Synopsis: Econazole1 is a recently introduced imidazole antifungal agent which is very closely related structurally to another imidazole derivative, miconazole. For local application the nitrate salt of econazole is used, while in preliminary investigations of systemic use in a few patients econazole base has been administered orally or intravenously.
In uncontrolled studies in large numbers of patients, econazole nitrate has been administered topically in the treatment of dermatomycoses due to a wide variety of fungi, and vaginally in the treatment of vaginal candidosis; but it has not been compared with any other antifungal drug in controlled therapeutic trials in mycoses of the skin and has only been compared with nystatin in a few patients with vaginal candidosis. Until adequate comparative studies are done the relative place of econazole in the treatment of dermatomycoses and vaginal candidosis, compared with traditional antifungal agents and with other imidazole derivatives such as miconazole or clotrimazole, cannot be clearly stated.
Nevertheless, econazole nitrate is an effective antifungal drug. In dermatological studies about 90% of a large number of patients were cured, often after a relatively short treatment period (2 to 6 weeks, as occurs with other imidazole antifungal agents). The cure rate was only slightly lower (about 85%) in patients with severe mycoses of many years’ duration than in those whose infections were of more recent onset. In vaginal candidosis a 3-day treatment regimen using a 150mg suppository once daily was only slightly less effective (85% mycological cure rate) than a 15-day regimen using a 50mg dose (suppository or cream) once daily (90 % cure rate). A 3 to 5 day ‘higher’ dose regimen was slightly more effective than a standard 15-day 1 ‘Ecostatin’ (Squibb); ‘Epi-Pevaryl’, ‘Gyno-Pevaryl’, ‘Mycopevaryl’, ‘Pevaryl’ (Cilag-Chemie). regimen of nystatin vaginal inserts in a small group of patients with vaginal candidosis. The convenience of the higher-dose shorter term regimen would likely be an important advantage to most patients. Whether other agents useful in vaginal candidosis would be as effective as econazole were they to be used in this way, has not been determined.
Topical or intravaginal econazole nitrate has usually been well tolerated, side effects being limited to local irritation in about 1 to 4% of patients in most studies.
Pharmacodynamic Studies: In standard in vitro sensitivity tests econazole has been shown to have activity against a wide variety of dermatophytes, yeasts, actinomycetes, moulds and other fungi, as well as some Gram-positive bacteria. It did not have useful activity against Gram-negative bacteria. Addition of bovine serum to the culture medium did not alter the activity of econazole against Candida albicans or C. tropicalis but decreased its activity against other fungi. In standard laboratory resistance-induction tests no apparent changes occurred in the sensitivity of Candida albicans or Trichophyton mentagrophytes to econazole, but in vivo emergence of cross resistance of Candida albicans to 3 imidazole drugs (miconazole, econazole and clotrimazole) has been reported in 1 patient.
Although the exact mechanism of econazole’s antimicrobial activity has not been conclusively determined, like other imidazole antifungal drugs it appears to act primarily by disrupting cell membrane systems.
In in vivo tests in mice with experimental systemic candidosis, both oral and intraperitoneal econazole were ineffective. However, intramuscular econazole prevented death in mice receiving lethal doses of Coccidioides immitis. In guinea pigs with dermatophytic cutaneous lesions, oral econazole and oral griseofulvin were of similar efficacy. Applied topically in animal tests, econazole was effective in vaginal and cutaneous candidosis and in dermatophytic skin infections.
Pharmacokinetic Studies: Only limited studies have been done on the pharmacokinetic properties of econazole in man. From the few patients tested in such studies it appears that about 90% of topically applied econazole nitrate (as the cream) remains on the skin surface, occlusion only slightly increasing the extent of absorption. Following vaginal application of econazole nitrate cream about 3 to 7 % of the dose was absorbed. From studies of systemic administration in a few volunteers it appears that likely therapeutic serum concentrations of econazole can be achieved after oral or intravenous administration (of econazole base), but not after administration of rectal suppositories. Further studies are needed in man on the extent of absorption and subsequent disposition of econazole after both local and systemic administration.
Therapeutic Trials: Although econazole nitrate has been studied in a large number of patients in uncontrolled trials, there have been no controlled comparisons with any other anti-fungal agent in therapeutic trials in patients with dermatological mycoses, and only 1 comparison with nystatin in a few patients with vaginal candidosis. Nevertheless, many of the uncontrolled studies were reasonably well designed, and used mycological and / or microscopical methods as well as clinical symptoms for diagnosis and evaluation of treatment. In such studies econazole nitrate appeared to be an effective agent for the topical treatment of dermatomycoses and vaginal candidosis; but until comparative studies have been done its relative place in the treatment of mycoses, compared with the traditional antimycotic agents and with other imidazole derivatives, cannot be clearly stated. In preliminary investigations, a few patients with ‘deep’ mycoses have been treated with oral or intravenous econazole (as the base), but its efficacy when used in this manner requires further study.
In patients with vaginal candidosis (econazole has not been studied in and is not recommended for treatment of trichomoniasis) 2 dosage regimens have been used: a 3-day treatment course using a 150mg vaginal suppository daily, or a 14 to 15 day course using a 50mg (suppository or cream) dose each day. The response rate to the short term regimen was only slightly less than to the longer regimen after 1 treatment course (85 and 90 % mycological cures, respectively), and after 2 treatment courses (in patients not responding to the first course) the overall mycological response rates were nearly identical (93 to 94%).
In the only study in which econazole was compared with another antifungal agent, a 3 to 5 day ‘higher’ dose (150mg suppository) regimen of econazole and a standard regimen of nystatin (a 100,000 unit vaginal tablet daily for 15 days) produced similar results in a small group of patients, although the response rate to econazole tended to be slightly higher.
The mycological response rate to econazole did not appear to be affected by the concomitant use of oral contraceptives, but in several studies pregnant women responded less frequently (about 78 %) than nonpregnant patients (about 88 %). Patients with positive rectal cultures on initiation of therapy had a lower response rate (71 %) than those with negative rectal cultures (90 % ) in 1 study. Symptomatic relief of vaginal burning and pruritus appeared to occur rapidly in most patients but vaginal discharge was relieved in a lesser proportion, and was less favourably influenced by the short term treatment regimen (relief in 42 to 96 % and 71 to 100 % of patients with short and longer term regimens, respectively). The rate of relapse and / or reinfection 4 weeks after completing a successful course of treatment with econazole appears to be about 10 %. Whether or not concurrent treatment of the patient’s sex partner with topical econazole has any influence on the relapse rate cannot be stated from present studies, as the results in patients in which this was done were not reported separately.
In dermatomycoses, and in a smaller number of patients with otomycoses, due to a wide variety of fungi, econazole has resulted in an overall clinical cure rate of about 90 %. Only a few patients with onychomycosis have been studied, and the response of this condition to econazole cannot be clearly stated. In most studies mycological tests were performed in addition to clinical evaluation, the reported mycological cure rate usually being 80 to 100 %. Recent and long standing mycoses seemed to respond nearly equally, the response rate in patients with severe chronic (10 to 30 years’ duration) infections in 1 study being only slightly less (85 %) than in patients with more recent infections (90 %). Some authors have reported that neither the infecting organism, the site of infection, nor the dosage form of econazole used affected the overall cure rate, but in other studies Candida albicans and Malassezia furfur (Pityrosporum orbiculare) infections responded slightly less frequently than those due to dermatophytes, and in 1 large study mycoses of the palms of the hands responded less often than those in other areas.
The onset of response of dermatomycoses to econazole treatment was usually fairly rapid, cures often being achieved in 2 to 6 weeks, although in 1 study inguinal mycoses required a longer duration of treatment to achieve a cure (average 16 weeks) than those in other areas.
Only a small number of patients with Gram-positive bacterial skin infections have been treated, the response rate varying from 54 % (pure bacterial infection) to 80 % (mixed bacterial / fungal infection).
Side Effects: Topical or intravaginal econazole nitrate has been well tolerated in most patients. When side effects occurred (about 1 to 4 % of patients in most studies) they involved irritation, redness, burning or itching. In dermatological studies they appeared to occur most frequently when econazole lotion was applied to the inguinal area. Discontinuing treatment due to adverse effects was necessary in about 1 to 2 % of dermatological patients, and only in isolated instances in patients with vaginal candidosis.
Dosage and Administration: In dermatomycoses a topical preparation of econazole should be applied twice daily (morning and evening), treatment continuing for several weeks (possibly with econazole powder) after the symptoms have disappeared.
In patients with vaginal candidosis, econazole may be administered in a short term regimen using a 150mg vaginal suppository inserted as high into the vagina as possible once daily for 3 days; or a longer regimen using a 50mg suppository or 1 applicator full of econazole vaginal cream inserted deeply into the vagina once daily for 15 days, regardless of whether the symptoms disappear sooner. (In some countries an initial treatment course of 7 days is recommended when the vaginal cream is used, to be followed by a second course if necessary.) In both regimens, treatment of the vulva and / or the prepuce and glans penis of the patient’s sex partner may be undertaken with econazole topical cream, applied twice daily after washing with warm water.
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Various sections of the manuscript reviewed by: JA. Balmer, Spiez, Switzerland; R. Becke, Gordon, New South Wales, Australia; G. Dennerstein, Essendon, Victoria, Australia; R.J. Holt, Queen Mary’s Hospital for Children, Carshalton, Surrey, England; Z.S. Itani, Medizinische Einrichtungen der Universitat Dusseldorf, Dusseldorf, Germany; G. Medoff, Washington University, St. Louis, Missouri, U.S.A.; R.G. Park, Wellington, New Zealand; W.P. Raab, Vienna, Austria; P. Schmid, Rapperswil, Switzerland; K. Schwarz, Stadtische Poliklinik fur Haut- und Geschlechtskrankheiten, Zurich, Switzerland; C.H. Tay, Singapore General Hospital, Singapore; J.P. Utz, Georgetown University, Washington D.C., U.S.A.; K.O. Wong, Hong Kong Government Medical and Health Department, Hong Kong.
‘Ecostatin’ (Squibb); ‘Epi-Pevaryl’, ‘Gyno-Pevaryl’, ‘Mycopevaryl’, ‘Pevaryl’ (Cilag-Chemie).
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Heel, R.C., Brogden, R.N., Speight, T.M. et al. Econazole: A Review of its Antifungal Activity and Therapeutic Efficacy. Drugs 16, 177–201 (1978). https://doi.org/10.2165/00003495-197816030-00001
- Pityriasis Versicolor
- Vaginal Suppository
- Vaginal Cream