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Efficacy and safety of combination therapy with itraconazole and terbinafine to treat dermatophyte toenail onychomycosis1
P406
P408
EFFICACY AND SAFETY OF COMBINATION THERAPY WITH ITRACONAZOLE AND TERBINAFINE TO TREAT DERMATOPHYTE TOENAIL ONYCHOMYCOSIS Aditya K Gupta, MD, PhD, University of Toronto, Lndon, ON, Canada A randomized, comparative study was performed to investigate the efficacy and safety of a combination of itraconazole and terbinafine therapy versus the standard continuous terbinafine therapy (250 mg daily for 12 weeks) and standard itraconazole therapy (pulse therapy: 200 mg twice daily for 7 days on, 21 days off; 3 pulses given). The combination therapy consisted of itraconazole (200 mg ⫻ 4 weeks) overlapping with terbinafine (250 mg daily for 4 weeks). Itraconazole was given for weeks 1-4 of therapy. After 2 weeks of itraconazole, terbinafine therapy was started, through weeks 3, 4, 5 and 6. It was hypothesized that the combination of mycological effects of itraconazole and terbinafine would produce a cure rate which was comparable to the standard regimens used alone, but would reduce the amount of drug given to the subject, therefore reducing the potential for adverse drug effects. Subjects with dermatophyte onychomycosis of at least one great toenail were enrolled into the study and followed up for as long as possible, regardless of treatment outcome. At week 48, mycological cure (KOH and culture negative) was found in 61.5% (24/39) subjects in the combination therapy group, versus 77.5%(31/40) in the continuous terbinafine group and 66.7% (22/33) in the itraconazole group. There was no significant difference in the mycological cure rates between groups. Few adverse events were noted in the combination therapy group, and the events were typical of those noted in monotherapy treatment. The study is ongoing. Combination therapy appears to be safe and effective in the treatment of dermatophyte onychomycosis.
EFFICACY AND SAFETY OF INTERMITTENT TERBINAFINE THERAPY TO TREAT DERMATOPHYTE TOENAIL ONYCHOMYCOSIS Aditya K Gupta, MD, PhD, University of Toronto, London, ON, Canada A randomized, comparative study was performed to investigate the efficacy and safety of intermittent terbinafine therapy versus the standard continuous terbinafine therapy (250 mg daily for 12 weeks) and standard itraconazole therapy (pulse therapy: 200 mg twice daily for 7 days on, 21 days off; 3 pulses given). Intermittent terbinafine therapy consisted of terbinafine (250 mg daily for 4 weeks) during weeks 1-4 and weeks 9-12, with no therapy given in weeks 5-8. It was hypothesized that the intermittent regimen would be sufficient to produce mycological effects comparable to standard monotherapies during the intermittent regimen, but would reduce the amount of drug given to the subject therefore reducing the potential for adverse drug effects. Subjects with dermatophyte onychomycosis of at least one great toenail were enrolled into the study and followed up for as long as possible, regardless of treatment outcome. At week 48, mycological cure (KOH and culture negative) was found in 70.6% (24/34) subjects in the intermittent therapy group, versus 78.0%(32/41) in the continuous terbinafine group and 66.7% (22/33) in the itraconazole group. There was no significant difference in the mycological cure rates between groups. Few adverse events were noted in the intermittent terbinafine therapy group, and the events were typical of those noted in standard terbinafine monotherapy. The study is ongoing. Intermittent terbinafine therapy appears to be safe and effective in the treatment of dermatophyte onychomycosis. Disclosure not available at press time.
Disclosure not available at press time.
P407 ASSESSING THE EFFICACY OF THE ORAL ANTIFUNGAL AGENTS IN THE MANAGEMENT OF DERMATOPHYTE TOENAIL ONYCHOMYCOSIS Aditya K Gupta, MD, PhD, University of Toronto, London, ON, Canada Onychomycosis is a common nail disease that is often chronic, difficult to eradicate, and has a tendency to recur. A cumulative meta-analysis of the randomized controlled trials (RCTs) for antimycotic agents was performed to determine whether the pooled estimate of the cure rates have remained consistent over the years. Furthermore, for each agent, we compared the overall meta-analytic average of both mycological and clinical response rates of RCTs vs. open studies. We searched MEDLINE (1966 to November 2002) for relevant studies evaluating the efficacy of oral antifungal agents, terbinafine, itraconazole (pulse or continuous), fluconazole, and griseofulvin, to treat dermatophyte toenail onychomycosis. Studies included in this meta-analysis required a standard accepted dosage regimen, treatment duration and follow-up period. To determine the cumulative metaanalytic average, studies were sequentially pooled by adding one study at a time according to the date of publication (i.e. earliest to the most recent). There were 36 studies included in the analyses. The change in efficacy of RCTs mycological cure rates from the first trial to the cumulative meta-average for each drug comparator is as follows: terbinafine: 78% ⫾ 6% (N ⫽ 2 studies, 79 patients) to 76% ⫾ 3% (N ⫽ 18 studies, 993 patients) (P ⫽ 0.68), itraconazole pulse: 75% ⫾ 10% (N ⫽ 1 study, 20 patients) to 63% ⫾ 7% (N ⫽ 6 studies, 318 patients) (P ⫽ 0.25), itraconazole continuous: 63% ⫾ 5% (N ⫽ 1 study, 84 patients) to 59% ⫾ 5% (N ⫽ 7 studies, 1131 patients) (P ⫽ 0.47), fluconazole: 53% ⫾ 6% (N ⫽ 1 study, 72 patients) to 48% ⫾ 5% (N ⫽ 3 studies, 131 patients) (P ⫽ 0.50), and griseofulvin: 55% ⫾ 8% (N ⫽ 2 studies, 109 patients) to 60% ⫾ 6% (N ⫽ 3 studies, 167 patients) (P ⫽ 0.41). The cumulative meta-analytic average of mycological cure rates when comparing RCTs vs. open studies include terbinafine: 76% ⫾ 3% (N ⫽ 18 studies, 993 patients) vs. 83% ⫾ 12% (N ⫽ 2 studies, 391 patients) (P ⫽ 0.0028), itraconazole pulse: 63% ⫾ 7% (N ⫽ 6 studies, 318 patients) vs. 84% ⫾ 9% (N ⫽ 3 studies, 194 patients) (P ⫽ 0.0001), and fluconazole: 48% ⫾ 5% (N ⫽ 3 studies, 131 patients) vs. 79% ⫾ 3% (N ⫽ 3 studies, 208 patients) (P ⫽ 0.0001). The cumulative meta-analysis of cure rates for RCTs suggests that over time, as new RCTs have been conducted the efficacy rates have remained consistent. The efficacy rates of open studies are substantially higher compared to RCTs and may therefore overestimate cure rates.
MOLECULAR IDENTIFICATION OF MALASSEZIA SPECIES BY AMPLIFIED FRAGMENT LENGTH POLYMORPHISM (AFLP) AND SEQUENCE ANALYSES OF THE INTERNAL TRANSCRIBED SPACER (ITS) AND LARGE SUBUNIT (LSU) REGIONS OF RIBOSOMAL DNA Aditya K Gupta, MD, PhD, University of Toronto, London, ON, Canada Malassezia yeasts are associated with several dermatological disorders. Identification of Malassezia yeasts by phenotypic characteristics is complicated and time consuming, and epidemiological surveys based on culture methods are difficult to interpret. A comparative molecular identification of the Malassezia yeasts based on the use of three alternative molecular approaches, namely amplified fragment length polymorphism (AFLP), sequencing of the ITS region and sequencing of the LSU region was done. We also searched for genetic diversity in clinical isolates of Malassezia species from Ontario region of Canada and compared them with those that had been isolated from other parts of the world. A few discrepancies were noted when the conventional method of identification was compared with the molecular methods. All species can be differentiated by these methods. This is also the first study that demonstrates the presence of a hybrid genotype in Malassezia furfur.
Disclosure not available at press time.
Disclosure not available at press time.
P106
J AM ACAD DERMATOL
P409
MARCH 2004
P408
EFFICACY AND SAFETY OF COMBINATION THERAPY WITH ITRACONAZOLE AND TERBINAFINE TO TREAT DERMATOPHYTE TOENAIL ONYCHOMYCOSIS Aditya K Gupta, MD, PhD, University of Toronto, Lndon, ON, Canada A randomized, comparative study was performed to investigate the efficacy and safety of a combination of itraconazole and terbinafine therapy versus the standard continuous terbinafine therapy (250 mg daily for 12 weeks) and standard itraconazole therapy (pulse therapy: 200 mg twice daily for 7 days on, 21 days off; 3 pulses given). The combination therapy consisted of itraconazole (200 mg ⫻ 4 weeks) overlapping with terbinafine (250 mg daily for 4 weeks). Itraconazole was given for weeks 1-4 of therapy. After 2 weeks of itraconazole, terbinafine therapy was started, through weeks 3, 4, 5 and 6. It was hypothesized that the combination of mycological effects of itraconazole and terbinafine would produce a cure rate which was comparable to the standard regimens used alone, but would reduce the amount of drug given to the subject, therefore reducing the potential for adverse drug effects. Subjects with dermatophyte onychomycosis of at least one great toenail were enrolled into the study and followed up for as long as possible, regardless of treatment outcome. At week 48, mycological cure (KOH and culture negative) was found in 61.5% (24/39) subjects in the combination therapy group, versus 77.5%(31/40) in the continuous terbinafine group and 66.7% (22/33) in the itraconazole group. There was no significant difference in the mycological cure rates between groups. Few adverse events were noted in the combination therapy group, and the events were typical of those noted in monotherapy treatment. The study is ongoing. Combination therapy appears to be safe and effective in the treatment of dermatophyte onychomycosis.
EFFICACY AND SAFETY OF INTERMITTENT TERBINAFINE THERAPY TO TREAT DERMATOPHYTE TOENAIL ONYCHOMYCOSIS Aditya K Gupta, MD, PhD, University of Toronto, London, ON, Canada A randomized, comparative study was performed to investigate the efficacy and safety of intermittent terbinafine therapy versus the standard continuous terbinafine therapy (250 mg daily for 12 weeks) and standard itraconazole therapy (pulse therapy: 200 mg twice daily for 7 days on, 21 days off; 3 pulses given). Intermittent terbinafine therapy consisted of terbinafine (250 mg daily for 4 weeks) during weeks 1-4 and weeks 9-12, with no therapy given in weeks 5-8. It was hypothesized that the intermittent regimen would be sufficient to produce mycological effects comparable to standard monotherapies during the intermittent regimen, but would reduce the amount of drug given to the subject therefore reducing the potential for adverse drug effects. Subjects with dermatophyte onychomycosis of at least one great toenail were enrolled into the study and followed up for as long as possible, regardless of treatment outcome. At week 48, mycological cure (KOH and culture negative) was found in 70.6% (24/34) subjects in the intermittent therapy group, versus 78.0%(32/41) in the continuous terbinafine group and 66.7% (22/33) in the itraconazole group. There was no significant difference in the mycological cure rates between groups. Few adverse events were noted in the intermittent terbinafine therapy group, and the events were typical of those noted in standard terbinafine monotherapy. The study is ongoing. Intermittent terbinafine therapy appears to be safe and effective in the treatment of dermatophyte onychomycosis. Disclosure not available at press time.
Disclosure not available at press time.
P407 ASSESSING THE EFFICACY OF THE ORAL ANTIFUNGAL AGENTS IN THE MANAGEMENT OF DERMATOPHYTE TOENAIL ONYCHOMYCOSIS Aditya K Gupta, MD, PhD, University of Toronto, London, ON, Canada Onychomycosis is a common nail disease that is often chronic, difficult to eradicate, and has a tendency to recur. A cumulative meta-analysis of the randomized controlled trials (RCTs) for antimycotic agents was performed to determine whether the pooled estimate of the cure rates have remained consistent over the years. Furthermore, for each agent, we compared the overall meta-analytic average of both mycological and clinical response rates of RCTs vs. open studies. We searched MEDLINE (1966 to November 2002) for relevant studies evaluating the efficacy of oral antifungal agents, terbinafine, itraconazole (pulse or continuous), fluconazole, and griseofulvin, to treat dermatophyte toenail onychomycosis. Studies included in this meta-analysis required a standard accepted dosage regimen, treatment duration and follow-up period. To determine the cumulative metaanalytic average, studies were sequentially pooled by adding one study at a time according to the date of publication (i.e. earliest to the most recent). There were 36 studies included in the analyses. The change in efficacy of RCTs mycological cure rates from the first trial to the cumulative meta-average for each drug comparator is as follows: terbinafine: 78% ⫾ 6% (N ⫽ 2 studies, 79 patients) to 76% ⫾ 3% (N ⫽ 18 studies, 993 patients) (P ⫽ 0.68), itraconazole pulse: 75% ⫾ 10% (N ⫽ 1 study, 20 patients) to 63% ⫾ 7% (N ⫽ 6 studies, 318 patients) (P ⫽ 0.25), itraconazole continuous: 63% ⫾ 5% (N ⫽ 1 study, 84 patients) to 59% ⫾ 5% (N ⫽ 7 studies, 1131 patients) (P ⫽ 0.47), fluconazole: 53% ⫾ 6% (N ⫽ 1 study, 72 patients) to 48% ⫾ 5% (N ⫽ 3 studies, 131 patients) (P ⫽ 0.50), and griseofulvin: 55% ⫾ 8% (N ⫽ 2 studies, 109 patients) to 60% ⫾ 6% (N ⫽ 3 studies, 167 patients) (P ⫽ 0.41). The cumulative meta-analytic average of mycological cure rates when comparing RCTs vs. open studies include terbinafine: 76% ⫾ 3% (N ⫽ 18 studies, 993 patients) vs. 83% ⫾ 12% (N ⫽ 2 studies, 391 patients) (P ⫽ 0.0028), itraconazole pulse: 63% ⫾ 7% (N ⫽ 6 studies, 318 patients) vs. 84% ⫾ 9% (N ⫽ 3 studies, 194 patients) (P ⫽ 0.0001), and fluconazole: 48% ⫾ 5% (N ⫽ 3 studies, 131 patients) vs. 79% ⫾ 3% (N ⫽ 3 studies, 208 patients) (P ⫽ 0.0001). The cumulative meta-analysis of cure rates for RCTs suggests that over time, as new RCTs have been conducted the efficacy rates have remained consistent. The efficacy rates of open studies are substantially higher compared to RCTs and may therefore overestimate cure rates.
MOLECULAR IDENTIFICATION OF MALASSEZIA SPECIES BY AMPLIFIED FRAGMENT LENGTH POLYMORPHISM (AFLP) AND SEQUENCE ANALYSES OF THE INTERNAL TRANSCRIBED SPACER (ITS) AND LARGE SUBUNIT (LSU) REGIONS OF RIBOSOMAL DNA Aditya K Gupta, MD, PhD, University of Toronto, London, ON, Canada Malassezia yeasts are associated with several dermatological disorders. Identification of Malassezia yeasts by phenotypic characteristics is complicated and time consuming, and epidemiological surveys based on culture methods are difficult to interpret. A comparative molecular identification of the Malassezia yeasts based on the use of three alternative molecular approaches, namely amplified fragment length polymorphism (AFLP), sequencing of the ITS region and sequencing of the LSU region was done. We also searched for genetic diversity in clinical isolates of Malassezia species from Ontario region of Canada and compared them with those that had been isolated from other parts of the world. A few discrepancies were noted when the conventional method of identification was compared with the molecular methods. All species can be differentiated by these methods. This is also the first study that demonstrates the presence of a hybrid genotype in Malassezia furfur.
Disclosure not available at press time.
Disclosure not available at press time.
P106
J AM ACAD DERMATOL
P409
MARCH 2004