Miconazole: A Preliminary Review of its Therapeutic Efficacy in Systemic Fungal Infections

Summary

Synopsis

Miconazole ¹ is an imidazole antifungal drug which has recently become available for systemic use. Its antifungal activity has been well studied and it is active in vitro against a wide range of fungi. Published and unpublished reports of the use of miconazole in conditions such as systemic or mucocutaneous candidosis, coccidioidomycosis, fungal meningitis, and paracoccidioidomycosis (which seems especially responsive) have often been encouraging, particularly in view of the serious, refractory nature of the conditions treated, but in most areas of use experience is limited. There are few effective drugs available for treating most systemic fungal infections, and if further studies confirm the encouraging results often seen to date, miconazole will be an important addition to the limited choices available for such conditions.

Antimicrobial Activity

Miconazole has useful in vitro activity against a wide range of dermatophytes (e.g. Trichophyton mentagrophytes, Epidermophyton floccosum), yeasts (e.g. Candida albicans, Pityrosporum orbiculare and pachydermatis, Cryptococcus neoformans) and actinomycetes (e.g. Streptomyces madurae, Nocardia asteroides), as well as some Gram-positive and anaerobic bacteria (e.g. Staphylococcus aureus, Streptococcus faecalis, Bacteroides fragilis). Like the closely related compound, econazole, it has no useful activity against Gram-negative rods. Candida albicans is moderately sensitive, most strains being inhibited by a miconazole concentration of 0.5 to 4µg/ml. Coccidioides immitis is also moderately sensitive. The causative organism of South American blastomycosis (Paracoccidioides brasiliensis), a serious endemic disease in parts of Central and South America, is highly sensitive in vitro, the minimum inhibitory concentration being about 0.001µg/ml.

In in vivo studies, intramuscular miconazole markedly increased the survival rate of rats with experimental systemic candidosis compared with placebo controls, and increased survival of mice infected with Coccidioides immitis. However, subcutaneous and intraperitoneal administration were ineffective in treating mice infected with Cryptococcus neoformans. ‘Higher’ oral doses (160mg/kg/day) were effective in treating cutaneous dermatophyte infections in guinea pigs, and oral doses of 1.5 to 3g daily markedly reduced colony counts in asymptomatic volunteers with C. albicans in their sputum.

The mode of antimicrobial action of miconazole may involve an effect on cell membranes or, according to more recent studies, miconazole may result in the accumulation of toxic reactive peroxide compounds within the microbial cell.

Pharmacokinetic Studies

Miconazole is only partially absorbed from the gastrointestinal tract, oral bioavailability being about 25 to 30%. After intravenous infusion of 522mg over 15 minutes in patients, peak plasma concentrations of 2 to 9µg/ml occurred, declining to 0.1 to 0.2µg/ml at 8 hours. Miconazole is widely distributed to body tissues. It readily penetrates into infected joints and into vitreous humour, but penetration into cerebrospinal fluid and sputum is variable and relatively low, CSF concentrations varying from less than 3% to about 50% of plasma concentrations. About 90% of the drug is bound to plasma proteins. The apparent volume of distribution in man is about 1400L. Miconazole is extensively metabolised, less than 1% being excreted in the urine unchanged. The elimination half-life in volunteers or patients is about 20 to 25 hours.

Neither renal impairment nor haemodialysis appear to affect the elimination of miconazole, but plasma concentrations are higher in patients with impaired renal function receiving the same dose as patients with normal renal function, due to a decreased distribution volume in renal impairment.

Clinical Use

Much of the clinical experience with miconazole has been reported in the form of individual case studies or reports of small series of patients. Methods of evaluation of treatment results, and duration of follow-up, often varied among reports or were not clearly stated. Most patients who have received miconazole to date have been seriously ill or dying, and many either did not respond to, or did not tolerate, previous treatment with amphotericin B or flucytosine. Nevertheless, further well designed studies are needed before the relative effectiveness of miconazole, as compared with other systemic antifungal drugs, can be stated with any certainty.

In patients with systemic or mucocutaneous candidosis, the overall response rates appear encouraging, about 80 to 90% of patients showing some improvement. The largest experience is in candidal septicaemia, and gastrointestinal, mucocutaneous and bronchopulmonary candidosis, with a small number of patients with genitourinary candidosis also reported in the literature.

The response rate in patients with chronic, severe coccidioidomycosis has varied somewhat between studies, 30% of a very small series of patients with severe disseminated disease responding and about 40 to 60% of patients with chronic pulmonary, skin and soft tissue, or musculoskeletal involvement. Many patients had been unsuccessfully treated with amphotericin B. The duration of follow-up was often not clear, but as with amphotericin B relapses occurred frequently after an initial response (about 25 to 50% of responders), and many patients received more than 1 treatment course of miconazole. The response rate in patients with paracoccidioidomycosis (South American blastomycosis) has been high (85 to 100%). This serious condition, endemic in some areas, may prove to be an important area of use. Encouragingly, when miconazole was administered orally* for 2 years (1.5g daily) following an adequate intravenous regimen, relapse did not occur. Indeed, oral therapy alone has been successful in some patients. However, the period of follow-up must be extended to confirm the absence of relapses.

A small number of patients with fungal meningitis, usually due to Coccidioides immitis or Cryptococcus neoformans, have been treated. All of these patients were seriously ill or moribund when miconazole therapy was begun. Although the response in some of these small series has been impressive (about 60% of patients), further well designed and reported studies are needed to expand the clinical experience. Many of these patients received intrathecal as well as intravenous treatment, but it has not been clearly shown that intrathecal administration improves the response.

Small numbers of patients with other fungal conditions, such as pulmonary or musculoskeletal cryptococcosis, North American blastomycosis, aspergillosis, histoplasmosis, Petriellidium boydii infections etc. have been treated with miconazole with varying degrees of success, but again further data are needed before clear statements about the response rates in such conditions can be made.

In the only controlled study available, oral miconazole (2g daily) was more effective than a placebo in preventing development of mycotic infections in cancer patients undergoing intensive cytotoxic drug therapy.

Side Effects

In data collated by the manufacturer from published and unpublished reports in the USA, the most frequent side effects were phlebitis (28%), pruritus, nausea (both about 20%), fever or chills, rash (both about 10%), vomiting and anaemia (6 to 7%). However, in a relatively large individual series of patients in the USA the incidence of some such reactions was higher, and hyponatraemia also occurred frequently (50%), especially in patients with meningitis. Other reversible haematological abnormalities (decreased haematocrit and thrombocytosis, leucopenia, erythrocyte aggregation on blood smears), possibly related to the carrier solution (a polyethoxylated castor oil; ‘Cremophor EL’), have also occurred. Reversible hyperlipidaemia also appears to be due to the carrier solution. Allergic reactions have occurred rarely.

Interestingly, the incidence of some adverse reactions was lower in studies conducted outside the USA, probably due to the generally lower doses used in non-USA studies or to formulation differences.

Dosage and Administration

Miconazole should be administered by intravenous infusion, each dose diluted in at least 200ml of 0.9% sodium chloride or 5% dextrose and infused over 30 to 60 minutes. The recommended daily dose, which may be given in 3 equal infusions 8-hourly, is 1.8 to 3.6g in coccidioidomycosis, 1.2 to 2.4g in cryptococcosis, 0.6 to 1.8g in candidosis and 0.2 to 1.2g in paracoccidioidomycosis. Children should receive about 20 to 40mg/kg daily, not exceeding 15mg/kg in a single infusion. An initial dose of 200mg should be given under observation in all patients. In the treatment of lower urinary tract infections, direct instillation into the bladder is necessary (200mg miconazole daily in an appropriate volume). In fungal meningitis, daily administration of the undiluted injection solution of miconazole (20mg per dose) by the various intrathecal routes is recommended by the manufacturer, in addition to intravenous therapy.