Ketoconazole: A Review of its Therapeutic Efficacy in Superficial and Systemic Fungal Infections

Summary

Synopsis: Ketoconazole1 is an imidazole antifungal drug structurally related to the earlier compounds in this series, such as miconazole and econazole. However, while retaining a similarly broad spectrum of antifungal activity, it differs from the earlier members of this group in that it can be administered orally to treat a wide variety of superficial or ‘deep’ fungal infections. In open studies in superficial mycoses orally administered ketoconazole was effective in patients with dermatophyte or yeast skin infections, pityriasis versicolor, onychomycoses and oral or vaginal candidosis. Additionally, results were encouraging in chronic mucocutaneous candidosis. In open studies in systemic mycoses it was effective in patients with systemic candidosis, paracoccidioidomycosis and histoplasmosis, and moderately effective in patients with coccidioidomycosis, chromomycosis or asymptomatic candiduria. Few controlled studies have been performed, and a small number of well-designed comparative studies are needed to more clearly establish the relative efficacy of ketoconazole, particularly with regard to amphotericin B in the systemic mycoses in which amphotericin B has proved useful.

Despite some aspects of the drug’s use which require further clarification, ketoconzole will make a major impact in the treatment of fungal infections. The extent to which it may become an ‘agent of choice’ in such conditions will be clarified by wider clinical experience.

Antimicrobial Activity: Ketoconazole is active in vitro against a wide range of fungi, with a spectrum of activity which qualitatively resembles that of miconazole, an earlier imidazole antifungal drug. The spectrum of activity includes dermatophytes (e.g. Microsporum, Trichophyton, Epidermophyton), yeasts (e.g. Candida, Cryptococcus neoformans), dimorphic fungi (e.g. Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis) and various other fungi. However, quantitatively ketoconazole was often less active in vitro than other imidazole antifungal drugs with quantitative results showing considerable variation depending on factors such as culture medium, inoculum size, conditions of incubation, etc. Thus, with ketoconazole, in vitro tests in agar media are not necessarily reliable indicators of useful in vivo activity (see below).

As with other imidazole antifungals, ketoconazole has some activity in vitro against Gram-positive cocci. Interestingly, it is also active in vitro against some parasites, including chloroquine-sensitive and -resistant Plasmodium falciparum and Leishmania tropica.

In in vivo animal models ketoconazole was effective in treating dermatophytic infections in guinea-pigs, and a wide variety of superficial and systemic candidal infections. In mice infected intravenously with Candida albicans, ketoconazole (160mg/kg/day) given orally was more effective than the same dose of miconazole and as comparably effective as amphotericin B given intravenously (0.25 or 1 mg/kg/day). In coccidioidomycosis in mice ‘higher’ doses of ketoconazole (40 to 160mg/kg daily) were effective in preventing mortality, but lower doses were not. In experimental murine cryptococcosis the drug was variably effective depending on the dose and model used. Combined treatment of cryptococcosis with ketoconazole plus amphotericin B tended to be more effective than either drug alone in reducing mortality, but ketoconazole combined with flucytosine was no more effective than ketoconazole alone in eradicating the fungus from spleen tissue of infected animals. ‘Higher’ doses of ketoconazole (160mg/kg/day) reduced mortality in murine blastomycosis and histoplasmosis, in the latter case a combination of ketoconazole and amphotericin B again tending to be more effective than single drug treatment.

The mechanism of action of ketoconazole at a biochemical level may be related to disturbances in sterol or fatty acid metabolism, or to effects on oxidative and peroxidative systems resulting in accumulation of toxic endoperoxides within the cell. There is also preliminary evidence suggesting the possibility of a complementary action between imidazole antifungal drugs and host defence cells, but the clinical importance of this (and whether such effects also occur with other antifungal drugs) is not yet clear.

Pharmacokinetic Studies: Although the oral bioavailability relative to intravenous administration has not been determined, ketoconazole appears to be well absorbed from the gastrointestinal tract. Peak serum concentrations after a single 200mg dose (about 3 to 4µg/ml) should be clinically useful against many fungal infections. Under conditions of markedly reduced gastric acidity, for example treatment with cimetidine or some antacids, absorption of ketoconazole may be impaired.

In animal studies the drug was widely distributed in the body, including to the fur of both rats and guinea-pigs. In man ketoconazole has been detected in urine, saliva, sebum and cerumen after a single dose of 200mg given orally. While the drug was present in varying concentrations in cerebrospinal fluid in a few patients so studied, the extent of penetration into cerebrospinal fluid needs additional clarification. In vitro, ketoconazole is about 99 % bound to human plasma proteins (primarily albumin) at a drug concentration of 1µg/ml.

Ketoconazole is extensively metabolised prior to elimination; about 2 to 4 % of total urinary excretion is in the form of unchanged drug. The elimination half-life of the drug in healthy subjects appears to be about 8 hours after a usual dose of 200mg, although shorter values have been reported and this requires further clarification. In patients with renal impairment the disposition of ketoconazole does not seem to be markedly altered, and dosage adjustment in such patients is probably unnecessary. Further studies are needed to clarify the effects of hepatic disease on ketoconazole elimination.

Therapeutic Trials: Most of the clinical experience with ketoconazole to date is derived from a series of open international multicentre studies. Many of the patients involved had previously been treated unsuccessfully with other antifungal drugs. In a large proportion of patients, both the initial diagnosis and the evaluation of treatment were based on clinical evaluation confirmed by mycological or serological evidence. Most patients received a dose of ketoconazole 200mg once daily. In superficial mycoses the response rates (remission/marked improvement) in the open multicentre studies were as follows: dermatophytic or yeast skin infections 67 % /21 %, onychomycosis or perionyxis 81% (remission or marked improvement), pityriasis versicolor 92 % /5 %, oral candidosis 77 % / 7 %, vaginal candidosis about 80 % to 90 % (negative cultures after 1 to 4 weeks) and chronic mucocutaneous candidosis 25 % /52 %. In ‘deep’ mycoses the following response rates, expressed similarly, occurred in the open multicentre studies: systemic candidosis about 70 % / 11 %, coccidioidomycosis 13 % / 22 %, paracoccidioidomycosis about 79 % / 16 %, histoplasmosis about 52 % / 32 % and chromomycosis about 24 % / 29 %. Ketoconazole has also been used in open studies in a few patients with various less common fungal infections such as mycetomas, sporotrichosis, lobomycosis, aspergillosis, alternariosis and cryptococcosis, often with encouraging results, but clinical experience in these areas is too limited to clearly evaluate the efficacy of the drug.

Only a small number of controlled studies have been performed. Ketoconazole 200mg daily was more effective than griseofulvin 250mg daily (ultramicrosize) or 500mg daily (microsize) in a few small studies in patients with fungal skin infections usually due to Trichophyton, and was more effective than a placebo in single small studies in patients with pityriasis versicolor or chronic mucocutaneous candidosis. A small number of additional well-designed comparative studies are needed to more clearly define the relative efficacy of ketoconazole, particularly in ‘deep’ fungal infections in which amphotericin B has been useful.

Most patients treated to date have not been followed up for adequate periods to determine the likelihood of relapse after ketoconazole therapy. Similarly, the prophylactic use of ketoconazole to prevent relapse has not been adequately studied, although preliminary findings suggest this may be worthwhile in some conditions.

Only limited information exists on the treatment of fungal meningitis with orally administered ketoconazole, and it is unclear at present whether use of this drug alone is appropriate in such patients.

Side Effects: Ketoconazole is well tolerated by most patients. Gastrointestinal reactions (about 5 % ) or pruritus (about 2 % ) occur most frequently, occasionally necessitating a dosage reduction or discontinuing treatment. Gynaecomastia has been reported in a few male patients on either usual or ‘higher’ doses. Transiently elevated liver enzymes occurred in about 10 % of patients, and symptomatic liver dysfunction during ketoconazole administration has occurred in a few patients but resolved on discontinuing therapy. Various other ‘side effects’, including dizziness, somnolence, arthralgia, myalgia, headache and many others have been reported, but only in 1 or a few of 1361 patients studied, and their association with drug treatment is open to question. Overall, treatment was permanently discontinued due to side effects in 1.5 % of these patients and temporarily discontinued in 1.3 %. In 62 children treated with the drug 2 cases of side effects were reported —transient fever and chills in one child and persistent nausea and vomiting in another, the latter necessitating discontinuation of therapy.

Dosage and Administration: For all conditions except vaginal candidosis the initial recommended adult dosage is 200mg once daily. If the clinical response is inadequate, the dose may be increased to 400 or 600mg once daily, but there is little evidence to support an improved response with ‘higher’ doses. In vaginal candidosis the recommended dosage schedule is 200mg twice daily for 5 days. The duration of treatment should be individualised, and based on clinical and mycological response. Generally, in ‘deep’ mycoses treatment should be continued for at least 1 week after apparent eradication of the infecting fungus. Continued prophylactic use to prevent relapse may be appropriate in some conditions, although this has not been well studied.

In children the recommended dose is 20mg 3 times daily for those weighing up to 15kg, 100mg once daily for those weighing between 15 and 30kg and 200mg once daily for those weighing 30kg or more.