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Pityriasis versicolor with ketoconazole
Volume 20 Number 4 April 1989
dermis; numerous solid strands of epithelial cells and small cystic ducts were embedded into a fibrous stroma. Some ductal structures were filled with colloidal material and showed a commalike taft of epithelial cells (Fig. 2). A cutaneous biopsy specimen of a papular lesion located on the lower right eyelid of the mother showed epithelial strands and ductal structures in the dermis, characteristic of papular syringoma. Keratin cysts were not observed.
Discussion. Friedman and Butler reported two cases of infraorbital syringomas in a milium-like pattern. Histotogic characteristics in these cases showed typical changes of syringoma, but the presence of large keratinfilled cysts in the superficial dermis made the lesions look like milia. Our patient had clinical and histologic features identical to the two previously reported patients, except for the family history of syringoma. It should be emphasized that familial syringoma is thought to be an uncommon variant of syringomaJ"3 Our patient's mother had typical infraorbital syringomas both clinically and histologicaUy. These data suggest that in our patient the syringomas were inherited. As far as we know, this is the first reported case of familial syringoma with this unusual clinical presentation. We think that to detect familial cases of syringoma, unusual clinical presentations such as mih'um-like lesions should be considered. M. Ribera, MD, a O. Servitje, M D ) J. Peyri, MD) and C. Ferrbndiz, MD ~ Hospital de Badalona, Germans Trias i Pujol, a and Hospital de Bellvitge, Princeps d'Espanya b Barcelona, Spain
REFERENCES 1. Baden HP. Hereditary syringomas [Letter]. Arch Dermatol 1977;113:1133. 2. Hashimoto K, Blum D, Fukaya T, Eto H. Familial syringoma. Arch Dermatol 1985;121:756-60. 3. Woringer F, Eichler A. Constatation et reflexionau subjet d'un cas d'hidrad6nome 6ruptive. Ann Dermatol Venereo[ 1951;78:152-64.
Methylchloroisothiazolinonemethylisothiazolinone (Kathon CG) To the Editor." In regard to the article entitled "Kathon CG: A Review" (J AM ACAD DERMATOL1988;18:3508), it should have been titled "Methylchloroisothiazolinone-methylisothiazolinone (Kathon CG)." Methylchloroisothiazolinone-methylisothiazolinone is the official Cosmetic, Toiletry, and Fragrance Association (CTFA) name; Kathon CG is one of many trade names. It is important to use the proper CTFA name because all cosmetics in America are labeled only with the
Correspondence
703
official standard CTFA name. Kathon CG is never used on the labels of cosmetics. The authors point out that we are fortunate indeed to have cosmetic ingredient labeling in the United States. This labeling requirement, however, does not include products used in beauty salons, topical medications such as sun blocks, or trial size cosmetics found in hotel rooms. I recently saw a lady who had a facial eruption caused by a cream containing methylchloroisothiazolinonemethylisothiazolinone. She assiduously avoided cosmetics containing this preservative and thus avoided dermatitis. She did break out, however, from the following unlabeled products: (1) a trial size moisturizer found in a hotel room, (2) a sun block, and (3) a soap that she used while hospitalized. Presumably these products contained the preservative but were unlabeled. Patients and physicians in the United States have greatly benefited from having cosmetic labeling for the last 10 years. We, however, must endeavor to have salon products and medicaments labeled with the ingredients also.
Waiter G. Larsen, MD Portland Dermatology Clinic, Portland, OR 97210
Pityriasis versicolor with ketoconazole To the Editor." Pityriasis (tinea) versicolor is a common superficial fungal infection caused by Pityrosporum orbiculare. The organism appears to reside in the scalp and seed the body. For this reason, therapy with an oral antimycotic is appropriate. In addition, topical administration can be tedious and messy. Oral ketoconazole has been studied in controlled' and open studies in pityriasis versicolor, z-4In these trials, 200 or 400 nag ketoconazole was administered for 1 week to 1 month. Cure rates ranged from 91% to 95%. Short courses of therapy with oral ketoconazole, lasting up to 10 days, appear to be as effective as longer courses lasting from 10 days to a month. No studies, however, have been conducted to compare short courses of oral ketoconazole therapy of different durations. In 1987, we conducted a double-blind study comparing the efficacy of two short courses of therapy with oral ketoconazole, lasting 5 and 10 days, with placebo in pityriasis versicolor. Patients enrolled in the study ranged in age from 13 to 59 years. All patients were required to have normal liver and kidney panels before enrollment. Pityriasis versicolor was confirmed microbiologicaUy by a potassium hydroxide examination with positive results. None of the patients had received
704
Journal of the American Academy of Dermatology
Correspondence
systemic antirnycotics in the month preceding enrollment in the study' or topical antimycotics in the preceding 2 weeks. They were not allowed to take any other antimycotics during the study. Patients were randomly allocated to receive 200 nag oral ketoconazole daffy for 5 days and placebo daily for the next 5 days, 200 mg oral ketoconazole daily for 10 days, or placebo daily for 10 days. All tablets were identical in appearance to maintain double-blinding. Patients returned 20 days after the end of the 10-day course for a clinical and mycologic workup. The liver and kidney panels were repeated at follow-up examination. Of the 61 patients enrolled in the study, 59 were evaluated. One patient was lost to follow-up, and one discontinued the course because of diarrhea and abdominal colic. Thirty-five of the 39 patients (90%) receiving ketoconazole were cured clinically and mierobiologieally at the 20-day follow-up compared with three patients (17%) receiving placebo. The cure rates for the two ketoconazole groups were similar: 90% for the 10-day regimen and 84% for the 5-day regimen. These cure rates were significant compared with the placebo group (p < 0.001). One patient had elevated transaminase values (GGT, ALT, and ALK-P) at follow-up: These values returned to normal levels 6 clays after follow-up and remained within normal range 2 weeks later. The ease of treatment and lack of side effects make oral ketoconazole the treatment of choice for pityriasis versicolor. A 5-day course is as effective as a 10-day one.
Nardo Zaias, MD 1680 Michigan Ave. Miami Beach, FL 33139
Reply To the Editor: The letter by Dr. Zaias provides additional evidence that a short course of oral ketoconazole is effective for tinea versicolor. In treating a benign condition like tinea versicolor, physicians must, of course, do no harm. Reports of adverse reactions to ketoconazole on file at Janssen Pharmaceutica, Piscataway, N.J., contain three ease reports of drug-associated hepatitis that developed during the course of treatment for tinea versicolor. In these eases the drug had been administered daffy for 15, 26, and 45 days before symptoms began. In each patient the hepatitis was self-limited and was not fatal. Reviewst3 of ketoconazole-asseciated hepatitis have emphasized that the risk of drug-associated hepatitis developing increases with the duration of treatment. Lewis et al, 1 and
Lake-Bakaar et al.3 determined the latency period in 48 patients with probable ketoconazole-associated hepatitis and reported that symptoms developed in only two patients in the first week, three in the second week, nine in the third week, and symptoms developed in the remainder (34 patients) in the next several weeks. Hay and Midgeley4 have shown that in England ketoconazole was equally effective when prescribed for 5 or 10 days for treatment of tinea versicolor. Zaias has now confirmed efficacy with only 200 mg for 5 days in treating this stubborn condition in tropical Miami. Rausch and Jacobs5reported from the Mediterranean climate of California that 400 mg of ketoconazole in a single-dose, single-day treatment was equally efficacious. My own experience with ketoconazole in the treatment of tinea versicolor in my subtropical Gulf Coast location 6 did not confirm this. Some patients responded, but additional treatment was required to produce a uniformly high response rate. After that experience, and with new knowledge of the pharmacokineties and bioavailability of ketoconazole, I have settled on a "two-Saturday" treatment schedule that is highly effective and safe. Given the impracticality of conducting a sufficiently large clinical trial to identify (1) the optimal dose, (2) the most effective dosage schedule, and (3) the relative risks of each treatment, dermatologists should at least review the rationale behind the "two-Saturday" treatment schedule. There are two pharmacologic considerations pertinent to therapy with ketoconazole for a stratum corneum infection. The first is to prescribe a dose that is adequate to produce a high blood level. After oral administration ketoconazole undergoes presystemic elimination, that is, hepatic rnicrosomal binding, which reduces the quantity of drug available for distribution in the body's fluid and electrolyte compartment. Huang et al. 7 demonstrated peak blood levels after a single oral dose with 200, 400, and 800 mg to be 5.4, 11.8, and 21.8 mg/L, respectively. Excellent blood levels are consistently obtained with a 400 mg dose, which is also well tolerated, whereas higher dosages frequently produce nausea and vomiting: For these reasons, 400 nag appears to be an optimal dose. The second consideration is that for ketoconazole to be effective, the drug must be bioavaffable at the site o f infection. Ketoconazole reaches the stratum corneum by means of the eccrine sweat pathway, where the drug is bound to the stratum corneum and concentrated by evaporation of sweat water: Sweat augmentation may produce drug levels in the stratum corneum that exceed the peak blood level and persist for days. Soap and water do not wash the drug from the stratum corneum. Significant levels in the skin have been documented 7 and 10 days after a single oral dose. For the following reasons a "two-Saturday" treat-
dermis; numerous solid strands of epithelial cells and small cystic ducts were embedded into a fibrous stroma. Some ductal structures were filled with colloidal material and showed a commalike taft of epithelial cells (Fig. 2). A cutaneous biopsy specimen of a papular lesion located on the lower right eyelid of the mother showed epithelial strands and ductal structures in the dermis, characteristic of papular syringoma. Keratin cysts were not observed.
Discussion. Friedman and Butler reported two cases of infraorbital syringomas in a milium-like pattern. Histotogic characteristics in these cases showed typical changes of syringoma, but the presence of large keratinfilled cysts in the superficial dermis made the lesions look like milia. Our patient had clinical and histologic features identical to the two previously reported patients, except for the family history of syringoma. It should be emphasized that familial syringoma is thought to be an uncommon variant of syringomaJ"3 Our patient's mother had typical infraorbital syringomas both clinically and histologicaUy. These data suggest that in our patient the syringomas were inherited. As far as we know, this is the first reported case of familial syringoma with this unusual clinical presentation. We think that to detect familial cases of syringoma, unusual clinical presentations such as mih'um-like lesions should be considered. M. Ribera, MD, a O. Servitje, M D ) J. Peyri, MD) and C. Ferrbndiz, MD ~ Hospital de Badalona, Germans Trias i Pujol, a and Hospital de Bellvitge, Princeps d'Espanya b Barcelona, Spain
REFERENCES 1. Baden HP. Hereditary syringomas [Letter]. Arch Dermatol 1977;113:1133. 2. Hashimoto K, Blum D, Fukaya T, Eto H. Familial syringoma. Arch Dermatol 1985;121:756-60. 3. Woringer F, Eichler A. Constatation et reflexionau subjet d'un cas d'hidrad6nome 6ruptive. Ann Dermatol Venereo[ 1951;78:152-64.
Methylchloroisothiazolinonemethylisothiazolinone (Kathon CG) To the Editor." In regard to the article entitled "Kathon CG: A Review" (J AM ACAD DERMATOL1988;18:3508), it should have been titled "Methylchloroisothiazolinone-methylisothiazolinone (Kathon CG)." Methylchloroisothiazolinone-methylisothiazolinone is the official Cosmetic, Toiletry, and Fragrance Association (CTFA) name; Kathon CG is one of many trade names. It is important to use the proper CTFA name because all cosmetics in America are labeled only with the
Correspondence
703
official standard CTFA name. Kathon CG is never used on the labels of cosmetics. The authors point out that we are fortunate indeed to have cosmetic ingredient labeling in the United States. This labeling requirement, however, does not include products used in beauty salons, topical medications such as sun blocks, or trial size cosmetics found in hotel rooms. I recently saw a lady who had a facial eruption caused by a cream containing methylchloroisothiazolinonemethylisothiazolinone. She assiduously avoided cosmetics containing this preservative and thus avoided dermatitis. She did break out, however, from the following unlabeled products: (1) a trial size moisturizer found in a hotel room, (2) a sun block, and (3) a soap that she used while hospitalized. Presumably these products contained the preservative but were unlabeled. Patients and physicians in the United States have greatly benefited from having cosmetic labeling for the last 10 years. We, however, must endeavor to have salon products and medicaments labeled with the ingredients also.
Waiter G. Larsen, MD Portland Dermatology Clinic, Portland, OR 97210
Pityriasis versicolor with ketoconazole To the Editor." Pityriasis (tinea) versicolor is a common superficial fungal infection caused by Pityrosporum orbiculare. The organism appears to reside in the scalp and seed the body. For this reason, therapy with an oral antimycotic is appropriate. In addition, topical administration can be tedious and messy. Oral ketoconazole has been studied in controlled' and open studies in pityriasis versicolor, z-4In these trials, 200 or 400 nag ketoconazole was administered for 1 week to 1 month. Cure rates ranged from 91% to 95%. Short courses of therapy with oral ketoconazole, lasting up to 10 days, appear to be as effective as longer courses lasting from 10 days to a month. No studies, however, have been conducted to compare short courses of oral ketoconazole therapy of different durations. In 1987, we conducted a double-blind study comparing the efficacy of two short courses of therapy with oral ketoconazole, lasting 5 and 10 days, with placebo in pityriasis versicolor. Patients enrolled in the study ranged in age from 13 to 59 years. All patients were required to have normal liver and kidney panels before enrollment. Pityriasis versicolor was confirmed microbiologicaUy by a potassium hydroxide examination with positive results. None of the patients had received
704
Journal of the American Academy of Dermatology
Correspondence
systemic antirnycotics in the month preceding enrollment in the study' or topical antimycotics in the preceding 2 weeks. They were not allowed to take any other antimycotics during the study. Patients were randomly allocated to receive 200 nag oral ketoconazole daffy for 5 days and placebo daily for the next 5 days, 200 mg oral ketoconazole daily for 10 days, or placebo daily for 10 days. All tablets were identical in appearance to maintain double-blinding. Patients returned 20 days after the end of the 10-day course for a clinical and mycologic workup. The liver and kidney panels were repeated at follow-up examination. Of the 61 patients enrolled in the study, 59 were evaluated. One patient was lost to follow-up, and one discontinued the course because of diarrhea and abdominal colic. Thirty-five of the 39 patients (90%) receiving ketoconazole were cured clinically and mierobiologieally at the 20-day follow-up compared with three patients (17%) receiving placebo. The cure rates for the two ketoconazole groups were similar: 90% for the 10-day regimen and 84% for the 5-day regimen. These cure rates were significant compared with the placebo group (p < 0.001). One patient had elevated transaminase values (GGT, ALT, and ALK-P) at follow-up: These values returned to normal levels 6 clays after follow-up and remained within normal range 2 weeks later. The ease of treatment and lack of side effects make oral ketoconazole the treatment of choice for pityriasis versicolor. A 5-day course is as effective as a 10-day one.
Nardo Zaias, MD 1680 Michigan Ave. Miami Beach, FL 33139
Reply To the Editor: The letter by Dr. Zaias provides additional evidence that a short course of oral ketoconazole is effective for tinea versicolor. In treating a benign condition like tinea versicolor, physicians must, of course, do no harm. Reports of adverse reactions to ketoconazole on file at Janssen Pharmaceutica, Piscataway, N.J., contain three ease reports of drug-associated hepatitis that developed during the course of treatment for tinea versicolor. In these eases the drug had been administered daffy for 15, 26, and 45 days before symptoms began. In each patient the hepatitis was self-limited and was not fatal. Reviewst3 of ketoconazole-asseciated hepatitis have emphasized that the risk of drug-associated hepatitis developing increases with the duration of treatment. Lewis et al, 1 and
Lake-Bakaar et al.3 determined the latency period in 48 patients with probable ketoconazole-associated hepatitis and reported that symptoms developed in only two patients in the first week, three in the second week, nine in the third week, and symptoms developed in the remainder (34 patients) in the next several weeks. Hay and Midgeley4 have shown that in England ketoconazole was equally effective when prescribed for 5 or 10 days for treatment of tinea versicolor. Zaias has now confirmed efficacy with only 200 mg for 5 days in treating this stubborn condition in tropical Miami. Rausch and Jacobs5reported from the Mediterranean climate of California that 400 mg of ketoconazole in a single-dose, single-day treatment was equally efficacious. My own experience with ketoconazole in the treatment of tinea versicolor in my subtropical Gulf Coast location 6 did not confirm this. Some patients responded, but additional treatment was required to produce a uniformly high response rate. After that experience, and with new knowledge of the pharmacokineties and bioavailability of ketoconazole, I have settled on a "two-Saturday" treatment schedule that is highly effective and safe. Given the impracticality of conducting a sufficiently large clinical trial to identify (1) the optimal dose, (2) the most effective dosage schedule, and (3) the relative risks of each treatment, dermatologists should at least review the rationale behind the "two-Saturday" treatment schedule. There are two pharmacologic considerations pertinent to therapy with ketoconazole for a stratum corneum infection. The first is to prescribe a dose that is adequate to produce a high blood level. After oral administration ketoconazole undergoes presystemic elimination, that is, hepatic rnicrosomal binding, which reduces the quantity of drug available for distribution in the body's fluid and electrolyte compartment. Huang et al. 7 demonstrated peak blood levels after a single oral dose with 200, 400, and 800 mg to be 5.4, 11.8, and 21.8 mg/L, respectively. Excellent blood levels are consistently obtained with a 400 mg dose, which is also well tolerated, whereas higher dosages frequently produce nausea and vomiting: For these reasons, 400 nag appears to be an optimal dose. The second consideration is that for ketoconazole to be effective, the drug must be bioavaffable at the site o f infection. Ketoconazole reaches the stratum corneum by means of the eccrine sweat pathway, where the drug is bound to the stratum corneum and concentrated by evaporation of sweat water: Sweat augmentation may produce drug levels in the stratum corneum that exceed the peak blood level and persist for days. Soap and water do not wash the drug from the stratum corneum. Significant levels in the skin have been documented 7 and 10 days after a single oral dose. For the following reasons a "two-Saturday" treat-