Background
Description of the condition
Biology
Fungal infections of the foot are common in people of all ages and can either affect the skin (tinea pedis) or the toenails (onychomycosis). The tenacity and duration of the infection can differ depending on the site. The cause of the infection is most frequently a dermatophyte (fungus) which inhabits and destroys keratin (a protein found in the outer layer of the skin). Tinea pedis, which tends to be restricted to the horny epidermal layers of the skin, is commonly known as 'athlete's foot' . It is contracted from infected skin fragments from other humans and in some cases animals (Brookes 1996). There are several clinical forms of tinea pedis, which can easily be confused with other non-infectious skin conditions, for example:
- interdigital tinea pedis, which is macerated and scaly in appearance and found mainly between the toes especially the outer ones.
- plantar type tinea pedis (moccasin foot), fine powdery scaling on a background of redness covering the skin of the soles, heels and sides of the foot.
- vesicular (bullous) type, an acute inflammatory condition, characterised by the formation of vesicles, pustules or blisters. This can mimic foot dermatitis of various causes.
The causative organisms, dermatophytes, are classified in three genera, Epidermophyton, Microsporum and Trychophyton. For tinea pedis the main agents are Trichophyton rubrum, Trichophyton interdigitale (mentagrophytes) and Epidermophyton floccosum. Roseeuw 1999 found Trichophyton rubrum and Trichophyton interdigitale (mentagrophytes) were the most common pathogens in his European survey.
Prevelance
Traditionally prevalence studies of tinea pedis have been conducted in school children (English 1959; English 1961), sailors (Catterall 1975) and coal-miners (Gentles 1957). More recently athletes and those frequenting public swimming baths or modern-day leisure centres have been studied. Gentles 1973 examined a random sample of 10% of all bathers at a public swimming bath and found the overall prevalence of tinea pedis was 8.5%. The prevalence was higher in adults (17%) than in children (4%). Auger 1993 investigated marathon runners and found a prevalence of 22%; with higher prevalence rates reaching 42% in the older age group (over 46 years). There is often a discrepancy between the methods of diagnosing tinea pedis whether by symptom (clinical) or microbiological confirmation (culture). For example Gentles 1957 found that 90% of the coal miners had abnormalities of the skin of the feet but only 21% were proven to be infected. A recent study in Australia (Merlin 1999) found that the prevalence of culture-proven tinea pedis was 5% in children, increasing with age from 2% in 4 to 6 year olds to 10% in 16 to 18 year olds. The increase in popularity of water based leisure facilities prompted Detandt 1995 to compare the level of dermatophyte contamination on the floors of traditional swimming pools and subtropical swimming complexes. They found that the floors of subtropical swimming complexes are more highly contaminated with dermatophytes than the floors of traditional swimming pools concluding that this was due to large visitor numbers, long opening hours, the complexity of construction and choice of materials.
There is a clear trend showing that tinea pedis increases in prevalence with age and Auger 1993 reports that his survey review of tinea pedis indicates that males are infected about four times as frequently as females. This trend is confirmed by the Achilles study (Roseeuw 1999) which found nearly twice as many males had fungal infections.
Description of the intervention
Before the late 1950s, only topical drugs were available. Griseofulvin, the first significant oral antifungal agent, became available in 1958 and there have been many advances since then (Gupta 1994a). Although widely used, griseofulvin is only effective for dermatophyte infections, and needs to be taken for long treatment periods. It is associated with relatively minor side effects.
The azole class of drugs, broad spectrum antifungals, were developed next. However the first azole, ketoconazole, has been associated with liver damage, although this appears to be an idiosyncratic reaction (Jones 1982), and is now less favoured as an oral therapy. The 1980s saw the introduction of itraconazole and fluconazole which were thought to have increased potency, decreased toxicity and a wider spectrum of action than earlier azoles (Gupta 1994b). Azoles are fungistatic (inhibit growth) and inhibit fungal cell development at a later stage. Finally terbinafine, an allylamine, was introduced which has a broad spectrum of antifungal activity and is fungicidal in its action i.e. it destroys the fungal cell at a much earlier stage in its development than the azoles.
How the intervention might work
The numerous antifungal products available to treat tinea pedis differ both in costs and length of treatment time. They can be taken as tablets (oral) or applied to the skin (topical). Clinical trials have focused mostly on topical treatments; oral therapy is more usually reserved for topical treatment failures and chronic conditions. Oral antifungal therapies are only available on prescription whereas many topical treatments are available over the counter (OTC). Topical therapies have usually been the first line treatment for tinea pedis. A systematic review by Hart 1999 examined all topical therapies for tinea pedis and found that there were no significant differences in effectiveness between individual allylamines or individual azoles. Topical allylamines, which are available only on prescription, were found to cure slightly more infections of tinea pedis than topical azoles or undecanoic acid, both of which are available OTC. The review concluded that for tinea pedis the initial line of treatment should be with azoles or undecanoic acid and that allylamines should be reserved for topical treatment failures. However tinea pedis can be resistant to treatment (Brautigam 1995) and topical treatments can be messy to apply and rely on the person complying with the recommended regimen.
The ideal oral antifungal compound for the treatment of fungal infection should be fungicidal so that the treatment can be of short duration. Ideally, these drugs should give high cure rates, minimise relapses, be easy for people to take and have minimal adverse side effects.
Why it is important to do this review
Research has shown that tinea pedis is not a minor disease which will resolve if left alone or treated inadequately. Fungal infections are treated by dermatologists, general practitioners and podiatrists. They are overwhelmed with large amounts of information and a systematic review of the research evidence is needed. To date the research evidence has not been systematically appraised and synthesised to answer the key questions set out below. This systematic review addresses the main research question as to whether or not there is an effective oral treatment for tinea pedis and if so which treatment is most effective, further research questions being:
- Is there an optimum treatment duration?
- Is there an optimum dosage?
- Which intervention has fewest side effects?
- Does any one clinical type of tinea pedis respond better to a particular treatment?
Objectives
To assess the effects and costs of oral treatments for fungal infections of the skin of the foot (tinea pedis).
Topical treatments for fungal infections of the skin and nails in the foot form the basis of another review published in the Cochrane Library (Crawford 2001).
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) of oral treatments for tinea pedis.
Types of participants
People who have a fungal infection of the skin of the foot (tinea pedis) that has been clinically diagnosed and confirmed by microscopy and growth of dermatophytes in culture.
Types of interventions
Any treatment administered orally which aims to treat the fungal infection.
Types of outcome measures
Primary outcomes
The main outcome measure is mycological cure, as demonstrated by negative results on microscopy and no growth of dermatophyte in culture. This outcome is recognized as the most effective way of assessing if the fungal infection has been eradicated; evaluating the condition by its appearance alone is not reliable (Elewski 1996).
Secondary outcomes
- Clinical assessment of signs such as redness, scaling, pustules and symptoms such as itching, burning and soreness.
- Measurement of any recurrence of the condition, after achieving a cure, 12 weeks after the start of the intervention.
- Side effects of the treatments as measured by the frequency of reported adverse events.
- Cosmetic acceptability of the end result to the patient, absence of itchiness and discomfort.
- Identification of the type of infecting dermatophytes at baseline and at final outcome assessment.
Search methods for identification of studies
Electronic searches
The first search was to identify if any systematic reviews and meta-analyses had already been published in this area and the search strategy suggested by the NHS CRD guidelines was used (NHS CRD 1996):
1. systematic adj review$.tw.
2. data adj synthesis.tw.
3. published adj studies.ab.
4. data adj extraction.ab.
5. meta-analysis/
6. meta-analysis.ti.
7. comment.pt
8. letter.pt
9. editorial.pt
10. animal/
11. human/
12. 10 not (10 and 11)
13. (search terms for subject area)
14. 13 not (7 or 8 or 9 or 12)
15. or/1-6
16. 14 and 15
Seven databases were available and relevant to this review.
MEDLINE has been searched using the on line Silver Platter version from 1966 to January 2000.
The MEDLINE search strategy was:
1. RANDOMIZED CONTROLLED TRIAL.pt.
2. CONTROLLED CLINICAL TRIAL.pt.
3. RANDOMIZED CONTROLLED TRIALS.sh.
4. RANDOM ALLOCATION.sh.
5. DOUBLE BLIND METHOD.sh.
6. SINGLE BLIND METHOD.sh.
7. OR/ 1 - 6
8. ANIMAL.sh.
9 HUMAN.sh.
10. 8 NOT (8 and 9)
11. 7 NOT 10
12. CLINICAL TRIAL.pt.
13. EXP CLINICAL TRIALS/
14. (CLIN$ ADJ 3 TRIAL$).ti,ab.
15. ((SINGL$ OR DOUBL$ OR TREB$ OR TRIPL$) ADJ3 (BLIND$ OR MASK$)).ti,ab.
16. PLACEBOS.sh.
17. PLACEBO$.ti,ab.
18. RANDOM. ti,ab.
19. RESEARCH DESIGN.sh.
20. OR/ 12 - 19
21. 20 NOT 10
22. 21 NOT 11
23. COMPARATIVE STUDY.sh.
24. EXP EVALUATION STUDIES/
25. FOLLOW-UP STUDIES.sh.
26. PROSPECTIVE STUDIES.sh.
27. (CONTROL$ OR PROSPECTIV$ OR VOLUNTEER$). ti,ab.
28. OR/ 23 - 27
29. 28 NOT 10
30. 29 NOT (11 OR 22)
31. (FOOT or FEET) ti,ab,sh.
32. (TOE or TOES) ti,ab,sh.
33. OR/ 31 - 32
34. (FUNGUS or FUNGAL or FUNGI or HYPHAE) ti,ab,sh.
35. (YEAST or SPORE or SPORES) ti,ab,sh.
36. (RINGWORM or ATHLETES FOOT or TINEA PEDIS) ti,ab,sh.
37. (DERMATOPHYT$ or DERMATOMYCOSES) ti,ab,sh.
38. (MYCELIUM or MYCOSIS or MYCOSES or MYCETES) ti,ab,sh.
39. OR/ 34 - 38
40. explode FOOT DERMATOSES/
41. (EPIDERMOPHYTON MICROSPORUM or MICROSPORUM CANIS or EPIDERMOPHYTON FLOCCOSUM or EPIDERMOPHYTOSIS) ti,ab,sh.
42. (TRICHOPHYTON RUBRUM or TRICHOPHYTON ERINACEI or TRICHOPHYTON TONSURANS) ti,ab,sh.
43. (TRICHOPHYTON MENTAGROPHYTES or TRICHOPHYTON INTERDIGITALE) ti,ab,sh.
44. (TRICHOPHYTON SOUDANESE or TRICHOPHYTON VIOLACEUM) ti,ab,sh.
45. OR/ 41 - 44
46. (GRISEOFULVIN or FULCIN or GRISOVIN or MICONAZOLE or BUTENAFINE) ti,ab,sh.
47. (TERBINAFINE or LAMISIL or NYSTATIN or NYSTAN) ti,ab,sh.
48. (KETOCONAZOLE or FLUCONAZOLE or ITRACONAZOLE or SPORANOX) ti,ab,sh.
49. OR/ 46 - 48
50. 33 AND 39
51. 33 AND 45
52. 33 AND 49
53. 40 OR 50 OR 51 OR 52
54. 53 AND (11 OR 22 OR 30)
Other databases that have been searched for randomised controlled trials were:
- CINAHL (on-line ARC version) to January 2000.
- Science Citation Index and Social Science Citation Index within BIDS from 1969 to January 2000.
- EMBASE from 1980 to January 2000.
- Cochrane Controlled Trials Register within the Cochrane Library (CD ROM 2000 Issue 1).
- CAB-Health 1973 to December 1997 and Healthstar 1975 to December 1997.
In addition the on-line versions of DARE, NHS Economic Evaluation Database and EconLit were screened to January 2000. The Internet was searched, using the Yahoo Search Engine, to identify any further useful sources of information.
Searching other resources
The following podiatry journals that are not listed in the electronic databases were hand searched by Jill Ferrari:
- Foot
- Journal of British Podiatric Medicine
- Journal of the American Podiatry Association.
The British Journal of Dermatology has recently been partly hand searched and the results were obtained from the Cochrane Skin Group.
The bibliographies of all review papers identified by these strategies were searched and relevant articles obtained.
A search for unpublished or unlisted studies was made by contacting all schools of podiatry in the UK with a request made for dissertation bibliographies. No studies were identified by this method.
The pharmaceutical industry was contacted to request reports of further published and unpublished trials. Replies were received from several companies. However, no new trials were identified that had not already been sourced from the database searches.
No additional studies were identified by the Cochrane Skin Group.
All references identified from the searches were entered into a database specific to the review within the bibliographic software package, ProCite (Version 4). This facilitated the tracking of studies as each part of the search process was completed.
No language restrictions were imposed.
Data collection and analysis
Selection of studies
Retrieved citations and abstracts were assessed by two reviewers (SBS and RH) independently and categorised into:
1 - clearly an RCT
2 - possibly an RCT, abstract or title providing insufficient evidence to make a firm decision
3 - clearly not an RCT
All papers from categories 1 and 2 were obtained in full and assessed against the inclusion criteria with a second opinion being sought where necessary.
Data extraction and management
A paper based data extraction form was constructed specifically for this review. The form included key elements such as description of condition, intervention details, demographic information, study design, outcome measures and assessment, analysis of results, effectiveness of the intervention from the author's perspective and from the appraiser's perspective.
Details of all included studies were extracted and summarised using this form. Studies that have been reported in duplicate publications were only included once. Two reviewers (SBS & RH) extracted the data independently and then discussed their findings. Any disagreement was resolved by a consensus method followed, if necessary, by scrutiny from other reviewers.
Assessment of risk of bias in included studies
A checklist for considering the quality of reporting of the included trials was devised which used as its source references Moher 1995; Jadad 1996 and Begg 1996.
Twelve criteria were included in the checklist as follows:
- method of randomisation defined
- aim of the trial clearly defined
- assessor of outcome blinded with respect to treatment allocation
- participants blinded with respect to treatment allocation
- baseline comparability of groups with respect to age
- baseline comparability of groups with respect to sex
- baseline comparability of groups with respect to duration of complaint
- inclusion and exclusion criteria defined
- interventions defined
- assessment of compliance with the treatment
- trial analysed by intention to treat
- prior sample size calculation undertaken
These quality criteria were appraised on the basis of reporting of information and scored as Yes (reported) or No (not reported). Each trial was given 1 point for each quality item it reported, the maximum being 12/12.
Assessment of heterogeneity
The trials that compared similar interventions were considered for a meta-analysis. These trials were also subject to an assessment of statistical heterogeneity in order to decide whether to adopt a fixed or random effects model. A fixed effects model is a mathematical model for combining the results of studies that assumes that the effect is truly constant in all the populations studied. Only variation within the study is taken to influence the uncertainty of results. A random effects model is a mathematical model for combining the results of studies that allows for variation in the effect amongst the populations studied. Therefore both within-study and between-study variations are included in the assessment of the uncertainty of results. Heterogeneity is caused by variability between studies in such areas as type of participants, the length of treatment or follow up, dose or frequency of the intervention, quality of the trial etc.
The evidence for heterogeneity is established using a chi-squared test (chi-sq). Large values of the chi-sq test indicate more variation in results between studies than would be expected by chance. The p-value associated with the chi-sq test is the probability of the observed variation occurring by chance. In this review p-values for heterogeneity of less than 0.1(10%) were taken as evidence of statistically significant heterogeneity. Statistical tests of heterogeneity generally have low power and so are likely to miss important variation.
Data synthesis
For each trial the cure rates (the primary outcome measure ) were calculated at each outcome point from the reported mycological results. The longest available follow up, within each trial, was generally used in summarising the overall effectiveness.
Where two interventions were being compared the risk difference (with 95% CI) and the relative risk of treatment success (with 95% CI) were calculated. Risk difference (or absolute risk reduction) is the absolute difference in the event rate between two comparison groups. If the 95% CI of the difference in response rates (risk difference) excludes the zero difference, one can reject the null hypothesis that the two treatments are the same, i.e. there is a difference in the treatment effects of the compared treatments (Gardner 1989). A risk difference of zero indicates no difference between comparison groups.
Individual studies with small sample sizes may not be able to estimate effects precisely. By combining the data from these studies a meta-analysis acquires the power to increase the precision of the estimate of effect.
Subgroup analysis and investigation of heterogeneity
A subset analysis was undertaken of the clinical presentation of tinea pedis.
The sponsorship of trials by the pharmaceutical industry was also investigated by noting all studies that have received sponsorship and whether the results of the study are in favour of the intervention manufactured by the sponsor. It is possible that publication bias exists by positive findings being preferably published by a pharmaceutical company (Begg 1989).
Results
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies.
Twenty-seven trials were identified; 12 met the inclusion criteria for the review and evaluated 5 different treatments. All trials were in the English language.
Nine trials compared different oral drugs (terbinafine, itraconazole, ketoconazole, fluconazole, griseofulvin) and one trial compared different doses of the same drug (fluconazole).
Two trials compared active drugs (terbinafine, itraconazole) with a placebo .
Fifteen trials did not meet the inclusion criteria (see Characteristics of excluded studies).
Most of the excluded trials looked at various sites of fungal infections and it was not possible to isolate the data relating only to the feet. In two other cases the trials did not perform tests of microscopy and culture to obtain a clear indication of the existence of a fungal infection.
All authors of excluded trials were contacted with a request for further information. To date no responses have been received which has enabled any of these trials to meet the inclusion criteria.
Potential conflict of interest was explored. Six studies reported receiving funding or support from drug companies (DeKeyser 1994; Difonzo 1995; Hay 1995; Roberts 1987; Savin 1990a; Svejgaard 1998). The drug companies were Novartis (formerly Sandoz Pharmaceuticals) (terbinafine); and Janssen Pharmaceuticals; (itraconazole, ketoconazole).
Risk of bias in included studies
Details of the quality of each individual study are included in the Characteristics of included studies table.
No trials reported that the assessor of the outcome measure had been blind to treatment allocation, however all trials did report that the participants were blind to treatment allocation. Most trials clearly stated the aim of the trial and gave a good description of the interventions used, but inclusion and exclusion criteria were absent from four trials (Kim 1993; Nozickova 1998; Roberts 1987; Voravutinon 1993). Eleven trials reported that the trial participants in all intervention groups were comparable at baseline for age and sex and seven trials for duration of the fungal condition.
All the included trials reported that they were RCTs by design but none were explicit in the method of randomisation used. Only one trial (DeKeyser 1994) undertook some measure of compliance to ensure that the intervention medication had been properly taken, an important factor when dealing with treatments which can be lengthy. Only three trials stated that they had performed an intention to treat analysis and only one trial made explicit the sample size calculations. Of those trials scoring 7/12 or below, none assessed compliance or reported a sample size calculation, and only one performed an intention to treat analysis.
No trials achieved a score of 10 or above out of a possible 12, 3 included trials satisfied 8 or more of the 12 quality criteria for trial reporting (DeKeyser 1994; Hay 1995; Svejgaard 1998). Loss to follow-up is reported in table 04.
Effects of interventions
Primary outcome -Mycological cure
1. Antifungals vs placebo
Two trials compared antifungal treatments against placebo: 1 trial of terbinafine (250 mg/day for 6 weeks) and 1 trial of itraconazole (400 mg/day for 1 week) against placebo, both found that the antifungal treatment is statistically significantly better than placebo (Savin 1990a; Svejgaard 1998). Both trials also demonstrated that the cure rate continues to improve beyond the end of treatment. In the case of terbinafine 65% of participants were cured 2 weeks after the end of the 6 weeks treatment period (RD 65%; 95% CI 45 to 86%). This equates to a relative risk (RR) of cure with terbinafine of 25 (95% CI 2 to 384). For itraconazole 55% of participants were cured 8 weeks after the 1 week treatment period (RD 47%; 95% CI 29 to 66%). This equates to a RR of cure with itraconazole of 7 (95% CI 2 to 20).
2. Different types of antifungals
2.1 Allylamines vs azoles
Terbinafine (250 mg/day for 2 weeks) and itraconazole (100 mg/day for either 2 weeks or 4 weeks) have been compared head to head in 4 trials (DeKeyser 1994; Hay 1995; Kim 1993; Voravutinon 1993). Although three trials showed a higher cure rate for terbinafine, only the single trial which used itraconazole for two weeks demonstrated a statistically significant difference in favour of terbinafine. In that trial (DeKeyser 1994) terbinafine achieved a cure of 86% compared to itraconazole at 54%, resulting in a risk difference of 32% (95% CI 16 to 47%) (RR 2; 95% CI 1 to 2).
Performing a meta-analysis (pooling of data from trials) achieves a more precise estimate of the treatment effect; however the issue of heterogeneity is important. In considering clinical heterogeneity the trials should look at a similar pool of patients, the same clinical condition, have similar treatment periods and length of follow up. These issues are initially assessed visually by the researcher and then tested for statistically.
As there was no evidence of heterogeneity (p=0.64) between the three trials with common treatment length of four weeks, the data for the final outcome measurements was pooled, using a fixed effects model. This gave a risk difference of 5% (95% CI -6 to 17%), which was not statistically significant.
2.2 Azole vs azole
Fluconazole (50 mg/day) has been compared against 100 mg/day itraconazole (Difonzo 1995) and 200 mg/day ketoconazole (Fischbein 1992). Both trials demonstrate broadly similar cure rates of about 90% for all 3 drugs. However as there were less than 30 evaluable patients in each intervention arm the trials were not sufficiently powered to detect a significant difference.
2.3 Griseofulvin vs newer drugs
2.3.1 One small trial compared griseofulvin (1000 mg/day) with ketoconazole (200 mg/day), both for 4 weeks treatment and no difference in cure rates was seen (Roberts 1987). The trial had a total of 29 participants which raises the question of a type II error (not detecting a significant difference when there really is a difference of magnitude).
2.3.2 Two small trials compared griseofulvin (500 mg/day) with terbinafine (250 mg/day) for either 4 (Widyanto 1993) or 6 weeks (Savin 1990b). Both trials showed that terbinafine had statistically significantly better cure rates, 100% and 86%, whereas griseofulvin achieved 50% and 33%. When the two trials were pooled, using a fixed effects model (chi2 = 0.03; df = 1 p=0.87), the risk difference was 52% (95% CI 33 to 71%).
2.4 Different doses of azoles
There has been only 1 trial comparing different doses and it compared fluconazole (50 mg per day for a maximum of 6 weeks) against fluconazole (150 mg once a week for a maximum of 6 weeks) (Nozickova 1998). No statistically significant difference in cure rates was achieved, but the trial was small (total n = 51).
3. Type of tinea pedis
3.1 Terbinafine vs itraconazole
Another source of heterogeneity considered was the type of tinea pedis. A random effects model was used to pool the data for the 2 trials that studied only plantar tinea pedis (Hay 1995; Kim 1993) and gave a risk difference of 4% in favour of terbinafine (95% CI -10 to 18%). Pooling the data, using a random effects model, for the 2 trials which did not differentiate between interdigital and plantar tinea pedis (DeKeyser 1994; Voravutinon 1993), gave a risk difference of 18% (95% CI -11 to 47%). Neither difference is statistically significant.
4. Summary of results for mycological cure rates:
4.1 Terbinafine and itraconazole are more effective than no treatment (placebo)
4.2 Terbinafine (two weeks treatment) is more effective than itraconazole (two weeks treatment)
4.3 Terbinafine is more effective than griseofulvin
4.4 No significant difference in effectiveness was found between:
- two weeks of terbinafine vs four weeks of itraconazole
- fluconazole vs either itraconazole or ketoconazole
- griseofulvin and ketoconazole
- different doses of fluconazole
4.5 The type of tinea pedis does not appear to influence response to oral antifungal treatment.
Secondary outcomes
All studies reported secondary outcomes but differed in the format of presentation and detail.
1. Clinical assessment
Secondary outcomes were reported as an assessment of clinical signs and symptoms of the condition, these signs and symptoms were reported as: exudation, erythema, scaling, vesiculation, pustules, crusting, desquamation, maceration, fissuring and pruritus, burning, rash, cellulitis and pain. Trials assessed on average six different clinical signs and symptoms; most commonly erythema, desquamation/scaling, vesiculation, pustules, pruritus/itching and maceration.
This assessment was usually a subjective scoring system where the individual sign or symptom was rated as absent, mild, moderate or severe and given a score from 0 to 3. None of the trials reported that the outcome assessor was blind to treatment allocation.
The trials presented the results in several different ways making it more difficult to make direct comparisons but allowing trends to be identified. Most trials calculated the mean clinical score across all assessed signs and symptoms at a stated point in time, in contrast some trials presented results as a percentage of the population whose score was two or less for a total of all signs and symptoms. In general the average clinical scores tended to reduce as the cure rate increased.
2. Measurement of recurrence
Further outcome measures were considered, namely the incidence of recurrence of the condition and maintenance of a cured condition 12 weeks after the start of treatment. Only 3 trials (Hay 1995; Roberts 1987; Savin 1990b) assessed the condition at 12 weeks or beyond. Roberts 1987 comparing ketoconazole and griseofulvin, did not report the cure rate at 12 weeks but found that the mean clinical score for signs and symptoms continued to improve in both groups. Hay 1995, however, demonstrated a continued improvement for patients treated with terbinafine at week 16 but in the itraconazole group the infection had begun to reappear. Savin 1990b showed 6% recurrence with terbinafine and 25% recurrence with griseofulvin, but this was demonstrated in a study with very small sample sizes.
3. Cosmetic acceptability
No trialists reported the cosmetic acceptability of the end result or the amount of discomfort. Svejgaard 1998 included pain as a clinical symptom and Difonzo 1995 mentions subjective symptoms but no detail is reported.
4. Adverse events
These were recorded in all but one trial (Roberts 1987). In general all treatment regimens reported adverse events. It was also noted that where trials had a placebo arm, these patients also reported adverse events. In all trials the most frequently reported events were associated with the gastrointestinal system, such as diarrhoea and nausea, followed by headaches and the occurrence of skin complaints such as rash, dermatitis and pruritus. Less frequently reported adverse events were those associated with dizziness, taste disorders and respiratory infections. No side effects represented symptoms or conditions that led to any long term or lasting damage to the patient.
5. Identified fungi
The analysis of identified dermatophytes showed Trichophyton rubrum to be the most prevalent infecting organism in the patients evaluated, in 10 out of the 12 trials included in this review. Trichophyton interdigitale (mentagrophytes) and Epidermophyton floccosum were also detected in these trials. Only one trial included in this review reported Trichophyton mentagrophytes to be the most prevalent (Widyanto 1993) and one trial (Svejgaard 1998) did not report on infecting dermatophyte species. Although most trials identified the infecting species at baseline, none analysed the residual dermatophytes in individuals not cured.
6. Conflict of interest and publication bias
Because it was necessary to exclude those studies that reported combined data for the treatment of fungal infections of the skin of the hands and feet, the data set used in the analyses was incomplete. Whilst we did attempt to resolve this situation (e.g. to request separate data for feet), we have had no productive responses from any of the authors of the excluded trials. The omission of this data may leave true effects of treatment undetected. Missing data is particularly relevant in drug studies in which a conflict of interest may arise in trials as a result of commercial sponsorship.
In this systematic review six studies clearly received funding or support from pharmaceutical companies, the sponsoring companies being Novartis, formerly Sandoz Pharmaceuticals (terbinafine) (DeKeyser 1994; Hay 1995; Savin 1990a) and Janssen Pharmaceuticals (itraconazole, ketoconazole) (Difonzo 1995; Roberts 1987; Svejgaard 1998). Four of these supported trials demonstrated a result in favour of the drug manufactured by the sponsor. Of the six studies not supported by a pharmaceutical company only two showed significant differences between two treatment arms, the other four trials showing no difference.
Although drug companies did reply to our requests for studies, no new trials were identified that had not already been located from the database searches.
Discussion
Tinea pedis is a common disease of the skin and in more than 80% of cases is caused by a dermatophyte infection. A number of factors may have contributed to the growing incidence of this infection, including an aging population and increasing participation in fitness and leisure related activities.
In the UK the National Health Service (NHS), the primary care team and the individual patient make treatment decisions. One of the key decisions is the medium of treatment as antifungal drugs are available in either topical or oral form. Most topical treatments for tinea pedis are available over the counter and as such are accessible to the patient for self-treatment, as well as being recommended by podiatrists and other health care professionals. Oral treatments are only available by prescription and are obtained through consultation with general practitioners, dermatologists or nurse prescribers. Many of the advantages of oral treatment regimens are obvious; they are less time consuming and thought to have better compliance. It is recognised that oral treatments are best suited in the case of either topical treatment failures or more chronic presentations of tinea pedis.
Twenty-seven RCTs were identified and 12 were included in the review. Of the included trials only two were published in recent years, with the other ten trials being published pre-1996. This is an indication that research into establishing the most effective oral treatment for tinea pedis does not attract a high level of current interest; another explanation may be publication bias.
Trials that compared antifungal drugs with a placebo were considered first as it is important to establish in the first instance whether a drug is actually effective when treating the target disease. There is evidence that both terbinafine and itraconazole are statistically significantly better than placebo.
The evidence from one small trial shows that terbinafine (250 mg) was statistically significantly better than itraconazole (100 mg) when given for 2 weeks. However, this trial result is based on a final evaluable sample of one third of the original number recruited to the trial (see table 04). The trialists do not report the reasons for the loss to follow up. A pooled comparison of trials comparing terbinafine with four weeks of itraconazole showed no difference between the two treatments that reached significance. Two small trials comparing terbinafine (250 mg) with griseofulvin (500 mg) demonstrate significant evidence that terbinafine cures 52% more patients than griseofulvin.
No difference was detected between ketoconazole and griseofulvin, or between fluconazole and either ketoconazole or itraconazole. As only 106 patients took part in these three trials, however, there is a real danger of false negative findings. Similarly the only dose finding trial showed no significant difference between giving fluconazole for 50 mg a day or 150 mg a week.
The two most common types of tinea pedis are plantar (side of the foot) and interdigital (between the toes). The type of tinea pedis was described in all studies except two, but no significant difference was demonstrated in the effectiveness of any one drug with respect to location. There is therefore no clear data that the type of tinea pedis is an important factor for the clinician when deciding on oral drug treatment.
With respect to length of treatment, terbinafine is routinely prescribed for 2 weeks (250 mg daily) and the most commonly evaluated regimen for itraconazole was 100 mg for 4 weeks. No trials investigated pulsing itraconazole, which gives 200 mg of itraconazole twice daily for only 7 days and is a regimen which is being introduced into clinical practice. In all trials terbinafine was given at the recommended dose of 250 mg per day but the treatment duration for terbinafine varied from 2 to 6 weeks in the trials with the most frequent being 2 weeks. Terbinafine prescribed for 2 weeks at 250 mg daily may be the optimum treatment period and dosage.
The effectiveness of oral antifungal drugs in treating secondary outcomes corresponded to their effectiveness in achieving primary outcomes. It appears that an antifungal drug's effectiveness in eradicating dermatophyte spores on the skin of the foot reflects the effectiveness of that drug in eradicating clinical signs and symptoms such as scaling, pustules, itching and burning.
All trials except one reported side effects. All drugs led to side effects, with gastrointestinal effects the most frequently reported. As fewer than 700 patients took part in the 12 trials reviewed, the small differences between drugs should be interpreted with caution. The lack of reported information about the types of dermatophytes surviving the treatment regimens evaluated in patients with positive culture at last outcome, prevents us from making any conclusions about the sensitivity of different species to each individual drug therapy.
The measurement of recurrence is important. There is little point in finding a drug treatment that achieves a good cure rate if the condition reappears some weeks after treatment has ended. The studies in this review were disappointing with respect to achieving good follow up, with only three trials assessing the condition beyond three months. Ideally the condition should be re-assessed 6 to 12 months after treatment has ended and if findings demonstrate a continuation of the cured condition this reinforces the effectiveness of the treatment. Whilst it is recognised that a long follow up adds to the cost of a trial it is important that the most effective treatments be those that not only achieve good cure rates but reduce relapse of the condition. Long follow-up periods also increase the possibility of loosing trial participants, five studies included in this review reported a decrease in the number of patients evaluable from those originally recruited to the studies. Concern must be expressed at any missing data which is not accounted for. Of course there is an ongoing discussion of whether it is relapse or re-infection that causes the infection to reappear. In the case of tinea pedis it is a condition that can coexist with a nail infection and unless both are treated together the nail might well prove a source of reinfection for the skin. Whether it is recurrence of the original condition or a re-infection, preventative measures should be considered. Routine oral treatments for prophylactic use cannot be justified due to possible side effects, drug interactions and high costs, however topical agents are a realistic alternative. Hart 1999 concluded that whilst allylamines (e.g. terbinafine) were slightly more effective than azoles (e.g. clotrimazole) for topical treatments of fungal skin and nail infections of the feet, the most cost effective option was to treat initially with topical azoles and use topical allylamines for azole treatment failures. This would be a realistic treatment plan for tinea pedis.
In summary terbinafine is more effective than griseofulvin and one trial demonstrated evidence to support the use of terbinafine over itraconazole when given for a two week treatment period.
No other treatment regimen was shown to be significantly more effective. The quality of reporting of the trials was variable with those of Kim 1993 and Roberts 1987 being of particularly poor quality. The most frequent omission was the lack of blinding of outcome assessors: this could be remedied for future research by coding the labels of the mycological samples sent to the laboratory for analysis. Blinding the outcome assessors of clinical signs and symptoms is particularly important as this outcome is by its nature a subjective measurement.
Although terbinafine cures about 50% more patients than griseofulvin, it is much more costly. Thus relative cost-effectiveness is equivocal. It should be recognised that the occurrence of side effects and whether or not they require treatment should be factored into a full cost effectiveness analysis as indeed should the basic costs of identifying the existence of the infection at the outset of treatment. Although current evidence suggests that terbinafine is more cost-effective than itraconazole, trials are few and sample sizes are small. Thus this comparison needs further investigation to consider the optimal dosages and different treatment regimens.
Authors' conclusions
Implications for practice Terbinafine appears to give a significantly better cure rate for tinea pedis than griseofulvin. In addition, terbinafine may require a shorter treatment period which is preferable in maximising patient compliance. |
Implications for research In order to produce more reliable data, a rigorous evaluation of different drug therapies needs to be undertaken with larger sample sizes. Little information was recorded in the trials about the effectiveness of specific oral antifungal drugs on specific dermatophytes. Future investigators should be advised to report the types of dermatophytes cultured at the last outcome assessment for the proportion of patients not cured. Collecting and reporting this information would not incur any additional costs to the research funding body as microscopy and culture at baseline and follow-up is the primary outcome measure in most trials. In addition the clinical presentation of tinea pedis should be clearly diagnosed. Future researchers should be encouraged to report baseline information about the study population patients' life styles, hobbies and activities, since it may be possible to detect differences in the types of infecting dermatophytes associated with different environments. An evaluation of epidemiological factors in tinea pedis was not possible from the data extracted from the trials but ultimately may influence the effectiveness of antifungal treatments. It is also important to continue to follow up and collect data for preferably six months after the end of the intervention period to inform whether or not the infection recurred. |
Acknowledgements
For help with this review we thank: Philip Young, Janette Colclough, Alison Eastwood, Trevor Sheldon, Jill Ferrari, Andrea Nelson, Hywel Williams, Tina Leonard and the referees.
The editorial base would like to thank the following people who were the external referees for this protocol: Rod Hay and Andrew Finlay (content experts), Sally Hollis (statistician) and Jack Tweed (consumer).
The Skin group has been part of a pilot project in which all its protocols and reviews have been sent to Philippa Middleton for copy-editing and comments on quality. We should like to thank Philippa for her help and advice.
Data and analyses
- Top of page
- Background
- Objectives
- Methods
- Results
- Discussion
- Authors' conclusions
- Acknowledgements
- Data and analyses
- Feedback
- What's new
- History
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
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Feedback
Comment received 2 May 2002
Summary
You seem to have restricted your review to Tinea pedis excluding Onchomycosis and LION study concerned mainly with Onchymocosis. However, what is the clinical or practical consideration to exclude onchomycosis when reviewing effective therapy for Tinea Pedis? Would the studies thus omitted not bring in important pieces of evidence to consider, as not cured infection of the toe nails will in the longer run lead to reinfection of the skin, perhaps after several months?
Reply
The LION study is not part of this review because the study compares two oral treatments for onchomycosis. As you observe our review is concerned with the effectiveness of oral treatments for fungal infections of the skin of the foot (Tinea pedis or athletes foot)and not oral treatments for fungal infections of the toenail (onchomycosis). The review considering oral treatments for onchomycosis is currently a published protocol within the Cochrane Library.
Contributors
Comment sent by:
Franz Piribauer ,Consultant in EBM to Association of Sickfunds of Austria
Reply from:
Sally Bell-Syer (lead reviewer)
Processed by:
Urbà González, Cochrane Skin Group Criticisms Editor
Tina Leonard, Review Group Co-ordinator for the Cochrane Skin Group
Comment received 10 November 2002
Summary
You have chosen to divide evidence on treatments of fungal skin infections in at least three reviews (oral/foot, topical foot/nail, and rest of body). I can understand that, considering the amount of trials.
However, to make this division, you excluded trials that compare data for topical and oral treatment (e.g. Barnetson 1998 and Lynfeld 1974). I think this consequence is quite unfortunate, because these studies may be very helpful to provide evidence whether indeed oral treatment is more effective than local treatment, which is generally assumed, as you also do in your introduction. Would it not be informative to include these trials in some way or some trial?
Reply
Thank you for your comment. You correctly observe that the review of treatments for fungal infections of the foot has been approached in three parts by considering the effectiveness of oral treatments for skin infections of the foot, the effectiveness of oral treatments for toenail infections and thirdly the effectiveness of topical treatments for both skin and toenail infections. This decision was made by the review team and was considered to be the most appropriate way of answering the question of effectiveness. Another point taken into consideration was that oral treatments are obtainable by prescription only and therefore usually require a consultation with a healthcare professional, topical preparations on the other hand are available over the counter.
The inclusion criteria of the review on Oral Treatments for fungal infections of the skin of the foot, state that only oral comparisons will be included, therefore any trial that compared an oral drug to a topical preparation would be excluded from the review.
I understand your observation that including the evidence on comparisons of oral and topical treatments may add a further perspective to the review; indeed this would have resulted in a review with over 80 included trails. As I have explained the decision of the review team was that oral and topical agents would be considered in separate reviews.
Thank you for your interest.
(Note from the Criticisms Editor: the Skin group would consider registering a review comparing oral and topical treatments for fungal infections of the skin of the foot)
Contributors
Comment sent by:
Sander Koning, GP
Reply from:
Sally Bell-Syer (lead reviewer)
Processed by:
Urbà González, Cochrane Skin Group Criticisms Editor
Tina Leonard, Review Group Co-ordinator for the Cochrane Skin Group
What's new
Last assessed as up-to-date: 4 December 2001.
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History
Protocol first published: Issue 3, 1998
Review first published: Issue 2, 2002
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Contributions of authors
SB-S wrote this review. SB-S & RH reviewed the trials and extracted the data. DT gave clinical and methodological advice. ITR, FC & WT secured the funding for the review. WT & FC gave clinical advice.
Declarations of interest
None
Sources of support
Internal sources
- University of York, UK.
- The Wales Office for Research and Development for Health and Social Care, UK.
- University of Wales Institute, Cardiff, UK.
External sources
- No sources of support supplied
Index terms
Medical Subject Headings (MeSH)
Administration, Oral; Antifungal Agents [*therapeutic use]; Chronic Disease; Randomized Controlled Trials as Topic; Tinea Pedis [*drug therapy]
MeSH check words
Humans
* Indicates the major publication for the study