. Itraconazole may also be used for superficial mycoses.
Pharmacokinetics
Itraconazole is administered orally, in capsules or suspension. Food increases absorption of capsules but decreases absorption of suspension. Interestingly, administration with cola enhances absorption. When absorbed, the drug is widely distributed to lipophilic tissues. Concentrations in aqueous fluids (e.g., saliva, CSF) are negligible. The drug undergoes extensive hepatic metabolism. About 40% of each dose is excreted in the urine as inactive metabolites.
Adverse Effects
Itraconazole is well tolerated in usual doses. Gastrointestinal reactions (nausea, vomiting, diarrhea) are most common. Other reactions include rash, headache, abdominal pain, and edema. Itraconazole may also cause two potentially serious effects: cardiac suppression and liver injury.
Cardiac Suppression.
Itraconazole has negative inotropic actions that can cause a transient decrease in ventricular ejection fraction. Cardiac function returns to normal by 12 hours after dosing. The drug may still be used to treat serious fungal infections in patients with heart failure, but only with careful monitoring and only if the benefits clearly outweigh the risks. If signs and symptoms of heart failure worsen, itraconazole should be stopped.
Black Box Warning: Negative Inotropic Actions With Itraconazole
Because of its negative inotropic actions, itraconazole should not be used for superficial fungal infections (dermatomycoses, onychomycosis) in patients with heart failure, a history of heart failure, or other indications of ventricular dysfunction.
Liver Injury.
Itraconazole has been associated with rare cases of liver failure, some of which were fatal. Although a causal link has not been established, caution is nonetheless advised. Patients should be informed about signs of liver impairment (persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain, jaundice, dark urine, pale stools) and, if they appear, should seek medical attention immediately.
Drug Interactions
Inhibition of Hepatic Drug Metabolizing Enzymes.
Itraconazole inhibits CYP3A4 (the 3A4 isoenzyme of cytochrome P450) and thus can increase levels of many other drugs (Table 77.3). The most important are cisapride, pimozide, dofetilide, and quinidine. When present at high levels, these drugs can cause potentially fatal ventricular dysrhythmias. Accordingly, concurrent use with itraconazole is contraindicated. Other drugs of concern include cyclosporine, digoxin, warfarin, and sulfonylurea-type oral hypoglycemics. In patients taking cyclosporine or digoxin, levels of these drugs should be monitored; in patients taking warfarin, prothrombin time should be monitored; and in patients taking sulfonylureas, blood glucose levels should be monitored.
TABLE 77.3
Some Drugs Whose Levels Can Be Increased by Azole Antifungal Drugs
| Target Drug | Class | Consequence of Excessive Level |
| Pimozide [Orap] | Antipsychotic | Fatal dysrhythmias |
| Dofetilide [Tikosyn] | Antidysrhythmic | Fatal dysrhythmias |
| Quinidine | Antidysrhythmic | Fatal dysrhythmias |
| Cisapride [Propulsid]* | Prokinetic agent | Fatal dysrhythmias |
| Warfarin [Coumadin] | Anticoagulant | Bleeding |
| Sulfonylureas | Oral hypoglycemic | Hypoglycemia |
| Phenytoin [Dilantin] | Antiseizure drug | Central nervous system toxicity |
| Cyclosporine [Sandimmune] | Immunosuppressant | Increased nephrotoxicity |
| Tacrolimus [Prograf] | Immunosuppressant | Increased nephrotoxicity |
| Lovastatin [Mevacor] | Antihyperlipidemic | Rhabdomyolysis |
| Simvastatin [Zocor] | Antihyperlipidemic | Rhabdomyolysis |
| Eletriptan [Relpax] | Antimigraine | Coronary vasospasm |
| Fentanyl [Duragesic, others] | Opioid analgesic | Fatal respiratory depression |
| Calcium channel blockers | Antihypertensive, antianginal | Cardiosuppression |
Drugs that Raise Gastric pH.
Drugs that decrease gastric acidity—antacids, histamine-2 (H2) antagonists, and proton pump inhibitors—can greatly reduce absorption of oral itraconazole. Accordingly, these agents should be administered at least 1 hour before itraconazole or 2 hours after. (Because proton pump inhibitors have a prolonged duration of action, patients using these drugs may have insufficient stomach acid for itraconazole absorption, regardless of when the proton pump inhibitor is given.)
Preparations, Dosage, and Administration
Itraconazole [Sporanox] is available in suspension (10 mg/mL) and capsules (100 mg) for oral use. The capsules should be taken with food or a cola beverage to increase absorption. The recommended dosage is 200 mg once a day. If needed, the dosage may be increased to 200 mg twice a day.
Fluconazole
Actions and Uses
Fluconazole [Diflucan], a member of the azole family, is an important antifungal drug. It has the same mechanism as itraconazole: inhibition of cytochrome P450–dependent synthesis of ergosterol, with resultant damage to the cytoplasmic membrane and accumulation of ergosterol precursors. The drug is primarily fungistatic. Fluconazole is used for blastomycosis; histoplasmosis; meningitis caused by Cryptococcus neoformans and Coccidioides immitis; and vaginal, oropharyngeal, esophageal, and disseminated Candida infections. In addition, fluconazole is used investigationally for leishmaniasis.
Pharmacokinetics
Fluconazole is well absorbed (90%) after oral dosing and undergoes wide distribution to tissues and body fluids, including the CSF. Most of each dose is eliminated unchanged in the urine. Fluconazole has a half-life of 30 hours, making once-a-day dosing sufficient.
Adverse Effects
Fluconazole is generally well tolerated. The most common reactions are nausea, headache, rash, vomiting, abdominal pain, and diarrhea. Rarely, treatment has been associated with hepatic necrosis, Stevens-Johnson syndrome, and anaphylaxis.
Use in Pregnancy
When taken in high doses (400–800 mg/day) throughout all or most of the first trimester, fluconazole can cause serious birth defects, including cleft palate, femoral bowing, congenital heart disease, and facial abnormalities. By contrast, treatment of vaginal candidiasis with a single low dose (150 mg) appears to be safe. High-dose therapy is now classified in U.S. Food and Drug Administration (FDA) Pregnancy Risk Category D, whereas low-dose therapy remains in Category C.
Drug Interactions
Like other azole antifungal drugs, fluconazole can inhibit CYP3A4 and increase levels of other drugs, including warfarin, phenytoin, cyclosporine, zidovudine, rifabutin, and sulfonylurea oral hypoglycemics.
Preparations, Dosage, and Administration
Fluconazole [Diflucan] is available in solution (2 mg/mL) for IV infusion and in tablets (50, 100, 150, and 200 mg) and suspension (10 and 40 mg/mL) for oral use. Because oral absorption is rapid and nearly complete, oral and IV dosages are the same. For treatment of oropharyngeal and esophageal candidiasis, the usual dosage is 200 mg on the first day, followed by 100 mg once daily thereafter. For treatment of systemic candidiasis and cryptococcal meningitis, the usual dosage is 400 mg on the first day, followed by 200 mg once daily thereafter. Duration of treatment ranges from 3 weeks to more than 3 months, depending on the infection.
Voriconazole
Actions and Uses
Voriconazole [Vfend], a member of the azole family, is an important drug for treating life-threatening fungal infections. Like other azoles, voriconazole inhibits cytochrome P450–dependent enzymes, suppressing synthesis of ergosterol, a critical component of the fungal cytoplasmic membrane. As a result, voriconazole is active against a broad spectrum of fungal pathogens, including Aspergillus species, Candida species, Scedosporium species, Fusarium species, Histoplasma capsulatum, Blastomyces dermatitidis, and C. neoformans. At this time, voriconazole has four approved indications: (1) candidemia, (2) invasive aspergillosis, (3) esophageal candidiasis, and (4) serious infections caused by Scedosporium apiospermum or Fusarium species in patients unresponsive to or intolerant of other drugs.
According to guidelines from the Infectious Disease Society of America, voriconazole has replaced amphotericin B as the drug of choice for invasive aspergillosis. Voriconazole is just as effective as amphotericin B and poses a much lower risk for kidney damage. However, voriconazole does have its own set of adverse effects, including hepatotoxicity, visual disturbances, hypersensitivity reactions, hallucinations, and fetal injury. In addition, like other azoles, voriconazole can interact with many drugs.
Pharmacokinetics
Voriconazole may be administered intravenously or orally. With oral dosing, bioavailability is high (96%) but can be reduced by food. Plasma levels peak 2 hours after ingestion. The drug’s half-life is dose dependent and can range from 6 hours up to 24 hours. Voriconazole undergoes extensive metabolism by hepatic cytochrome P450 isoenzymes.
Adverse Effects
The most common adverse effects are visual disturbances, fever, rash, nausea, vomiting, diarrhea, headache, sepsis, peripheral edema, abdominal pain, and respiratory disorders. During clinical trials, the effects that most often led to discontinuing treatment were liver damage, visual disturbances, and rash.
Hepatotoxicity.
Voriconazole can cause hepatitis, cholestasis, and fulminant hepatic failure. Fortunately, these events are both uncommon and generally reversible. To monitor for injury, liver function tests should be obtained before treatment and periodically thereafter.
Visual Disturbances.
Reversible, dose-related visual disturbances develop in 30% of patients. Symptoms include reduced visual acuity, increased brightness, altered color perception, and photophobia. As a rule, these begin within 30 minutes of dosing and then greatly diminish over the next 30 minutes. Owing to the risk for visual impairment, patients should be warned against driving, especially at night.
Hypersensitivity Reactions.
Voriconazole may cause dermatologic reactions, ranging from rash to life-threatening Stevens-Johnson syndrome. During infusion, anaphylactoid reactions have occurred, manifesting with tachycardia, chest tightness, dyspnea, faintness, flushing, fever, and sweating. If these symptoms develop, the infusion should stop.
Teratogenicity.
Voriconazole is teratogenic in rats and can cause fetal harm in humans. The drug is classified in FDA Pregnancy Risk Category D and hence should not be used during pregnancy unless the potential benefits are deemed to outweigh the risk to the fetus. Women taking the drug should use effective contraception.
PATIENT-CENTERED CARE ACROSS THE LIFE SPAN
Antifungal Agents
| Life Stage | Patient Care Concerns |
| Infants | Nystatin is used to treat oral candidiasis in premature and full-term infants. Fluconazole is also used safely to treat systemic candidiasis in newborn infants. |
| Children/adolescents | Many antifungal agents are used safely in children, in lower doses. Side-effect profiles are similar to those of adults. |
| Pregnant women | Many of the azole antifungals are classified in FDA Pregnancy Risk Category C or D. Risks and benefits must be considered for administration during pregnancy. |
| Breastfeeding women | Data are lacking regarding most antifungals and breastfeeding. Most antifungals are considered safe in lower doses. The exception to this is ketoconazole. Because it has high potential for hepatotoxicity, it should be avoided in breastfeeding women. |
| Older adults | Older adults have a higher risk for achlorhydria than do younger individuals and may not predictably absorb some antifungal agents. In addition, common drugs prescribed to older adults, including warfarin, phenytoin, and oral hypoglycemic agents, are increased by azoles. |
Drug Interactions
Voriconazole can interact with many other drugs. Several mechanisms are involved. Voriconazole is both a substrate for and inhibitor of hepatic cytochrome P450 isoenzymes. As a result, drugs that inhibit P450 can raise voriconazole levels, and drugs that induce P450 can lower voriconazole levels. On the other hand, because voriconazole itself can inhibit P450, voriconazole can raise levels of other drugs. Therefore the following precautions should be taken when administering voriconazole:
• To ensure that voriconazole levels are adequate, voriconazole should not be combined with powerful P450 inducers, including rifampin, rifabutin, carbamazepine, and phenobarbital.
• To avoid excessive voriconazole levels, voriconazole should not be combined with powerful P450 inhibitors.
• To avoid toxicity from accumulation of other drugs, voriconazole should not be combined with some agents that are P450 substrates, including cisapride, pimozide, and sirolimus.
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