Volume 23 Number 3, Part 2 September 1990
area, (3) type of infection, (4) the host's ability to respond, (5) use of combinations of drugs, (6) the vehicle to be used, (7) prophylactic therapy, and (8) ancillary therapy. Treatment to date has been directed toward elimination of the pathogen. It is time to ask ourselves a few questions: 1. Why is only one hand involved in the two-foot one-hand syndrome? 2. Why are dermatophyte infections rare on the scrotum and penis yet common in the groin? 3. Why lre some persons resistant to infection?
Therapy for skin mycoses The answers to these questions may enable us to treat the patient, not the organism, and to provide the ultimate solution to mycotic infections.
REFERENCES 1. Nyawalo JO, Hoire M. Single dose and intermittent griseofulvin regimens in the treatment of tinea capitis in Kenya. Mycoses 1988;31:229-34. 2. Faergemann J, Fredricksson T. Tinea versicolor: some new aspects on etiology, pathogenesis, and treatment. Int J DermatoI1982;21:8-22. 3. Rausch LJ, Jacobs PH. Tinea versicolor treatment and prophylaxis with monthly administration of ketoconazole. Cutis 1984;34:470-1.
I traconazole in tinea versicolor: A review 1. Delescluse, MD Brussels, Belgium
Itraconazole, a new orally active triazole antifungal, has been tested in patients with pityriasis versicolor. A number of studies have shown that itraconazole is effective for this mild fungal skin disease. The total dose required for effective treatment is 1000 mg, and it has been given as 200 mg for 5 days or 7 days. The organisms disappear slowly from the skin, even when dead, and the results should be assessed clinically and mycologically at around 3 to 4 weeks after treatment. Numerous studies have shown that itraconazole is superior to placebo and as effective as selenium sulfide, clotrimazole, and ciclopirox olamine. It is also better tolerated by patients than selenium sulfide. (J AM ACAD DERMATOL 1990;23:551-4.) Agents that are available for treatment of tinea versicolor (TV) are numerous, particularly topical agents. I -3 These topical agents vary in their effectiveness, and lengthy treatment periods are necessary. Surprisingly, the use of a 2% ketoconazole shampoo in one study resulted in excellent results with a single-day application. 4 At present the only oral agent available for the treatment of TV is ketoconazole. 5-7 Clinical trials have confirmed that treatment periods of 5 to 28 days give good results. Patients find oral treatment acceptable,8 but in view of ketoconazole's side effects a certain degree of hesitation continues to exist about the oral treatment of TV.9.11 Therefore new oral agents that are an improvement over the shortcomings of existing drugs are of From the Department of Dermatology, Clinic Cesar de Paepe. Reprint requests: J. Dc1csc1use, MD, Department of Dermatology, Clinic Cesar De Paepe, Cellebroersstraat II, B·IOOO Brussels, Bel· gium. 16/0/21856
considerable interest in the treatment of superficial mycoses. Itraconazole is an oral triazole- derivative that has been shown to be highly active in vitro against a range of fungi, including Pityrosporum species. 12, 13 Animal studies indicated that this drug is five to 10 times more potent than ketoconazole when administered orally. Itraconazole also shows a marked fungicidal effect on Pityrosporum species, the causative organisms ofTV. 14 More than 90% of the tested Pityrosporum strains were sensitive to itraconazole at a concentration of 0.1 J.Lg/ml. I5 MATERIAL AND METHODS
In TV, four different types of studies were performed worldwide on a total of 967 patients. The first type of study compared in an open trial the results obtained with itraconazolein dosages of 50 or 100 mg/day. The second type of study was placebo controlled. The third type of study compared in an open, randomized fashion different short treatment schedules. The last type compared itraconazole with short fixed treatment schedules versus top· ical reference drugs such as selenium sulfide, cic1opirox olamine, and c1otrimazole. 551
552 De/esc/use In all these studies patients were seen for clinical and mycologic examinations immediately before starting treatment, 1 week after the end of treatment, and 3 to 4 weeks after the end of therapy. At each visit signs and symptoms were scored. Findings of Wood's light examination and microscopy were recorded as negative or positive, and patients were asked about side effects.
RESULTS The first study of 33 patients compared the activity of 50 and 100 mg/day of itraconazole in the treatment of TV. 16 No fixed treatment length was used. The results showed that clinical response was obtained in more than 90% of the patients with either of the two dosages. Because it took a long time for all lesions to disappear and in view of past ketoconazole experience, short fixed treatment schedules with itraconazole were tested in the other studies. In the second phase placebo-controlled studies confirmed the effect of itraconazole versus placebo in the treatment ofTY. In a first small, double-blind study in Brussels 17 Roseeuwet al., using a treatment schedule of 100 mg itraconazole daily for 15 days, obtained an 88% mycologic cure rate versus 0% in the placebo group (p < 0.01). All placebo-treated patients were cured afterward with 100 mg itraconazole given daily for 15 days. These results were also confirmed in Sweden by Faergemann18 with the same treatment schedule. These results indicate that itraconazole is superior to placebo for the treatment of TV, although in these studies long-term follow-up data were not available to evaluate relapse rates after stopping therapy. An American study in which 200 mg/day itraconazole was given for 7 days also showed the superiority of itraconazole (89% mycologic cure) versus placebo (6% mycologic cure) 4 to 5 weeks after therapy (unpublished results; data on file). In the third type of study a comparison of different dose schedules was carried out first by Delescluse et at1 9 in Belgium with 73 patients. A regimen of 100 mg/day ofitraconazolefor 15 days gave a 100% response rate; 200 mg/day for 5 days gave an 85% response rate. Two patients who had received 50 mg itraconazole daily for 14 days had relapses within 2 months of finishing treatment. A review of the results worldwide of different treatment schedules suggests that a minimal total dose of 1000 mg is needed to obtain acceptable results. 20 ;21 The results can be divided into those patients (n = 135) treated with a total dosMe of less than 1000 mg, usually 100 mg once daily for 5 to 7 days, and those
Journal of the American Academy of Dermatology
treated with 1000 mg or more (n = 351), usually 100 mg once daily for 10 to 15 days or 200 mg daily as single or divided doses for 5 to 7 days. Treatment with itraconazole, 200 mg once daily or 100 mg twice daily, for 5 days, cured more than 90% of patients when assessed 3 weeks after therapy. Clinical and mycologic recovery continued in patients for several weeks after completion of therapy, probably because of the persistence of itraconazole in the epidermis. Repigmentation of affected skin lagged behind the relief of other symptoms, as is normally observed during recovery from TV, but by 2 months most responders had a normal skin color. Hyperpigmented lesions returned to normal faster than hypopigmented lesions. 22 Posttreatment surveillance of responding patients suggests that a minimal total dose of 1000 mg is required to prevent relapses. There is no major difference in response rate between 200 mg itraconazole given daily for 5 days or 200 mg itraconazole given daily for 7 days. In the last type ofstudy itraconazole's efficacy was compared with that of topical reference drugs such as selenium sulfide shampoo, clotrimazole, and ciclopirox 0Iamine. 23 , 24 In a single-blind study by Del Palacio et al. 23 of Spain, 200 mg itraconazole once daily for 5 days was compared with 2.5% selenium sulfide shampoo applied for 10 minutes each night for 7 days. When assessed 3 weeks after treatment, 17 of 20 patients in the itraconazole group versus 16 of 20 patients in the selenium sulfide group were lesion free and the remainder had mild residuallesions. The tolerance of itraconazole was described as excellent, whereas eight patients had burning and irritation of the skin as a result of selenium sulfide; in one patient it was sufficiently severe to require discontinuation of therapy and treatment for the resulting exudation and pustules. On questioning, all itraconazole-treated and half the selenium sulfide-treated patients expressed a preference for oral medication. In two double-blind double-dummy studies, itraconazole was compared with topical clotrimazole24 and with topical cic1opirox olamine (multicenter, unpublished results, data on file, France). Clinical response was obtained in 86% of the itraconazoletreated patients versus 71 % in the c1otrimazole group at week 4 (3 weeks after therapy). In the first study, 30 patients with TV were treated twice daily ona double-blind basis with either 100 mg itraconazole daily for 5 days (n = 15) or with 1% c1otrimazole cream for 14 days (n = 15).
Volume 23 Number 3, Part 2 September 1990
In both treatment groups there was a significant improvement in severity scores for pruritus, erythema, and scaling by day 6; significant improvement in mycologic characteristics and hypopigmentation was seen by day 15. Although no statistically significant intergroup differences were detected, it is relevant to note that new lesions developed during therapy in the clotrimazole-treated group (three patients). In contrast, new lesions were not observed until the final follow-up visit in the systemically treated group (one patient). A positive KOH preparation was seen in only 25% of the itraconazole-treated patients versus 50% of the clotrimazole-treated patients at week 4 (3 weeks after therapy). In the second study 102 patients were treated with either itraconazole, 200 mg once daily for 10 days, or with ciclopirox olamine cream once daily for 15 days. Although no significant differences were obtained, itraconazole therapy resulted in a higher mycologic cure rate than ciclopirox olamine (86% vs 74%). Adverse effects were reported for 55 (6%) of 954 itraconazole-treated patients. No difference in occurrence was shown among the three total dose groups. Gastrointestinal disorders (e.g., abdominal pain, nausea, dyspepsia, diarrhea, vomiting) and headache were the most common complaints. There seems to be no relation between the occurrence of adverse effects and the dosage. DISCUSSION
Only a limited range of drugs is available for the oral treatment of fungal diseases. All have shortcomings in terms of efficacy or safety. Thus a new oral agent, especially one such as itraconazole, which is well tolerated and has a broad spectrum of activity and a favorable pharmacokinetic profile, is of considerable interest. As with vaginal candidosis, the ideal treatment regimen for an oral agent in TV uses a low dose of drug given for a short period. By comparison, ketoconazole in TV is usually given in 200 mg daily doses for 10 days (total dose 2000 mg). Clinical experience with itraconazole in TV indicates that it is effective at a minimal total dose of 1000 mg given in 5 days. Further placebo-controlled studies have shown itraconazole's superiority in this skin infection. The comparison with selenium sulfide demonstrates that topical therapy may be associated with adverse effects in addition to the practical problems of treating large body areas. Double-blind comparisons with c1otrimazole and/or ciclopirox olamine have also
Itraconazole in tinea versicolor 553 shown that itraconazole is more potent or at least equivalent than these topical agents with short treatment schedules. So far, studies indicate that itraconazole has a lower toxicity profile than ketoconazole. No consistent blood biochemical abnormalities were observed in patients with TV who were treated with itraconazole. Therefore I conclude that itraconazole is highly active in TV with short treatment lengths of 200 mg/day for 5 to 7 days. Because of the few reported side effects of itraconazole, this drug may be used for both treatment and prophylaxis in patients with TV, although prophylactic treatment remains controversial and should be evaluated in carefully designed clinical studies. REFERENCES 1. Ive F. Treatment ofskin infections and infestations. Br Med J 1973;4:475. 2. Chu AC. Comparative clinical trial of bifonazole solution versus selenium sulphide shampoo in the treatment of pityriasis versicolor. Dermatologica 1984;169(suppl 1): 81-6. 3. Hay RJ. Treatment of superficial fungal infections. Clin Exp DermatoI1981;6:509-13. 4. Meisel C. Einmaltherapie der Pityriasis versicolor mit Ketoconazol Shampoo [Unpublished report]. Data on file, Janssen, Belgium. March 1986. 5. Borelli D. Treatment of pityriasis versicolor with ketoconazole. Rev Infect Dis 1980;2:592-5. 6. Savin RC. Systemic ketoconazo1e in tinea versicolor: a double-blind evaluation and I-year follow-up. J AM ACAD DERMATOL 1984;10:824-30. 7. Faergeman J, Djiirv L. Tinea versicolor: treatment and prophylaxis with ketoconazo1e. Cutis 1982:30;542-50. 8. Rausch LJ, Jacobs PH. Tinea versicolor: treatment and prophylaxis with monthly administration of ketoconazole. Cutis 1984;34:470-1. 9. Hanifin J. Adverse reactions. In: Levine HB, ed. Ketoconazole in the management of fungal disease. Hong Kong: ADIS Press, 1983:156-9. 10. Janssen PAJ, Symoens JE. Hepatic reactions during ketoconazole treatment. Am J Moo 1983;74:80-5. 11. Schuermeyer T, Nieschlag E. Ketoconazole induced drop in serum and saliva testosterone. Lancet 1982;2:1098. 12. Van Cutsem J, Van Gerven F, Zaman R, et al. Pharmacological and preclinical results with a new oral and topical broad-spectrum antifungal, R51211. Thirteenth International Congress of Chemotherapy. Vienna: Aug 28-Sept 2, 1983;40:1-11. 13. Van Cutsem J, Van Gerven F, Janssen PAJ. The antifungal activity of azoles: in vitro and in vivo activity. Ninth Congress of the National Society for Human and Animal Mycology. Atlanta, Ga: May 19-24, 1985:3-23. 14. Van Cutsem J, Janssen PAJ. Nouveaux antimycosiques: activite in vitro et in vivo. Bull Soc Fr Mycol Moo 1985; 14:1311-4. 15. Van Cutsem J, Van Gerven F, Janssen PAJ. The in vitro and in vivo antifungal activity ofitraconazole. In: Fromtling RA, ed. Recent trends in the discovery, development and evaluation of antifungal agents. JR Prous Science Publishers SA, 1987:177-92. 16. Delescluse J. Treatment of pityriasis versicolor with oral
Journal of the American Academy of Dermatology
Delescluse
17. 18. 19. 20. 21.
RS12ll: a pilot study. In: Clinical Research Report on RS1211, N34494. Janssen Pharmaceutica, 1983. Roseeuw D, Willemsen M, 't Kint R, et al. Itraconazole in the treatment of superficial mycoses: a double-blind study versus placebo. Clin Exp Derrnatol 1990;101-4. Faergeman J. TreatIl)ent of pityriasis versicolor with itraconazole: a double-blind placebo controlled study. Mycoses 1988;31:377-9. Delescluse J, Cauwenbergh G, Degreef H. Itraconazole, a new orally active antifungal in the treatment of pityriasis versicolor. Br J DermatoI1986;1l4:70l-3. Grant MS, Clissold SP. Itracc,mazole, a reviewofits pharmacodynamic and pharmacokinetic properties and therapeutic use in superficial and systemic. Drugs 1989;37:310-44. Cauwenbergh G, De Doncker P, Stoops K, et al. !tracon-
azole in the treatment ofmycoses in man: a review of3 years of clinical experience. Rev Infect Dis 1987;9(suppll):14652. 22. Galimberti RL, Villalba I, Galarza S, et al. Itraconazole in pityriasis versicolor: ultrastructural changes in Malassezia furfur produced during treatment. Rev Infect Dis 1987; 9(suppl 1):134-8. 23. Del Palacio Hernandez A, Delgado Vincente S, Menendez Ramos F, et al. Randomized comparative clinical trial of itraconazole and selenium sulfide shampoo for the treatment of pityriasis versicolor. Rev Infect Dis 1987;9(suppl 1):121-7. 24. Maddin S. Clinical evaluation of itraconazole versus c1otrimazo1e in pityriasis versicolor [Unpublished report). January 1989.
Itraconazole in common dermatophyte infections of the skin: Fixed treatment schedules Amado Saul, MD,a and Alejandro Bonifaz, MBa, b Guadalupe Tepeyac, Mexico Itraconazole is an effective medication against the most common dermatophytoses. It has been shown to be more active than griseofulvin and ketoconazole. Ease of use, affinity for keratinized tissues, lack of toxicity, continued activity after discontinuation, and the possibility of using fixed schedules are advantages of itraconazole. The fixed schedules indicated by pharmacokinetics and clinical studies are one 100 mg capsule daily for 15 days in cases of tinea corporis and tinea cruris and the same dosage for 30 days in cases of tinea pedis and tinea manuum. These fixed treatments have some limitations, and they are not recommended for treating tinea capitis and tinea unguium. The drug is well tolerated. (J AM ACAD DERMATOL 1990;23:554-8.)
REVIEW OF EFFICACY
The advent of new lipophilic triazole derivative itraconazole has greatly improved the treatment of dermatophytoses because it is more active than griseofulvin and ketoconazole and is better tolerated. Advantages of itraconazole include its ease of administration, affinity for keratinized tissues, continued action after drug discontinuation, lack of toxicity, and the possibility of fixed treatment schedules. 1 This short review will be limited to treatment of tinea corporis, tinea cruris, tinea manuum, and tinea pedis. In infections ofnails and scalp, fixed treatment schedules are not used and consequently are outside the scope of this review. From the Dermatologic Service" and the Department of Mycology;b General Hospital of Mexico, University of Mexico. Reprint requests: Amado Saul, MD, Martha 149, Guadalupe Tepeyac, Mexico, D.F., CP 07840. Mexico. 16/0/21855
554
The dosage used initially was 50 mg!day with a meal to facilitate absorption. Clinical and mycologic efficacy was shown, but the cure rate was relatively low even after 8 weeks of treatment. I In the first double-blind study Cauwenbergh and De Doncker 1 compared 50 mg/day of itraconazole versus placebo in 80 patients treated for a maximum of 2 months. Mycologic cure was obtained in 59% of patients with itraconazole and in 32% of those with placebo (p = 0.024). It had been commented in this study that the dosage was too low. We arrived at the same conclusion in an open pilot trial that we performed at the General Hospital of Mexico,2 where 29 patients were treated. They had dermatophytoses of the body, groin, and feet caused by Trichophyton rubrum, Microsporum canis, Trichophyton tonsurans, and Epidermophyton floccosum. The daily dose used was 50 mg for 30 to 60 days. Clinical improvement (as judged by disap-
area, (3) type of infection, (4) the host's ability to respond, (5) use of combinations of drugs, (6) the vehicle to be used, (7) prophylactic therapy, and (8) ancillary therapy. Treatment to date has been directed toward elimination of the pathogen. It is time to ask ourselves a few questions: 1. Why is only one hand involved in the two-foot one-hand syndrome? 2. Why are dermatophyte infections rare on the scrotum and penis yet common in the groin? 3. Why lre some persons resistant to infection?
Therapy for skin mycoses The answers to these questions may enable us to treat the patient, not the organism, and to provide the ultimate solution to mycotic infections.
REFERENCES 1. Nyawalo JO, Hoire M. Single dose and intermittent griseofulvin regimens in the treatment of tinea capitis in Kenya. Mycoses 1988;31:229-34. 2. Faergemann J, Fredricksson T. Tinea versicolor: some new aspects on etiology, pathogenesis, and treatment. Int J DermatoI1982;21:8-22. 3. Rausch LJ, Jacobs PH. Tinea versicolor treatment and prophylaxis with monthly administration of ketoconazole. Cutis 1984;34:470-1.
I traconazole in tinea versicolor: A review 1. Delescluse, MD Brussels, Belgium
Itraconazole, a new orally active triazole antifungal, has been tested in patients with pityriasis versicolor. A number of studies have shown that itraconazole is effective for this mild fungal skin disease. The total dose required for effective treatment is 1000 mg, and it has been given as 200 mg for 5 days or 7 days. The organisms disappear slowly from the skin, even when dead, and the results should be assessed clinically and mycologically at around 3 to 4 weeks after treatment. Numerous studies have shown that itraconazole is superior to placebo and as effective as selenium sulfide, clotrimazole, and ciclopirox olamine. It is also better tolerated by patients than selenium sulfide. (J AM ACAD DERMATOL 1990;23:551-4.) Agents that are available for treatment of tinea versicolor (TV) are numerous, particularly topical agents. I -3 These topical agents vary in their effectiveness, and lengthy treatment periods are necessary. Surprisingly, the use of a 2% ketoconazole shampoo in one study resulted in excellent results with a single-day application. 4 At present the only oral agent available for the treatment of TV is ketoconazole. 5-7 Clinical trials have confirmed that treatment periods of 5 to 28 days give good results. Patients find oral treatment acceptable,8 but in view of ketoconazole's side effects a certain degree of hesitation continues to exist about the oral treatment of TV.9.11 Therefore new oral agents that are an improvement over the shortcomings of existing drugs are of From the Department of Dermatology, Clinic Cesar de Paepe. Reprint requests: J. Dc1csc1use, MD, Department of Dermatology, Clinic Cesar De Paepe, Cellebroersstraat II, B·IOOO Brussels, Bel· gium. 16/0/21856
considerable interest in the treatment of superficial mycoses. Itraconazole is an oral triazole- derivative that has been shown to be highly active in vitro against a range of fungi, including Pityrosporum species. 12, 13 Animal studies indicated that this drug is five to 10 times more potent than ketoconazole when administered orally. Itraconazole also shows a marked fungicidal effect on Pityrosporum species, the causative organisms ofTV. 14 More than 90% of the tested Pityrosporum strains were sensitive to itraconazole at a concentration of 0.1 J.Lg/ml. I5 MATERIAL AND METHODS
In TV, four different types of studies were performed worldwide on a total of 967 patients. The first type of study compared in an open trial the results obtained with itraconazolein dosages of 50 or 100 mg/day. The second type of study was placebo controlled. The third type of study compared in an open, randomized fashion different short treatment schedules. The last type compared itraconazole with short fixed treatment schedules versus top· ical reference drugs such as selenium sulfide, cic1opirox olamine, and c1otrimazole. 551
552 De/esc/use In all these studies patients were seen for clinical and mycologic examinations immediately before starting treatment, 1 week after the end of treatment, and 3 to 4 weeks after the end of therapy. At each visit signs and symptoms were scored. Findings of Wood's light examination and microscopy were recorded as negative or positive, and patients were asked about side effects.
RESULTS The first study of 33 patients compared the activity of 50 and 100 mg/day of itraconazole in the treatment of TV. 16 No fixed treatment length was used. The results showed that clinical response was obtained in more than 90% of the patients with either of the two dosages. Because it took a long time for all lesions to disappear and in view of past ketoconazole experience, short fixed treatment schedules with itraconazole were tested in the other studies. In the second phase placebo-controlled studies confirmed the effect of itraconazole versus placebo in the treatment ofTY. In a first small, double-blind study in Brussels 17 Roseeuwet al., using a treatment schedule of 100 mg itraconazole daily for 15 days, obtained an 88% mycologic cure rate versus 0% in the placebo group (p < 0.01). All placebo-treated patients were cured afterward with 100 mg itraconazole given daily for 15 days. These results were also confirmed in Sweden by Faergemann18 with the same treatment schedule. These results indicate that itraconazole is superior to placebo for the treatment of TV, although in these studies long-term follow-up data were not available to evaluate relapse rates after stopping therapy. An American study in which 200 mg/day itraconazole was given for 7 days also showed the superiority of itraconazole (89% mycologic cure) versus placebo (6% mycologic cure) 4 to 5 weeks after therapy (unpublished results; data on file). In the third type of study a comparison of different dose schedules was carried out first by Delescluse et at1 9 in Belgium with 73 patients. A regimen of 100 mg/day ofitraconazolefor 15 days gave a 100% response rate; 200 mg/day for 5 days gave an 85% response rate. Two patients who had received 50 mg itraconazole daily for 14 days had relapses within 2 months of finishing treatment. A review of the results worldwide of different treatment schedules suggests that a minimal total dose of 1000 mg is needed to obtain acceptable results. 20 ;21 The results can be divided into those patients (n = 135) treated with a total dosMe of less than 1000 mg, usually 100 mg once daily for 5 to 7 days, and those
Journal of the American Academy of Dermatology
treated with 1000 mg or more (n = 351), usually 100 mg once daily for 10 to 15 days or 200 mg daily as single or divided doses for 5 to 7 days. Treatment with itraconazole, 200 mg once daily or 100 mg twice daily, for 5 days, cured more than 90% of patients when assessed 3 weeks after therapy. Clinical and mycologic recovery continued in patients for several weeks after completion of therapy, probably because of the persistence of itraconazole in the epidermis. Repigmentation of affected skin lagged behind the relief of other symptoms, as is normally observed during recovery from TV, but by 2 months most responders had a normal skin color. Hyperpigmented lesions returned to normal faster than hypopigmented lesions. 22 Posttreatment surveillance of responding patients suggests that a minimal total dose of 1000 mg is required to prevent relapses. There is no major difference in response rate between 200 mg itraconazole given daily for 5 days or 200 mg itraconazole given daily for 7 days. In the last type ofstudy itraconazole's efficacy was compared with that of topical reference drugs such as selenium sulfide shampoo, clotrimazole, and ciclopirox 0Iamine. 23 , 24 In a single-blind study by Del Palacio et al. 23 of Spain, 200 mg itraconazole once daily for 5 days was compared with 2.5% selenium sulfide shampoo applied for 10 minutes each night for 7 days. When assessed 3 weeks after treatment, 17 of 20 patients in the itraconazole group versus 16 of 20 patients in the selenium sulfide group were lesion free and the remainder had mild residuallesions. The tolerance of itraconazole was described as excellent, whereas eight patients had burning and irritation of the skin as a result of selenium sulfide; in one patient it was sufficiently severe to require discontinuation of therapy and treatment for the resulting exudation and pustules. On questioning, all itraconazole-treated and half the selenium sulfide-treated patients expressed a preference for oral medication. In two double-blind double-dummy studies, itraconazole was compared with topical clotrimazole24 and with topical cic1opirox olamine (multicenter, unpublished results, data on file, France). Clinical response was obtained in 86% of the itraconazoletreated patients versus 71 % in the c1otrimazole group at week 4 (3 weeks after therapy). In the first study, 30 patients with TV were treated twice daily ona double-blind basis with either 100 mg itraconazole daily for 5 days (n = 15) or with 1% c1otrimazole cream for 14 days (n = 15).
Volume 23 Number 3, Part 2 September 1990
In both treatment groups there was a significant improvement in severity scores for pruritus, erythema, and scaling by day 6; significant improvement in mycologic characteristics and hypopigmentation was seen by day 15. Although no statistically significant intergroup differences were detected, it is relevant to note that new lesions developed during therapy in the clotrimazole-treated group (three patients). In contrast, new lesions were not observed until the final follow-up visit in the systemically treated group (one patient). A positive KOH preparation was seen in only 25% of the itraconazole-treated patients versus 50% of the clotrimazole-treated patients at week 4 (3 weeks after therapy). In the second study 102 patients were treated with either itraconazole, 200 mg once daily for 10 days, or with ciclopirox olamine cream once daily for 15 days. Although no significant differences were obtained, itraconazole therapy resulted in a higher mycologic cure rate than ciclopirox olamine (86% vs 74%). Adverse effects were reported for 55 (6%) of 954 itraconazole-treated patients. No difference in occurrence was shown among the three total dose groups. Gastrointestinal disorders (e.g., abdominal pain, nausea, dyspepsia, diarrhea, vomiting) and headache were the most common complaints. There seems to be no relation between the occurrence of adverse effects and the dosage. DISCUSSION
Only a limited range of drugs is available for the oral treatment of fungal diseases. All have shortcomings in terms of efficacy or safety. Thus a new oral agent, especially one such as itraconazole, which is well tolerated and has a broad spectrum of activity and a favorable pharmacokinetic profile, is of considerable interest. As with vaginal candidosis, the ideal treatment regimen for an oral agent in TV uses a low dose of drug given for a short period. By comparison, ketoconazole in TV is usually given in 200 mg daily doses for 10 days (total dose 2000 mg). Clinical experience with itraconazole in TV indicates that it is effective at a minimal total dose of 1000 mg given in 5 days. Further placebo-controlled studies have shown itraconazole's superiority in this skin infection. The comparison with selenium sulfide demonstrates that topical therapy may be associated with adverse effects in addition to the practical problems of treating large body areas. Double-blind comparisons with c1otrimazole and/or ciclopirox olamine have also
Itraconazole in tinea versicolor 553 shown that itraconazole is more potent or at least equivalent than these topical agents with short treatment schedules. So far, studies indicate that itraconazole has a lower toxicity profile than ketoconazole. No consistent blood biochemical abnormalities were observed in patients with TV who were treated with itraconazole. Therefore I conclude that itraconazole is highly active in TV with short treatment lengths of 200 mg/day for 5 to 7 days. Because of the few reported side effects of itraconazole, this drug may be used for both treatment and prophylaxis in patients with TV, although prophylactic treatment remains controversial and should be evaluated in carefully designed clinical studies. REFERENCES 1. Ive F. Treatment ofskin infections and infestations. Br Med J 1973;4:475. 2. Chu AC. Comparative clinical trial of bifonazole solution versus selenium sulphide shampoo in the treatment of pityriasis versicolor. Dermatologica 1984;169(suppl 1): 81-6. 3. Hay RJ. Treatment of superficial fungal infections. Clin Exp DermatoI1981;6:509-13. 4. Meisel C. Einmaltherapie der Pityriasis versicolor mit Ketoconazol Shampoo [Unpublished report]. Data on file, Janssen, Belgium. March 1986. 5. Borelli D. Treatment of pityriasis versicolor with ketoconazole. Rev Infect Dis 1980;2:592-5. 6. Savin RC. Systemic ketoconazo1e in tinea versicolor: a double-blind evaluation and I-year follow-up. J AM ACAD DERMATOL 1984;10:824-30. 7. Faergeman J, Djiirv L. Tinea versicolor: treatment and prophylaxis with ketoconazo1e. Cutis 1982:30;542-50. 8. Rausch LJ, Jacobs PH. Tinea versicolor: treatment and prophylaxis with monthly administration of ketoconazole. Cutis 1984;34:470-1. 9. Hanifin J. Adverse reactions. In: Levine HB, ed. Ketoconazole in the management of fungal disease. Hong Kong: ADIS Press, 1983:156-9. 10. Janssen PAJ, Symoens JE. Hepatic reactions during ketoconazole treatment. Am J Moo 1983;74:80-5. 11. Schuermeyer T, Nieschlag E. Ketoconazole induced drop in serum and saliva testosterone. Lancet 1982;2:1098. 12. Van Cutsem J, Van Gerven F, Zaman R, et al. Pharmacological and preclinical results with a new oral and topical broad-spectrum antifungal, R51211. Thirteenth International Congress of Chemotherapy. Vienna: Aug 28-Sept 2, 1983;40:1-11. 13. Van Cutsem J, Van Gerven F, Janssen PAJ. The antifungal activity of azoles: in vitro and in vivo activity. Ninth Congress of the National Society for Human and Animal Mycology. Atlanta, Ga: May 19-24, 1985:3-23. 14. Van Cutsem J, Janssen PAJ. Nouveaux antimycosiques: activite in vitro et in vivo. Bull Soc Fr Mycol Moo 1985; 14:1311-4. 15. Van Cutsem J, Van Gerven F, Janssen PAJ. The in vitro and in vivo antifungal activity ofitraconazole. In: Fromtling RA, ed. Recent trends in the discovery, development and evaluation of antifungal agents. JR Prous Science Publishers SA, 1987:177-92. 16. Delescluse J. Treatment of pityriasis versicolor with oral
Journal of the American Academy of Dermatology
Delescluse
17. 18. 19. 20. 21.
RS12ll: a pilot study. In: Clinical Research Report on RS1211, N34494. Janssen Pharmaceutica, 1983. Roseeuw D, Willemsen M, 't Kint R, et al. Itraconazole in the treatment of superficial mycoses: a double-blind study versus placebo. Clin Exp Derrnatol 1990;101-4. Faergeman J. TreatIl)ent of pityriasis versicolor with itraconazole: a double-blind placebo controlled study. Mycoses 1988;31:377-9. Delescluse J, Cauwenbergh G, Degreef H. Itraconazole, a new orally active antifungal in the treatment of pityriasis versicolor. Br J DermatoI1986;1l4:70l-3. Grant MS, Clissold SP. Itracc,mazole, a reviewofits pharmacodynamic and pharmacokinetic properties and therapeutic use in superficial and systemic. Drugs 1989;37:310-44. Cauwenbergh G, De Doncker P, Stoops K, et al. !tracon-
azole in the treatment ofmycoses in man: a review of3 years of clinical experience. Rev Infect Dis 1987;9(suppll):14652. 22. Galimberti RL, Villalba I, Galarza S, et al. Itraconazole in pityriasis versicolor: ultrastructural changes in Malassezia furfur produced during treatment. Rev Infect Dis 1987; 9(suppl 1):134-8. 23. Del Palacio Hernandez A, Delgado Vincente S, Menendez Ramos F, et al. Randomized comparative clinical trial of itraconazole and selenium sulfide shampoo for the treatment of pityriasis versicolor. Rev Infect Dis 1987;9(suppl 1):121-7. 24. Maddin S. Clinical evaluation of itraconazole versus c1otrimazo1e in pityriasis versicolor [Unpublished report). January 1989.
Itraconazole in common dermatophyte infections of the skin: Fixed treatment schedules Amado Saul, MD,a and Alejandro Bonifaz, MBa, b Guadalupe Tepeyac, Mexico Itraconazole is an effective medication against the most common dermatophytoses. It has been shown to be more active than griseofulvin and ketoconazole. Ease of use, affinity for keratinized tissues, lack of toxicity, continued activity after discontinuation, and the possibility of using fixed schedules are advantages of itraconazole. The fixed schedules indicated by pharmacokinetics and clinical studies are one 100 mg capsule daily for 15 days in cases of tinea corporis and tinea cruris and the same dosage for 30 days in cases of tinea pedis and tinea manuum. These fixed treatments have some limitations, and they are not recommended for treating tinea capitis and tinea unguium. The drug is well tolerated. (J AM ACAD DERMATOL 1990;23:554-8.)
REVIEW OF EFFICACY
The advent of new lipophilic triazole derivative itraconazole has greatly improved the treatment of dermatophytoses because it is more active than griseofulvin and ketoconazole and is better tolerated. Advantages of itraconazole include its ease of administration, affinity for keratinized tissues, continued action after drug discontinuation, lack of toxicity, and the possibility of fixed treatment schedules. 1 This short review will be limited to treatment of tinea corporis, tinea cruris, tinea manuum, and tinea pedis. In infections ofnails and scalp, fixed treatment schedules are not used and consequently are outside the scope of this review. From the Dermatologic Service" and the Department of Mycology;b General Hospital of Mexico, University of Mexico. Reprint requests: Amado Saul, MD, Martha 149, Guadalupe Tepeyac, Mexico, D.F., CP 07840. Mexico. 16/0/21855
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The dosage used initially was 50 mg!day with a meal to facilitate absorption. Clinical and mycologic efficacy was shown, but the cure rate was relatively low even after 8 weeks of treatment. I In the first double-blind study Cauwenbergh and De Doncker 1 compared 50 mg/day of itraconazole versus placebo in 80 patients treated for a maximum of 2 months. Mycologic cure was obtained in 59% of patients with itraconazole and in 32% of those with placebo (p = 0.024). It had been commented in this study that the dosage was too low. We arrived at the same conclusion in an open pilot trial that we performed at the General Hospital of Mexico,2 where 29 patients were treated. They had dermatophytoses of the body, groin, and feet caused by Trichophyton rubrum, Microsporum canis, Trichophyton tonsurans, and Epidermophyton floccosum. The daily dose used was 50 mg for 30 to 60 days. Clinical improvement (as judged by disap-
