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Critical review of efficacy of pulse therapy regimens using terbinafine to treat dermatophyte toenail onychomycosis
P1810
P1812
COST-EFFECTIVENESS ANALYSIS COMPARING AMOROLFINE AND CICLOPIROX IN THE TREATMENT OF ONYCHOMYCOSIS WITHOUT MATRIX INVOLVEMENT Tania Furtado, Lucie Adjadj, Health Economics Department, La De´fense, France; Klara Halmy, MD, Hospital and Polyclinic, Department of Mycology, Kene´zy Gyula, Hungary Introduction: Onychomycosis is a common nail fungal disease that accounts for more than 50% of nail infections. Topical nail lacquers are often used for the treatment of onychomycosis without matrix involvement. A recent clinical trial comparing amorolfine 5% and ciclopirox 8% has proven that amorolfine is more effective. Since cost is an important element when selecting a given treatment, a cost-effectiveness analysis has been conducted to compare the monetary value of both drugs. Objective: To assess the relative cost-effectiveness of two topical antifungal nail lacquers: amorolfine 5% versus ciclopirox 8% in the treatment of onychomycosis without matrix involvement, in Germany, Mexico, and Venezuela. Methods: This pharmacoeconomic study was conducted from the society payer perspective of Germany. For Mexico and Venezuela, a patient payer perspective was adopted. This cost-effectiveness analysis is based on the results obtained in a prospective, randomized, open-label clinical trial, comparing the efficacy and safety of amorolfine and ciclopirox for the treatment of onychomycosis without matrix involvement. Amorolfine was applied once weekly and ciclopirox, three times per week for the first month, twice weekly for the second month, and once a week from the third month. Study products were applied during a 6-month period for fingernails and 12 months for toenails. For the pharmacoeconomic analysis, the clinical cure rate after treatment (clinical cure was defined as patient with no more than 1% to 2% of the nail surface infected) was chosen as the effectiveness measure. Regarding the cost elements, direct costs related to drug acquisition were used.
CUTANEOUS ALTERNARIOSIS Josep Pujol-Montcusi, MD, Pilar Turegano, MD, Raventos Antoni, MD, Richart Cristobal, MD Hospital Univeritari Joan XXIII, Tarragona, Tarragona, Spain Alternaria species are well-known plant pathogens that belong to the group of dematiaceous fungi (phaeohyphomycetes). Despite its frequent isolation from the skin surface, Alternaria is exceptionally pathogenic for humans. In recent years Alternaria spp. are increasingly recognized as pathogens in immunocompromised patients or those with significant underlying disease. We describe a case of cutaneous alternariosis in an elderly patient with chronic bronchitis receiving low-dose oral steroid therapy. He developed hyperkeratotic nodules on the lower legs, resembling multiple keratoacanthomas or squamous cell carcinomas. Surgical excision of one lesion was performed. Histological analysis showed a pseudoepitheliomatous hyperplasia and the presence of fungal structures, more evident with periodic acideSchiff staining. Culture of biopsy material permitted the identification of Alternaria alternata. Treatment with oral itraconazole was begun, and lesions resolved within 4 months. Recognition of Alternaria as a potential opportunistic pathogen is important for the differential diagnosis of dermatologic lesions. The clinical manifestations of cutaneous alternariosis vary greatly. Lesions can appear as shallow-based nonhealing ulcers that evolve to nodules, subcutaneous noninflammatory cysts, verrucous-like lesions, or erythemathous, confluent, scaly patches. Variations in the host response and the morphologic appearance of hyphae in the histological study create the potential for diagnostic confusion. We review the literature regarding the incidence and clinical manifestations of cutaneous alternariosis in immunosuppressed and immunocompetent patients and the efficacy of oral itraconozole for these infections. Nothing to disclose.
Results: The percentage of patients with clinical cure after treatment was higher in the amorolfine group (34.4%) than in the ciclopirox group (23.6%) (P \.05). The cost per fingernail and toenail treated, as well as the cost per fingernail and toenail cured, was lower with amorolfine than with ciclopirox in Germany, Venezuela, and Mexico. Therefore amorolfine is a dominant strategy compared with ciclopirox since it is more effective and less costly. Moreover, when the higher efficacy of amorolfine is taken into account, a greater difference in terms of cost is obtained in favor of amorolfine. Conclusion: Amorolfine 5% nail lacquer is more cost-effective than ciclopirox 8% nail lacquer in Germany, Venezuela, and Mexico. Two of the authors are employees of Galderma International Supported by Galderma International
P1811 CRITICAL REVIEW OF EFFICACY OF PULSE THERAPY REGIMENS USING TERBINAFINE TO TREAT DERMATOPHYTE TOENAIL ONYCHOMYCOSIS Aditya Gupta, MD, PhD, Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Sciences Centre (Sunnybrook site) and the University of Toronto, Toronto, ON, Canada and Mediprobe Research Inc., London, ON, Canada; Janine R. Schouten, BSc, Mediprobe Research Inc., London, ON, Canada; Amir Tavakkol, PhD, US Clinical Development and Medical Affairs, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States Terbinafine is the most commonly prescribed antimycotic agent to treat toenail onychomycosis in North America, with the indicated regimen being continuous therapy (250 mg/d for 12 weeks). Recently, several studies have been published using terbinafine ‘‘pulse’’ or intermittent regimens. We searched MEDLINE (1966 to July 2004) for relevant studies using the search criteria ‘‘pulse,’’ ‘‘terbinafine,’’ ‘‘onychomycosis.’’ Combination studies were excluded. Seven pulse studies were identified and included in our analysis. The following regimens were reported in one or more trials: (1) 1000 mg/mo for 4 months; (2) 500 mg/d for 1 week/mo for 3 or 4 months; (3) 250 mg/d for 1 week/mo for 1, 2, 3, or 4 months; (4) a single 1000-mg dose administered once, twice, or 3 times (each dose separated by 2 weeks). In addition, an extended-pause regimen was reported using 250 mg/d for 2 or 3 months with a pause for 3 months followed by 250 mg/d for 1 additional month. Mycological cure (negative KOH and culture) was the primary outcome in 5 of 7 studies; the remaining two trials reported clinical cure only. The average sample size of these studies is n = 47 (range, 11-128 patients). When considering studies enrolling more than 50 patients, meta-analysis indicated an average mycological cure rate (6 95% confidence interval [CI]) of 58.6% 6 26.3% (range of efficacy 48.9% to 82.5%, N = 3 studies, 218 patients). This large confidence interval suggests that well-conducted, blinded, randomized, controlled trials (RCTs) are required to identify an optimal pulse therapy regimen. Additionally, no meaningful conclusions can be drawn from this calculation because no consistent regimen or follow-up time was followed. In contrast, the efficacy of terbinafine 250 mg/d for 12 weeks for toenail onychomycosis has been reported in several well-controlled RCTs. In studies enrolling more than 50 patients, the meta-analytic average mycological cure rate (6 95% CI) of the continuous terbinafine regimen was 78% 6 3.4% (range of efficacy rate 74.9% to 81.6%, N = 13 studies, 2983 patients). The high efficacy and tolerability of the Food and Drug Administrationeapproved regimen of terbinabine has been shown in several RCTs and other large surveillance studies. Therefore more RCTs with adequate sample size powered to show statistical differences between treatment regimens would generate more meaningful data about the pulse dosing of terbinafine. Dr. Gupta has been an investigator for Novartis Pharmaceuticals Corporation. 100% supported by Novartis Pharmaceuticals Corporation
P124
J AM ACAD DERMATOL
P1813 DISSEMINATED CUTANEOUS COCCIDIOIDOMYCOSIS IN A ZOSTERIFORM DISTRIBUTION Joshua Sparling, MD, National Capital Consortium Residency Program (Walter Reed), Silver Spring, MD, United States A 22-year-old Filipino and African-American man initially presented in 1996 to several physicians for evaluation of a pruritic, erythematous, verrucous eruption on his right flank of 11 months’ duration. A tissue biopsy was performed at that time and demonstrated endosporulating spherules of Coccidioides immitis. Culture and polymerase chain reaction also confirmed this diagnosis. Serology was positive for IgG antibodies to C immitis, but IgM was negative. The patient denied any history of trauma to this area, pulmonary disease, or zoster. His only medical problem was minor eczema, which was well controlled with low- to mid-potency topical corticosteroids. The patient stated that a chest x-ray was normal at this initial presentation. Itraconazole 100 mg twice daily was initiated and the patient was lost to dermatological follow-up for 8 years. However, the patient relays excellent compliance with the aforementioned treatment regimen by obtaining needed prescription renewals through primary care practitioners. In December 2003 the patient presented to Walter Reed Army Medical Center Dermatology Service for reevaluation of continued nodular, keloidal lesions isolated to the right flank in a zosteriform distribution. The patient stated that these lesions had not changed since his initial evaluation in 1996. A chest x-ray was negative and the patient denied any other pertinent positives on review of symptoms. Multiple repeat 4-mm punch biopsies demonstrated granulomatous dermatitis with giant cells containing thickwalled spherules and evidence of endosporulation. Cerebrospinal fluid culture and Gram staining were negative, but a serum IgG to C immitis via complement fixation was positive. A fungal culture could not demonstrate viable growth. This case is unique for the lesion’s zosteriform distribution, the lack of any clear primary pulmonary disease, and the interesting dermatopathological results 8 years after treatment with an appropriate antifungal regimen. Treatment options for recalcitrant disseminated cutaneous coccidioidomycosis will be discussed in this case report. Nothing to disclose.
MARCH 2005
P1812
COST-EFFECTIVENESS ANALYSIS COMPARING AMOROLFINE AND CICLOPIROX IN THE TREATMENT OF ONYCHOMYCOSIS WITHOUT MATRIX INVOLVEMENT Tania Furtado, Lucie Adjadj, Health Economics Department, La De´fense, France; Klara Halmy, MD, Hospital and Polyclinic, Department of Mycology, Kene´zy Gyula, Hungary Introduction: Onychomycosis is a common nail fungal disease that accounts for more than 50% of nail infections. Topical nail lacquers are often used for the treatment of onychomycosis without matrix involvement. A recent clinical trial comparing amorolfine 5% and ciclopirox 8% has proven that amorolfine is more effective. Since cost is an important element when selecting a given treatment, a cost-effectiveness analysis has been conducted to compare the monetary value of both drugs. Objective: To assess the relative cost-effectiveness of two topical antifungal nail lacquers: amorolfine 5% versus ciclopirox 8% in the treatment of onychomycosis without matrix involvement, in Germany, Mexico, and Venezuela. Methods: This pharmacoeconomic study was conducted from the society payer perspective of Germany. For Mexico and Venezuela, a patient payer perspective was adopted. This cost-effectiveness analysis is based on the results obtained in a prospective, randomized, open-label clinical trial, comparing the efficacy and safety of amorolfine and ciclopirox for the treatment of onychomycosis without matrix involvement. Amorolfine was applied once weekly and ciclopirox, three times per week for the first month, twice weekly for the second month, and once a week from the third month. Study products were applied during a 6-month period for fingernails and 12 months for toenails. For the pharmacoeconomic analysis, the clinical cure rate after treatment (clinical cure was defined as patient with no more than 1% to 2% of the nail surface infected) was chosen as the effectiveness measure. Regarding the cost elements, direct costs related to drug acquisition were used.
CUTANEOUS ALTERNARIOSIS Josep Pujol-Montcusi, MD, Pilar Turegano, MD, Raventos Antoni, MD, Richart Cristobal, MD Hospital Univeritari Joan XXIII, Tarragona, Tarragona, Spain Alternaria species are well-known plant pathogens that belong to the group of dematiaceous fungi (phaeohyphomycetes). Despite its frequent isolation from the skin surface, Alternaria is exceptionally pathogenic for humans. In recent years Alternaria spp. are increasingly recognized as pathogens in immunocompromised patients or those with significant underlying disease. We describe a case of cutaneous alternariosis in an elderly patient with chronic bronchitis receiving low-dose oral steroid therapy. He developed hyperkeratotic nodules on the lower legs, resembling multiple keratoacanthomas or squamous cell carcinomas. Surgical excision of one lesion was performed. Histological analysis showed a pseudoepitheliomatous hyperplasia and the presence of fungal structures, more evident with periodic acideSchiff staining. Culture of biopsy material permitted the identification of Alternaria alternata. Treatment with oral itraconazole was begun, and lesions resolved within 4 months. Recognition of Alternaria as a potential opportunistic pathogen is important for the differential diagnosis of dermatologic lesions. The clinical manifestations of cutaneous alternariosis vary greatly. Lesions can appear as shallow-based nonhealing ulcers that evolve to nodules, subcutaneous noninflammatory cysts, verrucous-like lesions, or erythemathous, confluent, scaly patches. Variations in the host response and the morphologic appearance of hyphae in the histological study create the potential for diagnostic confusion. We review the literature regarding the incidence and clinical manifestations of cutaneous alternariosis in immunosuppressed and immunocompetent patients and the efficacy of oral itraconozole for these infections. Nothing to disclose.
Results: The percentage of patients with clinical cure after treatment was higher in the amorolfine group (34.4%) than in the ciclopirox group (23.6%) (P \.05). The cost per fingernail and toenail treated, as well as the cost per fingernail and toenail cured, was lower with amorolfine than with ciclopirox in Germany, Venezuela, and Mexico. Therefore amorolfine is a dominant strategy compared with ciclopirox since it is more effective and less costly. Moreover, when the higher efficacy of amorolfine is taken into account, a greater difference in terms of cost is obtained in favor of amorolfine. Conclusion: Amorolfine 5% nail lacquer is more cost-effective than ciclopirox 8% nail lacquer in Germany, Venezuela, and Mexico. Two of the authors are employees of Galderma International Supported by Galderma International
P1811 CRITICAL REVIEW OF EFFICACY OF PULSE THERAPY REGIMENS USING TERBINAFINE TO TREAT DERMATOPHYTE TOENAIL ONYCHOMYCOSIS Aditya Gupta, MD, PhD, Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Sciences Centre (Sunnybrook site) and the University of Toronto, Toronto, ON, Canada and Mediprobe Research Inc., London, ON, Canada; Janine R. Schouten, BSc, Mediprobe Research Inc., London, ON, Canada; Amir Tavakkol, PhD, US Clinical Development and Medical Affairs, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States Terbinafine is the most commonly prescribed antimycotic agent to treat toenail onychomycosis in North America, with the indicated regimen being continuous therapy (250 mg/d for 12 weeks). Recently, several studies have been published using terbinafine ‘‘pulse’’ or intermittent regimens. We searched MEDLINE (1966 to July 2004) for relevant studies using the search criteria ‘‘pulse,’’ ‘‘terbinafine,’’ ‘‘onychomycosis.’’ Combination studies were excluded. Seven pulse studies were identified and included in our analysis. The following regimens were reported in one or more trials: (1) 1000 mg/mo for 4 months; (2) 500 mg/d for 1 week/mo for 3 or 4 months; (3) 250 mg/d for 1 week/mo for 1, 2, 3, or 4 months; (4) a single 1000-mg dose administered once, twice, or 3 times (each dose separated by 2 weeks). In addition, an extended-pause regimen was reported using 250 mg/d for 2 or 3 months with a pause for 3 months followed by 250 mg/d for 1 additional month. Mycological cure (negative KOH and culture) was the primary outcome in 5 of 7 studies; the remaining two trials reported clinical cure only. The average sample size of these studies is n = 47 (range, 11-128 patients). When considering studies enrolling more than 50 patients, meta-analysis indicated an average mycological cure rate (6 95% confidence interval [CI]) of 58.6% 6 26.3% (range of efficacy 48.9% to 82.5%, N = 3 studies, 218 patients). This large confidence interval suggests that well-conducted, blinded, randomized, controlled trials (RCTs) are required to identify an optimal pulse therapy regimen. Additionally, no meaningful conclusions can be drawn from this calculation because no consistent regimen or follow-up time was followed. In contrast, the efficacy of terbinafine 250 mg/d for 12 weeks for toenail onychomycosis has been reported in several well-controlled RCTs. In studies enrolling more than 50 patients, the meta-analytic average mycological cure rate (6 95% CI) of the continuous terbinafine regimen was 78% 6 3.4% (range of efficacy rate 74.9% to 81.6%, N = 13 studies, 2983 patients). The high efficacy and tolerability of the Food and Drug Administrationeapproved regimen of terbinabine has been shown in several RCTs and other large surveillance studies. Therefore more RCTs with adequate sample size powered to show statistical differences between treatment regimens would generate more meaningful data about the pulse dosing of terbinafine. Dr. Gupta has been an investigator for Novartis Pharmaceuticals Corporation. 100% supported by Novartis Pharmaceuticals Corporation
P124
J AM ACAD DERMATOL
P1813 DISSEMINATED CUTANEOUS COCCIDIOIDOMYCOSIS IN A ZOSTERIFORM DISTRIBUTION Joshua Sparling, MD, National Capital Consortium Residency Program (Walter Reed), Silver Spring, MD, United States A 22-year-old Filipino and African-American man initially presented in 1996 to several physicians for evaluation of a pruritic, erythematous, verrucous eruption on his right flank of 11 months’ duration. A tissue biopsy was performed at that time and demonstrated endosporulating spherules of Coccidioides immitis. Culture and polymerase chain reaction also confirmed this diagnosis. Serology was positive for IgG antibodies to C immitis, but IgM was negative. The patient denied any history of trauma to this area, pulmonary disease, or zoster. His only medical problem was minor eczema, which was well controlled with low- to mid-potency topical corticosteroids. The patient stated that a chest x-ray was normal at this initial presentation. Itraconazole 100 mg twice daily was initiated and the patient was lost to dermatological follow-up for 8 years. However, the patient relays excellent compliance with the aforementioned treatment regimen by obtaining needed prescription renewals through primary care practitioners. In December 2003 the patient presented to Walter Reed Army Medical Center Dermatology Service for reevaluation of continued nodular, keloidal lesions isolated to the right flank in a zosteriform distribution. The patient stated that these lesions had not changed since his initial evaluation in 1996. A chest x-ray was negative and the patient denied any other pertinent positives on review of symptoms. Multiple repeat 4-mm punch biopsies demonstrated granulomatous dermatitis with giant cells containing thickwalled spherules and evidence of endosporulation. Cerebrospinal fluid culture and Gram staining were negative, but a serum IgG to C immitis via complement fixation was positive. A fungal culture could not demonstrate viable growth. This case is unique for the lesion’s zosteriform distribution, the lack of any clear primary pulmonary disease, and the interesting dermatopathological results 8 years after treatment with an appropriate antifungal regimen. Treatment options for recalcitrant disseminated cutaneous coccidioidomycosis will be discussed in this case report. Nothing to disclose.
MARCH 2005