Topical treatments for athlete's foot

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of topical treatments for athlete's foot (interdigital tinea pedis) caused by dermatophytes.

Background

Description of the condition

Clinical features

Tinea pedis - or athlete's foot - is a superficial inflammatory infection of the skin of the feet caused by dermatophyte fungi. Among the fungi responsible for athlete's foot are Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum ( Hsu 2012; Rinaldi 2000). There are three clinical subtypes of athlete's foot: interdigital, moccasin, and vesiculobullous, with interdigital being the most common (Hsu 2012). This review will focus specifically on the subtype interdigital tinea pedis.

The name 'athlete's foot' was derived from the increased occurrence of the condition among athletes, because of their use of occlusive footwear, which create the ideal conditions for dermatophyte reproduction (Macura 1993). Athlete's foot is characterised by whitish macerated skin and itchy or asymptomatic erythema between the toes, usually in the fourth and fifth spaces. Blisters and cracks in the skin between the toes may cause pain and inflammation of the exposed raw tissue. A concomitant bacterial infection may also be present and require antibiotic treatment. Athlete's foot is typically diagnosed by visual inspection of the lesions, microscopy, and cell culture (Rotta 2012) and may be differentially diagnosed as bacterial or candidal intertrigo, dermatitis, eczema, idiopathic keratoderma, or psoriasis (Rinaldi 2000).

Epidemiology

Because of the highly communicable nature of the disease, athlete's foot is one of the most common skin infections, affecting approximately 20% to 25% of the world's population (Havlickova 2008). Despite the development of antifungal agents, the incidence of athlete's foot has increased over the past two decades (Vena 2012). Athlete's foot has been said to occur in roughly 1 in 5 adults, with a prevalence rate of approximately 10% in developed countries (Nelson 2003). This rate is presumably higher in most developing countries whose warm and humid climates are conducive to fungal infection (Nweze 2010). The incidence of athlete's foot has also been shown to increase with age from adolescence (Male 1990), with infection being most common among men between the ages of 25 to 44 years (Panackal 2009; Vena 2012). Individuals at high risk of infection include those who use communal shower and changing rooms (e.g. arenas, swimming pools, fitness centres), those who wear occlusive footwear, those who are obese, and those who are immunosuppressed (e.g. individuals who are HIV positive, diabetic, or organ transplant recipients) (Rinaldi 2000). Studies also suggest that certain occupations that require heavy industrial or military footwear (e.g. miners, soldiers) and industries where workers share common shower and changing areas place people at higher than average risk of infection (Auger 1993; Djeridane 2007; Roberts 1992). People living in institutions and long-term care facilities also show a higher than average prevalence of infection (Roberts 1992) most likely attributable to cross-contamination from communal living.    

Treatment and prognosis

The primary treatment for athlete's foot includes topical antifungal medications, applied once or twice daily (Gupta 2008). With appropriate treatment, athlete's foot is usually eradicated within two to four weeks; however, reinfection is possible (Gupta 2008). The condition is not life-threatening in people with normal immune status, yet because some individuals are unaware of ongoing infection, it may result in persistent itching and ultimately fissuring in the spaces between the toes. The most common complications of athlete's foot are subsequent toenail infection or bacterial skin infection (Field 2008). Unresolved infection can also spread to other parts of the body (such as the hands and the trunk) as well as to other individuals. Therefore, prompt diagnosis, treatment, and patient education are essential to reduce the spread and transmission of this type of infection. Oral treatment is used for chronic conditions or when topical treatment has failed; this is the subject of another Cochrane review (Bell-Syer 2012).

Prevention

Strategies to reduce the risk of infection include ensuring that the feet and especially the spaces between the toes are kept dry; wearing socks made of natural fibres (cotton or wool); protecting feet while in public bathrooms, showers, swimming pools, and fitness centres; and wearing well-ventilated shoes whenever possible.

Description of the intervention

Topical interventions for the treatment of athlete's foot (interdigital tinea pedis) in the form of sprays, gels, creams, powders, or ointments.

How the intervention might work

Topical treatments for athlete's foot typically work by inhibiting fungal growth on the skin and can be categorised depending upon their specific mechanism of action. Most of these fungistatic treatments impede fungal growth by one of the following mechanisms:

a) inhibition of the formation of fungal membranes (e.g. itraconazole and terbinafine) (Joly 1992; Ryder 1985);
b) inhibition of microtubule synthesis (e.g. griseofulvin) (Borgers 1980); or
c) inhibition of protein synthesis (e.g. benzoxaboroles, which are transfer RNA (tRNA) synthetase inhibitors) (Baker 2006).

Fungicidal agents are believed to kill the fungus by destroying cell membrane integrity (tea tree oil) (Hammer 2003) or causing nucleic acid damage (ozonized oil) (Geweely 2006). Finally, some treatments, like undecylenic acid, which obstructs fatty acid biosynthesis, have both fungistatic and fungicidal activity (McLain 2000).

Why it is important to do this review

Numerous topical antifungal treatments have been investigated for the treatment of athlete's foot, including both over-the-counter and prescription medications. Moreover, new antifungal formulations are also under investigation for this condition. This review will assist people with athlete's foot, healthcare professionals, and healthcare decision-makers to revise the evidence on topical interventions for the treatment of interdigital tinea pedis.

Objectives

To assess the effects of topical treatments for athlete's foot (interdigital tinea pedis) caused by dermatophytes.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) of topical treatments for interdigital tinea pedis.

Types of participants

We will include men and women of any age who have an interdigital tinea pedis infection caused by dermatophytes, which has been confirmed by the use of potassium hydroxide to identify hyphae microscopically or by dermatophyte culture.

Types of interventions

We will compare any topical antifungal regimen administered for the treatment of athlete's foot to other treatments, placebo, or no treatment. The topical interventions can be administered as monotherapy or as combination therapy.

Types of outcome measures

We will categorise and analyse outcomes based on short-term (≥ 2 ≤ 6 weeks), mid-term (> 6 ≤ 10 weeks), and long-term (> 10 weeks) assessments. We will exclude studies with durations of < 2 weeks.

Primary outcomes
  1. Mycological cure rate: the proportion of participants who achieved negative mycological testing (microscopy or dermatophyte culture) at follow-up.

  2. Complete cure: the proportion of participants who achieved mycological cure plus the resolution of clinical signs and symptoms suggestive of dermatophyte infection, as judged by study investigators.

  3. Adverse events: the proportion of participants who reported any adverse event. The proportion of participants who reported adverse events deemed to be related or possibly related to the intervention, as judged by the study investigator(s).

Secondary outcomes
  1. Compliance: the proportion of participants who adhered to the treatment regimen.

  2. Recurrence: defined by the recurrence of either clinically or mycologically proven infection in participants having previously been documented as cured.

  3. Quality of life: defined by any indication of impact on participant well-being attributed to the treatment.

  4. Cost-effectiveness: defined as the comparison between the monetary cost and health effects of interventions.

Search methods for identification of studies

We aim to identify all relevant RCTs regardless of language or publication status (published, unpublished, in press, and in progress).

Electronic searches

We will search the following databases for relevant trials:

  • the Cochrane Skin Group Specialised Register;

  • the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library;

  • MEDLINE via OVID (from 1946);

  • EMBASE via OVID (from 1974); and

  • LILACS (Latin American and Caribbean Health Science Information database, from 1982).

We have devised a draft search strategy for randomised controlled trials (RCTs) for MEDLINE (OVID), which is displayed in Appendix 1. This will be used as the basis for search strategies for the other databases listed.

Trials registers

We will search the following trials registers:

Searching other resources

References from included studies

We will check the bibliographies of included and excluded studies for further references to relevant trials.

Unpublished literature

We will conduct online searches of pharmaceutical company websites and the U.S. Food and Drug Administration (FDA) website. We will contact experts in the field of dermatology regarding unpublished trials.

Conference proceedings

We will handsearch the following conference proceedings for relevant trials from years that have not already been handsearched by the Cochrane Skin Group:

  • the British Association of Dermatologists (1982 to 2013);

  • the Annual Meetings of the American Academy of Dermatology (1990 to 2013);

  • the European Academy of Dermatology (1996 to 2013);

  • the European Society for Dermatological Research (1970 to 2012); and

  • the Australasian College of Dermatologists (1996 to 2013).

Adverse effects

We will not perform a separate search for adverse effects of topical treatments for athlete's foot; however, we will examine adverse effects data from included studies.

Pharmacoeconomic studies

We will not perform a separate search for pharmacoeconomic studies; however, we will comment on any data from included studies.

Data collection and analysis

We plan to include at least one 'Summary of findings' table in our review. In this, we will summarise the primary outcomes for the most important comparison. If we feel there are several major comparisons or that our findings need to be summarised for different populations, we will include further 'Summary of findings' tables.

Selection of studies

We will manage references using Microsoft Excel 2010 software. At least two reviewers (DD, MP, FS, or DL) will independently perform study selection. In order to refine the criteria and clarify any discrepancies, we will pilot inclusion criteria on a small sample of the articles (˜ 10). We will examine trials to ensure compliance with review inclusion criteria and link all reports to the study to which they pertain. We will correspond with trial authors when necessary to clarify study eligibility.

We will only include a study if the results for tinea pedis are available separately in studies evaluating different infections (e.g. onychomycosis, tinea capitis, candida, tinea corporis, etc).

If any disagreements regarding study inclusion arise, we will achieve resolution via discussion between the review authors and, if needed, a mediator (AKG). We will quantify the percentage of agreement between the two review authors using the kappa statistic.

Data extraction and management

Two independent reviewers (DD and DL) will perform data extraction using data collection forms. The data recorded will include study design, number of participants randomised into each treatment group, baseline characteristics, health intervention, treatment regimen and duration, treatment success and failure, efficacy, safety, tolerability, the number of participants lost to follow up, and the duration of follow-up. We will pilot data collection forms prior to use and settle disagreements between reviewers by discussion. If agreement cannot be reached, a third author will assist in the resolution of any discrepancies. One author (DD) will verify and enter data into Review Manager 5.2, and a second author (DL) will also verify. In order to reduce bias, we will seek intention-to-treat (ITT) data. When possible, we will transform rates that are reported per-protocol according to ITT values. The authors will not be blinded to the names of trial authors, institutions, or journals.

For the outcome 'quality of life', we will report a qualitative summary of the evidence.

We shall comment on costs if they are reported in any of the included studies, but we will not analyse economics outcomes as they are so variable according to each country and year.

Assessment of risk of bias in included studies

Two review authors (AKG and DD (or a third co-author)) will assess the risk of bias of the selected studies independently using The Cochrane Collaboration's tool as described in Chapter 8, section 8.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). To resolve any inconsistencies between assessors, we will compare and discuss the independent evaluations. We will assess and report the following domains in the 'Risk of bias' tables:

(a) Selection bias
Sequence generation

We will report and examine the means of generating an allocation sequence for each trial.

Allocation concealment

We will report and assess the method of allocation concealment for each study.

(b) Performance bias
Blinding of participants and personnel

We will describe all methods used to blind participants and study personnel for each trial. If a blinding procedure was not implemented, we will make an assessment regarding the degree of bias introduced.

(c) Detection bias
Blinding of outcome assessment

We will determine and report the blinding of outcome assessors for each study.

(d) Attrition bias
Incomplete outcome data

We will examine studies for incomplete outcome data and compare the number of trial participants in each intervention arm who provide valid outcome data to the total number of randomised participants. We will note whether reasons for attrition have been reported.

We will assess the domains and overall risk of bias as 'low risk of bias', 'unclear' (uncertain risk of bias), or 'high risk of bias' as suggested by Higgins 2011. We will attempt to contact study authors for additional information about study methods as necessary.

Measures of treatment effect

For the treatment comparisons, we will calculate a risk ratio (RR) and 95% confidence interval (CI) for dichotomous outcomes using the Mantel-Haenszel model. Using the inverse-variance model, we will calculate a mean difference (MD) and 95% CI for continuous outcomes. The number needed to treat (NNT) will be calculated for significantly different dichotomous outcomes using the following formula: NNT = 1/ARC * (1-RR), where the RRs from the meta-analysis and the moderate assumed control risk (ARC) calculated in GRADEpro will be used.

Unit of analysis issues

The unit of analysis will be the participant. We will analyse data from cross-over trials using a paired analysis. We will attempt to assess carry-over and period effects descriptively, as recommended in section 16.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will consider as cluster trials results from within-participant trials (intra-individual, e.g. foot randomisation) where samples are taken from multiple sites in the same participant and treated as individual data points.

Dealing with missing data

We will contact study authors to ask them to provide additional information on missing data. In the event of missing data, we will perform the primary analysis using available cases as reported by the authors. In addition, we will undertake sensitivity analyses to assess the impact of such studies (i.e. those assessed as having 'high risk of bias' under the 'incomplete outcome data' domain) on the pooled effect estimate. For binary outcomes, we will undertake additional analysis involving limited imputation of missing data assuming that postrandomisation losses experienced either (1) the worse or (2) the better outcome in the binary event, as suggested by Gamble 2005. For continuous outcomes, we will employ a similar approach in which we will assume a fixed difference between the actual mean for the missing data and the mean assumed by the analysis of about one standard deviation (White 2007).

Assessment of heterogeneity

We will assess heterogeneity between studies using Chi² and I² statistics (Higgins 2011), and we will use a significance value of 0.10 rather than 0.05 for comparisons with small sample sizes or a small number of trials (Higgins 2011). We will not pool for meta-analyses studies whose I² statistic values exceed 75%.

Assessment of reporting biases

If sample size permits (≥ 10), we will investigate the possibility of selective reporting by generating and examining funnel plots for asymmetry.

Data synthesis

We will use a random-effects model for all meta-analysis where I² statistic ≤ 75%. In cases where I² statistic > 75%, we will present data as a narrative analysis, providing details of study results, trial interventions, and study design.

Subgroup analysis and investigation of heterogeneity

If I² statistic > 50%, we will perform subgroup analysis to explore the reasons for heterogeneity (Higgins 2011). These analyses will include subgroups defined by treatment regimen (i.e. dose, duration, frequency) and formulation (e.g. gel, cream, powder) and participant factors (e.g. obesity, immunosuppression, coinfection). However, an insufficient number of studies could limit the feasibility of such refined analyses.

Sensitivity analysis

In the event that substantial heterogeneity exists, we will exclude in a sensitivity analysis studies demonstrating poor methodological quality as judged by the 'Risk of bias' assessment to investigate this potential source of heterogeneity.

Acknowledgements

The Cochrane Skin Group editorial base wishes to thank Esther van Zuuren who was both the Cochrane Dermatology Editor and Methods Editor for this protocol; Matthew Grainge who was the Statistical Editor; the clinical referee, Rod Hay; and the consumer referee, Jack Tweed.

Appendices

Appendix 1. Draft search strategy for MEDLINE (OVID)

1. (fungal infection$1 adj5 (foot or feet)).mp.

2. ((foot or feet) adj3 ringworm).mp.

3. tinea pedum.mp.

4. tinea pectis.mp.

5. (tinea and (foot or feet)).ti,ab.

6. exp Tinea Pedis/

7. tinea pedis.mp.

8. athlete$ foot.mp.

9. or/1-8

10. randomised controlled trial.pt.

11. controlled clinical trial.pt.

12. randomized.ab.

13. placebo.ab.

14. clinical trials as topic.sh.

15. randomly.ab.

16. trial.ti.

17. 10 or 11 or 12 or 13 or 14 or 15 or 16

18. exp animals/ not humans.sh.

19. 17 not 18

20. 9 and 19

Contributions of authors

DD and MP drafted the protocol.
AKG, FS, BG, and DL reviewed and provided comments on drafts of the protocol.
MV checked the protocol for readability and clarity. He also ensured that the outcomes are relevant to consumers.
DD co-ordinated the contributions from the co-authors and wrote the final draft of the protocol.
AKG, DD, and MP responded to the clinical comments of the referees.
EV, DD, and MP responded to the methodology and statistics comments of the referees.

Disclaimer

The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health, UK.

Declarations of interest

AK Gupta was a roundtable participant for Bayer and an investigator for a clinical trial sponsored by Medicis Pharmaceutical Corporation (published in 2005). AK Gupta is the director of Mediprobe Research Inc..

Deanne Daigle, Fiona Simpson, Danika Lyons, Bharat Gandhi, and Maryse Paquet stated that their employer (Mediprobe Research Inc.) may be the site of future clinical trials in this area.

Sources of support

Internal sources

  • None, Not specified.

External sources

  • The National Institute for Health Research (NIHR), UK.

    The NIHR, UK, is the largest single funder of the Cochrane Skin Group.

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