Chapter 232. Oral Antifungal Agents

Oral antifungal agents are widely and frequently used for the treatment of fungal infections of the skin, nails, and mucous membranes.1 This chapter summarizes the four most widely used oral antifungal agents in dermatology: (1) terbinafine, (2) itraconazole, (3) fluconazole, and (4) griseofulvin.

Terbinafine hydrochloride is a topical and oral antimycotic agent that belongs to the family of compounds known as the allylamines. Naftifine, a topical antifungal agent, also belongs to this class. All allylamine derivatives possess a tertiary allylamine, a structural component crucial for antifungal activity (Fig. 232-1).2 In vitro, terbinafine is highly active against dermatophytes but less active against molds, dimorphic fungi, and yeasts.2

Mechanism of Action

Terbinafine inhibits the enzyme squalene epoxidase in the fungal cell membrane, thereby blocking the biosynthesis of ergosterol (Fig. 232-2).3 Squalene epoxidase, a complex, microsomal noncytochrome P450 enzyme, catalyzes the first enzymatic step of ergosterol synthesis: the conversion of squalene into squalene epoxide. Consequently, terbinafine causes an abnormal intracellular accumulation of squalene and a deficiency in ergosterol.4 In-vitro accumulation of squalene accounts for the drug's fungicidal activity by weakening the cell membrane, while deficiency of ergosterol is associated with the drug's fungistatic activity, as ergosterol is a component of fungal membranes required for normal growth.4

Pharmacology

Terbinafine is well absorbed from the gastrointestinal tract, mostly in chylomicrons. The distribution half-life is 1.5 hours, and the elimination half-life is 22 hours.5 Terbinafine is highly lipophilic and keratophilic in nature and, therefore, is widely distributed upon absorption throughout skin and adipose tissue. Terbinafine is extensively biotransformed by the liver through oxidation by CYP2D6. More than 80% of the drug is excreted in urine; the rest is eliminated with feces.6

Indications

The US Food and Drug Administration has approved terbinafine tablets for the treatment of onychomycosis due to dermatophytes. Terbinafine oral granules are approved for the treatment of tinea capitis in patients over 4 years old. Terbinafine also has clinically proven efficacy for select cases of tinea corporis, tinea pedis, or tinea cruris that are widespread, severe, or resistant to topical treatment (Box 232-1).

Pediatric

For the treatment of tinea capitis in children, terbinafine oral granules may be sprinkled over food such as pudding. The dosage is based on weight, with children weighing less than 25 kg receiving 125 mg/day, children weighing between 25 and 35 kg receiving 187.5 mg/day, and children weighing over 35 kg receiving 250 mg/day.7 The standard treatment course is 6 weeks.7 A study comparing a 6-week course of terbinafine 5–8 mg/kg versus a 6-week course of griseofulvin 10–20 mg/kg showed that mycological cure and complete (mycological plus clinical) cure rates were significantly higher for terbinafine than for griseofulvin.8 However, subgroup analysis revealed that among patients infected with Microsporum canis, mycological and complete cure rates were superior with griseofulvin.8 Conversely, among patients infected with Trichophyton tonsurans, mycological and complete cure rates were superior with terbinafine.8

Terbinafine can also be safely used in children for onychomycosis when dosed by weight as for tinea capitis.9

Adult

Terbinafine is indicated for the treatment of onychomycosis of the toenails and fingernails caused by dermatophytes.10 A dose of 250 mg/day for 12 weeks is typically used.

Several studies have compared the standard 12-week regimen of terbinafine to itraconazole, used in either a continuous or pulsed fashion. Terbinafine produced higher rates of clinical and mycological cures.11–14 In a study comparing continuous terbinafine with intermittent itraconazole (1 week of treatment per four weeks) in the treatment of toenail onychomycosis, terbinafine was significantly more effective than pulsed itraconazole.11 At week 72, the mycological cure in those patients treated with a 3-month daily course of terbinafine was 76%, compared with a mycological cure rate of 38% in those patients treated with a 3-month course of intermittent pulse therapy with itraconazole. A longer follow-up of these patients at an average of 54 months revealed 46% cure after continuous terbinafine versus 13% cure after the pulsed itraconazole12; similar results were found by others at 2-year follow-up.13 Twelve weeks of terbinafine 250 mg/day is clearly superior to itraconazole 200 mg/day, with mycological cure rates of 73% versus 46% after 48 weeks of follow-up.14

Studies comparing various intermittent dosing regimens of terbinafine to the gold standard of continuous 12-week therapy for toenail onychomycosis have yielded mixed results.15,16

No increase in mycological cure rate is gained by aggressive debridement of the toenail when combined with terbinafine; however, the clinical appearance of the nail is improved with debridement.17 Additionally, aggressive nail debridement, when combined with oral terbinafine, improves treatment satisfaction and reduces symptom frequency.18 The addition of a topical lacquer such as ciclopirox 8% lacquer or amorolfine 5% lacquer (see Chapter 219) enhances clinical efficacy when used with terbinafine and then continued for 6–9 months after the cessation of terbinafine.19,20

Tinea corporis, tinea cruris, and tinea pedis can be treated with oral terbinafine with high clinical and mycological cure rates. In a study of 22 patients with tinea corporis and tinea cruris who used terbinafine 250 mg daily for 1 week, 100% clinical and mycological clearing was observed at 6 weeks.21 In a study of moccasin tinea pedis and tinea manuum, after a 2-week course of terbinafine, 250 mg daily, there was an 86% mycological cure rate at 8 weeks.22 Two placebo-controlled trials demonstrated that a 4- to 6-week course of terbinafine 250 mg daily is effective in the treatment of seborrheic dermatitis23,24 (see Chapter 22). Interestingly, terbinafine is not effective orally for the treatment of tinea versicolor,21 but twice daily application of topical terbinafine 1% solution, cream or gel, has been effective in randomized placebo-controlled trials.25

Geriatric

Terbinafine is well tolerated by the elderly and requires no further cautions than those for the general population.26 A study of 504 patients older than 65 years of age confirmed efficacy and tolerance of the standard adult regimen for onychomycosis, with no reported drug interactions.27

Pregnancy Considerations

Terbinafine is a pregnancy category B drug.10

Dosage Schedules and Formulations

Terbinafine is supplied as a 250-mg tablet or packets of oral granules. See Table 232-1.

Initiating Therapy

Positive tests [potassium hydroxide (KOH), culture, histology] for fungal infection should be documented before initiation of oral terbinafine therapy. Pretreatment serum transaminase tests are advised for all patients before taking terbinafine, and the drug is not recommended for patients with liver or renal disease.22

Monitoring Therapy

Many physicians advocate monitoring liver function after 6 weeks of therapy, although the incidence of hepatic toxicity is very low [see Sections “Complications (Adverse Effects)” and “Risks and Precautions”]. Because of transient lymphopenia observed in patients on terbinafine, complete blood cell counts should be monitored in immunodeficient patients who are receiving terbinafine for longer than 6 weeks.28 If signs or symptoms of secondary infection occur in patients while on terbinafine, a complete blood count should be performed to rule out neutropenia.28 Cautions and monitoring in children are the same as for adults, but there is evidence that children may suffer fewer adverse events.9

Complications (Adverse Effects)

Because of its high selectivity, terbinafine is generally well tolerated with a low incidence of adverse side effects. The most common side effects after oral administration are of a gastrointestinal nature (3.5%–5.0%).29 Other rare side effects include headache, exanthematous eruption, acute generalized exanthematous pustulosis, pustular psoriasis, subacute cutaneous lupus erythematosus, chest pain, elevated laboratory parameters, loss of taste, fatigue, and malaise.28–33 A few cases of hepatocellular injury (including fulminant hepatic failure),34,35 reversible agranulocytosis,36 and severe skin reactions, including toxic epidermal necrolysis and erythema multiforme, were also reported.37

Risks and Precautions

Terbinafine should be prescribed with caution in patients with hepatic disease or history of hepatic toxicity with other medications (Box 232-2). Furthermore, there is insufficient data to recommend its use in patients with renal impairment. Because terbinafine rarely causes a lupus-like rash and neutropenia, patients with known systemic lupus erythematosus or immunodeficiency also may not be good candidates for this medication.10

Drug Interactions

Terbinafine is not contraindicated with any specific drug. However, cytochrome P450 (CYP) enzymes metabolize terbinafine. Plasma clearance of terbinafine is increased by the P450-inducer rifampin and decreased by the P450-inhibitor cimetidine.38 Terbinafine is also reported to decrease cyclosporine levels by increasing cyclosporine clearance.22,39 Isolated reports of interactions with warfarin have been reported; however, prospective pharmacokinetic studies have not revealed any clinically significant reactions.39 It was shown that terbinafine inhibits CYP2D6, a cytochrome P450 isoenzyme that metabolizes tricyclic antidepressants and other psychotropic drugs.40 Other drugs predominantly metabolized by this enzyme include β-blockers, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors type B.22 In a postmarketing surveillance study of patients on terbinafine, no adverse drug interactions with CYP2D6 substrates were reported.41 However, there have been two reports of nortriptyline intoxication induced by terbinafine.42,43

Both itraconazole and fluconazole are triazole antimycotic agents sharing a common structural moiety—a triazole ring—not found in azoles of the imidazole family.

Itraconazole

Itraconazole (Fig. 232-1) is a highly lipophilic compound that has a wide spectrum of activity.44 In vitro, it is fungistatic and effective against dermatophytes, yeast, molds, and dimorphic fungi.45–47

Mechanism of Action

Itraconazole inhibits 14-α-demethylase, a microsomal cytochrome P450 enzyme, in the fungal membrane (Fig. 232-2).48 14-α-Demethylase is necessary for the conversion of lanosterol to ergosterol, which is the principal structural component of the fungal cell membrane.46 Consequently, the accumulation of 14-α-methylsterols leads to the impairment of membrane permeability and membrane-bound enzyme activity and to the arrest of fungal cell growth.

Pharmacology

The serum concentration of itraconazole is influenced by several parameters, including food and gastric acidity.49,50 Itraconazole is extensively metabolized, primarily by the CYP3A4 isoenzyme system to more than 30 metabolites. Hydroxyitraconazole is the main metabolite. Approximately 54% of the metabolized drug is excreted in the feces, and 34% is excreted in the urine. After single-dose administration, the terminal elimination half-life is 21 hours for itraconazole and 12 hours for its active metabolite. The pharmacokinetic variables of itraconazole are not affected in patients with renal insufficiency.51 In patients with liver cirrhosis, the absorption is slightly increased and the half-life is prolonged because of a reduced first-pass metabolism. Absorption of the standard tablet formulation is decreased in patients with acquired immunodeficiency syndrome as a result of gastric hypochlorhydria.51 A new hydroxypropyl-β-cyclodextrin oral solution formulation is better absorbed in a fasting state than with food,52 appropriate for patients who cannot ingest large amounts of food or have high gastric pH. Young children, especially those less than 5 years of age, have lower serum levels than adults and usually require twice daily dosing.53

Indications

Itraconazole has the broadest efficacy compared to other commonly prescribed antifungals.47 Thus, it is a first-line therapy for infections due to Candida and other nondermatophyte species (Box 232-3).

Pediatric

Itraconazole can be used to treat tinea capitis in children. It is more often prescribed in the capsule formulation with food or acidic beverages such as colas because the cyclodextrin in the liquid form of itraconazole causes more gastrointestinal side effects such as diarrhea and also due to reports of neoplasms associated with high doses in murine and rat models.54 Nevertheless, for children who cannot swallow capsules or take capsules with food, the solution has a pleasant taste and is considered to be safe.55 Itraconazole is dosed at 5 mg/kg per day for 4–6 weeks.56 Children who weigh between 15 and 30 kg require one 100 mg capsule daily; children weighing 30–40 kg require 100 mg 1 day alternating with 200 mg the next day, to average 150 mg daily.57 Children weighing over 50 kg can be dosed as adults.55 Tinea capitis caused by T. tonsurans requires a course lasting 2–4 weeks58; however, a longer treatment course is recommended for M. canis.59 Because onychomycosis is less common in children than in adults, there is much less data available for treatment of pediatric onychomycosis. For better compliance due to decreased adverse effects, lower cost, and overall reduced exposure to drug, one can prescribe a pulsed regimen of 5 mg/kg/day for 1 week alternating with 3 weeks off; two pulses are recommended for fingernail involvement and three pulses for toenail involvement.9

The oral solution is a good option for oropharyngeal or esophageal candidiasis in children, even in fluconazole-resistant infections.53

Adult

Itraconazole has been approved for the treatment of onychomycosis caused by dermatophytes54 and is effective as continuous or pulse therapy. A 2-month course of itraconazole pulse therapy is necessary for fingernail onychomycosis, while toenail onychomycosis requires a 3-month course. A single course consists of 200 mg twice daily for 1 week per month. Itraconazole pulse therapy is at least equal in efficacy, if not superior, in the treatment of toenail onychomycosis when compared to continuous itraconazole therapy.60 Itraconazole has been used for the treatment of tinea pedis. A 1-week course of itraconazole, 200 mg twice daily, is more effective than 200 mg or 100 mg daily for 2–4 weeks.61 Nonetheless, itraconazole is less effective in the treatment of dermatophyte infections than terbinafine (see Section “Allylamines: Terbinafine”). Itraconazole at a dose of 200 mg daily for 5–7 days is effective in the treatment of pityriasis versicolor.62 Recurrence, which is common in this disease, can be prevented by taking 200 mg twice daily for 1 day a month.62

Geriatric

Itraconazole (pulse) therapy is effective and safe in the elderly and only requires caution in the setting of comorbidities and drug interactions [see Section “Complications (Adverse Effects)”].26

Pregnancy Considerations

Itraconazole is a pregnancy category C drug, and therefore, is not recommended during pregnancy or while nursing because it is excreted in human milk.54

Dosage Schedules and Formulations

Itraconazole is supplied in 100-mg capsules, a 10-mg/mL oral solution, and an intravenous solution. Capsules should be taken with a full meal to ensure maximum absorption54 (see Table 232-2).

Initiating Therapy

Positive tests (KOH, culture, histology) for fungal infection should be documented before initiation of oral itraconazole therapy. Baseline evaluation of hepatic function is recommended in patients with preexisting liver disease, or if lengthy treatment is anticipated.54

Monitoring Therapy

Hepatic function monitoring is indicated through therapy only for those patients with preexisting liver disease or those with a history of hepatic toxicity with other medications.54,63 When itraconazole must be administered with medications, it is known to compete with for hepatic enzymes, appropriate monitoring for drug levels or toxic effects of these medications is indicated (see Section “Drug Interactions”).

Complications (Adverse Effects)

The most common reported side effects associated with itraconazole therapy are of a gastrointestinal nature.64 Less-frequent adverse effects are hypertriglyceridemia, edema,65 urticaria, anaphylaxis, erythema multiforme, headache, neuropathy, impotence, hypertension, leukopenia, nephrotic syndrome, and mildly elevated liver enzymes.54,64 Instances of hepatic injury and, rarely, fulminant hepatotoxicity are associated with the administration of itraconazole. There are also rare reports of congestive heart failure and pulmonary edema. When administered intravenously to dogs and healthy human volunteers, negative inotropic effects were noted.66

Risks and Precautions

Administration of itraconazole to patients with a history of heart failure is contraindicated, and it is not recommended for patients with a history of liver disease.54 There are also several significant drug interactions to be aware of (see Box 232-4).

Drug Interactions

Itraconazole inhibits 14-α-demethylase, a fungal P450 enzyme48 and a member of the same group of enzymes present in the human liver that is responsible for the metabolism of many drugs (Fig. 232-2). Itraconazole specifically inhibits CYP3A4, and consequently, may increase plasma concentrations of drugs metabolized by this pathway. The concomitant use of itraconazole and sildenafil can lead to a reduction in sildenafil clearance.67 Cisapride, terfenadine, quinidine, dofetilide, oral midazolam, pimozide, triazolam, and 3-hydroxy-3-methylglutaryl coenzyme A–reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are contraindicated with itraconazole. Because itraconazole is metabolized by CYP3A4, inducers or inhibitors of CYP3A4 may alter itraconazole levels. Absorption of itraconazole may be decreased by the concomitant administration of antacids, H2-blockers, and proton pump inhibitors.3

Fluconazole

Fluconazole (Fig. 232-1) is fungistatic in vitro68 and is effective against many yeasts (with the exception of Candida krusei) and dermatophytes.69

Mechanism of Action

Fluconazole, like itraconazole, inhibits 14-α-demethylase, a microsomal cytochrome P450 enzyme, in the fungal membrane (Fig. 232-2).48

Pharmacology

The pharmacokinetic parameters of fluconazole are similar for both intravenous and oral administration.69 Near complete absorbtion of the triazole appears to be comparable in both postprandial and fasting states; absorbtion is not dependent on stomach acidity.50,70 Fluconazole exhibits a long half-life of 25–30 hours, and a steady-state level is reached after 7 days of once-daily administrations. Fluconazole is only weakly bound to plasma proteins, with about 90% of the drug circulating free in the plasma. The drug is resistant to hepatic metabolism, and hence, approximately 80% of fluconazole is excreted unchanged in urine, with 2% in feces and approximately 11% as metabolites in urine.71 The ability to diffuse substantially into the cerebrospinal fluid distinguishes this compound from many other antimycotic agents.72 The levels of fluconazole in cerebrospinal fluid, saliva, vaginal tissue, sputum, skin, and blister fluids are reported to be comparable with or to exceed simultaneous plasma concentrations.73 Altered fluconazole pharmacokinetics, including decreased plasma clearance, are detected in patients with cirrhosisand renal impairment.74,75 In children over 3 months of age, fluconazole clearance is more rapid than in adults.53

Indications

Fluconazole is established as a first-line therapy for mucocutaneous candidiasis (Box 232-5). It is useful for its convenient once-weekly dosing schedule (Table 232-3).

Pediatric

Fluconazole has been used successfully to treat tinea capitis at 6 mg/kg/day for 20 days for T. tonsurans infection and at 5 mg/kg/day for 30 days.57,76 A course as brief as 2 weeks may be equally effective as terbinafine and itraconazole for Trichophyton infections.58 When M. canis is present, a longer treatment course is recommended.59 A 6-week course of fluconazole 6 mg/kg/day produced comparable mycological and clinical cure rates compared to griseofulvin 11 mg/kg/day microsize formulation.77

Adult

Vaginal candidiasis can conveniently and safely be treated with a single 150-mg dose of fluconazole, or weekly for 6 months or longer in the case of recurrent vulvovaginal candidiasis.78 Interestingly, a daily oral probiotic Lactobacillus supplement enhances rates of clinical and mycological cure in vulvovaginal candidiasis after treatment with 150-mg single-dose fluconazole.79

When used to treat oropharyngeal candidiasis, fluconazle is typically given at doses of 200 mg on day 1 followed by 13 days of 100 mg per day. However, a single dose of 750 mg is as effective as the standard 14-day regimen in patients with HIV and offers greater convenience.80

For the treatment of tinea pedis, weekly doses of fluconazole 150 mg have been given for a period of 3–4 weeks,81 with a 75% mycological cure rate at 4 weeks. Fluconazole at a dose of 150 mg weekly for 24 weeks is significantly inferior to terbinafine 250 mg daily for 12 weeks in the treatment of onychomycosis.82 Pityriasis versicolor can be effectively treated with a single 400-mg dose of fluconazole.83 In a small, open-label randomized study of pityriasis versicolor treatment comparing a single 400-mg dose of fluconazole with a single 400-mg dose of itraconazole, fluconazole led to greater cure than itraconazole (65% vs. 20%, respectively) with fewer relapses noted (35% vs. 60%, respectively) at an 8-week follow-up assessment by KOH and culture tests.84 Oral fluconazole is not the treatment of choice for seborrheic dermatitis, as two 300 mg doses spaced one week apart showed essentially no improvement over placebo.85

Geriatric

Fluconazole is well tolerated in the elderly; however, dose modification is required in elderly patients with renal impairment.73,86

Pregnancy Considerations

Fluconazole is a pregnancy category C drug and is not recommended in pregnant or nursing mothers.87

Dosage Schedules and Formulations

Fluconazole is available in 50-mg, 100-mg, 150-mg, and 200-mg tablets; in 10-mg/mL and 40-mg/mL oral solutions; and in an intravenous form. It is approved for use in children age 6 months and older, although not specifically for tinea capitis (see Table 232-3).

Initiating Therapy

Positive tests (KOH, culture, histology) for fungal infection should be documented before initiation of oral fluconazole. There are no specific recommendations for baseline laboratories before starting fluconazole therapy.87

Monitoring Therapy

There are no specific monitoring recommendations other than drug levels in renal disease. Because fluconazole is prescribed as a one-time dose or once weekly, there is little need for laboratory monitoring other than that indicated by side effects.87

Complications (Adverse Effects)

The most common recognized side effects of fluconazole therapy are gastrointestinal.88 Adverse reactions such as fixed drug eruptions, thrombocytopenia, transient amenorrhea, elevated liver function tests, mild increase in levels of serum creatine phosphokinase, dizziness, anorexia, and alopecia have been observed, and most resolve with continuing fluconazole therapy.87,89 There are rare reports of fatal hepatotoxicity associated with fluconazole, but most studies in both humans and rats have shown less hepatoxicity when compared to other azoles.90 There are even fewer reports of torsades de pointes, with or without concomitant medications or underlying cardiac arrhythmias.91

Risks and Precautions

To prevent serious hepatic and cardiac toxicity, one should exercise caution when prescribing to patients with multiple comorbidities, immunosuppression or preexisting liver or cardiac disease; close monitoring may be helpful in these patients (see Box 232-6).

Drug Interactions

In humans, fluconazole inhibits both CYP3A4 and CYP2C9 in a dose-dependent manner,3 and consequently may increase plasma concentrations of drugs metabolized by these pathways. Therefore, a number of drugs that are metabolized by CYP3A4 or CYP2C9 are contraindicated or require close monitoring. Coadministration of terfenadine or cisapride with fluconazole is contraindicated.87 (See Box 232-6.)

Voriconazole is a second-generation triazole agent available in oral and intravenous formulations that is used widely outside of dermatology for the treatment of invasive fungal diseases, particularly invasive aspergillosis.92 Although this drug in infrequently prescribed by dermatologists, voriconazole has several important adverse effects that the dermatologist should be familiar with.93 Cutaneous adverse effects occur in fewer than 10% of patients taking voriconazole.94 Voriconazole can induce a spectrum of photosensitivity reactions, ranging from sunburn-like reactions after minimal photoexposure94,95 to premature photoaging in patients on long-term treatment96 to pseudoporphyria, with erythema and blistering in photoexposed areas accompanied by cheilitis.97,98 Photosensitivity and pseudoporphyria induced by voriconazole disappear promptly after discontinuation of the drug.93–98 In addition to photosensitivity, voriconazole is also a known cause of Steven-Johnson syndrome and life-threatening toxic epidermal necrolysis, although these reactions are rare.99,100 Skin cancers including melanoma in situ has been reported.101

Ketoconazole was introduced in the 1970s as the first effective oral azole antifungal. However, because of the drug's many adverse reactions and the availability of safer, efficacious medications, it is no longer used as a first-line agent for the treatment of dermatophyte or yeast infections.

Griseofulvin (Fig. 232-1; Box 232-7) has been used since 1958 for the treatment of dermatophyte infections.59 Griseofulvin is not effective for candidiasis, deep fungal infections, or pityriasis versicolor.

Mechanism of Action

Griseofulvin is fungistatic in vitro,59 and has a narrow spectrum of antimycotic activity. It disrupts microtubule mitotic spindle formation, thereby causing mitotic arrest at the metaphase stage.102

Pharmacology

The absorption of griseofulvin is enhanced by several factors, including concurrent intake of a fatty meal and a smaller particle size formulation. Griseofulvin is mainly metabolized by the liver before excretion.103

Indications

As one of the early antifungal medications, griseofulvin has been US Food and Drug Administration approved for several dermatophyte infections. However, because of its limited spectrum of coverage compared to other agents and the lengthy courses required, griseofulvin is not used as a first-line therapy for fungal infections other than tinea capitis.

Pediatric

Griseofulvin is an acceptable choice for the first-line treatment of tinea capitis in children.68 Griseofulvin is recommended at a dosage higher than that suggested by the manufacturers at 20–25 mg/kg/day (microsize), or 15–20 mg/kg/day (ultramicrosize) to complete a minimum course of 6–8 weeks for T. tonsurans.57 However, longer treatment with griseofulvin is recommended for M. canis infections.57

Adult

Although griseofulvin is indicated for the treatment of fingernail and toenail onychomycosis, therapy is prolonged with low cure and high relapse rates, requiring approximately 6 months for the treatment of fingernails and 12 months for toenails.102

Geriatric

The safety of griseofulvin therapy in the elderly has not been formally evaluated in trials. However, studies including elderly patients have not specifically reported an increased incidence of adverse effects among this age group.104,105

Pregnancy Considerations

Griseofulvin is a pregnancy category C drug. Because griseofulvin interferes with chromosomal distribution during cell division, males should wait at least 6 months after completing griseofulvin therapy before fathering a child.106

Dosage Schedules and Formulations

Griseofulvin is formulated as ultramicrosize tablets in 125-mg, 165-mg, 250-mg, and 330-mg doses.107 It is also formulated as griseofulvin microsize and is available as 250-mg and 500-mg tablets and in a 125-mg/5-mL suspension.108 To maximize absorption, it should be taken with fatty foods. The manufacturers recommend 5–10 mg/kg/day (ultramicrosize) or 10–20 mg/kg/day (microsize). See Table 232-4.

Initiating Therapy

Positive tests (KOH, culture, histology) for fungal infection should be documented before initiation of therapy. There are no specific recommendations for baseline laboratories before starting griseofulvin therapy.

Monitoring Therapy

There are no specific monitoring recommendations.

Complications (Adverse Effects)

The most common side effects are related to the gastrointestinal tract and the central nervous system, such as headache, dizziness, and insomnia.102 The drug is reported to precipitate lupus erythematosus and, rarely, severe skin reactions, including Stevens-Johnson and angioedema. As a result of impaired porphyrin metabolism, griseofulvin therapy is associated with photosensitivity reactions. Griseofulvin is contraindicated in patients with porphyria and hepatocellular failure.107

Risks and Precautions

Patients should be warned about potential photosensitivity induced by griseofulvin and the possibility of lupus erythematosus or a lupus-like syndrome.108 See Box 232-8.

Drug Interactions

Griseofulvin induces CYP3A4, leading to lower plasma levels of drugs metabolized by this pathway.3 Two important examples are decreased anticoagulation by warfarin and potential decreased effectiveness of oral contraceptive pills.

Oral antifungal therapy is increasingly important for the treatment and prevention of infection in immunocompromised individuals, even in an outpatient setting. For example, as more patients survive organ transplantation,109,110 more fungal infections are likely to be observed. In one report of 100 consecutive liver transplant patients seen by a dermatology clinic, fungal infections were much more common (19% of total skin infections) than bacterial (5%) or viral (2%).111

Candidiasis and aspergillosis are the most common opportunistic fungal infections in many immunocompromised populations. The extensive use of fluconazole prophylactically in patients with acquired immunodeficiency syndrome, transplants, hematologic malignancies, and other causes of immunosuppression has led to decreased susceptibility of some Candida infections to fluconazole.112 Itraconazole solution, 100 mg/day for 14 days, is equivalently effective as fluconazole, 100 mg/day for 14 days, with the added advantages of broader coverage than fluconazole, greater bioavailability than itraconazole capsules on an empty or hypochloridic stomach, easier swallowing by dysphagic patients, and potential effectiveness in cases of fluconazole-resistant strains of C. albicans.113,114 Itraconazole solution has shown superior prevention of death from disseminated candidiasis and aspergillosis than fluconazole solution in immunosuppressed pediatric patients.53 One should keep in mind, however, that itraconazole solution has more drug interactions and potential compliance issues due to nausea and diarrhea. Posaconazole is an extended-spectrum triazole with activity against strains of fluconazole-resistant Candida. In patients with oropharyngeal candidiasis and HIV/AIDS, a comparison of a two-week course of posaconazole to fluconazole demonstrated that posaconazole was as effective as fluconazole in producing a successful clinical outcome, yet posaconazole was more effective in sustaining clinical success after treatment was stopped.115

New antifungal medications with activity against resistant species and excellent safety profiles continue to be developed. The new class of antifungals, echinocandins, provides both benefits by specifically targeting fungal cell wall β-1,3-D-glucan synthesis (absent in mammalian cells). However, poor oral bioavailability currently limits these drugs to intravenous formulations.116

Interpretation of competing studies continues to be difficult because endpoints have not been uniform. Such endpoints may be mycological cure, clinical cure, complete cure, and effective treatment. Criticisms of these studies include the fact that many were open label, leading to investigator bias.117 Many studies fail to take into account the physiology of nail growth.13 Toenails can take up to 18 months to grow out fully. Therefore, studies at 48–52 weeks might not accurately reflect clinical or mycological cure.

Several studies of the treatment of tinea pedis did not specify the type of tinea pedis, despite known variations amongst forms of tinea pedis in response rate to therapy. Studies of moccasin tinea pedis are preferred, as successful treatment usually indicates that the antifungal drug will be effective in the milder forms of tinea pedis as well as tinea corporis and tinea cruris.117 Finally, the efficacy of antifungal agents depends on the sensitivity of the dermatophyte. For example, in the treatment of tinea capitis, if the causative organism is M. canis, longer treatments may be needed than if the organism is T. tonsurans.44 In North America, most tinea capitis is caused by T. tonsurans, while surveys in the United Kingdom demonstrate that the predominant dermatophyte is M. canis.59 Consequently, trials assessing the efficacy of a drug may be influenced by the culprit dermatophyte and indirectly by the location of the study.

Both tinea capitis and onychomycosis due to dermatophytes remain challenging infections to cure. Oral terbinafine has emerged as a safe and effective treatment of tinea capitis, surpassing griseofulvin in mycological and complete cure rates for patient infected with T. tonsurans.8 Oral terbinafine has remained the most effective monotherapy for onychomycosis.11–14 Moreover, the addition of a topical antifungal lacquer such as ciclopirox 8% lacquer or amorolfine 5% lacquer enhances clinical efficacy when used with terbinafine and then continued for 6–9 months after the cessation of terbinafine.19,20