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Citation: Ward, H.; Parkes, N.; Smith,
C.; Kluzek, S.; Pearson, R. Consensus
for the Treatment of Tinea Pedis: A
Systematic Review of Randomised
Controlled Trials. J. Fungi 2022,8, 351.
https://doi.org/10.3390/jof8040351
Academic Editors: Célia F. Rodrigues
and Natália Cruz-Martins
Received: 25 February 2022
Accepted: 25 March 2022
Published: 29 March 2022
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Fungi
Journal of
Systematic Review
Consensus for the Treatment of Tinea Pedis: A Systematic
Review of Randomised Controlled Trials
Harry Ward 1,2,*, †, Nicholas Parkes 1, 2,†, Carolyn Smith 2, Stefan Kluzek 3and Richard Pearson 3
1Versus Arthritis Centre for Sport, Exercise and Osteoarthritis Research, University of Nottingham,
Nottingham NG7 2UH, UK; nicholas.parkes1@gmail.com
2Bodleian Health Care Libraries, Oxford University, Oxford OX3 9DU, UK;
carolyn.smith@bodleian.ox.ac.uk
3Orthopaedics, Trauma and Sports Medicine, School of Medicine, Queen’s Medical, Centre University of
Nottingham, Nottingham NG7 2UH, UK; stefan.kluzek@ndorms.ox.ac.uk (S.K.);
richard.pearson@nottingham.ac.uk (R.P.)
*Correspondence: harry.ward4@nhs.net
† These authors contributed equally to this work.
Abstract:
Objective: To systematically review literature enabling the comparison of the efficacy
of pharmaceutical treatments for tinea pedis in adults. Design: Systematic review of randomised
controlled trials (RCTs) with mycological cure as the primary outcome. Secondary outcomes did
include the clinical assessment of resolving infection or symptoms, duration of treatment, adverse
events, adherence, and recurrence. Eligibility Criteria: Study participants suffering from only tinea
pedis that were treated with a pharmaceutical treatment. The study must have been conducted using
an RCT study design and recording age of the participant > 16 years of age. Results: A total of seven
studies met the inclusion criteria, involving 1042 participants. The likelihood of resolution in study
participants treated with terbinafine was RR 3.9 (95% CI: 2.0–7.8) times those with a placebo. Similarly,
the allylamine butenafine was effective by RR 5.3 (95% CI: 1.4–19.6) compared to a placebo. Butenafine
was similarly efficacious to terbinafine RR 1.3 (95% CI: 0.4–4.4). Terbinafine was marginally more
efficacious than itraconazole, RR 1.3 (95% CI: 1.1–1.5). Summary/Conclusion: Topical terbinafine and
butenafine treatments of tinea pedis were more efficacious than placebo. Tableted terbinafine and
itraconazole administered orally were efficacious in the drug treatment of tinea pedis fungal infection.
We are concerned about how few studies were available that reported the baseline characteristics
for each treatment arm and that did not suffer greater than 20% loss to follow-up. We would like to
see improved reporting of clinical trials in academic literature. Registration name: Treatment’s for
athlete’s foot—systematic review with meta-analysis [CRD42020162078].
Keywords: tinea pedis; athlete’s foot; treatment
1. Background
Summary
What is already known?
•Azoles and allylamines are superior to placebo in the treatment of tinea pedis;
•Allylamines may be superior to azoles, but the evidence is conflicting;
•The field has remained relatively unchanged since 1999.
What are the new findings?
•
There is huge inconsistency in RCTs for the treatment of tinea pedis, especially in
terms of outcome measures;
•
Many peer-reviewed RCTs for the treatment of tinea pedis have a high risk of bias,
especially attrition bias;
•
A common problem for these RCTs is the poor reporting of baseline characteristics for
the treatment arms;
J. Fungi 2022,8, 351. https://doi.org/10.3390/jof8040351 https://www.mdpi.com/journal/jof
J. Fungi 2022,8, 351 2 of 11
•
Addressing these issues will streamline the application of future treatments for tinea
pedis in clinical practice.
Tinea pedis, or athlete’s foot, is a superficial fungal infection of the skin of the feet
caused by dermatophytes, most commonly Trichophyton rubrum,Trichophyton mentagrophyte
and Epidermophyton floccosum [
1
,
2
]. Diagnosis is confirmed by the detection of segmented
hyphae in skin scrapings using a potassium hydroxide (KOH) preparation and fungal
culture from these skin flakes [
3
]. Increasingly rapid real-time diagnostic polymerase chain
reaction (PCR) is being used, which not only allows the rapid identification of infection
and the species, but also quantification, which can prove helpful in cases of recurrence
of infection where there is clinical uncertainty over resolving pre-existing infection or
recurrence [4].
Tinea pedis is common worldwide, with more than 70% of the population experienc-
ing this infection during their lifetime [
5
]. Despite the advent of anti-fungal medication,
incidence has increased in recent years [
6
]. Tinea pedis onychomycosis is more prevalent
in older people [
7
]. Some groups are more at risk of dermatophyte infection due to oc-
clusive footwear, sweating, and barefoot contact, such as miners, soldiers, and marathon
runners [
8
–
10
]. Preventative adjunct treatment strategies include ensuring that the inter-
digital spaces remain dry, wearing well-ventilated shoes and socks composed of natural
fibres, and covering feet when using communal facilities [11,12].
The first topical anti-fungal was developed in 1949. More recently, other compounds
have been shown to have anti-fungal activity, such as tolnaftate, ciclopirox and undecylenic
acid [
11
]. The list of compounds used to treat tinea pedis is expanding, with RCTs being
used to assess the efficacy of herbal remedies [13]. While tinea pedis can be cured in most
people, medical attention is often sought late. Even for those with treatment, tinea pedis
can become severe and chronic. In those that have been successfully treated, reinfection is
common and often does not self-resolve [1].
Prior systematic reviews assessing the treatment of tinea pedis include those within
the Cochrane Database of Systematic Reviews. Crawford et al., 2007, concluded that
placebo-controlled trials of topically applied allylamines and azoles for athlete’s foot
consistently produce much higher percentages of cure than a placebo [
12
]. Then, in 2012,
Bell-Syer et al. reported on oral treatments of tinea pedis; terbinafine is more effective than
griseofulvin, and terbinafine and itraconazole are more effective than no treatment [
14
].
Not within the Cochrane systematic review structure, Rotta et al. reported in 2012 and 2013
their conclusions reached through systematic review regarding topical treatments [
15
,
16
].
Their manuscript indicated the superiority of topical antifungals over a placebo, but also
that there is no consistent difference between classes. The efficacy of allylamines over
azoles was implied in 1999 [
17
]; however, in this research, when allylamines and azoles
were compared to a placebo, these two drug classes demonstrated similar efficacy. This
superiority of allylamines over azoles was also further implied in the systematic review
of the published literature [
12
,
14
,
18
], but has also been contested [
15
,
16
]. Given these
conflicting results from previous RCTs and systematic reviews, there is a need for clarity in
the field. We not only provide an update on this topic with the current evidence, but we
also notice that many RCTs have a high risk of bias, particularly attrition bias, and often
do not provide sufficient data on the baseline characteristics. We therefore employ careful
inclusion criteria to exclude studies with high risk of bias that may have clouded previous
systematic reviews.
Many now question the need for placebo-controlled trials when there is a known
benefit of both classes of anti-fungal agents in treating tinea pedis [
18
]. Some consider that
there is a lack of long-term data, e.g., 6-month follow-ups, to assess the efficacy of treatments
on the recurrence rate of tinea pedis [
14
]. More recently, concerns regarding community
Trichophyton resistance to terbinafine particularly in India have been raised [
19
,
20
]. The aim
of this systematic review is to streamline current evidence for clinicians whilst highlighting
areas for future research and troubleshooting problems in study design and interpretation
so that future RCTs can be translated into clinical benefit.
J. Fungi 2022,8, 351 3 of 11
2. Methods
This systematic review adheres to the PRISMA (Preferred Reporting Items for System-
atic Reviews and Meta-Analyses) guidelines, including the use of the PRISMA checklist
(see Supplementary Material TP PRISMA checklist). The search strategies for MEDLINE,
Embase, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Central
Register of Controlled Trials, ClinicalTrials.gov, ICTRP, and LILACS were generated by
CH, Bodleian Library (see Supplementary Material TP example search strategy Medline).
Databases were searched on the 26th of May 2021. The initial dates for the literature search
were database-dependent, for example, Ovid MEDLINE 1946, EMBASE 1974.
The selection of studies employed the conventional PICO approach. Participants were
>16 years old with tinea pedis only treated with an accurately described pharmaceutical
treatment. Intervention was described in detail, recording pharmaceutically active ingredi-
ents and formulations, including the dose and frequency of administration. The comparator,
arm or arms that could have been a control treatment (placebo) were reported with the
baseline characteristics of participants within each arm. The outcomes, mycological cure
rates as determined by mycological culture and KOH microscopy, clinical cure, duration
of treatment, adverse events, adherence to treatment, reoccurrence of infection, use and
efficacy of adjuvants.
2.1. Inclusion Criteria
Participants were patients over 16 years old with only tinea pedis, well-described
interventions, comprising of two different treatments, including the formulation, dose
and frequency, a minimum of age and sex baseline characteristics reported in each arm,
and outcomes reported as the mycological efficacy based on both the KOH and culture
and reported separately to clinical data. Studies were required to follow the randomised
controlled trial (RCT) experimental design within a hospital setting; however, registered
trials by pharmaceutical companies also met the inclusion criteria. RCTs conducting
intervention must be described in detail, recording the pharmaceutically active ingredient
and formulation; for example, tablet or topical antifungal medications in the form of sprays,
gels, creams, powders or ointments; including the dose and frequency.
2.2. Exclusion Criteria
A heterogeneous participants group i.e., not only tinea pedis, was an exclusion crite-
rion, as was studies with participants < 16 years. The control group was required to be
either a different treatment or placebo arm. We stipulated that the study must be excluded
if the control arm or placebo group did not report the baseline characteristics; they must
have included a minimum of the age and sex for each arm, and if there was more than 20%
loss of participants in follow up.
2.3. Data Analysis
A total of 1850 study titles with abstracts were screened by two independent reviewers
(NP and HW) for eligibility against the inclusion/exclusion criteria. This was followed
by screening the full text of 140 full-text manuscripts. Disagreements between reviewers
were resolved by consensus or by the decision of a third senior reviewer. Of the 1850 titles,
7 were deemed to meet the inclusion criteria and not fulfil the exclusion criteria (Figure 1).
Data were extracted using a data extraction proforma for each included study. This
was used for the review and where the data were not suited to such an analysis; a text
summary of the extracted data is described in the results section of this manuscript.
2.4. Risk of Bias Assessment
The Cochrane Risk risk-of-bias tool embedded within the ReviewManager (RevMan)
software, V.5.4 (The Cochrane Collaboration, London, UK, 2020), was used to assess
potential study bias. It was reported using a traffic light icon plot, where green represents
low risk and red high risk of bias. Risk of bias analysis was performed over several
J. Fungi 2022,8, 351 4 of 11
domains: selection bias, performance bias, detection bias, attrition bias, and reporting bias.
For selection bias, we assessed the methods of randomisation and allocation concealment.
We assessed the blinding of participants and personnel for performance bias and blinding of
outcome measures for detection bias. For attrition bias, we calculated the loss of participants
from the baseline to the final outcome and we deemed a loss greater than 20% as high
attrition bias. We then assessed reporting bias by comparing their proposed study design
and their published data to determine if all of the outcomes were reported as intended
from the outset of the study and also to determine if these outcomes were reported equally
for both arms. We also assessed for any other bias, such as cross-over between arms.
J. Fungi 2022, 8, x FOR PEER REVIEW 4 of 12
Figure 1. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow di-
agram.
Data were extracted using a data extraction proforma for each included study. This
was used for the review and where the data were not suited to such an analysis; a text
summary of the extracted data is described in the results section of this manuscript.
2.4. Risk of Bias Assessment
The Cochrane Risk risk-of-bias tool embedded within the ReviewManager (RevMan)
software, V.5.4 (The Cochrane Collaboration, London, UK, 2020), was used to assess po-
tential study bias. It was reported using a traffic light icon plot, where green represents
low risk and red high risk of bias. Risk of bias analysis was performed over several do-
mains: selection bias, performance bias, detection bias, attrition bias, and reporting bias.
For selection bias, we assessed the methods of randomisation and allocation concealment.
We assessed the blinding of participants and personnel for performance bias and blinding
of outcome measures for detection bias. For attrition bias, we calculated the loss of partic-
ipants from the baseline to the final outcome and we deemed a loss greater than 20% as
high attrition bias. We then assessed reporting bias by comparing their proposed study
Figure 1.
PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow
diagram.
3. Results
All of the included clinical studies were randomised controlled trials. Seven studies
met the inclusion criteria while not meeting the exclusion criteria. Five involved topical
application, whereas tablet formulations were used in two studies. These studies involved
a total of 1042 participants, 680 not lost to follow-up, and had mycological data, which
were both microscopy and cultures. The included studies were Smith et al., 1990 [
21
],
Evans et al., 1991 [
22
], De Keyser et al., 1994 [
23
], Hay et al., 1995 [
24
], Syed et al., 2000 [
25
],
Korting et al., 2001 [
26
], and Li et al., 2014 [
27
] (see Table 1). These studies were all clinical
trials that were published in English. In general, the studies tended to be small in size, with
between 10 and 35 participants within each study arm. De Keyser et al., 1994, Hay et al.,
1995, and Li et al., 2014, were larger studies, with 88 to 184 participants in each study arm.
J. Fungi 2022,8, 351 5 of 11
Although these participant numbers were declared in the recruitment and demographic
description of the study participants, the marked percentages of those constituting the
study arms were excluded either due to factors such as negative mycology at the time of
commencing treatment or attrition. This was most evident in the larger studies, where those
not included in the analysis ranged between 23 and 133 within a study treatment arm.
Table 1. Summary of the included randomised controlled trials.
Smith et al.,
1990
Evans et al.,
1991
De Keyser
et al., 1994
Hay et al.,
1995 Syed et al., 2000 Korting
et al., 2001 Li et al., 2014
Arms
Placebo
Terbinafine
Placebo
Terbinafine
Terbinafine
Itraconazole
Terbinafine
Itraconazole
Placebo
Terbinafine
Butenafine
Placebo
Terbinafine
Placebo
Terbinafine
Number of Patients 10 10 20 28 184 182 88 100 20 20 20 35 35 145 145
Number of Patients
with Mycology Data 10 10 20 27 51 66 65 64 20 20 20 35 35 122 115
Follow-Up (weeks) 6 6 8 16 4 8 6
% Male 80 66.7 60.2 53.7 100 80 66.9
Average age 29 40 47.7 46.5 40.6 38.5 46.6 45.7 35.2 34.8 35.9 46 42 34.1 35.3
3.1. Participant Characteristics
The reported mean or median age of the study participants ranged from 29 to 48 years
for the placebo arms, 35 to 47 years for the terbinafine arms, and the itraconazole and
butenafine arms having mean ages of 46 and 36 years, respectively. The proportion of males
in the studies ranged from 54 to 80%, with the exception of the Syed et al., 2000, study being
all male [
25
]. The infection status of all participants was confirmed by both culture and
microscopy prior to the study, and any participants later found to be culture negative at
baseline were removed from the analysis. All participants had clinical signs and symptoms
of tinea pedis, although the studies varied in the signs and symptoms assessed. Several
studies reported disease status on a four-point ordinal scale: absent, mild, moderate, or
severe. The two disease criteria of erythema and pruritis were unanimously reported. Other
commonly reported disease phenotypic characteristics included vesiculation (in eight out
of nine audited studies), pustules (in seven out of nine), incrustation (in six out of nine) and
scaling (in five out of nine). Erosions and macerations were only reported in one study.
3.2. Treatment and Outcome
The included studies tended to cover topical application formulations. All topical
applications contained a 1% active ingredient formulation. However, De Keyser, 1994, and
Hay, 1995, both trialled terbinafine (250 mg) against itraconazole (100 mg) as tablets, each
being dosed once daily for 2 weeks. The duration of treatment varied across the trials,
ranging from a single application of an alcohol-containing film-forming solution in the
Li et al., 2014, study to a 4-week treatment period in the Smith et al., 1990, randomised
controlled trial [
21
,
27
]. The duration of the study was variable, ranging from 4 to 16 weeks
(Table 1). There was some variation in the timepoint chosen to assess the treatment efficacy.
In the included studies, this ranged from the point when the treatment period ended, as in
the Syed et al., 2000, study, up to 7 weeks after the completion of treatment, as reported
by Korting et al., 2001 [
25
,
26
]. Mycological cure data derived from KOH microscopy and
culture were used in our efficacy analyses, even if the paper chose to report in addition to
the overall efficacy using a combination of clinical cure and mycological cure. Therefore,
for a study to be included in this systematic review, it was a requirement that these data
were reported separately in the published manuscript [
21
]. This was conducted in an effort
to reduce inter-trial variability. Clinical cure data across the included studies did not refer
to validated clinical assessment tools.
J. Fungi 2022,8, 351 6 of 11
The specific clinical criterion used to define the resolution of the infection and hence
the clinical efficacy varied between the RCT protocols for the different studies. The most
common method was the sum of signs and symptoms on a 0–3 scale composed of absent,
mild, moderate, and severe. However, not all studies used the same number of signs and
symptoms. Some studies used percentages to gauge the amount of clinical improvement
from poor, fair, good, excellent, to complete response, which corresponded to 0–25%,
25–50%
, 50–79%, 80–99% and 100%, respectively. Some studies defined a ‘clinical cure’ as
a total score of less than two on the 0–3 scale for each sign and symptom, whereas others
defined it as less than 50% of signs and symptoms remaining, and some studies did not
define it at all.
Each study was reviewed for the number of adverse events in each arm, adher-
ence to treatment, recurrence of signs and symptoms and the use of any adjunct treat-
ments/preventative strategies, such as advice on dry shoes and socks or specific insoles.
No study precisely described how adherence to treatment was assessed, and no study
addressed the benefit of adjunct treatments. The reviewed RCTs did not have experimental
protocols designed to assess the recurrence rate.
3.3. Efficacy of Drug Treatment of Tinea Pedis
The likelihood of resolving tinea pedis infection in the study participants treated with
terbinafine was 3.9 (95% CI: 2.0–7.8) times those treated with a placebo (Figure 2). Similarly,
the allylamine butenafine was also more effective at treating tinea pedis by 5.3 (95% CI:
1.4–19.6) compared to a placebo. For comparison between butenafine and terbinafine,
butenafine had similar efficacy to terbinafine 1.3 (95% CI: 0.4–4.4).
J. Fungi 2022, 8, x FOR PEER REVIEW 7 of 12
Figure 2. Forest plot of the likelihood of resolution of tinea pedis infections through topically ap-
plied treatments in randomised controlled trials, either placebo-controlled or multi comparator
treatment arms.
There were two two-arm studies that compared the oral administration of terbinafine
versus itraconazole [23,24]. The tableted terbinafine and itraconazole analysis identified
that terbinafine was 1.3 (95% CI: 1.1–1.5) more efficacious than the azole itraconazole.
Our analysis showed that five of the seven studies used in the analysis had a high
risk of bias in one component of their study (Figure 3). This was predominantly regarding
attrition bias, where incomplete outcome data were reported. One study illustrated a se-
lective reporting bias. Although five of the seven studies reported one high risk of bias,
there were a considerable number of occasions where there was an unclear risk of bias.
This is indicative of a potential bias, as the bias topic received no or poor coverage in the
published manuscript; therefore, the bias cannot be assessed.
Figure 2.
Forest plot of the likelihood of resolution of tinea pedis infections through topically
applied treatments in randomised controlled trials, either placebo-controlled or multi comparator
treatment arms.
J. Fungi 2022,8, 351 7 of 11
There were two two-arm studies that compared the oral administration of terbinafine
versus itraconazole [
23
,
24
]. The tableted terbinafine and itraconazole analysis identified
that terbinafine was 1.3 (95% CI: 1.1–1.5) more efficacious than the azole itraconazole.
Our analysis showed that five of the seven studies used in the analysis had a high
risk of bias in one component of their study (Figure 3). This was predominantly regarding
attrition bias, where incomplete outcome data were reported. One study illustrated a
selective reporting bias. Although five of the seven studies reported one high risk of bias,
there were a considerable number of occasions where there was an unclear risk of bias.
This is indicative of a potential bias, as the bias topic received no or poor coverage in the
published manuscript; therefore, the bias cannot be assessed.
J. Fungi 2022, 8, x FOR PEER REVIEW 8 of 12
Figure 3. Risk-of-bias table for the tinea pedis randomised controlled trials.
4. Discussion
A total of seven studies met inclusion the criteria, involving 1042 study participants
over the age of 16 years being treated for tinea pedis. A total of 680 participants had full
mycological data reported. There were five studies assessing the efficacy of topical formu-
lations, and two assessing tableted oral formulations. For topical formulations, the likeli-
hood of resolving tinea pedis in study participants treated with terbinafine was RR 3.9
(95% CI: 2.0–7.8) times that of those treated with a placebo. Similarly, the allylamine bu-
tenafine was also effective at treating tinea pedis RR 5.3 (95% CI: 1.4–19.6) compared to a
placebo. Butenafine was similarly efficacious to terbinafine by RR 1.3 (95% CI: 0.4–4.4).
For tableted oral formulations: terbinafine showed increased efficacy compared with the
azole itraconazole, RR 1.3 (95% CI: 1.1–1.5). The caveat regarding the analysis is the lim-
ited amount of data contributing to the analysis. This was principally due to our inclusion
criteria stipulating that the participant demographics must be reported for each arm of
the study. We chose to not combine topical applications with tableted formulations, as
Figure 3. Risk-of-bias table for the tinea pedis randomised controlled trials.
4. Discussion
A total of seven studies met inclusion the criteria, involving 1042 study participants
over the age of 16 years being treated for tinea pedis. A total of 680 participants had
full mycological data reported. There were five studies assessing the efficacy of topical
formulations, and two assessing tableted oral formulations. For topical formulations, the
J. Fungi 2022,8, 351 8 of 11
likelihood of resolving tinea pedis in study participants treated with terbinafine was RR
3.9 (95% CI: 2.0–7.8) times that of those treated with a placebo. Similarly, the allylamine
butenafine was also effective at treating tinea pedis RR 5.3 (95% CI: 1.4–19.6) compared to
a placebo. Butenafine was similarly efficacious to terbinafine by RR 1.3 (95% CI: 0.4–4.4).
For tableted oral formulations: terbinafine showed increased efficacy compared with the
azole itraconazole, RR 1.3 (95% CI: 1.1–1.5). The caveat regarding the analysis is the limited
amount of data contributing to the analysis. This was principally due to our inclusion
criteria stipulating that the participant demographics must be reported for each arm of
the study. We chose to not combine topical applications with tableted formulations, as
topicals are first-line treatments, whereas tableted formulations are second-line, or used if
there is severe and extensive disease [
28
]. To summarise the certainty of our outcome in the
review, we used the GRADE (Grading of Recommendations, Assessment, Development
and Evaluations) scoring system [
29
]. This is a subjective evaluation of the certainty of an
outcome from very low to high based on several factors, including risk of bias, imprecision,
inconsistency, indirectness and publication bias. Given the limited number of studies, we
were able to analyse and the high or unclear risk of bias in many of these studies, and we
would rate the certainty of our outcomes as moderate.
Common Pharmacological Treatment Groups for Tinea Pedis
Prior systematic reviews assessing the treatment of tinea pedis include those within the
Cochrane Database of Systematic Reviews. Crawford et al., 2007, concluded that placebo-
controlled trials of topically applied allylamines and azoles for athlete’s foot reduced the
risk of tinea pedis treatment failure compared to a placebo [
12
]. Reporting risk in relation
to treatment failure is counterintuitive from a clinical point of view; we took the more
conventional approach of treatment success. Then, in 2012, Bell-Syer et al. reported on oral
treatments of tinea pedis; terbinafine was more effective than griseofulvin, and terbinafine
and itraconazole were more effective than no treatment [
14
]. Their analysis did not identify
a difference between terbinafine and itraconazole, where we report a difference with RR
1.3 (95% CI: 1.1–1.5). In non-Cochrane systematic reviews, Rotta et al. reported in 2012
and 2013 the superiority of topical antifungals over a placebo, but also that there was no
difference between classes [
15
,
16
]. Their data reported odds ratios and, due to the high
prevalence in the numerator when making these calculations, the odds are not numerically
comparable with the relative risk we report. The benefit of allylamines over azoles has been
implied in systematic reviews [12,14,18], but also contested [15,16].
There are a priori relevant assumptions to consider when performing a systematic
review; sensitivity, similarity, transitivity and consistency, respectively. Sensitivity analysis
was not performed due to the limited number of included studies. Similarity addresses
the methodology using the conventional PICO approach of population, intervention, com-
parison, and outcome. In this systematic review, as is usual, this was conducted initially
when screening for eligibility through the inclusion criteria of the systematic reviews.
Specifically, similarity was based upon four main aspects: the clinical characteristics of
the study, treatment interventions, comparison treatments, and outcome measures. The
clinical study design could vary to a degree, often regarding when the outcome assess-
ment was scheduled. There was a range of signs and symptoms assessed, which were not
consistent across the studies, making the extent of disease at baseline difficult to compare.
Comparison was further confounded by the variety of methods used in different studies
to rationalise these signs and symptoms into numerical correlates of ‘clinical cure’ after
treatment. In this meta-analysis, the minimum requirement for inclusion was studies that
reported baseline characteristics to ensure similarity between arms. We did not exclude
studies where the attrition was due to negative cultures at baseline, although this may
introduce a degree of selection bias. One study we excluded on the basis of selection bias as
the population was previous non-responders [
30
]. Regarding the treatment interventions,
the topical formulations were consistent in that they all contained 1% of active ingredient.
The oral formulation doses differed between terbinafine and itraconazole, but were consis-
J. Fungi 2022,8, 351 9 of 11
tent for each drug and in line with prescription guidance. Topical formulations contained
a range of excipients; the topical terbinafine formulation could contain alcohol to enable
the terbinafine to enter the skin. Enabling the penetration of the active ingredient into the
skin is likely to promote retention and hence affect the dynamics of exposure to the fungal
infection. Factors such as this make it difficult to determine if the duration of exposure
required to eradicate fungi differs between drug classes (allylamines and azoles). The
adherence to these treatments was also never directly assessed in any of the studies. We
ensured that, if the clinical assessment of tinea pedis was reported, it was in addition to
mycology in the form of KOH microscopy and culture; we focused upon the eradication
of the mycology associated with the disease. This was in part due to the lack of a vali-
dated clinical assessment protocol for tinea pedis and, hence, it could not be applied in
the studies. On occasion it is likely for fungi to be present on the epidermis of feet where
disease is not evident; similarly, symptoms associated with the disease may continue after
the resolution of the infection—for example, nail changes in onychomycosis persist after
eradication of tinea pedis [
31
]. In this review the comparison treatments did not present
significant variation. Inconsistency and testing between direct and indirect treatments were
not evident either globally (p= 0.42) or locally p> |z| 0.42.
Future Perspectives
In order to clarify the overwhelming literature in the field, the standardisation of
RCT protocols for assessing tinea pedis treatment is required going forward, together
with a standardised approach to reporting [
32
,
33
]. There needs to be a consensus on the
clinical assessment of tinea pedis with a set list of signs and symptoms. This could be on
the 0–3 scale (absent, mild, moderate, and severe), but needs to be validated so that it is
reproducible across trials. All participants should have both a clinical and mycological
diagnosis of tinea pedis at baseline, and the mycological diagnosis of tinea pedis should
be defined as a positive culture and microscopy. Outcomes should be standardised so
that they can be easily compared across studies. Mycological data for both culture and
microscopy should be reported together at all time points so that the number of patients
with mycological cure can be assessed. Ideally, PCR could be used to quantify fungal
colonisation over time during treatment regimes. Studies should also accurately report
the baseline demographics of the treatment arms and assess adherence to treatment, for
example, by measuring the volume of topical ointment used at each visit and control this
for the size (extent) of fungal infection.
Long-term data, e.g., 6-month follow-ups, to assess the efficacy of treatments on the
recurrence rate of tinea pedis is a complex scenario [
14
]. This is due to the local foot
environment. The role of the foot environment in the re-inoculation of the foot with fungi
associated with tinea pedis is in question. Tinea pedis is associated with high rates of
relapse. An effective anti-fungal should eradicate the infection and be suited to prevent
relapse. A systematic approach is required to consider long-term follow-up within the
context of adjunct treatments. Furthermore, we should not overlook topical formulation
excipients aimed at promoting the penetration of the active ingredient (AI), namely alcohol,
into the skin in multiarmed studies. It is also plausible that the eradication of commensal
bacterial flora can greatly affect the resolution of symptoms, but equally the reoccurrence
rate. The development of resistance to terbinafine [
19
] has led to
in vitro
susceptibility
testing [20].
A consensus on the methodology of future trials would allow direct comparison across
treatments for tinea pedis and provide clinicians with reproducible measures of the efficacy
of different treatments, including newer experimental drugs, that would inform clinical
practice. The efficacy of adjunct treatments demands further research. It is commonly
advised by clinicians to maintain good foot hygiene, keep feet dry and wear textiles that
wick moisture away from tinea-prone areas. None of the studies included in this systematic
review investigated the role of these adjunct treatments and practices.
J. Fungi 2022,8, 351 10 of 11
There is a large body of data demonstrating that currently approved pharmaceuticals
increase the likelihood of successful treatment over a placebo, including this systematic
review. Many now question the need for placebo-controlled trials when there is known
benefit of many classes of anti-fungal agents suited to the treatment of tinea pedis. From
a study design point of view, it enables conventional meta-analysis [
18
]. However, the
network meta-analysis methodology enables comparison between studies without a consis-
tent reference trial arm (placebo). The authors support stopping the use of the placebo arm
from an ethical standpoint.
This review demonstrated the superiority of both topical allylamines and azoles over
a placebo, and the superiority of terbinafine over itraconazole. The understanding of
the relative effect of the foot environment, formulation and adjunct treatments is still
poorly understood.
Supplementary Materials:
The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/jof8040351/s1, Table S1: PRISMA checklist, Table S2: PRISMA
abstract checklist.
Funding: There is no specific funding for this review.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement:
Ethical approval was not required for this meta-analysis. There is no
patient or public involvement in this meta-analysis.
Data Availability Statement:
We confirm that the manuscript is an honest, accurate, and transparent
account of the study being reported; that no important aspects of the study have been omitted; and
that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
Acknowledgments: CH Bodleian library.
Conflicts of Interest:
There are no competing interests of review authors. The Corresponding
Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an
exclusive licence (or non-exclusive for government employees) on a worldwide basis to the BMJ
Publishing Group Ltd. to permit this article (if accepted) to be published in BMJ editions and any
other BMJPGL products and sublicences such use and exploit all subsidiary rights, as set out in our
licence. All authors have completed the Unified Competing Interest form (available on request from
the corresponding author) and declare no support from any organisation for the submitted work, no
financial relationships with any organisations that might have an interest in the submitted work in
the previous three years, and no other relationships or activities that could appear to have influenced
the submitted work.
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