PEDIATRICS Vol. 114 No. 5 November 2004, pp. 1312-1315 (doi:10.1542/peds.2004-0428)
REVIEW ARTICLE |
Griseofulvin Versus Terbinafine in the Treatment of Tinea Capitis: A Meta-analysis of Randomized, Clinical Trials
* Departments of Pediatrics
Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Objective. Tinea capitis, a common pediatric infection in the United States, is caused mainly by Trichophyton species and affects many urban children. Although the current treatment of choice is oral griseofulvin, terbinafine has been shown to be variably effective in several comparative, randomized trials. The purpose of this study was to perform a meta-analysis of randomized, clinical trials comparing the efficacies of oral terbinafine and oral griseofulvin for the treatment of childhood tinea capitis.
Methods.The Medline database was searched for randomized, clinical studies comparing griseofulvin and terbinafine for the treatment of tinea capitis. Acceptance criteria included oral administration of griseofulvin for at least 6 weeks and the identification of a pathogenic dermatophyte from the scalp at the time of enrollment in the study. Scalp culture status at least 8 weeks after enrollment was used as the outcome. The common odds ratio (OR) with 95% confidence intervals (CIs), the Cochran-Mantel-Haenszel test for significance, and the Breslow-Day test for homogeneity were calculated.
Results.Six articles that satisfied all inclusion criteria were identified. These studies were combined by using outcomes at 12 to 16 weeks after enrollment. The common OR was 0.86 (95% CI: 0.57–1.27). When the 5 studies that identified Trichophyton species as the predominant pathogen were combined, using outcomes 12 weeks after enrollment, the results nearly favored terbinafine (OR: 0.65 [95% CI: 0.42–1.01]). For outcomes at 8 weeks after enrollment, no difference was found between the agents (OR: 0.84 [95% CI: 0.54–1.32]).
Consclusions.A 2- to 4-week course of terbinafine is at least as effective as a 6- to 8-week course of griseofulvin for the treatment of Trichophyton infections of the scalp. Griseofulvin is likely to be superior to terbinafine for the rare cases caused by Microsporum species.
Key Words: tinea capitis • Trichophyton • Microsporum • terbinafine • griseofulvin • meta-analysis
Abbreviations: OR, odds ratio • CI, confidence interval
Tinea capitis is an increasingly common pediatric infection, with the highest incidence in this country occurring primarily in black children in inner-city populations.1,2 The most common etiology in the United States is Trichophyton tonsurans, with recent data showing a rise in both the prevalence and percentage of cases of tinea capitis caused by this organism.3,4 Current treatment requires a 6- to 8-week course of oral griseofulvin given once daily. Recent studies have investigated the use of newer oral antifungal agents including terbinafine, fluconazole, and itraconazole in the treatment of tinea capitis. Potential advantages over griseofulvin include improved efficacy as well as a shorter treatment course with associated cost savings and improved compliance.5 Of the newer antifungal agents, terbinafine is the most widely studied in trials against griseofulvin. To determine if any therapeutic difference exists between terbinafine and griseofulvin, we undertook this meta-analysis of randomized, comparative trials of the treatment of tinea capitis.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Study Identification
The Medline and EBM (Evidence-Based Medicine) Reviews/Cochrane Central Register of Controlled Trials databases were searched using both the Ovid and PubMed search engines, covering the period from 1966 to the present. "English only" was used as a filter. Search terms included "tinea capitis," "terbinafine," and "griseofulvin," with a focus on the subtopics "treatment" and "therapy." A review of the bibliographies of selected references was also performed.
Study Selection and Data Abstraction
Inclusion criteria were selected to identify studies that compared terbinafine and griseofulvin in a randomized fashion, identified an infecting agent, and used posttherapy culture results as an outcome measure. A minimum duration of 6 weeks of griseofulvin therapy was required, which represents current standard treatment duration.
Abstracts of all recovered articles were reviewed to select only those studies that compared terbinafine and griseofulvin for the treatment of tinea capitis. The methods section of each study that survived the initial culling was evaluated independently by 2 reviewers (S.C.A. and Marla Mikelait, MD) to ensure compliance with inclusion criteria. The reviewers were blinded with respect to title, authors, study size, and results.
Data Analysis
The data for each trial were expressed in 2 x 2 tables and compared cures and failures for each treatment. "Cure" was defined as having a negative scalp fungal culture and either no symptoms ("complete cure") or minimal symptoms ("mycologic cure"). Odds ratios (ORs) were calculated such that values < 1 favored terbinafine, and values >1 favored griseofulvin. The Cochran-Mantel-Haenszel test for conditional independence was used to test the null hypothesis that the conditional odds for each 2 x 2 table = 1; the Breslow-Day statistic was used to test for homogeneity among the ORs for each 2 x 2 table. Common ORs with 95% confidence intervals (CIs) were also calculated by using the Mantel-Haenszel method.6 All statistics and calculations used SAS 9.1 (SAS Institute Inc, Cary, NC).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The initial search yielded 43 articles; 8 of these articles included both griseofulvin and terbinafine in the abstract and were subjected to additional review.7–14 One study12 was rejected because it did not meet the outcome criterion, and 1 study14 was rejected because it contained preliminary data that were included in another article. Table 1 is a summary of the studies included in the analysis.
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Table 2 presents a comparison of the cure rates of griseofulvin and terbinafine for each of the studies included. Of the 6 studies, 2 revealed statistically significant differences in cure rates. Lipozencic et al7 found a higher cure rate for griseofulvin than for terbinafine (88.0% vs 64.2%). Conversely, Cáceres-Ríos et al10 found that the cure rates favored terbinafine over griseofulvin at 12 weeks (76.0 vs 44.0, respectively) but not at 8 weeks (72.0 vs 76.0, respectively).
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The results of the meta-analysis are shown in Table 3 and Fig 1. The ORs are calculated such that values <1 favor terbinafine, and values >1 favor griseofulvin. Three separate meta-analyses were performed. Analysis I included all 6 studies using culture status at least 12 weeks after enrollment in the study as the outcome. The common OR was 0.86 (95% CI: 0.57–1.27; P = .444). The Breslow-Day test for homogeneity was significant (P = .015), indicating that the studies were heterogeneous. Unlike the other reports, the study by Lipozencic et al7 strongly favored griseofulvin, and Microsporum species were the predominant pathogens. Analysis II included only the 5 studies in which Trichophyton species were the predominant pathogens and outcome was assessed at least 12 weeks postenrollment. The test for homogeneity was not significant. The common OR favored terbinafine and almost achieved significance (OR: 0.65; 95% CI: 0.042–1.01; P = .054). Analysis III included the 4 studies that provided outcome data at 8 weeks postenrollment. This analysis was undertaken given the finding by Cáceres-Ríos et al10 of diminishing efficacy for griseofulvin in the month after treatment. The test for homogeneity was not significant. The overall common OR failed to show any difference between the drugs (OR: 0.84; 95% CI: 0.54–1.32; P = .462).
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indicates OR; —, 95% CI. |
DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Currently, the recommended therapy for tinea capitis is a 6- to 8-week course of oral griseofulvin. Griseofulvin has a long-standing history of safety and efficacy when used to treat fungal scalp infections in children.15 For these reasons, it has remained the current standard first-line therapy for tinea capitis in the United States. Issues that would favor alternative, equally effective therapies include compliance, cost, and tolerability. Griseofulvin must be taken daily for 6 weeks and has potentially significant gastrointestinal side effects. Newer antifungal agents including terbinafine offer the potential advantages of improved compliance, shorter courses of therapy, and cost savings.
Compared with griseofulvin, terbinafine has been shown to be less effective against Microsporum species in 2 separate trials.7,16 Dragos and Lunder16 treated 22 children infected with Microsporum canis with a 6-week course of terbinafine. At 14 weeks, only 7 of the 22 patients had achieved mycologic cure. Lipozencic et al7 compared the efficacy of griseofulvin and terbinafine in a population of 134 children with tinea capitis caused by Microsporum species; the cure rate for griseofulvin was significantly higher than that for terbinafine (88% vs 64%; P = .03). These observations suggest that griseofulvin may be the preferred agent for Microsporum infections. Memi
o
lu et al,11 however, treated a population of 67 children in which the etiologies were split between Microsporum and Trichophyton species and found no significant difference between terbinafine and griseofulvin.
Recent studies suggest that the incidence and prevalence of tinea capitis caused by Microsporum infections in American children has declined significantly.1–4 Weitzman et al4 surveyed dermatophyte culture results from 23 states and >40 laboratories between 1993 and 1995. Compared with prior studies performed 10 to 15 years earlier, T tonsurans increased in prevalence from 28% to 41%; M canis accounted for only 3% of the total isolates. Williams et al1 cultured 224 black school students in Philadelphia aged 5 to 13 years. Of 125 positive cultures, T tonsurans was recovered from 96%. Ghannoum et al2 cultured the scalps of 937 elementary school children in Cleveland. Fungal cultures from 13% of the children were positive, and all but 1 yielded T tonsurans. Similar results were reported from the San Francisco Bay area.3 These studies suggest that Trichophyton species are the predominant cause of tinea capitis among American children.
Our initial meta-analysis combining all 6 studies and including 603 patients failed to show a significant difference between the efficacies of the 2 medications. Notably, 1 of the studies was markedly different in that all pathogens were from the Microsporum genus. When this study was removed from the meta-analysis, the 5 remaining studies were homogeneous. When outcomes 12 weeks after enrollment were compared, 469 patients were included; the common OR favored short courses of terbinafine, and statistical significance was almost reached (OR: 0.65; 95% CI: 0.42–1.01; P = .054). When outcomes 8 weeks after enrollment were compared, 4 studies with a total of 369 patients were included; no significant difference was found between the drugs. These observations suggest that if a difference between the agents does exist, it may become more apparent with increasing time after treatment.
Together, these observations suggest that 2 to 4 weeks of terbinafine therapy is at least as effective as 6 to 8 weeks of griseofulvin therapy for the treatment of tinea capitis caused by Trichophyton species in children. Additional factors that may influence the choice between equally effective therapies include tolerability, safety, compliance, and cost. None of the 6 studies included here found any significant differences in tolerability or adverse effects between terbinafine and griseofulvin, with all authors concluding that both drugs were safe and well tolerated. There is some uncertainty as to the need for hematologic and biochemical monitoring when using the newer antifungal agents in children. In this series, 3 of the 6 studies required blood work during treatment, including complete blood counts and serum transaminases. No clinically serious laboratory abnormalities were identified.
The potential cost savings from using terbinafine depend on the length of the treatment course. In our hospital's outpatient pharmacy, a 6-week course of griseofulvin liquid for a 25-kg child would cost approximately $280, compared with $145 for a 4-week course of terbinafine and only $70 to $80 for a 2-week course. Factors that currently deter routine first-line use of terbinafine in children with tinea capitis include the lack of both a liquid preparation and Food and Drug Administration approval for this indication.
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ACKNOWLEDGMENTS |
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We thank Marla Mikelait, MD, for help in independently reviewing the articles before their inclusion in the meta-analysis.
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FOOTNOTES |
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Accepted May 10, 2004.
Address correspondence to David Fleece, MD, Department of Pediatrics, Temple University Children's Medical Center, 5th Floor, 3509 N Broad St, Philadelphia, PA 19140. E-mail: fleeced{at}tuhs.temple.edu
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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
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