Goodman and Gilman Manual of Pharmacology and Therapeutics
Chemotherapy of Microbial Diseases
There are 200,000 known species of fungi, and estimates of the total size of Kingdom Fungi range to well over a million. Residents of the kingdom are quite diverse and include yeasts, molds, mushrooms, smuts, the pathogens Aspergillus fumigatus and Candida albicans, and the source of penicillin, Penicillium chrysogenum. Fortunately, only ~400 fungi cause disease in animals, and even fewer cause significant human disease. However, fungal infections are becoming more common in patients with compromised immune systems. Fungi are eukaryotes with unique cell walls containing glucans and chitin, and their eradication requires different strategies than those for treatment of bacterial infections. Available agents have effects on the synthesis of membrane and cell-wall components, on membrane permeability, on the synthesis of nucleic acids, and on microtubule/mitotic spindle function (Figure 57–1). Antifungal agents described in this chapter are discussed under two major headings, systemic and topical, although this distinction is somewhat arbitrary. The imidazole, triazole, and polyene antifungal agents may be used either systemically or topically, and many superficial mycoses can be treated either systemically or topically. Table 57–1 summarizes common mycoses and their pharmacotherapy.
Figure 57–1 Sites of action of antifungal drugs. Amphotericin B and other polyenes (e.g., nystatin) bind to ergosterol in fungal cell membranes and increase membrane permeability. The imidazoles and triazoles (itraconazole, et al.) inhibit 14-α-sterol demethylase, prevent ergosterol synthesis, and lead to the accumulation of 14-α-methylsterols. The allylamines (e.g., naftifine and terbinafine) inhibit squalene epoxidase and prevent ergosterol synthesis. The echinocandins, such as caspofungin, inhibit the formation of glucans in the fungal cell wall.
Pharmacotherapy of Mycoses
SYSTEMIC ANTIFUNGAL AGENTS
DRUGS FOR DEEPLY INVASIVE FUNGAL INFECTIONS
AMPHOTERICIN B. Amphotericin B is an amphoteric polyene macrolide with broad spectrum antifungal activity.
MECHANISM OF ACTION. Amphotericin B has useful clinical activity against a broad range of pathogenic fungi and limited activity against the protozoa Leishmania spp. and Naegleria fowleri. 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 (see Figure 57–1).
FORMULATIONS. Table 57–2 summarizes the pharmacokinetic properties of the 4 available 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.
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.
ABLC (ABELCET). Amphotericin B lipid complex is a complex of amphotericin B with lipids (dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol).
The 3 lipid formulations collectively appear to reduce the risk of the patient’s serum creatinine doubling during therapy by 58%. However, the cost of the lipid formulations greatly exceeds that of C-AMB, making them unavailable in many countries.
ADME. GI absorption of all amphotericin B formulations is negligible and IV delivery is indicated for systemic use. Amphotericin B in plasma is more than 90% bound to proteins. Pharmacokinetic parameters vary with the formulation. 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; FUNGAL RESISTANCE. 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 protozoaLeishmania spp. and N. fowleri. The drug has no antibacterial activity. 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.
THERAPEUTIC USES. The recommended doses for each formulation are summarized in Table 57–2. 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.
Pharmocokinetic Parameters for Amphotericin B Formulations after Multiple Administrations in Humans
UNTOWARD EFFECTS. The major acute reactions to intravenous amphotericin B formulations are fever and chills. Infusion-related reactions are worst with ABCD 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 min; meperidine may shorten it. Pretreatment with oral acetaminophen or use of intravenous glucocorticoids at the start of the infusion decreases reactions.
Azotemia occurs in 80% of patients who receive C-AMB for deep mycoses. 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. 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, often requiring repletion. 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.
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 and often responds to administration of recombinant erythropoietin. Headache, nausea, vomiting, malaise, weight loss, and phlebitis at peripheral infusion sites are common. Arachnoiditis has been observed as a complication of injecting C-AMB into the CSF.
Flucytosine (5-fluorocytosine) has a spectrum of antifungal activity that is considerably more restricted than that of amphotericin B.
MECHANISM OF ACTION. All susceptible fungi are capable of deaminating flucytosine to 5-fluorouracil (5-FU) (Figure 57–2), a potent antimetabolite that is used in cancer chemotherapy (see Chapter 61). Fluorouracil is metabolized first to 5-fluorouracil-ribose monophosphate (5-FUMP) by the enzyme uracil phosphoribosyl transferase (UPRTase). 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 and thus of DNA synthesis. The selective action of flucytosine is due to the lack of cytosine deaminase in mammalian cells, which prevents metabolism to fluorouracil.
Figure 57–2 Action of flucytosine in fungi. Flucytosine (5-fluorocytosine) is transported by cytosine permease into the fungal cell, where it is deaminated to 5-fluorouracil (5-FU). The 5-FU is converted to 5-fluorouracil-ribose monophosphate (5-FUMP) and then is either converted to 5-fluorouridine triphosphate (5-FUTP) and incorporated into RNA or converted to 5-fluoro-2′-deoxyuridine-5′-monophosphate (5-FdUMP), a potent inhibitor of thymidylate synthase. 5-FUDP, 5-fluorouridine-5′-diphosphate; dUMP, deoxyuridine-5′-monophosphate; dTMP, deoxythymidine-5′-monophosphate; PRT, phosphoribosyltransferase.
ANTIFUNGAL ACTIVITY. Flucytosine has clinically useful activity against C. neoformans, Candida spp., and the agents of chromoblastomycosis.
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. The mechanism for this resistance can be loss of the permease necessary for cytosine transport or decreased activity of either UPRTase or cytosine deaminase (see Figure 57–2).
ADME. Flucytosine is absorbed rapidly and well from the GI tract and widely distributed in the body. Approximately 80% of a given dose is excreted unchanged in the urine. The t1/2 of the drug is 3-6 h but may reach 200 h in renal failure. 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 (desirable range of peak concentrations, 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.
THERAPEUTIC USES. Flucytosine (ANCOBON) is given orally at 50-150 mg/kg/day, in 4 divided doses at 6-h intervals. Flucytosine is used predominantly in combination with amphotericin B. 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. 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. The guidelines for the treatment of cryptococcal meningoencephalitis recommend addition of flucytosine (100 mg/kg orally in 4 divided doses) for the first 2 weeks of treatment with amphotericin B in AIDS patients.
Untoward Effects. Flucytosine may depress the bone marrow and lead to leukopenia. Other untoward effects include rash, nausea, vomiting, diarrhea, and severe enterocolitis. 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 and when plasma drug concentrations exceed 100 μ/mL.
IMIDAZOLES AND TRIAZOLES
The azole antifungals include two broad classes, imidazoles and triazoles. Of the drugs now on the market in the U.S., clotrimazole, miconazole, ketoconazole, econazole, butoconazole, oxiconazole, sertaconazole, and sulconazole are imidazoles; terconazole, itraconazole, fluconazole, voriconazole, and posaconazole are triazoles. The topical use of azole antifungals is described in the second section of this chapter.
MECHANISM OF ACTION. The major effect of imidazoles and triazoles on fungi is inhibition of 14-α-sterol demethylase, a microsomal CYP (see 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.
ANTIFUNGAL ACTIVITY. Azoles as a group have clinically useful activity against C. albicans, Candida tropicalis, Candida parapsilosis, Candida glabrata, C. neoformans, B. dermatitidis, H. capsulatum, Coccidioides spp., Paracoccidioides brasiliensis, and ringworm fungi (dermatophytes). Aspergillus spp., Scedosporium apiospermum (Pseudallescheria boydii), Fusarium, and S. schenckii are intermediate in susceptibility. Candida krusei and the agents of mucormycosis are more resistant. These drugs have 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-,-sterol demethylase; cross-resistance is conferred to all azoles.
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 coadministered drugs (Table 57–4). Other coadministered 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).
Interaction of Azole Antifungal Agents with Hepatic CYPs
Drugs Exhibiting Elevated Plasma Concentrations When Co-Administered with Azole Anti-Fungal Agents
Some Agents that Decrease Triazole Concentration
Some Additional Contraindicated Azole Drug Combinations
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. Ketoconazole sometimes is used to inhibit excessive production of glucocorticoids in patients with Cushing syndrome (see Chapter 42) and is available for topical use.
Itraconazole lacks ketoconazole’s corticosteroid suppression while retaining most of ketoconazole’s pharmacological properties and expanding the antifungal spectrum. This synthetic triazole is an equimolar racemic mixture of 4 diastereoisomers.
ADME. 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. The native drug and metabolite are >99% bound to plasma proteins. Neither appears in urine or CSF. The t1/2 of itraconazole at steady state is ~30-40 h. 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.
DRUG INTERACTIONS. Tables 57–4, 57–5, and 57–6 list select interactions of azoles with other drugs.
THERAPEUTIC USES. Itraconazole is the drug of choice for patients with indolent, nonmeningeal infections due to B. dermatitidis, H. capsulatum, P. brasiliensis, and Coccidioides 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. 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 P. marneffei infections have a decreased incidence of relapse if given prolonged itraconazole “maintenance” therapy (see 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. 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.
Dosage. In treating deep mycoses, a loading dose of 200 mg of itraconazole is administered 3 times daily for the first 3 days. After the loading doses, two 100-mg capsules are given twice daily with food. Divided doses may increase the AUC. 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, 2 monthly cycles consisting of 200 mg twice daily for 1 week followed by a 3-week period of no therapy—so-called pulse therapy. Once-daily terbinafine (250 mg) 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.
UNTOWARD EFFECTS; PRECAUTIONS. Adverse effects of itraconazole therapy can occur as a result of interactions with many other drugs (see Tables 57–3 and 57–4). Serious hepatotoxicity has rarely led to hepatic failure and death. 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. Diarrhea, abdominal cramps, anorexia, and nausea are more common with the suspension than with the capsules. In patients receiving 50-400 mg of the capsules per day, nausea and vomiting, hypertriglyceridemia, hypokalemia, increased serum aminotransferase, and rash occurred in 2-10% of patients. 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 1 case, rhabdomyolysis. Doses >400 mg/day are not recommended for long-term use. Anaphylaxis has been observed rarely, as well as severe rash, including Stevens-Johnson syndrome. Itraconazole is pregnancy Category C and is contraindicated for the treatment of onychomycosis during pregnancy or for women contemplating pregnancy.
ADME. Fluconazole is almost completely absorbed from the GI tract. Plasma concentrations are essentially the same whether the drug is given orally or intravenously; its bioavailability is unaltered by food or gastric acidity. Renal excretion accounts for >90% of elimination; the elimination t1/2 ~25-30 h. Fluconazole diffuses readily into body fluids, including breast milk, sputum, and saliva; concentrations in CSF can reach 50-90% of the values in plasma. The dosage interval should be increased in renal insufficiency. A dose of 100-200 mg should be given after each hemodialysis.
DRUG INTERACTIONS. Fluconazole is an inhibitor of CYP3A4 and CYP2C9 (see 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.
Candidiasis. Fluconazole, 200 mg on day 1 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 non-immunosuppressed patients. The drug has been used successfully as empirical treatment of febrile neutropenia in patients not responding to antibacterial agents and who are not at high risk of mold infections. 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, Candida krusei would not be expected to respond to fluconazole or other azoles.
Cryptococcosis. 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. 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 intrathecal amphotericin B. In other forms of coccidioidomycosis, fluconazole is comparable to itraconazole. Fluconazole has no useful activity against histoplasmosis, blastomycosis, or sporotrichosis and is not effective in the prevention or treatment of aspergillosis. Fluconazole has no activity in mucormycosis.
UNTOWARD EFFECTS. Side effects in patients receiving >7 days of drug, regardless of dose, include nausea, headache, skin rash, vomiting, abdominal pain, and diarrhea (all in the range of 2-4%). 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 has been associated with skeletal and cardiac deformities in several infants born to women taking high doses during pregnancy. Fluconazole is a Category C agent that should be avoided during pregnancy.
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. 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 an expanded spectrum and poor aqueous solubility.
ADME. Oral bioavailability is 96%. Volume of distribution is high (4.6 L/kg), with extensive drug distribution in tissues. Metabolism occurs through CYPs 2C19 and 2C9; CYP3A4 plays a limited role. Plasma elimination t1/2 is 6 h. 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: ~20% of Asians are homozygous poor metabolizers, compared with 2% of whites and African Americans. Less than 2% of parent drug is recovered from urine; 80% of the inactive metabolites are excreted in the urine. The oral dose does not have to be adjusted for azotemia or hemodialysis. Patients with mild-to-moderate cirrhosis should receive the same loading dose of voriconazole but half the maintenance dose. The intravenous formulation of voriconazole contains sulfobutyl ether β-cyclodextrin (SBECD), which is excreted by the kidney. Significant accumulation of SBECD occurs with a creatinine clearance <50 mL/min; in that setting, oral voriconazole is preferred.
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. Voriconazole and its major metabolite can increase the plasma concentrations of other drugs metabolized by these enzymes (see Tables 57–3, 57–4, and 57–5). Because the sirolimus AUC increases 11-fold when voriconazole is given, coadministration is contraindicated. When starting voriconazole in a patient receiving ≥40 mg/day of omeprazole, reduce the dose of omeprazole by half.
THERAPEUTIC USES. Voriconazole provided superior efficiency to C-AMB in the primary therapy of invasive aspergillosis. Although not approved, voriconazole has been used in the empirical therapy of neutropenic patients whose fever did not respond to >96 h of antibacterial therapy. Voriconazole is approved for use in esophageal candidiasis. Voriconazole is approved for initial treatment of candidemia and invasive aspergillosis, as well as for salvage therapy in patients with P. boydii (S. 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 is contraindicated in pregnancy (Category D). Although voriconazole is generally well-tolerated, occasional cases of hepatotoxicity have been reported; liver function should be monitored. Voriconazole can prolong the QTc interval, which can become significant in patients with other risk factors for torsade de pointes. Transient visual or auditory hallucinations are frequent after the first dose, usually at night and particularly with intravenous administration; symptoms diminish with time. Patients receiving their first intravenous infusion have had anaphylactoid reactions requiring drug discontinuation. Rash occurs in 6% of patients.
DOSAGE. Treatment is usually initiated with an intravenous infusion of 6 mg/kg every 12 h for two doses, followed by 3-4 mg/kg every 12 h, administered no faster than 3 mg/kg/h. As the patient improves, oral administration is continued as 200 mg every 12 h. Patients failing to respond may be given 300 mg every 12 h. Because high-fat meals reduce voriconazole bioavailability, oral drug should be given either 1 h before or 1 h after meals.
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. As for other imidazoles, the mechanism of action is inhibition of sterol 14-α demethylase.
ADME. Bioavailability is variable and significantly enhanced by the presence of food. The drug has a long t1/2 (25-31 h), a large volume of distribution (331-1341 L), and extensive binding (>98%) to protein. Systemic exposure is 4 times higher in homozygous CYP2C19 slow metabolizers than in homozygous wild-type metabolizers. Steady-state concentrations are reached in 7-10 days when dosed 4 times daily. Hepatic impairment causes a modest increase in plasma concentrations. Almost 80% of the drug and its metabolites are excreted in the stool, with 66% as unchanged drug. The major metabolic pathway is hepatic UDP glucuronidation. Hemodialysis does not remove drug from the circulation. Gastric acid improves absorption. Drugs that reduce gastric acid (e.g., cimetidine and esomeprazole) decrease posaconazole exposure by 32-50%. Diarrhea reduces the average plasma concentration by 37%.
THERAPEUTIC USE. Posaconazole is used for treatment of oropharyngeal candidiasis, although fluconazole is preferred because of safety and cost. Posaconazole is approved for prophylaxis against candidiasis and aspergillosis in patients >13 years of age who have prolonged neutropenia or severe graft-versus-host disease (GVHD). It is approved in the E.U. as salvage therapy for aspergillosis and several other infections, as are itraconazole and voriconazole. Posaconazole is available as a flavored suspension containing 40 mg/mL. Dosage for adults and children >8 years of age is 200 mg (5 mL suspension) 3 times daily for prophylaxis. Treatment of active infection is begun at 200 mg 4 times daily and changed to 400 mg twice daily once infection has improved. All doses should be taken with a full meal.
DRUG INTERACTIONS. Posaconazole inhibits CYP3A4. Coadministration with rifabutin or phenytoin increases the plasma concentration of these drugs and decreases posaconazole exposure by 2-fold. Posaconazole is not known to prolong cardiac repolarization but should not be coadministered with drugs that are CYP3A4 substrates and prolong the QTc interval (see Tables 57–4 and 57–6).
UNTOWARD EFFECTS. Common adverse effects include nausea, vomiting, diarrhea, abdominal pain, and headache. 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 is pregnancy Category C.
DOSAGE. Dosage for adults and children >8 years of age is 200 mg (5 mL suspension) 3 times daily for prophylaxis. Treatment of active infection is begun at 200 mg 4 times daily and changed to 400 mg twice daily once infection has improved. All doses should be taken with a full meal.
Isavuconazole (BAL8557) is an investigational water-soluble prodrug of the synthetic triazole, BAL4815. The prodrug is readily cleaved by esterases in the human body to release the active triazole. In vitro activity is comparable to voriconazole. Following oral administration, the drug has a long half-life, ~100 h, and is well tolerated. Phase III trials are enrolling patients with deeply invasive candidiasis and aspergillosis.
Echinocandins inhibit formation of 1,3-β-D-glucans in the fungal cell wall, reducing its structural integrity (Figure 57–3), resulting in osmotic instability and cell death. Three echinocandins are approved for clinical use: caspofungin, micafungin, and anidulafungin. All are cyclic lipopeptides with a hexapeptide nucleus. Susceptible fungi include Candidaand Aspergillus species.
Figure 57–3 The action of echinocandins. The strength of the fungal cell wall is maintained by fibrillar polysaccharides, largely β-1,3-glucan and chitin, which bind covalently to each other and to proteins. A glucan synthase complex in the plasma membrane catalyzes the synthesis of β-1,3-glucan; the glucan is extruded into the periplasm and incorporated into the cell wall. Echinocandins inhibit the activity of the glucan synthase complex, resulting in loss of the structural integrity of the cell wall. A subunit of glucan synthase designated Fks1p is thought to be the target of the echinocandin. Mutations in Fks1p, coded by FSK1, cause resistance to echinocandins.
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. Adverse effects are minimal. All 3 agents are pregnancy Category C.
Pharmacokinetics of Echinocandins in Humans
Caspofungin acetate (CANCIDAS) is a water-soluble, semisynthetic lipopeptide.
CLINICAL PHARMACOLOGY. Catabolism is largely by hydrolysis and N-acetylation, with excretion of the metabolites in the urine and feces. Mild and moderate hepatic insufficiency increase the AUC by 55% and 76%, respectively. Caspofungin increases tacrolimus levels by 16%, which should be managed by standard monitoring. Cyclosporine slightly increases caspofungin levels. Rifampin and other drugs activating CYP3A4 can cause reduction in caspofungin levels. Caspofungin is approved for initial therapy of deeply invasive candidiasis and as salvage therapy for patients with invasive aspergillosis who are failing approved drugs, such as amphotericin B formulations or voriconazole. Caspofungin is also approved for esophageal candidiasis and for the treatment of persistently febrile neutropenic patients with suspected fungal infections. Caspofungin is 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.
Caspofungin is administered intravenously once daily over 1 h. 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.
Micafungin (MYCAMINE) is a water-soluble semisynthetic echinocandin. Micafungin has linear pharmacokinetics over a large range of doses (1-3 mg/kg) and ages. Small amounts of drug are metabolized in the liver by arylsulfatase and catechol O-methyltransferase. About 71% of both native drug and metabolites are excreted in the feces. Reduction of dose in moderate hepatic failure is not required. Clearance is more rapid in premature infants compared to older children and adults. Micafungin is a mild inhibitor of CYP3A4, increasing AUC of nifedipine by 18% and sirolimus by 21%. Micafungin has no effect on tacrolimus clearance.
The drug is approved for the treatment of deeply invasive candidiasis and esophageal candidiasis and for prophylaxis of deeply invasive candidiasis in hematopoietic stem cell transplant recipients. Micafungin is given intravenously as 100 mg daily over 1 h for adults, with 50 mg recommended for prophylaxis and 150 mg for esophageal candidiasis.
Anidulafungin (ERAXIS) is a water-insoluble semisynthetic compound extracted from the fungus A. nidulans. The drug is cleared from the body by slow chemical degradation. No metabolism by the liver or renal excretion occurs. There are no known drug interactions. Anidulafungin appears noninferior to fluconazole in candidemia of non-neutropenic patients and is approved for the treatment of esophageal candidiasis. 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/min. 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 is a practically insoluble fungistatic that inhibits microtubule function and thereby disrupts assembly of the mitotic spindle. Although the effects of the drug are similar to those of colchicine and the vinca alkaloids, griseofulvin’s binding sites on the tubulin are distinct; griseofulvin also interacts with microtubule-associated protein.
ADME. Blood levels after oral administration are quite variable. Absorption is improved 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). Griseofulvin has a plasma t1/2 of 1 day, and 150% 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 remains tightly bound to 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 h of oral administration. 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.
THERAPEUTIC USES. Mycotic disease of the skin, hair, and nails responds to griseofulvin therapy. For tinea capitis in children, griseofulvin remains the drug of choice; 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 Trichophyton mentagrophytes) and beard (Trichophyton species).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-h intervals. 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. Headache occurs in 15% of patients. Other side effects include GI and nervous system manifestations, and augmentation of the effects of alcohol. 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. 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 a synthetic allylamine, structurally similar to the topical agent naftifine (see below). It acts by inhibiting fungal squalene epoxidase, thereby reducing ergosterol biosynthesis (see Figure 57–1).
Terbinafine is well absorbed, but bioavailability is ~40% due to first-pass metabolism in the liver. The drug accumulates in skin, nails, and fat. The initial t1/2 is ~12 h but extends to 200-400 h at steady state. Terbinafine is not recommended in patients with marked azotemia or hepatic failure. 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. Terbinafine (LAMISIL, others), given as one 250-mg tablet daily for adults, is somewhat more effective for nail onychomycosis than itraconazole. 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. Terbinafine also is effective in tinea capitis and is used off-label for ringworm elsewhere on the body.
TOPICAL ANTIFUNGAL AGENTS
Topical treatment is useful in many superficial fungal infections, i.e., those confined to the stratum corneum, squamous mucosa, or cornea. Such diseases include dermatophytosis (ringworm), candidiasis, tinea versicolor, piedra, tinea nigra, and fungal keratitis.
The preferred formulation for cutaneous application usually is a cream or solution. Ointments are messy and are too occlusive. The use of powders is largely confined to the feet and moist lesions of the groin and other intertriginous areas. Topical administration of antifungal agents usually is not successful for mycoses of the nails (onychomycosis) and hair (tinea capitis) and has no place in the treatment of subcutaneous mycoses, such as sporotrichosis and chromoblastomycosis. Regardless of formulation, penetration of topical drugs into hyperkeratotic lesions often is poor. Removal of thick, infected keratin is sometimes a useful adjunct to therapy.
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.
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. 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. None is useful in trichomoniasis. 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 doses. These preparations are administered for 3-7 days. Approximately 3-10% of the vaginal dose is absorbed. No adverse effects on the human fetus have been attributed to the vaginal use of imidazoles or triazoles.
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.
CLOTRIMAZOLE. 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. 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. 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). 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 5 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% with the 7-day regimen. 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. Less than 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 recommend avoiding its use during the first trimester.
THERAPEUTIC USES. Miconazole nitrate is available as a 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 C. glabrata also respond.
TERCONAZOLE AND BUTOCONAZOLE
Terconazole (TERAZOL, others) is a ketal triazole with a mechanism of action 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 comparable to clotrimazole. Butoconazole nitrate (FEMSTAT 3, others) is available as a 2% vaginal cream. 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.
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.
STRUCTURALLY DIVERSE ANTIFUNGAL AGENTS
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 t1/2 is 1.7 h, 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% topical solution (PENLACNAIL LACQUER, others) is available for onychomycosis. Ciclopirox gel and 1% shampoo are also used for the treatment of seborrheic dermatitis of the scalp. Cure rates in the dermatomycoses and candidal infections are 81-94%. No topical toxicity has been noted.
Haloprogin is a halogenated phenolic ether. It is fungicidal to Epidermophyton, Pityrosporum, Microsporum, Trichophyton, and Candida. 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. 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. It is effective in the treatment of most cutaneous mycoses caused by T. rubrum, T. mentagrophytes, Trichophyton 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. 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. Pruritus is usually relieved in 24-72 h. Involution of interdigital lesions caused by susceptible fungi is very often complete in 7-21 days. Toxic or allergic reactions to tolnaftate have not been reported.
Naftifine, a synthetic allylamine, inhibits 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. Although not approved for these uses, naftifine may be efficacious for cutaneous candidiasis and tinea versicolor.
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 M. furfur, but the cream also can be used in cutaneous candidiasis and tinea versicolor.
Butenafine hydrochloride (MENTAX, LOTRIMIN ULTRA) is a benzylamine derivative with a mechanism of action and spectrum of activity similar to those of terbinafine, naftifine, and other allylamines.
POLYENE ANTIFUNGAL AGENTS
Nystatin, 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. 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 2 to 3 times daily. Creams or ointments are used twice daily. Combinations of nystatin with antibacterial agents or corticosteroids also are available. Imidazoles or triazoles are more effective agents than nystatin for vaginal candidiasis. Nystatin suspension is usually effective for oral candidiasis of the immunocompetent host. Other than the bitter taste and occasional complaints of nausea, adverse effects are uncommon.
MISCELLANEOUS ANTIFUNGAL AGENTS
Undecylenic acid is primarily fungistatic and 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 usually are not irritating to tissue, and sensitization to them is uncommon. In tinea pedis, the infection frequently persists despite intensive treatment and the clinical “cure” rate is ~50%, which is much lower than that obtained with the imidazoles, haloprogin, or tolnaftate. 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 (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. 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.