Chapter 57: Antifungal Agents

Major pharmaceutical companies have closed their antifungal development programs, although a few small firms continue to sponsor research in this field. Thus, the near future in this area is likely to be limited to expansion of experience with existing compounds (Table 57–1). The most recent systemic antifungals to reach clinical development, posaconazole (noxafil) and isavuconazole (in phase III trials in the U.S.), are both triazoles.

Chemistry. Amphotericin B is one of a family of some 200 polyene macrolide compounds with antifungal activity. Those studied to date share the characteristics of four to seven conjugated double bonds, an internal cyclic ester, poor aqueous solubility, substantial toxicity on parenteral administration, and a common mechanism of antifungal action. Amphotericin B (see following structure) is a heptaene macrolide containing seven conjugated double bonds in the trans position and 3-amino-3,6-dideoxymannose (mycosamine) connected to the main ring by a glycosidic bond. The amphoteric behavior for which the drug is named derives from the presence of a carboxyl group on the main ring and a primary amino group on mycosamine; these groups confer aqueous solubility at extremes of pH. X-ray crystallography has shown the molecule to be rigid and rod-shaped, with the hydrophilic hydroxyl groups of the macrolide ring forming an opposing face to the lipophilic polyenic portion.

Drug Formulations. There are currently four formulations of amphotericin B commercially available: conventional amphotericin B (C-AMB), liposomal amphotericin B (L-AMB), amphotericin B lipid complex (ABLC), and amphotericin B colloidal dispersion (ABCD). Table 57–2 summarizes the pharmacokinetic properties of these preparations.

C-AMB (Conventional amphotericin B, fungizone). Amphotericin B is insoluble in water but is formulated for intravenous infusion by complexing it with the bile salt deoxycholate. The complex is marketed as a lyophilized powder for injection. C-AMB forms a colloid in water, with particles largely <0.4 μm in diameter. Filters in intravenous infusion lines that trap particles >0.22 μm in diameter will remove significant amounts of drug. Addition of electrolytes to infusion solutions causes the colloid to aggregate.

ABCD. Amphotericin B colloidal dispersion (amphotec, amphocil) contains roughly equimolar amounts of amphotericin B and cholesteryl sulfate formulated for injection. Like C-AMB, ABCD forms a colloidal solution when dispersed in aqueous solution. ABCD provides much lower blood levels than C-AMB in mice and humans. In a study in patients with neutropenic fever comparing daily ABCD (4 mg/kg) with C-AMB (0.8 mg/kg), chills and hypoxia were significantly more common with ABCD than with C-AMB (White et al., 1998). Hypoxia was associated with severe febrile reactions. In a comparison of ABCD (6 mg/kg) and C-AMB (1-1.5 mg/kg) in invasive aspergillosis patients, ABCD was less nephrotoxic than C-AMB (49% vs. 15%) but caused more fever (27% vs. 16%) and chills (53% vs. 30%) (Bowden et al., 2002). Administration of the recommended ABCD dose over 3-4 hours and use of premedication to reduce febrile reactions are advised, particularly with initial infusions. ABCD is approved at a recommended dose of 3-4 mg/kg intravenously daily for patients with invasive aspergillosis who are not responding to or are unable to tolerate C-AMB.

L-AMB. Liposomal amphotericin B is a small, unilamellar vesicle formulation of amphotericin B (ambisome). The drug is supplied as a lyophilized powder, which is reconstituted with sterile water for injection. Blood levels following intravenous infusion are almost equivalent to those obtained with C-AMB, and because l-amb can be given at higher doses, blood levels have been achieved that exceed those obtained with C-AMB (Boswell et al., 1998) (Table 57–2). Amphotericin B accumulation in the liver and spleen is higher with l-amb than with C-AMB. Adverse effects include nephrotoxicity, hypokalemia, and infusion-related reactions, such as fever, chills, hypoxia, hypotension, and hypertension, but these do not commonly lead to drug discontinuation. Infusion-related pain in the back, abdomen, or chest occurs in occasional patients, usually with the first few doses. Anaphylaxis also has been reported. As empirical therapy or prophylaxis in febrile neutropenic patients, CAMB and l-amb are equivalent. As induction therapy of disseminated histoplasmosis in AIDS patients, l-amb 3 mg/kg was superior to C-AMB 0.7 mg/kg (Johnson, 2002). L-AMB is approved for initial therapy of cryptococcal meningitis of AIDS patients and is listed as an alternative to C-AMB for induction therapy of both disseminated histoplasmosis and cryptococcal meningoencephalitis in AIDS patients (Kaplan et al., 2009). l-amb is approved for empirical therapy of fever in the neutropenic host not responding to appropriate antibacterial agents, as well as for salvage therapy of aspergillosis and candidiasis. The recommended daily intravenous dose for empirical therapy is 3 mg/kg; for treatment of mycoses, the dosage is 3-5 mg/kg. l-amb also is effective in visceral leishmaniasis at doses of 3-4 mg/kg daily. The drug is administered in 5% dextrose in water, with initial doses infused over 2 hours. If well tolerated, infusion duration can be shortened to 1 hour. Doses up to 10 mg/kg have been used but are associated with higher toxicity and, in one randomized trial of aspergillosis, no improvement in efficacy (Cornely, 2007a).

ABLC (abelcet). Amphotericin B lipid complex is a complex of amphotericin B with lipids (dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol). ABLC is given in a dose of 5 mg/kg in 5% dextrose in water, infused intravenously once daily over 2 hours. Blood levels of amphotericin B are much lower with ABLC than with the same dose of C-AMB. ABLC is effective in a variety of mycoses, with the possible exception of cryptococcal meningitis. The drug is approved for salvage therapy of deep mycoses.

The three lipid formulations collectively appear to reduce the risk of the patient's serum creatinine doubling during therapy by 58% (Barrett et al., 2003). In patients at high risk for nephrotoxicity, ABLC is more nephrotoxic than l-amb (Wingard et al., 2000). In some patients, the additive burden of amphotericin B nephrotoxicity can help precipitate advanced renal failure, with attendant morbidity. Infusion-related reactions are not consistently reduced with the use of lipid preparations. ABCD causes more infusion-related reactions than C-AMB. Although l-amb reportedly causes fewer infusion-related reactions than ABLC during the first dose (Wingard et al., 2000), the difference depends on whether premedication is given and varies considerably between patients. Infusion-related reactions typically decrease with subsequent infusions.

The cost of the lipid formulations of amphotericin B greatly exceeds that of C-AMB, making them unavailable in many countries.

Mechanism of Action. The antifungal activity of amphotericin B depends principally on its binding to a sterol moiety, primarily ergosterol in the membrane of sensitive fungi. By virtue of their interaction with these sterols, polyenes appear to form pores or channels that increase the permeability of the membrane, allowing leakage of a variety of small molecules (Figure 57–1).

Absorption, Distribution, and Excretion. Gastrointestinal (GI) absorption of all amphotericin B formulations is negligible. Pharmacokinetic properties differ markedly between preparations with L-AMB having the highest plasma concentrations at therapeutic doses (Table 57–2). C-AMB is released from its complex with deoxycholate in the bloodstream, and the amphotericin B that remains in plasma is more than 90% bound to proteins, largely β-lipoprotein. Excretion into the urine is negligible with all the formulations. Azotemia, liver failure, or hemodialysis does not have a measurable impact on plasma concentrations. Concentrations of amphotericin B (via C-AMB) in fluids from inflamed pleura, peritoneum, synovium, and aqueous humor are approximately two-thirds of trough concentrations in plasma. Little amphotericin B from any formulation penetrates into cerebrospinal fluid (CSF), vitreous humor, or normal amniotic fluid.

Antifungal Activity. Amphotericin B has useful clinical activity against Candida spp., Cryptococcus neoformans, Blastomyces dermatitidis, Histoplasma capsulatum, Sporothrix schenckii, Coccidioides spp., Paracoccidioides braziliensis, Aspergillus spp., Penicillium marneffei, and the agents of mucormycosis. Amphotericin B has limited activity against the protozoa Leishmania spp. and Naegleria fowleri. The drug has no antibacterial activity.

Fungal Resistance. Some isolates of Candida lusitaniae have been relatively resistant to amphotericin B. Aspergillus terreus and perhaps Aspergillus nidulans may be more resistant to amphotericin B than other Aspergillus species (Steinbach et al., 2004). Mutants selected in vitro for resistance to nystatin (a polyene antifungal discussed later) or amphotericin B replace ergosterol with certain precursor sterols. The rarity of significant amphotericin B resistance arising during therapy has left it unclear whether ergosterol-deficient mutants retain sufficient pathogenicity to survive in deep tissue.

Therapeutic Uses. The recommended doses were given earlier for each formulation. Candida esophagitis responds to much lower doses than deeply invasive mycoses. Intrathecal infusion of C-AMB is useful in patients with meningitis caused by Coccidioides. Too little is known about intrathecal administration of lipid formulations to recommend them. C-AMB can be injected into the CSF of the lumbar spine, cisterna magna, or lateral cerebral ventricle. Fever and headache are common reactions that may be decreased by intrathecal administration of 10-15 mg of hydrocortisone. Local injections of amphotericin B into a joint or peritoneal dialysate fluid commonly produce irritation and pain. Intraocular injection following pars plana vitrectomy has been used successfully for fungal endophthalmitis.

Intravenous administration of amphotericin B is the treatment of choice for mucormycosis and is used for initial treatment of cryptococcal meningitis, severe or rapidly progressing histoplasmosis, blastomycosis, coccidioidomycosis, and penicilliosis marneffei, as well as in patients not responding to azole therapy of invasive aspergillosis, extracutaneous sporotrichosis, fusariosis, alternariosis, and trichosporonosis. Amphotericin B (C-AMB or l-amb) is often given to selected patients with profound neutropenia who have fever that does not respond to broad-spectrum antibacterial agents over 5-7 days.

Untoward Effects. The major acute reactions to intravenous amphotericin B formulations are fever and chills. Infusion-related reactions are worst with ABCD, slightly less with C-C-AMB, even less with ABLC, and least with L-AMB. Tachypnea and respiratory stridor or modest hypotension also may occur, but true bronchospasm or anaphylaxis is rare. Patients with pre-existing cardiac or pulmonary disease may tolerate the metabolic demands of the reaction poorly and develop hypoxia or hypotension. The reaction ends spontaneously in 30-45 minutes; meperidine may shorten it. Pretreatment with oral acetaminophen or use of intravenous hydrocortisone hemisuccinate, 0.7 mg/kg, at the start of the infusion decreases reactions. Febrile reactions abate with subsequent infusions. Infants, children, and patients receiving therapeutic doses of glucocorticoids are less prone to reactions.

Azotemia occurs in 80% of patients who receive C-AMB for deep mycoses (Carlson and Condon, 1994). Lipid formulations are less nephrotoxic, being much less with ABLC, even less with L-AMB, and minimal with ABCD. Toxicity is dose-dependent and usually transient and increased by concurrent therapy with other nephrotoxic agents, such as aminoglycosides or cyclosporine. Although permanent histological changes in renal tubules occur even during short courses of C-AMB, permanent functional impairment is uncommon in adults with normal renal function prior to treatment unless the cumulative dose exceeds 3-4 g. Renal tubular acidosis and renal wasting of K⁺ and Mg²⁺ also may be seen during and for several weeks after therapy. Supplemental K⁺ is required in one-third of patients on prolonged therapy. Saline loading has decreased nephrotoxicity, even in the absence of water or salt deprivation. Administration of 1 L of normal saline intravenously on the day that C-AMB is to be given has been recommended for adults who are able to tolerate the Na⁺ load and who are not already receiving that amount in intravenous fluids.

Hypochromic, normocytic anemia commonly occurs during treatment with C-AMB. Anemia is less with lipid formulations and usually not seen over the first 2 weeks. The anemia is most likely due to decreased production of erythropoietin. Patients with low plasma erythropoietin may respond to administration of recombinant erythropoietin. Anemia reverses slowly following cessation of therapy. Headache, nausea, vomiting, malaise, weight loss, and phlebitis at peripheral infusion sites are common. Thrombocytopenia or mild leukopenia is observed rarely. Hepatotoxicity is not firmly established with any amphotericin B formulation. Arachnoiditis has been observed as a complication of injecting C-AMB into the CSF.

Chemistry. Flucytosine is 5-fluorocytosine, a fluorinated pyrimidine related to fluorouracil and floxuridine.

Mechanism of Action. All susceptible fungi are capable of deaminating flucytosine to 5-fluorouracil (Figure 57–2), a potent antimetabolite that is used in cancer chemotherapy (Chapter 61). Fluorouracil is metabolized first to 5-fluorouracil-ribose monophosphate (5-FUMP) by the enzyme uracil phosphoribosyl transferase (UPRTase; also called uridine monophosphate pyrophosphorylase). As in mammalian cells, 5-FUMP then is either incorporated into RNA (via synthesis of 5-fluorouridine triphosphate) or metabolized to 5-fluoro-2′-deoxyuridine-5′-monophosphate (5-FdUMP), a potent inhibitor of thymidylate synthetase. DNA synthesis is impaired as the ultimate result of this latter reaction. The selective action of flucytosine is due to the lack of cytosine deaminase in mammalian cells, which prevents metabolism to fluorouracil.

Antifungal Activity. Flucytosine has clinically useful activity against Cryptococcus neoformans, Candida spp., and the agents of chromoblastomycosis. Within these species, determination of susceptibility in vitro has been extremely dependent on the method employed, and susceptibility testing performed on isolates obtained prior to treatment has not correlated with clinical outcome.

Fungal Resistance. Drug resistance arising during therapy (secondary resistance) is an important cause of therapeutic failure when flucytosine is used alone for cryptococcosis and candidiasis. In chromoblastomycosis, resurgence of lesions after an initial response has led to the presumption of secondary drug resistance. In isolates of Cryptococcus and Candida species, secondary drug resistance has been accompanied by a change in the minimal inhibitory concentration from <2.5 μg/mL to >360 μg/mL. The mechanism for this resistance can be loss of the permease necessary for cytosine transport or decreased activity of either UPRTase or cytosine deaminase (Figure 57–2). In Candida albicans, substitution of thymidine for cytosine at nucleotide 301 in the gene encoding UPRTase (FURl) causes a cysteine to become an arginine, modestly increasing flucytosine resistance (Dodgson et al., 2004). Flucytosine resistance is further increased if both FURl alleles in the diploid fungus are mutated.

Absorption, Distribution, and Excretion. Flucytosine is absorbed rapidly and well from the GI tract. It is widely distributed in the body, with a volume of distribution that approximates total body water, and is minimally bound to plasma proteins. The peak plasma concentration in patients with normal renal function is ~70-80 μg/mL, achieved 1-2 hours after a dose of 37.5 mg/kg. Approximately 80% of a given dose is excreted unchanged in the urine; concentrations in the urine range from 200-500 μg/mL. The t_1/2 of the drug is 3-6 hours in normal individuals. In renal failure, the t_1/2 may be as long as 200 hours. The clearance of flucytosine is approximately equivalent to that of creatinine. Reduction of dosage is necessary in patients with decreased renal function, and concentrations of drug in plasma should be measured periodically. Peak concentrations should range between 50 and 100 μg/mL. Flucytosine is cleared by hemodialysis, and patients undergoing such treatment should receive a single dose of 37.5 mg/kg after dialysis; the drug also is removed by peritoneal dialysis.

Flucytosine concentration in CSF is ~65-90% of that found simultaneously in the plasma. The drug also appears to penetrate into the aqueous humor.

Therapeutic Uses. Flucytosine (ancobon) is given orally at 50-150 mg/kg per day, in four divided doses at 6-hour intervals. Dosage must be adjusted for decreased renal function. Flucytosine is used predominantly in combination with amphotericin B. Flucytosine caused no added toxicity when added to 0.7 mg/kg of amphotericin B for the initial 2 weeks of therapy of cryptococcal meningitis in AIDS patients. Although the CSF colony count diminished more rapidly with combination therapy, there was no apparent impact on mortality or morbidity (van der Horst et al., 1997). An all-oral regimen of flucytosine plus fluconazole also has been advocated for therapy of AIDS patients with cryptococcosis, but the combination has substantial GI toxicity with no evidence that flucytosine adds benefit (Larsen et al., 1994). In cryptococcal meningitis of non-AIDS patients, the role of flucytosine is more conjectural. The addition of flucytosine to ≥6 weeks of therapy with C-AMB runs the risk of substantial bone marrow suppression or colitis if the flucytosine dose is not promptly adjusted downward as amphotericin B–induced azotemia occurs. In the 2008 IDSA guidelines for the treatment of cryptococcal meningoencephalitis, addition of flucytosine (100 mg/kg orally in four divided doses) is recommended for the first 2 weeks of treatment with amphotericin B in AIDS patients. A similar practice is often used in HIV-negative patients but the benefit is unknown (Pappas et al., 2001).

Untoward Effects. Flucytosine may depress the bone marrow and lead to leukopenia and thrombocytopenia; patients are more prone to this complication if they have an underlying hematological disorder, are being treated with radiation or drugs that injure the bone marrow, or have a history of treatment with such agents. Other untoward effects—including rash, nausea, vomiting, diarrhea, and severe enterocolitis—have been noted. In ~5% of patients, plasma levels of hepatic enzymes are elevated, but this effect reverses when therapy is stopped. Toxicity is more frequent in patients with AIDS or azotemia (including those who are receiving amphotericin B concurrently) and when plasma drug concentrations exceed 100 μg/mL. Toxicity may result from conversion of flucytosine to 5-fluorouracil by the microbial flora in the intestinal tract of the host.

Mechanism of Action. At concentrations achieved following systemic administration, the major effect of imidazoles and triazoles on fungi is inhibition of 14-α-sterol demethylase, a microsomal CYP (Figure 57–1). Imidazoles and triazoles thus impair the biosynthesis of ergosterol for the cytoplasmic membrane and lead to the accumulation of 14-α-methylsterols. These methylsterols may disrupt the close packing of acyl chains of phospholipids, impairing the functions of certain membrane-bound enzyme systems, thus inhibiting growth of the fungi. Some azoles directly increase permeability of the fungal cytoplasmic membrane, but the concentrations required are likely only obtained with topical use.

Antifungal Activity. Azoles as a group have clinically useful activity against Candida albicans, Candida tropicalis, Candida parapsilosis, Candida glabrata, Cryptococcus neoformans, Blastomyces dermatitidis, Histoplasma capsulatum, Coccidioides spp., Paracoccidioides brasiliensis, and ringworm fungi (dermatophytes). Aspergillus spp., Scedosporium apiospermum (Pseudallescheria boydii), Fusarium, and Sporothrix schenckii are intermediate in susceptibility. Candida krusei and the agents of mucormycosis are more resistant. Thus, these drugs do not have any useful antibacterial or antiparasitic activity, with the possible exception of antiprotozoal effects against Leishmania major. Posaconazole has slightly improved activity in vitro against the agents of mucormycosis.

Resistance. Azole resistance emerges gradually during prolonged azole therapy, causing clinical failure in patients with far-advanced HIV infection and oropharyngeal or esophageal candidiasis. The primary mechanism of resistance in C. albicans is accumulation of mutations in ERG11, the gene coding for the 14-α-sterol demethylase. These mutations protect heme in the enzyme pocket from binding to the azole but allow access of the natural substrate for the enzyme lanosterol. Cross-resistance is conferred to all azoles. Increased azole efflux by both ATP-binding cassette (ABC) and major facilitator superfamily transporters can add to fluconazole resistance in C. albicans and C. glabrata. Increased production of C14-α-sterol demethylase is another potential cause of resistance. Mutation of the C5,6 sterol reductase gene ERG3 also can increase azole resistance in some species.

Primary azole resistance has been described in some isolates of Aspergillus fumigatus with increased azole transport and decreased ergosterol content, but the clinical significance is unknown. Decreased fluconazole susceptibility has been described in Cryptococcus neoformans isolated from AIDS patients failing prolonged therapy.

Interaction of Azole Anti-Fungals with Other Drugs. The azoles interact with hepatic CYPs as substrates and inhibitors (Table 57–3), providing myriad possibilities for the interaction of azoles with many other medications. Thus, azoles can elevate plasma levels of some co-administered drugs (Table 57–4). Other co-administered drugs can decrease plasma concentrations of azole antifungal agents (Table 57–5). As a consequence of myriad interactions, combinations of certain drugs with azole antifungal medications may be contraindicated (Table 57–6).

Ketoconazole, administered orally, has been replaced by itraconazole for the treatment of all mycoses except when the lower cost of ketoconazole outweighs the advantage of itraconazole. Itraconazole lacks ketoconazole's corticosteroid suppression while retaining most of ketoconazole's pharmacological properties and expanding the antifungal spectrum. Ketoconazole sometimes is used to inhibit excessive production of glucocorticoids in patients with Cushing's syndrome (Chapter 42) and is available for topical use, as described later.

Absorption, Distribution, and Excretion. Itraconazole (sporanox, others) is available as a capsule and a solution in hydroxypropyl-β-cyclodextrin for oral use. The capsule form of the drug is best absorbed in the fed state, but the oral solution is better absorbed in the fasting state, providing peak plasma concentrations >150% of those obtained with the capsule. Itraconazole is metabolized in the liver. It is both a substrate for and a potent inhibitor of CYP3A4. Itraconazole is present in plasma with an approximately equal concentration of a biologically active metabolite, hydroxy-itraconazole. Bioassays may report up to 3.3 times as much itraconazole in plasma as do physical methods such as high-performance liquid chromatography, depending on the susceptibility of the bioassay organism to hydroxy-itraconazole. The native drug and metabolite are >99% bound to plasma proteins. Neither appears in urine or CSF. The t_1/2 of itraconazole at steady state is ~30-40 hours. Steady-state levels of itraconazole are not reached for 4 days and those of hydroxy-itraconazole for 7 days; thus, loading doses are recommended when treating deep mycoses. Severe liver disease will increase itraconazole plasma concentrations, but azotemia and hemodialysis have no effect. Itraconazole is not carcinogenic but is teratogenic in rats and contraindicated for the treatment of onychomycosis during pregnancy or for women contemplating pregnancy (Category C).

Drug Interactions. Tables 57–4, 57–5, and 57–6 list select interactions of azoles with other drugs. Many of the interactions can result in serious toxicity from the companion drug, such as inducing potentially fatal cardiac arrhythmias when used with quinidine, halofantrine (an orphan drug used for malaria), levomethadyl (an orphan drug used for heroin addiction), pimozide (orap) or cisapride (only available under an investigational limited access program in the U.S.). Other drugs may decrease itraconazole serum levels below therapeutic concentrations (Table 57–5).

Therapeutic Uses. Itraconazole is the drug of choice for patients with indolent, nonmeningeal infections due to B. dermatitidis, H. capsulatum, P. brasiliensis, and C. immitis. The drug also is useful in the therapy of indolent invasive aspergillosis outside the CNS, particularly after the infection has been stabilized with amphotericin B. Approximately half the patients with distal subungual onychomycosis respond to itraconazole (Evans and Sigurgeirsson, 1999). Although not an approved use, itraconazole is a reasonable choice for the treatment of pseudallescheriasis, an infection not responding to amphotericin B therapy, as well as cutaneous and extracutaneous sporotrichosis, tinea corporis, and extensive tinea versicolor. HIV-infected patients with disseminated histoplasmosis or Penicillium marneffei infections have a decreased incidence of relapse if given prolonged itraconazole "maintenance" therapy. According to the 2008 CDC/IDSA guidelines, discontinuation of itraconazole may be considered in AIDS patients with disseminated histoplasmosis who have completed 1 year of itraconazole, have responded to highly active antiretroviral therapy (HAART) with a CD4 >150/mm³ for 6 months, have a urine histoplasma antigen <2 units and a negative blood culture for histoplasma (Kaplan et al., 2009) (Chapter 59). Itraconazole is not recommended for maintenance therapy of cryptococcal meningitis in HIV-infected patients because of a high incidence of relapse. Long-term therapy has been used in non-HIV–infected patients with allergic bronchopulmonary aspergillosis to decrease the dose of glucocorticoids and reduce attacks of acute bronchospasm (Salez et al., 1999).

Itraconazole solution is effective and approved for use in oropharyngeal and esophageal candidiasis. Because the solution has more GI side effects than fluconazole tablets, itraconazole solution usually is reserved for patients not responding to fluconazole.

Untoward Effects. Adverse effects of itraconazole therapy can occur as a result of interactions with many other drugs (Tables 57–3 and 57–4). Serious hepatotoxicity has rarely led to hepatic failure and death. If symptoms of hepatotoxicity occur, the drug should be discontinued and liver function assessed. Intravenous itraconazole causes a dose-dependent inotropic effect that can lead to congestive heart failure in patients with impaired ventricular function. In the absence of interacting drugs, itraconazole capsules and suspension are well tolerated at 200 mg daily. Some patients complain of the taste of the solution, and GI side effects are common, although adherence is generally unimpaired. Diarrhea, abdominal cramps, anorexia, and nausea are more common than with the capsules. In one series of patients receiving 50-400 mg of the capsules per day, nausea and vomiting were recorded in 10%, hypertriglyceridemia in 9%, hypokalemia in 6%, increased serum aminotransferase in 5%, rash in 2%, and at least one side effect in 39%. Occasionally, rash necessitates drug discontinuation, but most adverse effects can be handled with dose reduction. Profound hypokalemia has been seen in patients receiving ≥600 mg daily and in those who recently have received prolonged amphotericin B therapy. Doses of 300 mg twice daily have led to other side effects, including adrenal insufficiency, lower limb edema, hypertension, and in at least one case, rhabdomyolysis. Doses >400 mg per day are not recommended for long-term use. Anaphylaxis has been observed rarely, as well as severe rash, including Stevens-Johnson syndrome.

Dosage. In treating deep (life-threatening) mycoses, a loading dose of 200 mg of itraconazole is administered three times daily for the first 3 days. After the loading doses, two 100-mg capsules are given twice daily with food. The divided doses are alleged to increase the area under the plasma concentration versus time curve (AUC), even though the t_1/2 is ~30 hours. For maintenance therapy of HIV-infected patients with disseminated histoplasmosis, 200 mg once daily is used. Onychomycosis can be treated with either 200 mg once daily for 12 weeks or for infections isolated to fingernails, two monthly cycles consisting of 200 mg twice daily for 1 week followed by a 3-week period of no therapy—so-called pulse therapy (Evans and Sigurgeirsson, 1999). Retention of active drug in the nail keratin permits intermittent treatment. Daily therapy is preferred by some authorities for infections likely to be more refractory, but it costs twice as much as pulse therapy. Once-daily terbinafine (250 mg), however, is superior to pulse therapy with itraconazole. For oropharyngeal candidiasis, itraconazole oral solution should be taken fasting in a dose of 100 mg (10 mL) once daily and swished vigorously in the mouth before swallowing to optimize any topical effect. Patients with esophageal thrush unresponsive or refractory to treatment with fluconazole tablets are given 100 mg of the solution twice a day for 2-4 weeks.

Absorption, Distribution, and Excretion. Fluconazole is almost completely absorbed from the GI tract. Plasma concentrations are essentially the same whether the drug is given orally or intravenously, and its bioavailability is unaltered by food or gastric acidity. Peak plasma concentrations are 4-8 μg/mL after repetitive doses of 100 mg. Renal excretion accounts for >90% of elimination, and the elimination t_1/2 is 25-30 hours. Fluconazole diffuses readily into body fluids, including breast milk, sputum, and saliva; concentrations in CSF can reach 50-90% of the simultaneous values in plasma. The dosage interval should be increased from 24-48 hours with a creatinine clearance of 21-40 mL/minute and to 72 hours at 10-20 mL/minute. A dose of 100-200 mg should be given after each hemodialysis. About 11-12% of drug in the plasma is protein bound.

Drug Interactions. Fluconazole is an inhibitor of CYP3A4 and CYP2C9. Fluconazole's drug–drug interactions are shown in Tables 57–3 and 57–4. Patients who receive >400 mg daily or azotemic patients who have elevated fluconazole blood levels may experience drug interactions not otherwise seen.

Therapeutic Uses. Candidiasis. Fluconazole, 200 mg on the first day and then 100 mg daily for at least 2 weeks, is effective in oropharyngeal candidiasis. Doses of 100-200 mg daily have been used to decrease candiduria in high-risk patients. A single dose of 150 mg is effective in uncomplicated vaginal candidiasis. A dose of 400 mg daily decreases the incidence of deep candidiasis in allogeneic bone marrow transplant recipients and is useful in treating candidemia of nonimmunosuppressed patients. In patients who have not been receiving fluconazole prophylaxis, the drug has been used successfully as empirical treatment of febrile neutropenia in patients not responding to antibacterial agents and who are not judged to be at high risk of mould infections. Although response to C. glabrata bloodstream infections in randomized trials using fluconazole has been comparable to that with C. albicans, C. glabrata becomes resistant upon prolonged exposure to fluconazole. Empirical use of fluconazole for suspected candidemia may not be advisable in patients who have been receiving long-term fluconazole prophylaxis and may be colonized with azole-resistant C. glabrata. Based on resistance in vitro, Candida krusei would not be expected to respond to fluconazole or other azoles.

Cryptococcosis. Following IDSA guidelines (Perfect et al., 2010), fluconazole, 400 mg daily, is used for the initial 8 weeks in the treatment of cryptococcal meningitis in patients with AIDS after the patient's clinical condition has been stabilized with at least 2 weeks of intravenous amphotericin B. After 8 weeks in patients no longer symptomatic, the dose is decreased to 200 mg daily and continued indefinitely. If the patient has completed 12 months of treatment for cryptococcosis, responds to HAART, has a CD4 count maintained >200/mm³ for at least 6 months, and is asymptomatic from cryptococcal meningitis, it is reasonable to discontinue maintenance fluconazole as long as the CD4 response is maintained. Some would add that an undetectable viral load for 3 months is required. Fluconazole, 400 mg daily, has been recommended as continuation therapy in non-AIDS patients with cryptococcal meningitis who have responded to an initial course of C-AMB or L-AMB and for patients with pulmonary cryptococcosis.

Other Mycoses. Fluconazole is the drug of choice for treatment of coccidioidal meningitis because of good penetration into the CSF and much less morbidity than with intrathecal amphotericin B. In other forms of coccidioidomycosis, fluconazole is comparable to itraconazole. Fluconazole has no useful activity against histoplasmosis, blastomycosis, or sporotrichosis. Fluconazole is not effective in the prevention or treatment of aspergillosis. Fluconazole has some activity in ringworm but is not approved for that indication. As with other azoles, with the possible exception of posaconazole, there is no activity in mucormycosis.

Untoward Effects. Side effects in patients receiving >7 days of drug, regardless of dose, include the following: nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%. Use of high doses may be limited by nausea. Reversible alopecia may occur with prolonged therapy at 400 mg daily. Rare cases of deaths due to hepatic failure or Stevens-Johnson syndrome have been reported. Fluconazole is teratogenic in rodents and has been associated with skeletal and cardiac deformities in at least three infants born to two women taking high doses during pregnancy. Fluconazole is a Category C agent that should be avoided during pregnancy unless the potential benefit justifies the possible risk to the fetus.

Dosage. Fluconazole (diflucan, others) is marketed in the U.S. as tablets of 50, 100, 150, and 200 mg for oral administration, powder for oral suspension providing 10 and 40 mg/mL, and intravenous solutions containing 2 mg/mL in saline and in dextrose solution. The daily dose of fluconazole should be based on the infecting organism and the patient's response to therapy. Generally recommended dosages are 50-400 mg once daily for either oral or intravenous administration. A loading dose of twice the daily maintenance dose is generally administered on the first day of therapy. Prolonged maintenance therapy may be required to prevent relapse. Children are treated with 3-12 mg/kg once daily (maximum: 600 mg/day).

Voriconazole (vfend) is a triazole with a structure similar to fluconazole but with increased activity in vitro, an expanded spectrum, and poor aqueous solubility.

Absorption, Distribution, and Excretion. Oral bioavailability is 96% and protein binding 56% (Jeu et al., 2003). Volume of distribution is high (4.6 L/kg), with extensive drug distribution in tissues. Metabolism occurs through CYP2C19 and to a lesser extent CYP2C9; CYP3A4 plays a limited role. Less than 2% of parent drug is recovered from urine, although 80% of the inactive metabolites are excreted in the urine. The oral dose does not have to be adjusted for azotemia or hemodialysis. Peak plasma concentrations after oral doses of 200 mg orally twice daily are ~3 μg/mL. CSF concentrations of 1-3 μg/mL have been reported in a patient with fungal meningitis.

Plasma elimination t_1/2 is 6 hours. Voriconazole exhibits nonlinear metabolism so that higher doses cause greater-than-linear increases in systemic drug exposure. Genetic polymorphisms in CYP2C19 can cause up to 4-fold differences in drug exposure; 15-20% of Asians are homozygous poor metabolizers, compared with 2% of whites and African Americans. Patients >65 years and patients with mild or moderate hepatic insufficiency have elevated areas under the curve (AUCs). Patients with mild-to-moderate cirrhosis should receive the same loading dose of voriconazole but half the maintenance dose. There are no data to guide dosing in patients with severe hepatic insufficiency.

The intravenous formulation of voriconazole contains sulfobutyl ether β-cyclodextrin (SBECD). When voriconazole is given intravenously, SBECD is excreted completely by the kidney. Significant accumulation of SBECD occurs with a creatinine clearance <50 mL/minute. Because toxicity of SBECD at high plasma concentrations is unclear, oral voriconazole is preferred in azotemic patients.

Drug Interactions. Voriconazole is metabolized by, and inhibits, CYPs 2C19, 2C9, and CYP3A4 (in that order of decreasing potency) The major metabolite of voriconazole, the voriconazole N-oxide, also inhibits these CYPs. Inhibitors or inducers of these CYPs may increase or decrease voriconazole plasma concentrations, respectively. In addition, there is potential for voriconazole and its major metabolite to increase the plasma concentrations of other drugs metabolized by these enzymes (Tables 57–3, 57–4, and 57–5). Because the sirolimus AUC increases 11-fold when voriconazole is given, co-administration is contraindicated. When starting voriconazole in a patient receiving ≥40 mg/day of omeprazole, the dose of omeprazole should be reduced by half.

Therapeutic Uses. In an open randomized trial, voriconazole provided superior efficiency to C-AMB in the primary therapy of invasive aspergillosis (Herbrecht et al., 2002). In a secondary analysis, survival also was superior in the voriconazole arm. Voriconazole was compared to l-amb in an open randomized trial in the empirical therapy of neutropenic patients whose fever did not respond to >96 hours of antibacterial therapy. Because the 95% confidence interval in this noninferiority trial permitted the possibility that voriconazole might be >10% worse than l-amb, the Food and Drug Administration did not approve voriconazole for this use (Walsh et al., 2002). However, in a secondary analysis, there were fewer breakthrough infections with voriconazole (1.9%) than with l-amb (5%). Voriconazole is approved for use in esophageal candidiasis on the basis of a double-blind randomized comparison with fluconazole (Ally et al., 2001). In non-neutropenic patients with candidemia, voriconazole was comparable in efficacy and less toxic than initial C-AMB followed by fluconazole (Kullberg, 2005). Voriconazole is approved for initial treatment of candidemia and invasive aspergillosis, as well as for salvage therapy in patients with Pseudallescheria boydii (Scedosporium apiospermum) and Fusarium infections. Positive response of patients with cerebral fungal suggest that the drug penetrates infected brain.

Untoward Effects. Voriconazole is teratogenic in animals and generally contraindicated in pregnancy (Category D). Women of childbearing potential should use effective contraception during treatment. Although voriconazole is generally well tolerated, occasional cases of hepatotoxicity have been reported, and liver function should be monitored. Voriconazole, like some other azoles, causes a prolongation of the QTc interval, which can become significant in patients with other risk factors for torsades de pointes. Patients must be warned about possible visual effects. Transient visual or auditory hallucinations are frequent after the first dose, usually at night and particularly with intravenous administration. Symptoms diminish with time (Zonios et al., 2008). Patients receiving their first intravenous infusion have had anaphylactoid reactions, with faintness, nausea, flushing, feverishness, and rash. In such patients, the infusion should be stopped. Rash has been reported in 5.8% of patients.

Dosage. Voriconazole for intravenous infusion is packaged as 200 mg with 3.2 g SBECD. Treatment is usually initiated with an intravenous infusion of 6 mg/kg every 12 hours for two doses, followed by 3-4 mg/kg every 12 hours. It should be administered no faster than 3 mg/kg/hr (e.g., over 1-2 hours, not as an intravenous bolus). As the patient improves, oral administration is continued as 200 mg every 12 hours. Patients failing to respond may be given 300 mg every 12 hours. Voriconazole is available as 50- or 200-mg tablets or a suspension of 40 mg/mL when hydrated. The tablets, but not the suspension, contain lactose. Because high-fat meals reduce voriconazole bioavailability, oral drug should be given either 1 hour before or 1 hour after meals. Children metabolize voriconazole more rapidly that adults (Walsh, 2004a).

Posaconazole (noxafil) is a synthetic structural analog of itraconazole with the same broad antifungal spectrum but with up to 4-fold greater activity in vitro against yeasts and filamentous fungi, including the agents of mucormycosis (Guinea et al., 2008; Frampton, 2008). Activity against yeasts in vitro is similar to voriconazole. The mechanism of action is the same as other imidazoles, inhibition of sterol 14-α demethylase.

Absorption, Distribution, and Excretion. Posaconazole is available as a cherry-flavored suspension containing 40 mg/mL. Bioavailability is significantly enhanced by the presence of food (Courtney et al., 2003; Krieter, 2004). The drug has a long terminal phase t_1/2 (25-31 hours), a large volume of distribution (331-1341 L), and extensive binding (>98%) to protein, predominantly albumin. Systemic exposure is four times higher in homozygous CYP2C19 slow metabolizers than in homozygous wild-type metabolizers. Steady-state concentrations are reached in 7-10 days when dosed four times daily. Saturation of absorption occurs at 800 mg/day (Ezzet et al., 2005; Ullmann et al., 2006). Renal impairment does not alter plasma concentrations; hepatic impairment causes a modest increase (Moton, 2008). With radiolabeled drug given to volunteers, 77% was excreted in the stool, with 66% of the administered dose appearing as unchanged drug. The major metabolic pathway is hepatic UDP glucuronidation (Krieter, 2004). Hemodialysis does not remove detectable amounts of this highly protein-bound drug from the circulation. Gastric acid improves absorption in that an acidic beverage, ginger ale, increased the AUC by 70% in the fasting state (Krishna et al., 2009b). Drugs that reduce gastric acid (e.g., cimetidine and esomeprazole) decreased posaconazole exposure by 32-50% (Frampton and Scott, 2008). Diarrhea reduced the average plasma concentration by 37% (Smith et al., 2009). Plasma concentrations in allogeneic stem cell transplant recipients were 52% lower than in patients not receiving a stem cell transplant (Ullmann et al., 2006). Although monitoring plasma concentrations has been advocated (Smith et al., 2009), the lower limit of therapeutic effect for any indication is unknown.

Therapeutic Use. Posaconazole is not inferior to fluconazole for treatment of oropharyngeal candidiasis, although fluconazole is the preferred drug because of safety, cost, and extensive experience. The dose is 100 mg twice daily the first day and once daily thereafter for 13 days. Posaconazole is approved for prophylaxis against candidiasis and aspergillosis in patients >13 years of age who have prolonged neutropenia or severe graft-vs-host disease (GVHD) (Ullmann et al., 2007). Posaconazole and other "azoles" have recently been compared for prophylaxis effect in patients with neutropenia (Cornely et al., 2007b). The broad applicability of posaconazole for prophylaxis of patients with prolonged neutropenia or GVHD remains unsettled, although the drug clearly remains an option for those indications (De Pauw, 2007).

Posaconazole is approved in the E.U. as salvage therapy for aspergillosis and several other infections, as are itraconazole and voriconazole. A number of clinical reports of favorable response to posaconazole as salvage therapy in mucormycosis have appeared in the literature, leaving the issue unresolved (Dannaoui et al., 2003; Greenberg et al., 2006). Lack of an intravenous formulation continues to limit studies of critically ill patients.

Drug Interactions. Posaconazole inhibits CYP3A4. Co-administration with rifabutin or phenytoin increases the plasma concentration of these drugs and decreases posaconazole exposure by 2-fold. The mechanism of induced posaconazole clearance is unknown but may involve hepatic phase 2 glucuronidation, rather than phase 1 oxidative enzymes. Oxidative products have not been recovered in the serum of treated patients. Posaconazole increases the AUC of cyclosporine, tacrolimus (121%), sirolimus (790%), midazolam (83%) and other CYP3A4 substrates (Table 57–4) (Frampton and Scott, 2008; Krishna et al., 2009a; Moton et al., 2009). Posaconazole is not known to prolong cardiac repolarization, as other azoles may, but posaconazole should not be co-administered with drugs that are CYP3A4 substrates and prolong the QTc interval, such as methadone, haloperidol, pimozide, quinidine, risperidone, sunitinib, tacrolimus, and halofantrine (Table 57–6).

Untoward Effects. The safety profile of posaconazole is good, with nausea, vomiting, diarrhea, abdominal pain, and headache the most commonly reported adverse effects (Smith et al., 2009). Although adverse effects occur in at least a third of patients, discontinuation due to adverse effects in long-term studies has been only 8%, Posaconazole causes fetal bone malformation in pregnant rats and is pregnancy Category C. Safety in children <8 years of age has not been established.

Dosage. Dosage for adults and children >8 years of age is 200 mg (5 mL suspension) three times daily for prophylaxis. Treatment of active infection is begun at 200 mg four times daily and changed to 400 mg twice daily once infection has improved. All doses should be taken with a full meal.

The pro-drug is readily cleaved by esterases in the human body to release the active triazole. In vitro activity is comparable to voriconazole (Guinea et al., 2008; Perkhofer et al., 2009).

Absorption, Distribution, and Excretion. Oral administration of once-daily doses equivalent to 100 mg BAL4815 for loading followed by 50 mg daily and 200 mg loading followed by 100 mg resulted in peak plasma concentrations at 21 days of 1.37 μg/mL and 3.5 μg/mL at 2.25 and 3.5 hours, respectively. The AUCs _0-24h were 21.6 and 40.3 μg·h/mL, respectively (Schmitt-Hoffman et al., 2006). With intravenous administration there was close to a linear dose response, with a 5-fold accumulation over 14 days, a t_1/2 of 84.5-117 hours, and a volume of distribution at steady state of 308-542 L. Excretion is by the liver with most drug appearing in feces.

Therapeutic Use. Isavuconazole has been found comparable to fluconazole in Candida esophagitis with all three isavuconazole regimens tested: loading dose of 200 followed by 50 mg daily, loading dose of 400 mg followed by 100 mg daily, or 400 mg once weekly for 14 days (Odds, 2006). The drug was well tolerated. Phase III trials are enrolling patients with deeply invasive candidiasis and aspergillosis.

General Pharmacological Characteristics. Echinocandins differ somewhat pharmacokinetically (Table 57–7) but all share lack of oral bioavailability, extensive protein binding (>97%), inability to penetrate into CSF, lack of renal clearance, and only a slight to modest effect of hepatic insufficiency on plasma drug concentration (Kim et al., 2007; Wagner et al., 2006). Adverse effects are minimal and rarely lead to drug discontinuation (Kim et al., 2007). All three agents are pregnancy Category C. For a review of the basic and clinical pharmacology of the echinocandins, see Wiederhold and Lewis (2007).

The minimum inhibitory concentration (MIC) of Candida albicans and several other Candida species are in the range of 0.015-0.5 μg/mL, higher for caspofungin than micafungin or anidulafungin. In Candida spp., echinocandins cause cell death at concentrations only 2- to 4-fold higher than that needed to inhibit growth. Azole-resistant Candida species remain susceptible to echinocandins. MIC of Candida parapsilosis and C. guilliermondii are consistently higher than other Candida spp., usually 2 μg/mL with all three echinocandins. In none of the clinical trials of the three echinocandins has the higher MIC of C. parapsilosis been reflected in lower response rates. An unexplained and paradoxical effect of increased growth at concentrations above the MIC has been seen more often in C. parapsilosis than with other Candida spp. and more commonly with caspofungin than micafungin or anidulafungin (Chamilos et al., 2007). In Aspergillus, echinocandins are not cidal but change the shape of hyphae; thus, in vitro susceptibility testing is done with a "morphological" end point (change in hyphal shape). Animal models do not suggest activity against dimorphic fungi such as Histoplasma capsulatum. Echinocandins have no activity against Cryptococcus neoformans, Trichosporon spp., or agents of mucormycosis. In vitro studies have consistently failed to show synergism or antagonism between echinocandins and amphotericin B. There is no antagonism between echinocandins and azoles; an additive effect has been reported with Aspergillus in some in vitro systems and animals models. Echinocandin resistance can be selected in Candida albicans under drug pressure both in vitro and clinically during prolonged echinocandin therapy. Resistance is from mutations in a conserved region of the FKS1 gene, coding for amino acids Phe ⁶⁴¹-Asp ⁶⁵⁸ (Park et al., 2005). FKS1p is an essential component of the 1,3-β-D-glucan synthase complex (Figure 57–3).

Metabolism and Excretion. Catabolism is largely by hydrolysis and N-acetylation, with excretion of the metabolites in the urine and feces. Mild and moderate hepatic insufficiency increases the AUC by 55% and 76%, respectively.

Drug Interactions. Caspofungin increase tacrolimus levels by 16%, which should be managed by standard monitoring. Cyclosporine slightly increases caspofungin levels. Rifampin and other drugs activating CYP3A4 can cause a slight reduction in caspofungin levels.

Therapeutic Use. Caspofungin is approved for initial therapy of deeply invasive candidiasis and as salvage therapy for patients with invasive aspergillosis who are failing or intolerant of approved drugs, such as amphotericin B formulations or voriconazole. Approval for salvage therapy of aspergillosis was based on a study of 63 patients in a noncomparative salvage trial. Caspofungin is also approved for esophageal candidiasis, based on randomized trials that found noninferiority to fluconazole and C-AMB (Villanueva et al., 2001). A blinded randomized clinical trial of caspofungin in deeply invasive candidiasis found noninferiority to C-AMB, leading to approval for that indication (Mora-Duarte et al., 2002). Most patients in that multicenter study were not neutropenic and had catheter-acquired candidemia. Efficacy was comparable to that of fluconazole in other studies of the same general patient population. Caspofungin is also approved for the treatment of persistently febrile neutropenic patients with suspected fungal infections, based on noninferiority to L-AMB in a randomized trial (Walsh et al., 2004b).

Untoward Effects. Caspofungin has been remarkably well tolerated, with the exception of phlebitis at the infusion site. Histamine-like effects have been reported with rapid infusions. Other symptoms have been equivalent to those observed in patients receiving fluconazole in the comparator arm.

Dosage. Caspofungin is administered intravenously once daily over 1 hour. In candidemia and salvage therapy of aspergillosis, the initial dose is 70 mg, followed by 50 mg daily. The dose should be increased to 70 mg daily in patients receiving rifampin as well as in those failing to respond to 50 mg. Esophageal candidiasis is treated with 50 mg daily. In moderate hepatic failure, the dose should be reduced to 35 mg daily.

Absorption, Distribution, and Excretion. Micafungin has linear pharmacokinetics over a large range of doses (1-3 mg/kg) and ages (premature infants to elderly). Feces contain 71% of intravenously administered radiolabeled drug, including both native drug and metabolites (Wiederhold and Lewis, 2007). Small amounts of drug are metabolized in the liver by arylsulfatase and catechol O-methyltransferase. Hydroxylation by CYP3A4 is barely detectable. Reduction of dose in moderate hepatic failure is not required. Clearance is more rapid in premature infants and intermediate in children 2-8 years of age, compared to older children and adults.

Drug Interactions. In normal volunteers, micafungin appears to be a mild inhibitor of CYP3A4, increasing AUC of nifedipine by 18% and sirolimus by 21%. Micafungin has no effect on tacrolimus clearance.

Therapeutic Use. Micafungin is approved for the treatment of deeply invasive candidiasis (Fritz et al., 2008). Doses of 100 mg and 150 mg daily of micafungin were equivalent to caspofungin (Pappas et al., 2007). Micafungin, 100 mg/day, was also not inferior to L-AMB, 3 mg/kg (Kuse et al., 2007). Micafungin is also approved for treatment of esophageal candidiasis and prophylaxis of deeply invasive candidiasis in hematopoietic stem cell transplant recipients.

Doses. Micafungin is given intravenously as 100 mg daily over 1 hour for adults, with 50 mg recommended for prophylaxis and 150 mg for esophageal candidiasis. No loading dose is needed.

Absorption, Distribution and Excretion. Anidulafungin is cleared from the body by slow chemical degradation, first by opening the hexapeptide ring and then proteolysis of peptide bonds (Vazquez and Sobel, 2006). No metabolism by the liver or renal excretion of active drug occurs. No dose adjustment for hepatic or renal failure is needed. The drug diluent for intravenous infusion contains 3 mg ethanol for every 50 mg anidulafungin, an amount of ethanol insufficient to have a pharmacological effect.

Drug interactions. None are known.

Therapeutic Use. In a randomized double-blinded clinical trial, anidulafungin was noninferior to fluconazole in candidemia of non-neutropenic patients (Reboli et al., 2007). Anidulafungin is also approved for the treatment of esophageal candidiasis.

Dose. Drug dissolved in the supplied diluent is infused once daily in saline or 5% dextrose in water at a rate not exceeding 1.1 mg/minute. For deeply invasive candidiasis, anidulafungin is given daily as a loading dose of 200 mg followed by 100 mg daily. For esophageal candidiasis, a loading dose of 100 mg is followed by 50 mg daily.

Mechanism of Action. Griseofulvin inhibits microtubule function and thereby disrupts assembly of the mitotic spindle. Thus, a prominent morphological manifestation of the action of griseofulvin is the production of multinucleate cells as the drug inhibits fungal mitosis. Although the effects of the drug are similar to those of colchicine and the vinca alkaloids, griseofulvin's binding sites on the microtubular protein are distinct. In addition to its binding to tubulin, griseofulvin interacts with microtubule-associated protein.

Absorption, Distribution, and Excretion. The oral administration of a 0.5 g dose of griseofulvin produces peak plasma concentrations of ~1 μg/mL in ~4 hours. Blood levels are quite variable, however. Some studies have shown improved absorption when the drug is taken with a fatty meal. Because the rates of dissolution and disaggregation limit the bioavailability of griseofulvin, micro-sized and ultra-micro-sized powders are now used in preparations (grifulvin v and gris-peg, respectively). Although the bioavailability of the ultra-microcrystalline preparation is said to be 50% greater than that of the conventional micro-sized powder, this may not always be true. Griseofulvin has a plasma t_1/2 of ~1 day, and ~50% of the oral dose can be detected in the urine within 5 days, mostly in the form of metabolites. The primary metabolite is 6-methylgriseofulvin. Barbiturates decrease griseofulvin absorption from the GI tract.

Griseofulvin is deposited in keratin precursor cells; when these cells differentiate, the drug is tightly bound to, and persists in, keratin, providing prolonged resistance to fungal invasion. For this reason, the new growth of hair or nails is the first to become free of disease. As the fungus-containing keratin is shed, it is replaced by normal tissue. Griseofulvin is detectable in the stratum corneum of the skin within 4-8 hours of oral administration. Sweat and transepidermal fluid loss play an important role in the transfer of the drug in the stratum corneum. Only a very small fraction of a dose of the drug is present in body fluids and tissues.

Antifungal Activity. Griseofulvin is fungistatic in vitro for various species of the dermatophytes Microsporum, Epidermophyton, and Trichophyton. The drug has no effect on bacteria or on other fungi. Although failure of ringworm lesions to improve is not rare, isolates from these patients usually are still susceptible to griseofulvin in vitro.

Therapeutic Uses. Mycotic disease of the skin, hair, and nails due to Microsporum, Trichophyton, or Epidermophyton responds to griseofulvin therapy. For tinea capitis in children, griseofulvin remains the drug of choice for efficacy, safety, and availability as an oral suspension; efficacy is best for tinea capitis caused by Microsporum canis, Microsporum audouinii, Trichophyton schoenleinii, and Trichophyton verrucosum. Griseofulvin is also effective for ringworm of the glabrous skin; tinea cruris and tinea corporis caused by M. canis, Trichophyton rubrum, T. verrucosum, and Epidermophyton floccosum; and tinea of the hands (T. rubrum and T. mentagrophytes) and beard (Trichophyton species). Griseofulvin also is highly effective in tinea pedis, the vesicular form of which is most commonly due to T. mentagrophytes and the hyperkeratotic type to T. rubrum. Topical therapy is sufficient for most cases of tinea pedis. T. rubrum and T. mentagrophytes infections may require higher-than-conventional doses of griseofulvin.

Dosage. The recommended daily dose of griseofulvin is 2.3 mg/kg (up to 500 mg) for children and 500 mg to 1 g for adults. Doses of 1.5-2 g daily may be used for short periods in severe or extensive infections. Best results are obtained when the daily dose is divided and given at 6-hour intervals, although the drug often is given once or twice per day. Treatment must be continued until infected tissue is replaced by normal hair, skin, or nails, which requires 1 month for scalp and hair ringworm, 6-9 months for fingernails, and at least a year for toenails. Itraconazole or terbinafine is much more effective for onychomycosis.

Untoward Effects. The incidence of serious reactions due to griseofulvin is very low. One of the minor effects is headache (incidence as high as 15%), which is sometimes severe and usually disappears as therapy is continued. Other nervous system manifestations include peripheral neuritis, lethargy, mental confusion, impairment of performance of routine tasks, fatigue, syncope, vertigo, blurred vision, transient macular edema, and augmentation of the effects of alcohol. Among the side effects involving the alimentary tract are nausea, vomiting, diarrhea, heartburn, flatulence, dry mouth, and angular stomatitis. Hepatotoxicity also has been observed. Hematological effects include leukopenia, neutropenia, punctate basophilia, and monocytosis; these often disappear despite continued therapy. Blood studies should be carried out at least once a week during the first month of treatment or longer. Common renal effects include albuminuria and cylindruria without evidence of renal insufficiency. Reactions involving the skin are cold and warm urticaria, photosensitivity, lichen planus, erythema, erythema multiforme–like rashes, and vesicular and morbilliform eruptions. Serum sickness syndromes and severe angioedema develop rarely during treatment with griseofulvin. Estrogen-like effects have been observed in children. A moderate but inconsistent increase of fecal protoporphyrins has been noted with chronic use.

Griseofulvin induces hepatic CYPs, thereby increasing the rate of metabolism of warfarin; adjustment of the dosage of the latter agent may be necessary in some patients. The drug may reduce the efficacy of low-estrogen oral contraceptive agents, probably by a similar mechanism.

Terbinafine is well absorbed, but bioavailability is decreased to ~40% because of first-pass metabolism in the liver. Proteins bind >99% of the drug in plasma. Drug accumulates in skin, nails, and fat. The initial t_1/2 is ~12 hours but extends to 200-400 hours at steady state. Terbinafine is not recommended in patients with marked azotemia or hepatic failure because in the latter condition, terbinafine plasma levels are increased by unpredictable amounts. Rifampin decreases and cimetidine increases plasma terbinafine concentrations. The drug is well tolerated, with a low incidence of GI distress, headache, or rash. Very rarely, fatal hepatotoxicity, severe neutropenia, Stevens-Johnson syndrome, or toxic epidermal necrolysis may occur. The drug is pregnancy Category B and it is recommended that systemic terbinafine therapy for onychomycosis be postponed until after pregnancy is complete. Its mechanism of action is inhibition of fungal squalene epoxidase, blocking ergosterol biosynthesis. Increased intracellular squalene also impairs cell growth.

Terbinafine (lamisil, others), given as one 250-mg tablet daily for adults, is somewhat more effective for nail onychomycosis than 200 mg daily of itraconazole, and definitely more effective than pulse itraconazole therapy (Fernandez-Obregon et al., 2007). Duration of treatment varies with the site being treated but typically is 6-12 weeks. Efficacy in onychomycosis can be improved by the simultaneous use of amorolfine 5% nail lacquer (Baran et al., 2007). Terbinafine (250 mg daily) also is effective in tinea capitis and is used off-label for ringworm elsewhere on the body. Oral granules are available for use against tinea capitis, usually a disease of children. The recommended dose is 125-250 mg (depending on weight) daily for 6 weeks. The topical use of terbinafine is discussed later.

Among the topical agents, the preferred formulation for cutaneous application usually is a cream or solution. Ointments are messy and are too occlusive for macerated or fissured intertriginous lesions. The use of powders, whether applied by shake containers or aerosols, is largely confined to the feet and moist lesions of the groin and other intertriginous areas.

The systemic agents used for the treatment of superficial mycoses were discussed earlier. Some of these agents also are administered topically; their uses are described here and also in Chapter 65.

Imidazoles and Triazoles for Topical Use. These closely related classes of drugs are synthetic antifungal agents that are used both topically and systemically. Indications for their topical use include ringworm, tinea versicolor, and mucocutaneous candidiasis. Resistance to imidazoles or triazoles is very rare among the fungi that cause ringworm. Selection of one of these agents for topical use should be based on cost and availability because testing in vitro for fungal susceptibility to these drugs does not predict clinical responses.

Cutaneous Application. The preparations for cutaneous use described below are effective for tinea corporis, tinea pedis, tinea cruris, tinea versicolor, and cutaneous candidiasis. They should be applied twice a day for 3-6 weeks. Despite some activity in vitro against bacteria, this effect is not clinically useful. The cutaneous formulations are not suitable for oral, vaginal, or ocular use.

Vaginal Application. Vaginal creams, suppositories, and tablets for vaginal candidiasis are all used once a day for 1-7 days, preferably at bedtime to facilitate retention. None is useful in trichomoniasis, despite some activity in vitro. Most vaginal creams are administered in 5-g amounts. Three vaginal formulations—clotrimazole tablets, miconazole suppositories, and terconazole cream—come in both low- and high-dose preparations. A shorter duration of therapy is recommended for the higher dose of each. These preparations are administered for 3-7 days. Approximately 3-10% of the vaginal dose is absorbed. Although some imidazoles are teratogenic in rodents, no adverse effects on the human fetus have been attributed to the vaginal use of imidazoles or triazoles. The most common side effect is vaginal burning or itching. A male sexual partner may experience mild penile irritation. Cross-allergenicity among these compounds is assumed to exist, based on their structural similarities.

Oral Use. Use of the oral troche of clotrimazole is properly considered as topical therapy. The only indication for this 10-mg troche is oropharyngeal candidiasis. Antifungal activity is due entirely to the local concentration of the drug; there is no systemic effect.

Absorption of clotrimazole is <0.5% after application to the intact skin; from the vagina, it is 3-10%. Fungicidal concentrations remain in the vagina for as long as 3 days after application of the drug. The small amount absorbed is metabolized in the liver and excreted in bile. In adults, an oral dose of 200 mg/day will give rise initially to plasma concentrations of 0.2-0.35 μg/mL, followed by a progressive decline.

In a small fraction of recipients, clotrimazole on the skin may cause stinging, erythema, edema, vesication, desquamation, pruritus, and urticaria. When it is applied to the vagina, ~1.6% of recipients complain of a mild burning sensation, and rarely of lower abdominal cramps, a slight increase in urinary frequency, or skin rash. Occasionally, the sexual partner may experience penile or urethral irritation. By the oral route, clotrimazole can cause GI irritation. In patients using troches, the incidence of this side effect is ~5%.

Therapeutic Uses. Clotrimazole is available as a 1% cream, lotion, powder, aerosol solution, and solution (lotrimin af, mycelex, others), 1% or 2% vaginal cream, or vaginal tablets of 100, 200, or 500 mg (gyne-lotrimin, others), and 10-mg troches (mycelex, others). On the skin, applications are made twice a day. For the vagina, the standard regimens are one 100-mg tablet once a day at bedtime for 7 days, one 200-mg tablet daily for 3 days, one 500-mg tablet inserted only once, or 5 g of cream once a day for 3 days (2% cream) or 7 days (1% cream). For oropharyngeal candidiasis, troches are to be dissolved slowly in the mouth five times a day for 14 days.

Topical clotrimazole cures dermatophyte infections in 60-100% of cases. The cure rates in cutaneous candidiasis are 80-100%. In vulvovaginal candidiasis, the cure rate is usually >80% when the 7-day regimen is used. A 3-day regimen of 200 mg once a day appears to be similarly effective, as does single-dose treatment (500 mg). Recurrences are common after all regimens. The cure rate with oral troches for oral and pharyngeal candidiasis may be as high as 100% in the immunocompetent host.

Econazole is the deschloro derivative of miconazole. Econazole readily penetrates the stratum corneum and is found in effective concentrations down to the mid-dermis. However, <1% of an applied dose appears to be absorbed into the blood. Approximately 3% of recipients have local erythema, burning, stinging, or itching. Econazole nitrate (spectazole, ecostatin, others) is available as a water-miscible cream (1%) to be applied twice a day.

Miconazole readily penetrates the stratum corneum of the skin and persists there for >4 days after application. Less than 1% is absorbed into the blood. Absorption is no more than 1.3% from the vagina.

Adverse effects from topical application to the vagina include burning, itching, or irritation in ~7% of recipients, and infrequently, pelvic cramps (0.2%), headache, hives, or skin rash. Irritation, burning, and maceration are rare after cutaneous application. Miconazole is considered safe for use during pregnancy, although some authors avoid its vaginal use during the first trimester.

Therapeutic Uses. Miconazole nitrate is available as a 2% cream, ointment, lotion, powder, gel, aerosol powder, and aerosol solution (micatin, zeasorb-af, others). To avoid maceration, only the lotion should be applied to intertriginous areas. Miconazole is available as a 2% and 4% vaginal cream, and as 100-mg, 200-mg, or 1200-mg vaginal suppositories (monistat 7, monistat 3, monistat 1, others), to be applied high in the vagina at bedtime for 7, 3, or 1 day(s), respectively.

In the treatment of tinea pedis, tinea cruris, and tinea versicolor, the cure rate may be >90%. In the treatment of vulvovaginal candidiasis, the mycologic cure rate at the end of 1 month is ~80-95%. Pruritus sometimes is relieved after a single application. Some vaginal infections caused by Candida glabrata also respond.

Terconazole (terazol, others) is a ketal triazole. The mechanism of action of terconazole is similar to that of the imidazoles. The 80-mg vaginal suppository is inserted at bedtime for 3 days; the 0.4% vaginal cream is used for 7 days and the 0.8% cream for 3 days. Clinical efficacy and patient acceptance of both preparations are at least as good as for clotrimazole in patients with vaginal candidiasis.

Butoconazole is an imidazole that is pharmacologically quite comparable to clotrimazole. Butoconazole nitrate (femstat 3, others) is available as a 2% vaginal cream; it is used at bedtime in nonpregnant females. Because of the slower response during pregnancy, a 6-day course is recommended (during the second and third trimester).

Tioconazole (vagistat 1, others) is an imidazole marketed for treatment of Candida vulvovaginitis. A single 4.6-g dose of ointment (300 mg) is given at bedtime.

Oxiconazole, Sulconazole, and Sertaconazole.

These imidazole derivatives are used for the topical treatment of infections caused by the common pathogenic dermatophytes. Oxiconazole nitrate (oxistat) is available as a 1% cream and lotion; sulconazole nitrate (exelderm, sulcosyn) is supplied as a 1% solution and/or cream. Sertaconazole (ertaczo) is a 2% cream marketed for tinea pedis.

Ketoconazole.

This imidazole is available as a 0.5% cream, foam, gel, and shampoo (nizoral, others) for common skin dermatophytes infections, for tinea versicolor, and seborrheic dermatitis.

Ciclopirox olamine (loprox, others) has broad-spectrum antifungal activity. It is fungicidal to C. albicans, E. floccosum, M. canis, T. mentagrophytes, and T. rubrum. It also inhibits the growth of Malassezia furfur. After application to the skin, it penetrates through the epidermis into the dermis, but even under occlusion, <1.5% is absorbed into the systemic circulation. Because the t_1/2 is 1.7 hours, no systemic accumulation occurs. The drug penetrates into hair follicles and sebaceous glands. It can sometimes cause hypersensitivity. It is available as a 0.77% cream, gel, suspension, and lotion for the treatment of cutaneous candidiasis and for tinea corporis, cruris, pedis, and versicolor. An 8% nail lacquer is available for onychomycosis. Cure rates in the dermatomycoses and candidal infections are 81-94%. No topical toxicity has been noted.

Ciclopirox 0.77% gel and 1% shampoo are also used for the treatment of seborrheic dermatitis of the scalp. An 8% topical solution (penlac nail lacquer, others) is an effective treatment for mild to moderate superficial white onychomycosis. An oral agent would be preferred for distal or lateral onychomycosis.

Haloprogin is a halogenated phenolic ether:

It is fungicidal to various species of Epidermophyton, Pityrosporum, Microsporum, Trichophyton, and Candida. During treatment with this drug, irritation, pruritus, burning sensations, vesiculation, increased maceration, and "sensitization" (or exacerbation of the lesion) occasionally occur, especially on the foot if occlusive footgear is worn. Haloprogin is poorly absorbed through the skin; it is converted to trichlorophenol in the body. The systemic toxicity from topical application appears to be low.

Haloprogin (halotex) cream or solution is applied twice a day for 2-4 weeks. Its principal use is against tinea pedis, for which the cure rate is ~80%; it is thus approximately equal in efficacy to tolnaftate. It also is used against tinea cruris, tinea corporis, tinea manuum, and tinea versicolor. Haloprogin is no longer available in the U.S.

Tolnaftate is a thiocarbamate with the following structure:

Tolnaftate is effective in the treatment of most cutaneous mycoses caused by T. rubrum, T. mentagrophytes, T. tonsurans, E. floccosum, M. canis, M. audouinii, Microsporum gypseum, and M. furfur, but it is ineffective against Candida. In tinea pedis, the cure rate is ~80%, compared with ~95% for miconazole. Toxic or allergic reactions to tolnaftate have not been reported.

Tolnaftate (aftate, tinactin, others) is available in a 1% concentration as a cream, gel, powder, aerosol powder, and topical solution, or as a topical aerosol liquid. The preparations are applied locally twice a day. Pruritus is usually relieved in 24-72 hours. Involution of interdigital lesions caused by susceptible fungi is very often complete in 7-21 days.

Naftifine is representative of the allylamine class of synthetic agents that inhibit squalene-2,3-epoxidase and thus inhibit fungal biosynthesis of ergosterol. The drug has broad-spectrum fungicidal activity in vitro. Naftifine hydrochloride (naftin) is available as a 1% cream or gel. It is effective for the topical treatment of tinea cruris and tinea corporis; twice-daily application is recommended. The drug is well tolerated, although local irritation has been observed in 3% of treated patients. Allergic contact dermatitis also has been reported. Naftifine also may be efficacious for cutaneous candidiasis and tinea versicolor, although the drug is not approved for these uses.

Terbinafine 1% cream or spray is applied twice daily and is effective in tinea corporis, tinea cruris, and tinea pedis. Terbinafine is less active against Candida species and Malassezia furfur, but the cream also can be used in cutaneous candidiasis and tinea versicolor. The systemic use of terbinafine was discussed earlier.

Butenafine hydrochloride (mentax, lotrimin ultra) is a benzylamine derivative with a mechanism of action similar to that of terbinafine and naftifine. Its spectrum of antifungal activity and use also are similar to those of the allylamines.

Polyene Antifungal Antibiotics

Nystatin. Nystatin was discovered in the New York State Health Laboratory and was named accordingly; it is a tetraene macrolide produced by Streptomyces noursei, is structurally similar to amphotericin B, and has the same mechanism of action. The drug is not absorbed from the GI tract, skin, or vagina. A liposomal formulation (nyotran) is in clinical trials for candidemia.

Nystatin (mycostatin, nilstat, others) is useful only for candidiasis and is supplied in preparations intended for cutaneous, vaginal, or oral administration for this purpose. Infections of the nails and hyperkeratinized or crusted skin lesions do not respond. Powders are preferred for moist lesions and are applied two to three times daily. Creams or ointments are used twice daily. Combinations of nystatin with antibacterial agents or corticosteroids also are available. Allergic reactions to nystatin are very uncommon. Although vaginal tablets of nystatin are well tolerated, imidazoles or triazoles are more effective agents than nystatin for vaginal candidiasis.

Nystatin suspension is usually effective for oral candidiasis of the immunocompetent host. Patients should be instructed to swish the drug around in the mouth and then swallow; otherwise, the patient may expectorate the bitter liquid and fail to treat the infected mucosa in the posterior pharynx or esophagus. Other than the bitter taste and occasional complaints of nausea, adverse effects are uncommon.

Miscellaneous Antifungal Agents

Undecylenic Acid. Undecylenic acid is 10-undecenoic acid, an 11-carbon unsaturated compound. It is a yellow liquid with a characteristic rancid odor. It is primarily fungistatic, although fungicidal activity may be observed with long exposure to high concentrations of the agent. The drug is active against a variety of fungi, including those that cause ringworm. Undecylenic acid (desenex, others) is available in a cream, powder, spray powder, soap, and liquid. Zinc undecylenate is marketed in combination with other ingredients. The zinc provides an astringent action that aids in the suppression of inflammation. Compound undecylenic acid ointment contains both undecylenic acid (~5%) and zinc undecylenate (~20%). Calcium undecylenate (caldesene, cruex) is available as a powder.

Undecylenic acid preparations are used in the treatment of various dermatomycoses, especially tinea pedis. Concentrations of the acid as high as 10%, as well as those of the acid and salt in the compound ointment, may be applied to the skin. The preparations as formulated are usually not irritating to tissue, and sensitization to them is uncommon. It is of undoubted benefit in retarding fungal growth in tinea pedis, but the infection frequently persists despite intensive treatment with preparations of the acid and the zinc salt. At best, the clinical "cure" rate is ~50%, which is much lower than that obtained with the imidazoles, haloprogin, or tolnaftate. Efficacy in the treatment of tinea capitis is marginal, and the drug is no longer used for that purpose. Undecylenic acid preparations also are approved for use in the treatment of diaper rash, tinea cruris, and other minor dermatologic conditions.

Benzoic Acid and Salicylic Acid. An ointment containing benzoic and salicylic acids is known as Whitfield's ointment. It combines the fungistatic action of benzoate with the keratolytic action of salicylate. It contains benzoic acid and salicylic acid in a ratio of 2:1 (usually 6-3%) and is used mainly in the treatment of tinea pedis. Because benzoic acid is only fungistatic, eradication of the infection occurs only after the infected stratum corneum is shed, and continuous medication is required for several weeks to months. The salicylic acid accelerates the desquamation. The ointment also is sometimes used to treat tinea capitis. Mild irritation may occur at the site of application.