Evaluations on New Drugs Drugs 16: 171· 20 1 (1978) ~ ADIS Press 1978
Econazole: A Review of its Antifungal Activity and Therapeutic Efficacy R.C. Heel, R.N. Brogden. T.M. Speight and G.s. A very Australasian Dr ug Information Services, Auckland
Various sectcns of the manusc ript reviewed by : JA. Balmer, Spiez, Switzerl.and: R. Becke, Gordon, New South Wales , A ustra lia; G. Dennerstein, Essendon, Victoria, Australia: R J Holt, Quoon Mary 's Hospita l f or Children, Carshalton. Surray, Eng land; Z.S. Irani. Medizinische Einrichtungen der Universitat Dusseldorf , Dusseklorl. GermarlY: G. Medoff. W ashington Univer _ sity , St . Louis. Missou ri, U.S,A.; R.G. Pari l00llg!ml: E. coti, Klebsiella pneumoniae. Enterobacter cloacae, Pseudomonas 8erugino.sa. S81monelle typ/tlmurium. Shigell8 Hexneri.
/ . / .4 Mechanism of Action
Although the exact mechanism of'econazole's antimicrobial activity cannot be conclusively stated, like other imidazole antifungal drugs (see Sawyer et al. 1975a,b) its primary site of action appears to be the cell membrane systems. In vitro tests with Trichophyton rubrum , Sa ccharomyces cerevisiae and Candida otbtcans have shown an initial increase in permeability of the cell envelope on exposure to econezote, and after several hours an increase in electro n-dense material in the cytoplasm, possibly representing lipid-containing metabolic end-products released into the cytoplasm through lysed intracytoplasmic membranes (Kern and Zimmermann, 1977; Preusser, 1975, 1976 ; Preusser and Roster, 1978). Candida albicans cells exposed to SOpg/ml of econazole or 2.5 to 2Spg/ml of amphotericin B showed numerous fissures under scanning electron microscopy, while control cells and those exposed to Spg/ml of econazole showed smooth surfaces (Ansehn and W inblad, 1978). A relatively high concentration of econazole (7Spg/mJ) caused complete
lysis of cell organelles of Trichophyton rubrum within I hour of exposure (Preusser, 1975). Increased cell membrane permeability on exposure to econezoie appears to occur in non-growing cells, as well as dur ing growth (Zimmermann, 1975), suggesting that this effect is exerted on formed membranes and is not the result of the formation of defective membranes during growth phases. Pityrosporum orbicutare (M , f urf ur) cells showed the format ion of multilayer membrane systems within the cytoplasm on exposure to econazole(Scherwitz and Martin , 1978), similar findings having been reported with T. rubrum (Preusser , 197S), but the overall significance of such findings with respect to econazole's ant ifungal activity remain to be clarified. /./ .5 Devetopmem oj Resistance Culturing Candida albicans and Trichophyton mentagmphytes on solid medium in the presence of increasing concentrations of eccnazole did not alter the minimum inhibitory concentrations for these microbials in subsequent serial dilution tests, as com -
t cco e eore: A Revoew
pared with control strains cultured without the presence of econazote in the culture medium (unpublished data, C uag-Cbernie Ltd). However. Holt and Azmi ( 1978) have reported the emergence of a st rain of Candida atbtcans with high ill l'itro cross resistance to econazole and clotrimazole. as well as to miconazole which the patient was receiving, during prolonged systemic treatment for urinary candidosis in a newborn male. Previous treat ment of the same patient with another antifu ngal drug , 5fluorocytosine. had also resulted in the development of resistance, despite serum and urine drug levels which were far in excess of the initial in vitro minimum cidal concentration.
1.2 Antimicrobial Activity in rivo Both oral and intraperitoneal econazole were ineffective in treating experimental systemic candidosis in mice. However, in mice receiving normally lethal doses ot Coccidiotdes immitis intram uscular econazole prevented death. Oral econazole was as effective as oral griseofulvin in treating cutaneous Trichophyton mel1lagrophyte5 or Microsporu m canis lesions in guinea pigs. Applied topically, econazole was effective in treating candidosis of the skin and vagina and dermatophytic skin infections.
'85
vaginal candidosis. the same oral dose ( 160mg l kg/day) produced all negative cultures after 7 days of treat ment and 80mg/ kg/ day did so after 14 days of treatmen t. Placebo-treated animals had positive cultures throughout the experiment (Thienpont et ai.. 1975). 1.2.1 Experimental Dermaraphytic lntecnons
Applied prophylactically against lesion development in guinea pigs infected with Trtchanhy son mentagrophytes, 0.5 % or 2 9(, topical econazole wa.s of similar efficacy as the same concentrations of tolnaftate (Thienponr et al.. 1975), both drugs inhibiting lesion development more than a placebo. In Microsporum ca nis infections econazole was slightly more active than tolnaftate. Similarly, in curative tests in ani mals with developed lesions topical econazole was active against both organisms (although slightly less so against Microsporum canis) , resulting in the disappearance of most lesions by day 4 2 of treatment. Oral administration of 160mg/k g/ day for 14 days of either econazole or griseofulvin cured all animals of Trichophyton mentagrophytes or Micro sporum ca nis lesions , while 40mg/kg/ day doses were less effective ew
'"
fro m either s ite remained relatively consta nt 00 to In a s ingle dose study in wh ich 5g of radiolabelled 40 % of the applied dose ) in all tests, s kin abrasion econazole cream I % or 2 96 was ad ministered intrao nly slightly increas ing the amount absorbed . Addi- vaginally, each to 3 healthy premenopausal volun tion of 0. 1 % tr iamcinolone acetonide to t he test teers, the mean cumulative recovery (urine a nd cream s lo wed but did not alter the overall extent of faeces) of radioactivity o ver 96 hours was 2.5 % and cuta neous absor ption . 2.8 % of the ad ministe red dose , respectively In t he only pub lished huma n pharmacokinetic (Vuko vich et al.• 1971). In a n additional J subjects study dealin g with top ical admi nistration (Schaefer given a 5g dose of miconazole crea m the corr esponda nd Stu ttgen, 1976. 1978). about 90 % of an applied ing recovery was 1.4 % . In all groups. mo re tha n dose (70 to IOOmg) of I % econazole cream rema ined 50 % of the adm inistered dose was found to have o n the skin s urface afte r occlusive (I patient) or non- leaked from the vagina . occlusive 0 patients) application for 0 .5 to 18 hours .l./ .2 S.ul(·mit;Admi" islralirll/ in 4 pat ients with dermatoses hype not slated): occluOral R IIUI t': In animal species t he rate of ora l absion o nly s lightly increasing the overall extent of skin penetra tio n. After occlusive and non -occlusive ap- sorpt ion of econazole varied. being relatively s low in plicat io n fo r 90 a nd 30 m inutes , respect ively, to 2 monkeys (peak plas ma level of 1.8pg/ml occur ring 8 patients. the concentration of econazole in the middle hours after dos ing in I study; Dean er al.. 1971). but region of the dermis wa s about I pg / ml of tissue. mor e rapid in rats (peak plasma levels at 2 to 8 hours) with higher concentratio ns in the epidermis (about 10 and dogs (peak plasma levels at I to 2 hours) [unto 100 pg / mll and the ho rn y layer (more tha n published data . C ilag-Chem ie Ltd). In a single dose study in 8 healthy volunteers, o ral IOOOl!g / mil. Followi ng occlus ive application of 70 to 100 mg of I % rad iolabelled crea m fo r 16 hours in a absorption was very poo r a nd erratic after adsingle patient. 0.6 1% of the applied dose of econazole ministrati on of an ente ric coated caps ule but was inwas excre ted in the urine. all w ithin 30 .5 hou rs from creased when the d rug was admi nistered in a gelatin capsule or as a suspension, s uggesting that the s ite of the time of application. In un published human st udies (unpublished data. absorption may be the upper pan of the s mall intes Ci lag-Che mie ltd) in 8 healthy volunteers . peak tine (Can.....right. 1978), Th us. following a 250 mg plasma levels of radioactivity after no nccclusive ap- dose of econazole (as the base) average peak seru m plication of Ig of 2 % econazole cream were less than levels of 3.0 and 2.6 mg / L occurred at 2.25 a nd 2.6 I ng /ml wit h inta ct skin and 20ng / ml with skin hour s with the suspensio n and gelatin capsules. restr ipped of the st ratu m corneum. Total urinar y and spect ively, There was wide inter-subject var iation in faecal recovery was 0 . 196 and 3.69 % with intact a nd peak seru m levels, but the same subjects usuall y ach ieved the highest serum levels with bot h formulast ripped skin, respectively. In 6 fema le volunteers . vaginal application of I % tions. In 6 subjects who received 500 mg of econazole econazole crea m (dose not sla ted) daily for 14 days. 30. Maximu m urin- (aged 2.5 to 9 years) a nd Ig in I I adul ts were ary and faecal radioactivity after the first radiolabelled followed by rapid a bsorption. aga in with a wide interdose occu rred o n days I a nd 3. respectively, the total patient var iatio n in serum levels
Econazole: A Review of its Antifungal Activity and Therapeutic Efficacy R.C. Heel, R.N. Brogden. T.M. Speight and G.s. A very Australasian Dr ug Information Services, Auckland
Various sectcns of the manusc ript reviewed by : JA. Balmer, Spiez, Switzerl.and: R. Becke, Gordon, New South Wales , A ustra lia; G. Dennerstein, Essendon, Victoria, Australia: R J Holt, Quoon Mary 's Hospita l f or Children, Carshalton. Surray, Eng land; Z.S. Irani. Medizinische Einrichtungen der Universitat Dusseldorf , Dusseklorl. GermarlY: G. Medoff. W ashington Univer _ sity , St . Louis. Missou ri, U.S,A.; R.G. Pari l00llg!ml: E. coti, Klebsiella pneumoniae. Enterobacter cloacae, Pseudomonas 8erugino.sa. S81monelle typ/tlmurium. Shigell8 Hexneri.
/ . / .4 Mechanism of Action
Although the exact mechanism of'econazole's antimicrobial activity cannot be conclusively stated, like other imidazole antifungal drugs (see Sawyer et al. 1975a,b) its primary site of action appears to be the cell membrane systems. In vitro tests with Trichophyton rubrum , Sa ccharomyces cerevisiae and Candida otbtcans have shown an initial increase in permeability of the cell envelope on exposure to econezote, and after several hours an increase in electro n-dense material in the cytoplasm, possibly representing lipid-containing metabolic end-products released into the cytoplasm through lysed intracytoplasmic membranes (Kern and Zimmermann, 1977; Preusser, 1975, 1976 ; Preusser and Roster, 1978). Candida albicans cells exposed to SOpg/ml of econazole or 2.5 to 2Spg/ml of amphotericin B showed numerous fissures under scanning electron microscopy, while control cells and those exposed to Spg/ml of econazole showed smooth surfaces (Ansehn and W inblad, 1978). A relatively high concentration of econazole (7Spg/mJ) caused complete
lysis of cell organelles of Trichophyton rubrum within I hour of exposure (Preusser, 1975). Increased cell membrane permeability on exposure to econezoie appears to occur in non-growing cells, as well as dur ing growth (Zimmermann, 1975), suggesting that this effect is exerted on formed membranes and is not the result of the formation of defective membranes during growth phases. Pityrosporum orbicutare (M , f urf ur) cells showed the format ion of multilayer membrane systems within the cytoplasm on exposure to econazole(Scherwitz and Martin , 1978), similar findings having been reported with T. rubrum (Preusser , 197S), but the overall significance of such findings with respect to econazole's ant ifungal activity remain to be clarified. /./ .5 Devetopmem oj Resistance Culturing Candida albicans and Trichophyton mentagmphytes on solid medium in the presence of increasing concentrations of eccnazole did not alter the minimum inhibitory concentrations for these microbials in subsequent serial dilution tests, as com -
t cco e eore: A Revoew
pared with control strains cultured without the presence of econazote in the culture medium (unpublished data, C uag-Cbernie Ltd). However. Holt and Azmi ( 1978) have reported the emergence of a st rain of Candida atbtcans with high ill l'itro cross resistance to econazole and clotrimazole. as well as to miconazole which the patient was receiving, during prolonged systemic treatment for urinary candidosis in a newborn male. Previous treat ment of the same patient with another antifu ngal drug , 5fluorocytosine. had also resulted in the development of resistance, despite serum and urine drug levels which were far in excess of the initial in vitro minimum cidal concentration.
1.2 Antimicrobial Activity in rivo Both oral and intraperitoneal econazole were ineffective in treating experimental systemic candidosis in mice. However, in mice receiving normally lethal doses ot Coccidiotdes immitis intram uscular econazole prevented death. Oral econazole was as effective as oral griseofulvin in treating cutaneous Trichophyton mel1lagrophyte5 or Microsporu m canis lesions in guinea pigs. Applied topically, econazole was effective in treating candidosis of the skin and vagina and dermatophytic skin infections.
'85
vaginal candidosis. the same oral dose ( 160mg l kg/day) produced all negative cultures after 7 days of treat ment and 80mg/ kg/ day did so after 14 days of treatmen t. Placebo-treated animals had positive cultures throughout the experiment (Thienpont et ai.. 1975). 1.2.1 Experimental Dermaraphytic lntecnons
Applied prophylactically against lesion development in guinea pigs infected with Trtchanhy son mentagrophytes, 0.5 % or 2 9(, topical econazole wa.s of similar efficacy as the same concentrations of tolnaftate (Thienponr et al.. 1975), both drugs inhibiting lesion development more than a placebo. In Microsporum ca nis infections econazole was slightly more active than tolnaftate. Similarly, in curative tests in ani mals with developed lesions topical econazole was active against both organisms (although slightly less so against Microsporum canis) , resulting in the disappearance of most lesions by day 4 2 of treatment. Oral administration of 160mg/k g/ day for 14 days of either econazole or griseofulvin cured all animals of Trichophyton mentagrophytes or Micro sporum ca nis lesions , while 40mg/kg/ day doses were less effective ew
'"
fro m either s ite remained relatively consta nt 00 to In a s ingle dose study in wh ich 5g of radiolabelled 40 % of the applied dose ) in all tests, s kin abrasion econazole cream I % or 2 96 was ad ministered intrao nly slightly increas ing the amount absorbed . Addi- vaginally, each to 3 healthy premenopausal volun tion of 0. 1 % tr iamcinolone acetonide to t he test teers, the mean cumulative recovery (urine a nd cream s lo wed but did not alter the overall extent of faeces) of radioactivity o ver 96 hours was 2.5 % and cuta neous absor ption . 2.8 % of the ad ministe red dose , respectively In t he only pub lished huma n pharmacokinetic (Vuko vich et al.• 1971). In a n additional J subjects study dealin g with top ical admi nistration (Schaefer given a 5g dose of miconazole crea m the corr esponda nd Stu ttgen, 1976. 1978). about 90 % of an applied ing recovery was 1.4 % . In all groups. mo re tha n dose (70 to IOOmg) of I % econazole cream rema ined 50 % of the adm inistered dose was found to have o n the skin s urface afte r occlusive (I patient) or non- leaked from the vagina . occlusive 0 patients) application for 0 .5 to 18 hours .l./ .2 S.ul(·mit;Admi" islralirll/ in 4 pat ients with dermatoses hype not slated): occluOral R IIUI t': In animal species t he rate of ora l absion o nly s lightly increasing the overall extent of skin penetra tio n. After occlusive and non -occlusive ap- sorpt ion of econazole varied. being relatively s low in plicat io n fo r 90 a nd 30 m inutes , respect ively, to 2 monkeys (peak plas ma level of 1.8pg/ml occur ring 8 patients. the concentration of econazole in the middle hours after dos ing in I study; Dean er al.. 1971). but region of the dermis wa s about I pg / ml of tissue. mor e rapid in rats (peak plasma levels at 2 to 8 hours) with higher concentratio ns in the epidermis (about 10 and dogs (peak plasma levels at I to 2 hours) [unto 100 pg / mll and the ho rn y layer (more tha n published data . C ilag-Chem ie Ltd). In a single dose study in 8 healthy volunteers, o ral IOOOl!g / mil. Followi ng occlus ive application of 70 to 100 mg of I % rad iolabelled crea m fo r 16 hours in a absorption was very poo r a nd erratic after adsingle patient. 0.6 1% of the applied dose of econazole ministrati on of an ente ric coated caps ule but was inwas excre ted in the urine. all w ithin 30 .5 hou rs from creased when the d rug was admi nistered in a gelatin capsule or as a suspension, s uggesting that the s ite of the time of application. In un published human st udies (unpublished data. absorption may be the upper pan of the s mall intes Ci lag-Che mie ltd) in 8 healthy volunteers . peak tine (Can.....right. 1978), Th us. following a 250 mg plasma levels of radioactivity after no nccclusive ap- dose of econazole (as the base) average peak seru m plication of Ig of 2 % econazole cream were less than levels of 3.0 and 2.6 mg / L occurred at 2.25 a nd 2.6 I ng /ml wit h inta ct skin and 20ng / ml with skin hour s with the suspensio n and gelatin capsules. restr ipped of the st ratu m corneum. Total urinar y and spect ively, There was wide inter-subject var iation in faecal recovery was 0 . 196 and 3.69 % with intact a nd peak seru m levels, but the same subjects usuall y ach ieved the highest serum levels with bot h formulast ripped skin, respectively. In 6 fema le volunteers . vaginal application of I % tions. In 6 subjects who received 500 mg of econazole econazole crea m (dose not sla ted) daily for 14 days. 30. Maximu m urin- (aged 2.5 to 9 years) a nd Ig in I I adul ts were ary and faecal radioactivity after the first radiolabelled followed by rapid a bsorption. aga in with a wide interdose occu rred o n days I a nd 3. respectively, the total patient var iatio n in serum levels
