Evidence based topical treatments for tinea cruris and tinea corporis: A summary of a Cochrane...

SYSTEMATIC REVIEWBJD

British Journal of Dermatology

Evidence-based topical treatments for tinea cruris and tineacorporis: a summary of a Cochrane systematic reviewE.J. van Zuuren,1 Z. Fedorowicz2 and M. El-Gohary3

1Department of Dermatology, B1-Q, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, The Netherlands2Bahrain Branch, The Cochrane Collaboration, Awali, Bahrain3Primary Care and Population Sciences, Faculty of Medicine, Aldermoor Health Centre, University of Southampton, Southampton, U.K.

Correspondence

Esther J. van Zuuren.

E-mail [email protected]

Accepted for publication

23 September 2014

Funding sourcesNone.

Conflicts of interest

None declared.

This paper is based on a Cochrane review published

in Issue 8, August 2014 of The Cochrane Library

(see http://www.CochraneLibrary.net for further

information).

Cochrane reviews are regularly updated as new

evidence emerges and in response to comments and

criticisms. The Cochrane Library should be

consulted for the most recent version of this

review.

DOI 10.1111/bjd.13441

Summary

Tinea cruris and tinea corporis are common fungal infections. Most can be trea-ted with a variety of topical antifungals. This review aimed to assess the evidencefor the effectiveness and safety of topical treatments for tinea cruris and tineacorporis. Searches included the Cochrane Skin Group Specialised Register, CEN-TRAL in The Cochrane Library, Medline, Embase, LILACS and ongoing trials reg-istries (August 2013). One hundred and twenty-nine randomized controlledtrials (RCTs) with 18 086 participants evaluated a range of interventions –mostly azoles. Pooling of data for several outcomes was only possible for twoindividual treatments. In five studies, terbinafine showed a statistically significanthigher clinical cure rate compared with placebo [risk ratio (RR) 4�51, 95% confi-dence interval (CI) 3�10–6�56]. Data for mycological cure could not be pooledowing to substantial heterogeneity. Across three studies, mycological cure ratesfavoured naftifine (1%) compared with placebo (RR 2�38, 95% CI 1�80–3�14)but the quality of the evidence was low. Combinations of azoles with corticoster-oids were slightly more effective than azoles for clinical cure, but there was nostatistically significant difference with regard to mycological cure. Sixty-five stud-ies were assessed as ‘unclear’ and 64 as being at ‘high risk’ of bias; many wereover 20 years old, and most were poorly designed and inadequately reported.Although most active interventions showed sufficient therapeutic effect, thisreview highlights the need for further, high-quality, adequately powered RCTs toevaluate the effects of these interventions, which can ultimately provide reliableevidence to inform clinical decision making.

What’s already known about this topic?

• Tinea cruris and tinea corporis are common fungal infections of the skin.

• A range of treatment options is available but it is unclear which is the most effec-

tive.

What does this study add?

• All included treatments appeared to be effective but most comparisons, except for

terbinafine and naftifine, were only evaluated in single studies.

• Owing to limitations in study design and reporting, the quality of the evidence

was graded low to very low.

Tinea cruris and tinea corporis are dermatological conditions

frequently seen by general practitioners and dermatologists.

Tinea corporis (ringworm) refers to dermatophytosis of the

trunk occurring mainly in children and adolescents, while

tinea cruris (jock itch) affects the groin and is most frequently

seen in adult men.1,2

© 2014 British Association of Dermatologists616 British Journal of Dermatology (2015) 172, pp616–641

http://www.CochraneLibrary.net

Clinical diagnosis based on history and appearance should

be supported by microscopy and/or culture to rule out other

diagnoses, for example eczema, erythrasma, intertrigo, psoria-

sis and contact dermatitis. Most infections can be cured with

topical treatments, whereas immunocompromised hosts or

very extensive and severe infections might require additional

oral treatment.1,2 Different groups of antifungals are available,

which include azoles, allylamines, benzylamines, hydroxy

pyridones and thiocarbamates, but it is uncertain which are

the most effective. Furthermore, general practitioners tend to

prescribe preferentially topical corticosteroid and antifungal

combination treatments, but it remains unclear if the benefits

of these combination therapies exceed those of topical antifun-

gals used as monotherapy.1–4

This is a summary of a Cochrane systematic review that was

conducted to evaluate the effects of different topical antifungal

treatments in people with tinea corporis and tinea cruris.1

Materials and methods

A systematic review of randomized controlled trials (RCTs)

was conducted according to a previously published protocol.1

Search strategies

We searched in 10 electronic databases and trial registers up

to August 2013 for eligible trials (Table 1). Earlier issues of

the journal Mycoses (1957–1990) had to be hand-searched

(M.E.-G), whereas studies from later issues were more readily

accessible as they were identified in the MEDLINE search. The

bibliographies of all included studies were also checked for

further references to relevant trials.

No language restrictions were imposed, and several studies

had to be translated prior to assessment. Two of the authors

(E.J.v.Z. and Z.F.) independently screened the titles and

abstracts for eligible RCTs.

Inclusion criteria

RCTs that compared any topical regimen, either used alone or

in combination with other therapies, for tinea cruris or tinea

corporis were included. Dermatophyte infection must have

been confirmed by microscopy and/or culture, and people

with a mix of infections (e.g. additional tinea pedis) were

included. Trials including photodynamic treatment were

excluded.

Outcome measures

The two primary outcomes were (i) rate of mycological cure

(negative mycological testing) and (ii) clinical cure (resolution

of sign and symptoms). Secondary outcomes were relapse and

recurrence; adverse events; duration of treatment and partici-

pant-judged cure.

Data extraction and synthesis

Study details and data were independently extracted and sum-

marized using a structured and pilot-tested data extraction

form, and any disagreements over data entry were resolved by

discussion. Using the Cochrane Collaboration’s domain-based

evaluation tool as described in Chapter 8, Section 8�5, of theCochrane Handbook for Systematic Reviews of Interventions, two authors

(E.J.v.Z. and Z.F.) independently assessed the risk of bias in

the included studies.5 If data were missing from trials, we

attempted, wherever possible, to contact the trial investigators

or sponsors of these studies to provide missing data or to clar-

ify study details. However, as most of these studies were more

than 10 years old we were not always successful in obtaining

these.

Dichotomous outcome data were reported as risk ratios

(RR) with their associated 95% confidence intervals (CI). In

accordance with Chapter 9 of the Cochrane Handbook for Systematic

Reviews of Interventions, using a random-effects model and only if

heterogeneity, as measured by the I2 statistic, was < 50%, data

were combined from individual studies into a meta-analysis.5

We reported heterogeneity as important if it was at least mod-

erate-to-substantial (I² > 50%).5 Most of the treatment

comparisons were presented as a narrative synthesis.

Results

Description of the included studies

The results of the literature search are shown in Figure 1. Of

the 364 references identified from the searches, 129 studies

Table 1 Electronic databases and trial registers searched

Electronic databases Trial registers

The Cochrane Skin Group Specialised Register ISRCTN registry (www.controlled-trials.com)

The Cochrane Central Register of Controlled Trials The U.S. National Institutes of Health ongoing trials register (www.clinicaltrials.gov)Medline The Australian and New Zealand Clinical Trials Registry (www.anzctr.org.au)

Embase The World Health Organization International Clinical Trials Registry Platform(www.who.int/trialsearch)

LILACS Cochrane Skin Group: Ongoing Skin Trials Register (www.nottingham.ac.uk/ongoingskintrials)

© 2014 British Association of Dermatologists British Journal of Dermatology (2015) 172, pp616–641

Evidence-based topical treatments for tinea cruris and tinea corporis, E.J. van Zuuren et al. 617

http://www.clinicaltrials.gov

http://www.anzctr.org.au

http://www.who.int/trialsearch

http://www.nottingham.ac.uk/ongoingskintrials

http://www.nottingham.ac.uk/ongoingskintrials

met our inclusion criteria.6–134 However, 63 of these con-

tained no usable or retrievable data owing mainly to the

unavailability of separate data for the different tinea infections

(Table S1; see Supporting Information).72–134 The characteris-

tics of the remaining 66 studies are summarized in Table 2.6–71

Of the 129 included studies, 27 had a placebo arm as control,

98 had an active control arm and four studies included both.

The interventions comprised different groups of antifungals,

such as azoles (the majority), allylamines, benzylamines,

hydroxy pyridones, thiocarbamates and other topical antifun-

gals. Study duration was generally between 2 and 4 weeks.

Our primary outcomes and reports of adverse events were

addressed in most trials; however, duration of treatment,

participant-assessed cure and relapse were hardly or inade-

quately addressed.

Risk of bias of included studies

Each of the studies was assessed for risk of bias, and this was

reported for the individual domains (Fig. S1; see Supporting

Information). A risk of bias summary is presented in Figure 2.

The assessments of overall risk of bias indicated that 64 of the

129 studies were categorized as being at ‘high risk of bias’

(plausible bias that seriously weakens confidence in the

results) because one or more domains received a judgement

of ‘high risk’. The remaining studies (n = 65) were rated as

having an ‘unclear risk of bias’ (plausible bias that raises some

doubt about the result). Almost half (n = 63) of the 129

included studies contained no retrievable or usable data; in

the 66 that provided data, 35 were categorized as being at

‘high risk of bias’ and 31 as having an ‘unclear risk of bias’,

indicating that a judgement of high risk of bias was not spe-

cifically associated with having ‘no retrievable or usable data’.

Effects of interventions

A summary of the key results is provided in Table 2. In view

of the large variety of interventions, pooling was only possible

for several outcomes from just two comparisons: terbinafine

vs. placebo and naftifine 1% vs. placebo. For the comparison

of terbinafine vs. placebo, data for mycological cure are

reported in Table 2; however, in view of the considerable

degree of heterogeneity for this specific outcome, the data

could not be pooled (I2 = 76%). The results are presented in

a Grading Recommendations Assessment, Development and

Evaluation summary of findings table (see Table 3).135 Pooled

data on adverse events showed there were slightly fewer

adverse events in the terbinafine group, and that these were

generally mild, consisting of pruritus and dermatitis (see

Table 3).

For the comparison of naftifine 1% vs. placebo, data from

three studies could be pooled for mycological cure. In the

naftifine group, 83 of 95 patients were considered cured com-

pared with 33 of 92 in the placebo group (RR 2�38, 95% CI

1�80–3�14; P < 0�01). There was no statistically significant

difference in the number of adverse events between the inter-

ventions, with three of 99 occurring in the naftifine group

and seven of 96 in the placebo group (RR 0�44, 95% CI

0�13–1�57).Very limited pooling of outcomes data was possible for

studies that compared azoles with allylamines, or azoles with

combinations of azoles/moderate potent corticosteroid or

azoles vs. benzylamines, and azoles vs. placebo.

With regard to mycological cure there was no apparent dif-

ference in effectiveness between azoles and allylamines (data

not pooled; in view of considerable heterogeneity,

I2 = 75%),9,27,28,30,32,67 except for one study in which allyl-

amines were shown to be more effective.66 Additionally, the

279 recordsidentified through databasesearching(5 duplicates).

364 Records

7 in ‘ongoingstudies’

Total = 44

12 in ‘studiesawaitingclassification’

1 (Banerjee 2012)was a furtherreport of(Banerjee 2011)providingadditional data

24 Full-text articlesexcluded: 15CCTs, 2 caseseries, 5 nocomparator, 2 didnot meet inclusioncriteria

191 Recordsexcluded

173 Full-textarticles assessed for eligibility

129 Studiesincluded inqualitativesynthesis

26 studiesincluded inquantitativesynthesis(meta-analysis)

364 Recordsscreened

87 additionalrecords identifiedthrough othersources(4 duplicates) = 83

Total 274 + 7ongoingstudies = 281

Fig 1. Search results. CCT, controlled clinical trial.

© 2014 British Association of DermatologistsBritish Journal of Dermatology (2015) 172, pp616–641

618 Evidence-based topical treatments for tinea cruris and tinea corporis, E.J. van Zuuren et al.

Table

2Characteristics

ofinclud

edrand

omized

controlledtrials(RCTs)andsummaryof

results

Stud

yParticipants

Intervention

sSummaryou

tcom

esCom

ments

Azoles

Azolesvs.placebo

Bagatell,

6do

uble-blin

d(U

.S.A.;

nomoreinform

ation)

33men,four

wom

en(m

eanage

42years)

withtineacorporis/cruris

3weeks

A:bifonazole

1%cream

once

daily

B:vehicleon

cedaily

Mycologicalcure

(KOH):

grou

pA17

/19compared

with10

/14in

grou

pB(RR1�2

5,95

%CI0�8

7–1�8

1)

Mycologicalcure

(culture):

RR1�3

9,95

%CI0�9

9–1

�95Clin

icalcure:grou

pA17

/19comparedwith13

/

14in

grou

pB(RR1�02

,95

%CI0�8

5–1�2

2)NoAEs

wererepo

rted

Stud

yassessed

tobe

athigh

risk

ofbias

owingto

drop

outsin

vehiclegrou

p

andper-protocol

analysis

Bifonazole

isno

tmore

effectivethan

vehiclein

this

stud

y

Miura

etal.,4

4

doub

le-blin

d,multicentre

(Japan)

389men,26

6wom

en(age

rang

e9

–70years)

withdifferenttinea

infections,includ

ingtinea

corporis/cruris

2weeks

A:econ

azole1%

cream

twicedaily

B:clotrimazole1%

cream

twice

daily

C:placebocream

twicedaily

Mycologicalcure

(tinea

cruris):

28/3

4in

grou

pA

comparedwith30

/34in

grou

pBand10

/37in

grou

pC

Mycologicalcure

(tinea

corporis):

32/3

4in

grou

p

Acomparedwith28

/31in

grou

pBand12

/29in

grou

pC

Clin

icalcure

(tinea

cruris):

26/4

3in

grou

pA

comparedwith30

/34in

grou

pBand11

/40in

grou

pC

Clin

icalcure

(tinea

corporis):

26/4

1in

grou

pA

comparedwith28

/39in

grou

pBand8/

45in

grou

pC

AEs:n=2in

grou

pAcomparedwithn=3in

grou

pBandn=6in

grou

pC

Thisstud

yalso

compares

differentazoles

(see

section

below)

Spiekerm

annandYou

ng,55

doub

le-blin

d,multicentre

(U.S.A.,tw

ostud

ies)

n=13

61(sex

andageun

repo

rted)

withdifferenttineainfections,

includ

ingtineacorporis/cruris

4weeks

Stud

y1:

A:clotrimazole1%

solution

twice

daily

B:vehicletw

icedaily

Stud

y2

A:clotrimazole1%

cream

twice

daily

Vehicle

twicedaily

Mycologicalcure

ofthecombinedstud

ies(KOH):

103/

111in

grou

pAcomparedwith42

/102

in

grou

pB(RR2�2

5,95

%CI1�7

8–2�8

6)Nodata

onclinicalcure

Stud

yassessed

tobe

athigh

risk

ofbias:high

drop

out

rate

(33%

),un

clearfrom

which

grou

ps,reason

s

unrepo

rted;per-protocol

analysis

(con

tinu

ed)



Table

2(con

tinu

ed)

Stud

yParticipants

Intervention

sSummaryou

tcom

esCom

ments

Tanenbaum

etal.,5

7do

uble-

blind(Colom

bia,

twostud

ies)

117men

(meanage29

years)

with

tineacorporis/cruris

3weeks

Stud

y1

A:sulcon

azole1%

cream

once

daily,vehicleon

cedaily

B:clotrimazole1%

cream

twice

daily

Stud

y2

A:sulcon

azole1%

cream

twice

daily

B:vehicletw

icedaily

Stud

y1:

Mycologicalcure

(KOH

andculture):allpatients

inbo

thgrou

pswerecuredafter3weeks

of

treatm

ent

Clin

icalcure:allpatientsin

both

grou

pswere

cured

AEs:0/

30in

grou

pA,4/

27in

grou

pB(RR0�1

0,

95%

CI0�0

1–1�7

8)Stud

y2:

Mycologicalcure

(KOH):

26/2

6in

grou

pA

comparedwith10

/23in

grou

pB(RR2�2

4,95

%CI1�4

2–3�5

4;P<0�0

1)

Clin

icalcure:25

/26in

grou

pAcomparedwith

2/26

ingrou

pB(RR12

�50,95

%CI3�2

9–47

�44;

P<0�0

1)AEs:0/

28in

grou

pAcomparedwith5/

29in

grou

pB(RR0�0

9,95

%CI0�0

1–1�6

3)

Resultsof

cultu

rewere

similar(study

2)Firststud

yalso

compares

differentazoles

(section

below)

Com

parisons

ofdifferentazoles

Banerjee

etal.7(Kolkata,India)

85men,65

wom

en(m

eanage

31years)

withtineacorporis

4weeks

A:am

orolfine

0�25%

cream

twice

daily

B:clotrimazole1%

cream

twice

daily

C:flucon

azole0�5

%geltw

icedaily

Mycologicalcure:grou

pA30

/38comparedwith

32/4

2in

grou

pB(RR1�0

4,95

%CI0�8

2–1�3

1)

Clin

icalcure:grou

pA35

/38comparedwith40

/42

ingrou

pC(RR1�0

6,95

%CI0�9

3–1�1

9)

AEs:on

eparticipantin

grou

pBrepo

rted

increased

erythemaat

theapplicationsite

Participant-judged

cure:grou

pA34

/38compared

with38

/42in

grou

pB(RR0�9

9,95

%CI0�8

5–1�1

5)Mycologicalcure:grou

pB32

/42comparedwith

33/4

1in

grou

pC(RR0�9

5,95

%CI0�7

5–1�1

9)Clin

icalcure:grou

pB40

/42comparedwith37

/

41in

grou

pC(RR1�0

6,95

%CI0�9

3–1�1

9)AEs:on

eparticipantin

each

grou

prepo

rted

increasederythemaat

theapplicationsite

Participant-judged

cure:grou

pB38

/42compared

with36

/41in

grou

pC(RR1�0

3,95

%CI0�8

9–1�2

0)

DataforAvs.Cno

trepo

rted

buttherewas

nostatistically

sign

ificant

difference

betw

eenthetw

otreatm

ent

armsforanyou

tcom

eThisstud

yalso

compared

azoles

withanothertopical

antifung

al(see

correspo

ndingsection

below)

(con

tinu

ed)



Table

2(con

tinu

ed)

Stud

yParticipants

Intervention

sSummaryou

tcom

esCom

ments

Clayton

andKnigh

t,11

doub

le-blin

d(Lon

don,

U.K.)

n=13

6[74men,44

wom

en(sex

ofrestun

clear);agerang

e5–

62years)

withdifferenttinea

infections,includ

ingtineacorporis

4weeks

A:micon

azole2%

cream

twice

daily

B:clotrimazole1%

cream

twice

daily

Mycologicalcure

(culture):

grou

pA14

/15

comparedwith10

/11in

grou

pB(RR1�0

3,95

%

CI0�8

2–1�2

9)Clin

icalcure:no

separate

data

fortineacorporis/

cruris

Relapse:grou

pA=1,

grou

pB=2

AEs:no

separate

data

fortineacorporis/cruris

Stud

yat

high

risk

ofbias;of

thetotalinclud

edat

week

8,56

/136

(41%

)lostto

follo

w-up

Per-protocol

analysis

Clerico

andRibuffo,13

doub

le-blin

d(Rom

e,Italy)

Three

men,37

wom

en(age

rang

e7

–74years)

withdifferenttinea

infections,includ

ingtineacorporis

30days

A:fenticon

azole2%

cream

twice

daily

B:micon

azole2%

cream

twice

daily

Mycologicalcure:insufficientseparate

data

were

repo

rted

forthethreeparticipantswithtinea

corporis

Clin

icalcure:1/

1in

grou

pAcomparedwith2/

3in

grou

pB

NoAEs

wererepo

rted

ineither

grou

p

Onlyon

eparticipantwith

tineacrurisin

grou

pAand

threewithtineacorporisin

grou

pBinclud

ed

Kalisetal.,3

3do

uble-blin

d,

multicentre

(France)

n=79

(sex

andageun

repo

rted)

withtineacruris

2–3weeks

A:oxicon

azole1%

once

daily

B:ketoconazole

2%on

cedaily

Mycologicalcure

andclinicalcure

werecombined:

35/3

6in

grou

pAcomparedwith26

/30in

grou

pB(RR1�12

,95

%CI0�9

–61�3

0)

AEs:0/

42in

grou

pAcomparedwith9/

37in

grou

pB(RR0�0

5,95

%CI0�0

0–0�7

7;P=0�0

8)

AEs

inketoconazole

grou

p

consistedmainlyof

irritant

derm

atitis(n

=3)

and

contactderm

atitis(n

=3)

Sharmaetal.,5

0do

uble-blin

d,

multicentre

(Ind

ia)

217men,43

wom

en(m

eanage

37years)


2weeks

A:sertacon

azole2%

cream

twice

daily

B:micon

azole2%

cream

twice

daily

Mycologicalcure

(culture):

76/1

22in

grou

pA

comparedwith57

/128

ingrou

pB(R

1�40,

95%

CI1�1

0–1�7

7;P=0�0

1)

Clin

icalcure

rateswereidentical

AEs:5/

128in

grou

pAcomparedwith9/

132in

grou

pB(RR0�5

3,95

%CI0�1

8–1�5

4)Sivayathornand

Piam

phon

gsant,54do

uble-

blind(Bangkok,

Thailand

)

n=14

0(70men/3

1wom

en/3

9

sexun

repo

rted;meanage

27years)


2weeks

A:Whitfield’sointmentthreetimes

daily

B:tolnaftate

2%ointmentthree

times

daily

C:clotrimazole1%

cream

three

times

daily

D:micon

azole2%

cream

three

times

daily

Mycologicalcure:6/

28in

grou

pAcomparedwith

12/1

9in

grou

pB,

16/2

7in

grou

pCand21

/27

ingrou

pD

Clin

icalcure:14

/28in

grou

pAcomparedwith

14/1

9in

grou

pB,

21/2

7in

grou

pCand22

/27

ingrou

pD

AEs:no

nein

anygrou

p

Stud

yassessed

tobe

athigh

risk

ofbias;39

/140

(28%

)no

tinclud

edin

theanalysis

Per-protocol

analysis

Thisstud

yalso

compares

othertopicalantifung

als

(see

correspo

ndingsection)

Tho

mas

andEvans,59

investigator-

blind(W

ales,U.K.)

106men

(meanage43

years)

with

tineacrurisor

pedis

4weeks

A:bifonazole

1%gelon

cedaily

B:sulcon

azole1%

twicedaily

Mycologicalandclinicalcure:1/

1in

grou

pA

comparedwith1/

1in

grou

pB

Relapse:no

tin

grou

pAandtheon

ein

grou

pB

failedto

attend

NoAEs

Onlyon

epatientwithtinea

crurisin

each

grou

p

(con

tinu

ed)



Table

2(con

tinu

ed)

Stud

yParticipants

Intervention

sSummaryou

tcom

esCom

ments

VanderPloegandDe

Villez,61(San

Anton

io,TX,

U.S.A.)

48men

and29

wom

en(m

eanage

42years)

withdifferenttinea

infections,includ

ingtinea

corporis/cruris

4weeks

A:tiocon

azole1%

cream

twice

daily

B:micon

azole2%

twicedaily

Mycologicalcure

(KOH

andculture):9/

10in

grou

pAcomparedwith6/

6in

grou

pB(RR

0�93,

95%

CI0�6

8–1�2

7)

Noseparate

data

forclinicalcure

AEs:no

separate

data

fortineacruris/corpo

ris

Participantswithothertinea

infections

includ

ed

Venaetal.,6

4

investigator-blin

d(Bari,Italy)

24men,sixwom

en(m

eanage16

–78

years)

withtineacruris

2weeks

A:bifonazole

1%cream

once

daily

B:micon

azole2%

cream

twice

daily

Mycologicalcure

(KOH

andculture):30

/30sites

treatedwithbifonazole,23

/30sitestreatedwith

micon

azole

Clin

icalcure,allsiteswerehealed

Norecurrences,no

AEs

Thiswas

awithin-participant

stud

y,participantswereno

t

blindedandthestud

ywas

assessed

asbeingat

high

risk

ofbias

Com

parisons

ofsameazolewithdifferentdo

sing

regimens

delPalacioetal.,1

5do

uble-

blind(M

adrid,

Spain)

n=60

(38men/2

2wom

en;mean

age45

years)

withtineacruris/

corporis

6weeks

A:eberconazole

1%cream

once

daily

B:eberconazole

1%cream

twice

daily

C:eberconazole

2%cream

once

daily

D:eberconazole

1%cream

twice

daily

Mycologicalcure

(KOH):

100%

inallgrou

ps

Mycologicalcure

(culture):

10/1

5grou

pA,12

/13

grou

pB,

11/1

3grou

pC,10

/14grou

pD

Clin

icalcure:10

/15in

grou

pA,12

/15in

grou

pB,

8/15

ingrou

pC,8/

15in

grou

pD

Relapse:n=3(unclear

inwhich

grou

ps)

AEs:0/

15grou

pA,2/

15grou

pB,

2/15

grou

p

C,2/

15grou

pD

The

data

werecombinedfor

mycologicalcure

(KOH

+cultu

re)to

allow

a

comparisonbetw

eenon

ce-

andtw

ice-daily

regimens.

Thisshow

edno

difference

betw

eengrou

ps(RR0�9

2,

95%

CI0�7

0–1�2

2)

Ram

elet

andWalker-Nasir,49

doub

le-blin

d,multicentre

(Switzerland)

95men,43

wom

en(m

eanage

38years)

withdifferenttinea

infections,includ

ingtinea

corporis/cruris

7–60

days

A:oxicon

azole1%

cream

once

daily

+placebocream

once

daily

B:oxicon

azole1%

cream

twice

daily

Clin

icalcure

(tinea

cruris):

19/1

9in

grou

pA

comparedwith22

/23in

grou

pB(RR1�0

4,95

%

CI0�9

2–1�1

8)Clin

icalcure

(tinea

corporis):

9/13

ingrou

pA

comparedwith8/

10in

grou

pB(RR0�8

7,95

%CI0�5

4–1�3

9)

AEs:no

separate

data


ris

Other

tineainfections

includ

ed.Dataon

mycologicalcure

couldno

tbe

extractedfrom

therepo

rt

ason

lythecure

ratesfor

each

organism

were

provided

andno

tforeach

site

ofinfection

(con

tinu

ed)



Table

2(con

tinu

ed)

Stud

yParticipants

Intervention

sSummaryou

tcom

esCom

ments

Allylamines

Allylamines

vs.placebo

Budimuljaetal.,1

0do

uble-

blind,

twocentres(Ind

onesia)

n=12

0(53men,64

wom

en,sex

ofrestun

clear;meanage

35�5

years)

withtineacruris/

corporis

7days

A:terbinafine

1%cream

once

daily

B:placeboon

cedaily

Mycologicalcure

(KOH

+culture):grou

pA53

/57

comparedwith11

/60in

grou

pB(RR5�0

7,95

%

CI2�9

6–8�6

9)Clin

icalcure:themeanclinicalsign

sand

symptom

sscorein

grou

pAwas

1comparedwith

ascoreof

6in

grou

pB

Relapse:no

relapsein

either

grou

p

One

AE(dermatitis)was

repo

rted

ingrou

pAand

eigh

tin

grou

pB(nodetails)

Participant-judged

cure:grou

pA48

/56compared

with9/

58in

grou

pB(RR5�5

2,95

%CI3�0

0–10

�22)

Each

symptom

(e.g.itch,

pustules)measuredon

a

four-point

scale,

0=no

nexistent,3=severe.

Each

symptom

scorewas

addedup

foreach

participantandthemean

scoreused.Scores

of0–

1wou

ldhave

torepresent

very

mild

disease,

althou

ghitisim

possible

toqu

antify

exactlyho

wmanypeop

lewou

ldbe

cured

Cordero

etal.,1

4

doub

le-blin

d,multicentre

(U.S.A.,Dom

inican

Repub

licGuatemalaandPanama)

n=74

(36men,29

wom

en,nine

sexun

repo

rted;agerang

e5–

76years)

withtineacruris/corpo

ris

1week

A:terbinafine

1%cream

once

daily

B:placeboon

cedaily

Mycologicalcure

(KOH

+culture):grou

pA27

/29

comparedwith5/

16in

grou

pB(RR2�9

8,95

%

CI1�4

3–6�2

0)Clin

icalcure:totalsign

sandsymptom

sscore

redu

cedfrom

7�8to

1�0in

grou

pAcompared

with7�6

to4�1

ingrou

pB

AEs:grou

pA=0,

grou

pB=1

Stud

yat

high

risk

ofbias.

Missing

data

at2-week

follo

w-up:

grou

pA7/

36(19%

);22

/34(58%

)in

grou

pB.

Per-protocol

analysis

Evansetal.,1

8do

uble-blin

d

(U.K.)

22men,nine

wom

en(m

eanage

39years)


ris

1week

A:terbinafine

1%cream

once

daily

B:vehiclecream

once

daily

Mycologicalcure

(KOH

+culture):12

/14in

grou

p

Acomparedwith9/

17in

grou

pB(RR1�6

2,95

%CI0�9

9–2�6

6)

Clin

icalcure:meansign

sandsymptom

sscorewas

just<2in

grou

pA,suggesting

minim

alevidence

ofdiseasecomparedwithascoreof

>4in

grou

pB AEs:no

neGreer

andJolly,24do

uble-blin

d

(U.S.A.)

23men

withtineacruris(m

eanage

38years)

2weeks

A:terbinafine

1%cream

twicedaily

B:vehiclecream

twicedaily

Mycologicalcure

(KOH

+culture):9/

9in

grou

pA

comparedwith2/

11in

grou

pB(RR4�5

6,95

%CI1�5

0–13

�87;P=0�0

1)

Clin

icalcure:7/

9in

grou

pAcomparedwith2/

11in

grou

pB(RR4�2

8,95

%CI1�1

6–15

�72;

P=0�0

3)AEs:0/

11in

grou

pAcomparedwith1/

12in

grou

pB

(con

tinu

ed)



Table

2(con

tinu

ed)

Stud

yParticipants

Intervention

sSummaryou

tcom

esCom

ments

Lebw

ohletal.,3

5do

uble-blin

d,multicentre

(U.S.A.)

n=66

(35men,17

wom

en,14

sex

unrepo

rted;meanage42

years)

7days

A:terbinafine

1%lotion

once

daily

B:vehiclelotion

once

daily

Mycologicalcure

(KOH

+culture):21

/23in

grou

pAcomparedwith10

/16in

grou

pB(RR1�4

6,

95%

CI0�9

8–2�1

8)Clin

icalcure:17

/23in

grou

pAcomparedwith

2/16

ingrou

pB(RR5�9

1,95

%CI1�5

8–22

�11;

P=0�0

1)

AEs:2/

32in

grou

pAcomparedwith1/

34in

grou

pB(RR2�1

3,95

%CI0�2

0–22

�31)

Stud

yassessed

atbeingof

high

risk

ofbias,20

%

discon

tinu

edandper-

protocol

analysis

Millikan,43do

uble-blin

d(N

ewOrleans,LA

,U.S.A.)

30men

(meanage29

years)

with

tineacruris

2weeks

A:terbinafine

1%cream

B:vehiclecream

twicedaily

Mycologicalcure

(culture):

9/9in

grou

pA

comparedwith3/

9in

grou

pB(RR2�7

1,95

%CI

1�15–

6�39;

P=0�0

2)Clin

icalcure:6/

9in

grou

pAcomparedwith0/

9

ingrou

pB(RR13

�00,95

%CI0�8

4–20

1�26;

P=0�0

7)

Relapse:2/

9in

grou

pA,un

clearin

grou

pB

AEs:no

nein

either

grou

p

Stud

yassessed

asbeingat

high

risk

ofbias.Losses

to

follo

w-upin

vehiclegrou

pof

25%,andper-protocol

analysis

Van

Heerden

and

Vismer,63do

uble-blin

d,

multicentre

(Sou

thAfrica)

n=83

(48men,13

wom

en,22

sex

unrepo

rted;meanage39

years)

withtineacorporis

1week

A:terbinafine

1%gelon

cedaily

B:vehiclegelon

cedaily

Mycologicalcure

(KOH

andculture):20

/27in

grou

pAcomparedwith5/

33in

grou

pB(RR

4�89,

95%

CI2�1

2–11

�30;P<0�0

1)Clin

icalcure:16

/27in

grou

pAcomparedwith

4/30

ingrou

pB(P

<0�0

1)AEs:5/

40in

grou

pAcomparedwith12

/43in

grou

pB(RR0�4

5,95

%CI0�1

7–1�1

6)Zaiasetal.,7

1do

uble-blin

d,

multicentre

(severalcoun

tries,

twostud

ies)

n=13

9(sex

andmeanage

unrepo

rted)withtineacorporis/

cruris

1week

A:terbinafine

1%cream

once

daily

B:placebocream

once

daily

Clin

icalcure:58

/66in

grou

pAcomparedwith

15/7

3in

grou

pB(RR4�2

8,95

%CI2�7

0–6�7

7;P<0�0

1)

Participant-judged

cure:62

/66in

grou

pA

comparedwith17

/73in

grou

pB(RR4�0

3,95

%CI2�6

5–6�1

4)

Stud

yassessed

asbeingat

high

risk

ofbias;nu

mberof

participantsthat

were

rand

omized

isun

repo

rted;

per-protocol

analysis.No

separate

data

foreach

ofthe

twostud

ies

Dob

sonetal.,1

7do

uble-blin

d,

multicentre

(U.S.A.)

n=85

(41men,21

wom

en,23

sex

unrepo

rted;meanage39

years)


ris

4weeks

A:naftifine

1%cream

twicedaily

B:vehiclecream

twicedaily

Mycologicalcure

(KOH

+culture):28

/34in

grou

p

Acomparedwith9/

28in

grou

pB(RR2�5

6,95

%CI1�4

6–4�4

9;P=0�0

1)

Clin

icalcure:on

lydata

onim

provem

entbu

tin

concordancewithmycologicalcure

AEs

2/34

ingrou

pAcomparedwith4/

28(RR

0�41,

95%

CI0�0

8–2�0

8)

Stud

yassessed

asbeingat

high

risk

ofbias;27

%delayedexclusions;per-

protocol

analysis.Unclear

how

manyparticipantsin

each

grou

panddelayed

exclusions

ineach

grou

p

Gip

andBrun

din,

23do

uble-

blind(Sun

dsvall,

Sweden)

58men,five

wom

en(m

eanage

31years)

withtineacruris

2weeks

A:naftifine

1%cream

twicedaily

B:placebocream

twicedaily

Mycologicalcure

(KOH

+culture):30

/32in

grou

pAcomparedwith14

/31in

grou

pB(RR2�0

8,

95%

CI1�3

9–3�0

9;P<0�0

1)

(con

tinu

ed)



Table

2(con

tinu

ed)

Stud

yParticipants

Intervention

sSummaryou

tcom

esCom

ments

Jordon

etal.,3

1do

uble-blin

d,

multicentre

(U.S.A.)

57men,13

wom

en(m

eanage

40�6

years)

withtineacruris/

corporis

4weeks

A:naftifine

1%cream

once

daily

B:vehiclecream

once

daily

Mycologicalcure:25

/29in

grou

pAcompared

with10

/33in

grou

pB(RR2�3

8,95

%CI1�6

6–

4�87;

P<0�0

1)

AEs:no

nein

grou

pA,tw

oin

grou

pB

Parish

etal.,4

7do

uble-blin

d,

multicentre

(U.S.A.)

282men,52

wom

en(m

eanage

47years)

withtineacruris

2weeks

A:naftifine

2%cream

once

daily

B:vehiclecream

once

daily

Mycologicalcure

(KOH

andculture):50

/75

participantsin

grou

pAcomparedwith8/

71in

grou

pB(RR5�9

2,95

%CI3�0

2–11

�59;

P<0�0

1).

Clin

icalcure:53

/75in

grou

pAcomparedwith

3/71

ingrou

pB(RR16

�72,95

%CI5�4

7–51

�10;

P<0�0

1)

AEs:7/

166in

grou

pAcomparedwith4/

168in

grou

pB(RR1�7

7,95

%CI0�5

3–5�9

4)Com

parisons

withsameallylaminewithdifferentdo

sing

regimens

Evansetal.,2

0do

uble-blin

d,multicentre

(U.K.)

16men,five

wom

en(m

eanage

37years)


ris

1week

A:terbinafine

1%cream

once

daily

for1day,

placebosubsequent

6days

B:terbinafine

1%cream

once

daily

for3days,placebosubsequent

4days

C:terbinafine

1%cream

once

daily

for5days,placebosubsequent

2days

D:terbinafine

1%cream

once

daily

for7days

Mycologicalcure:4/

4in

grou

pAcomparedwith

2/4in

grou

pB,

1/2in

grou

pCand4/

4in

grou

pD

Clin

icalcure:4/

4in

grou

pAcomparedwith1/

4

ingrou

pB,

1/2in

grou

pCand3/

4in

grou

pD

Relapse:on

lyin

grou

pA(n

=1)

AEs:no

ne

Stud

yassessed

asbeingat

high

risk

ofbias;34

%

delayedexclusions;per-

protocol

analysis

Azolesvs.allylamines

Azolesvs.terbinafine

Budimulja,9

doub

le-blin

d,multicentre

(Ind

onesia)

100men,85

wom

en(age

rang

e18

–64years)

withtineacruris

3weeks

A:terbinafine

cream

1%on

cedaily

for1weekand2weeks

placebo

B:bifonazole

cream

1%applied

once

daily

Mycologicalcure

(KOH):

grou

pA87

/89compared

with83

/86in

grou

pB(RR1�0

1,95

%CI0�9

6–

1�07)

Mycologicalcure

(culture):

RR1�0

0,95

%CI0�9

6

–1�05

Clin

icalcure:grou

pA88

/89comparedwith82

/

86in

grou

pB(RR1�0

4,95

%CI0�9

8–1�0

9)One

AEwas

repo

rted

ingrou

pA(con

tact

derm

atitis)

Inbo

thgrou

psthere

appeared

tobe

anu

mberof

mycologicalrelapses

atweek8,

althou

ghitwas

not

possible

toconfi

rmthe

precisenu

mberin

view

of

thedrop

outsoccurring

betw

eenweeks

3and8

(con

tinu

ed)



Table

2(con

tinu

ed)

Stud

yParticipants

Intervention

sSummaryou

tcom

esCom

ments

Jerajani

etal.,3

0op

enstud

y,

multicentre

(Ind

ia)

54men,29

wom

en(age

rang

e28

–33

years)


ris

2–4weeks

A:sertacon

azole2%

cream

twice

daily

B:terbinafine

1%cream

once

daily

C:lulicon

azole1%

cream

once

daily

Mycologicalcure:20

/20in

grou

pAcompared

with22

/22in

grou

pBand20

/20in

grou

pC

Clin

icalcure:20

/20in

grou

pAcomparedwith

19/2

2in

grou

pBand20

/20in

grou

pC

Norelapsein

anygrou

p

Stud

yassessed

asbeingat

high

risk

ofbias,25

%drop

outsandper-protocol

analysis

Wangetal.,6

6do

uble-blin

d

(Beijin

g,China)

121men,89

wom

en(m

eanage

35years)

withdifferenttinea

infections,includ

ingtinea

corporis/cruris

2–5weeks

A:terbinafine

1%po

wdertw

ice

daily

B:micon

azole2%

twicedaily

Mycologicalcure

(KOH):

26/2

6in

grou

pA

comparedwith9/

10in

grou

pBand23

/24(RR

1�04,

95%

CI0�9

3–1�1

7)and10

0%cure

intinea

corporis:4/

4in

grou

pAand5/

5grou

pB

Clin

icalcure:15

/26in

grou

pAcomparedwith

13/2

4in

grou

pBand27

/30(RR1�0

7,95

%CI

0�65–

1�75)

Intineacorporis:0/

4in

grou

pAvs.1/

5in

grou

pB

Noseparate

data

forAEs

Azolesvs.naftifine

Haroo

netal.,2

8op

enstud

y(Lahore,

Pakistan)

n=42

(30men,threewom

en,nine

sexun

repo

rted;agerang

e

19–7

0years)

withtineacruris

4weeks

A:naftifine

1%cream

once

daily

B:tiocon

azole1%

cream

twice

daily

Mycologicalcure

(KOH):

15/1

5in

grou

pA

comparedwith18

/18in

grou

pB

Clin

icalcure:after4weeks,theestimated

mean

scorewas

0�25in

grou

pAand0�2

1in

grou

pB

(0=no

symptom

s,1=mild

symptom

sup

to3=severe)

Relapse:no

nein

either

grou

p

Stud

yassessed

asbeingat

high

risk

ofbias;21

%

drop

outs;andper-protocol

analysis

Kagaw

a,32do

uble-blin

d

(Tokyo,Japan)

n=39

3(231

men,14

8wom

en,14

sexun

repo

rted;meanage

42years)

withtineacruris/

corporis/p

edis

2weeks

A:naftifine

1%cream

twicedaily

B:clotrimazole1%

cream

twice

daily

Mycologicalcure

(tinea

cruris):

44/5

1in

grou

pA

comparedwith42

/55in

grou

pB(RR1�1

3,95

%CI0�9

4–1�3

6)

Mycologicalcure

(tinea

corporis):

46/5

6in

grou

p

Acomparedwith46

/62in

grou

pB(RR1�1

1,95

%CI0�9

1–1�3

4)

Clin

icalcure

(tinea

cruris):

44/5

1in

grou

pA

comparedwith40

/55in

grou

pB(RR1�1

9,95

%

CI0�9

8–1�4

4)Clin

icalcure

(tinea

corporis):

46/5

6in

grou

pA

comparedwith44

/62in

grou

pB(RR1�1

6,95

%CI0�9

5–1�4

1)

Noseparate

data

onAEs

are

repo

rted

forparticipants

withtineacrurisandtinea

corporis

Betw

een15

%and20

%per

grou

pno

tinclud

edin

the

analysis;wejudged

thisas

beingat

high

risk

ofbias

Millikan

etal.,4

2do

uble-blin

d,multicentre

(U.S.A.)

n=12

6(78men,26

wom

en,22

sexun

repo

rted;meanage

42years)

withtineacruris/

corporis/p

edis

4weeks

A:naftifine

1%cream

twicedaily

B:econ

azole1%

cream

twicedaily

Com

binedmycologicalandclinicalcure:as

mean

sum

ofclinicalscore,

notas

cure.

AEs:2/

64in

grou

pAcomparedwith8/

62in

grou

pB(RR0�24

,95

%CI0�0

5–1�1

0;P=0�0

7)

Stud

yassessed

asbeingat

high

risk

ofbias;17

�5%missing

outcom

edata;per-

protocol

analysis

(con

tinu

ed)



Table

2(con

tinu

ed)

Stud

yParticipants

Intervention

sSummaryou

tcom

esCom

ments

Top

icalantifung

alscombinedwithtopicalcorticosteroids

Azolesvs.corticosteroid

andazolecombination

Evansetal.,1

9do

uble-blin

d,multicentre

(U.K.)

75men,37

wom

en(age

rang

e12

–81

years)


ris

4weeks

A:naftifine

1%cream

twicedaily

B:clotrimazole

1%+hydrocortisone

1%cream

twicedaily

Mycologicalcure

(KOH

+cultu

re):

13/1

5in

grou

pAcomparedwith8/

10in

grou

pB(RR1�0

8,95

%

CI0�7

5–1�5

7)Clin

icalcure:meantotalclinicalsymptom

scores

wererepo

rted

butno

actualcure

rates

AEs:no

separate

data

forparticipantswithtinea

corporis/cruris

Katzetal.,3

4do

uble-blin

d,

multicentre

(U.S.A.)

241men

and90

wom

en(m

eanage

40years)


ris

2weeks

A:clotrimazole

1%+betamethasone

diprop

ionate

0�05%

cream

twicedaily

B:clotrimazole1%

cream

twice

daily

C:Betamethasone

diprop

ionate

0�05%

cream

twicedaily

Mycologicalcure

(tinea

cruris):

39/6

0in

grou

pA

comparedwith34

/51in

grou

pBand4/

48in

grou

pC

Mycologicalcure

(tinea

corporis):

32/5

1in

grou

pAcomparedwith25

/49in

grou

pBand12

/38in

grou

pC

Clin

icalcure:no

data

onactualclinicalcure

were

provided

intherepo

rt

AEs:2/

112in

grou

pAcomparedwith3/

113in

grou

pBand9/

106in

grou

pC

AEs

consistedof

mild

-to-

mod

erateparaesthesia

and

skin

erup

tion

Lietal.,3

8do

uble-blin

d,multicentre

(China)

n=13

5(sex

unrepo

rted,meanage

33years)

withdifferenttinea

infections,includ

ingtinea

corporis/cruris

2–3weeks

A:econ

azole1%

+triamcino

lone

aceton

ide0�1

%cream

twicedaily

B:econ

azole1%

ointmenttw

ice

daily

Mycologicalcure

(KOH

+cultu

re):

39/4

1in

grou

pAcomparedwith37

/41in

grou

pB(RR1�0

5,

95%

CI0�9

3–1�1

9)Clin

icalcure:23

/43in

grou

pAcomparedwith

25/4

2in

grou

pB(RR0�9

0,95

%CI0�6

2–1�3

1)AEs:no

seriou

sside-effectsin

either

grou

p

Pariseretal.,4

6investigator-

blind,

multicentre

(U.S.A.)

n=26

0(sex

andageun

repo

rted)

withtineacruris

2weeks

A:clotrimazole

1%+betamethasone

diprop

ionate

0�05%

cream

twicedaily

B:ketoconazole

2%cream

twice

daily

Mycologicalcure

(KOH

+cultu

re):

81/9

9in

grou

pAcomparedwith81

/99in

grou

pB(RR1�0

3,

95%

CI0�9

0–1�1

7)Clin

icalcure:65

/93in

grou

pAcomparedwith

44/9

9in

grou

pB(RR1�5

7,95

%CI1�2

2–2�0

3;P<0�0

1)

AEs:10

/128

ingrou

pAcomparedwith14

/131

ingrou

pB(RR0�7

3,95

%CI0�3

4–1�5

9)

Totalof

62/2

60(24%

)no

tinclud

edin

efficacy

analysis,

puttingstud

yat

high

risk

ofbias

Shen

etal.,5

1do

uble-blin

d(Shang

hai,China)

69(51men,12

wom

en,sixsex

unrepo

rted;meanage36

years)


3weeks

A:micon

azole2%

cream

twice

daily

B:econ

azole1%

+triamcino

lone

acetate0�1

%cream

twicedaily

Mycologicalcure

(culture):

22/2

3in

grou

pA

comparedwith17

/19in

grou

pB(RR1�0

7,95

%

CI0�9

0–1�2

8)Clin

icalcure:22

/32in

grou

pAcomparedwith

27/3

1in

grou

pB(RR0�7

9,95

%CI0�6

0–1�0

3)AEs:1/

35in

grou

pAcomparedwith1/

34in

grou

pB(RR0�9

7,95

%CI0�0

6–14

�91)

(con

tinu

ed)



Table

2(con

tinu

ed)

Stud

yParticipants

Intervention

sSummaryou

tcom

esCom

ments

SuandPan,

56do

uble-blin

d

(China)

150men

aged

16–6

3yearswith

tineacruris

2weeks

A:econ

azole1%

+triamcino

lone

acetate0�1

%cream

twicedaily

B:micon

azole2%

+clob

etasol

0�5%

cream

twicedaily

Mycologicalcure

(KOH):

74/7

5in

grou

pA

comparedwith63

/75in

grou

pB(RR1�17

,95

%CI1�0

6–1�3

0;P<0�0

1)

Clin

icalcure:66

/75in

grou

pAcomparedwith

47/7

5in

grou

pB(RR1�4

0,95

%CI1�1

6–1�7

0;

P<0�0

1)Wangetal.,6

8do

uble-blin

d,

multicentre

(China)

n=16

2(120

men,19

wom

en,23

sexun

repo

rted;meanage

40years)

withtineacorporisor

tineapedis

2weeks

A:econ

azole1%

+triamcino

lone

aceton

ide0�1

%cream

twicedaily

B:econ

azole1%

cream

twicedaily

Mycologicalcure

(KOH

+cultu

re):

30/3

3in

grou

p

Acomparedwith31

/35in

grou

pB(RR1�0

3,95

%CI0�8

7–1�2

1)

Clin

icalcure:29

/33in

grou

pAcomparedwith

21/3

5in

grou

pB(RR1�4

6,95

%CI1�0

9–1�9

7;

P=0�0

1)AEs:no

separate

data

Stud

yalso

includ

edpatients

withtineapedis

Wortzel,70do

uble-blin

d,multicentre

(U.S.A.)

270(sex

andmeanageun

repo

rted)

withtineacruris

2weeks

A:clotrimazole1%

cream

twice

daily

B:betamethasone

diprop

ionate

cream

twicedaily

C:Com

bination

ofAandBtw

ice

daily

Mycologicalcure

(KOH

andcultu

re):

13/1

5in

grou

pAcomparedwith15

/15in

grou

pBand6/

15in

grou

pC

Clin

icalcure:15

/15in

grou

pAcomparedwith

3/15

ingrou

pBand2/

15in

grou

pC

AEs:on

ein

grou

pB(burning

andstinging

)

Multicentre

trialbu

tthe

repo

rton

lyinclud

eddata

for45

/47participantsfrom

onecentre

Other

topicalantifung

als

Azolescomparedwithothertopicalantifung

als

Bogaertetal.,8

doub

le-blin

d,multicentre

(Dom

inican

Repub

lic,Guatemalaand

U.S.A.;tw

ostud

ies)

Stud

y1,

n=13

9andstud

y2,

n=90


ris

Age

andsexun

clearin

both

stud

ies

4weeks

Stud

y1

A:ciclop

irox

olam

ine1%

cream

twicedaily

B:vehicletw

icedaily

stud

yII

A:ciclop

irox

olam

ine1%

cream

twicedaily

B:clotrimazole1%

cream

twice

daily

Stud

y1Mycologicalcure

(KOH):

grou

pA57

/70

comparedwith31

/69in

grou

pB(RR1�81

,95

%

CI1�3

6–2�4

1;P<0�0

1)Mycologicalcure

(culture):

RR1�8

1,95

%CI1�3

6

–2�41

;P<0�0

1Clin

icalcure:grou

pA50

/70comparedwith12

/

69in

grou

pB(RR4�1

1,95

%CI2�4

1–7

�01;

P<0�0

1)

One

AEin

vehiclegrou

p(burning

)Stud

y2Mycologicalcure

(KOH):

grou

pA33

/40

comparedwith43

/50in

grou

pB(RR0�96

,95

%CI0�8

0–1�1

5)

Mycologicalcure

(culture):

RR1�0

1,95

%CI0�8

5–1

�19Clin

icalcure:grou

pA28

/40comparedwith34

/50

ingrou

pB(RR1�0

3,95

%CI0�7

8–1

�36)

One

AEin

each

grou

p(burning

,stinging

)

The

effect

ofthevehicleon

mycologicalcure

rateswas

greaterthan

wou

ldno

rmally

beexpected

(con

tinu

ed)



Table

2(con

tinu

ed)

Stud

yParticipants

Intervention

sSummaryou

tcom

esCom

ments

Clayton

etal.,1

2do

uble-blin

d(Lon

don,

U.K.)

n=13

6(74men,44

wom

en,rest

unclear;agerang

e5–

62years)


includ

ingtineacorporis

4weeks

A:micon

azole2%

cream

twice

daily

B:clotrimazole1%

cream

once

daily

Mycologicalcure

(culture):

grou

pA14

/15

comparedwith10

/11in

grou

pB(RR1�0

3,95

%

CI0�8

2–1�2

9)Clin

icalcure:no

separate

data

fortineacorporis/

cruris

Relapse

(n):

grou

pA=1,

grou

pB=2

AEs:no

separate

data

fortineacorporis/cruris

Stud

yat

high

risk

ofbias;of

thetotalinclud

edat

week

8,56

/136

(41%

)lostto

follo

w-up.

Per-protocol

analysis

Guillano

andAlabado

,26

doub

le-blin

d(D

avao,Philipp

ines)

26men,14

wom

en(m

eanage

32years)


ris

3weeks

A:kakawate/madre

decacao(50%

)ointmentGliricidiasepticum

twice

daily

B:micon

azole2%

ointmenttw

ice

daily

Mycologicalcure:5/

12in

grou

pAcomparedwith

11/1

8in

grou

pB(RR0�6

8,95

%CI0�3

2–1�4

6)Clin

icalcure:no

exactdata

wereprovided.‘Global

respon

seassessmentim

proved

inbo

thtreatm

ent

grou

ps(reportedP<0�0

1)’

AEs:5/

15in

grou

pAcomparedwith1/

18in

grou

pBun

clearho

wmanyparticipantshad>1

AE

Participant-judged

cure:micon

azoleismore

effectivethan

kakawate(P

=0�0

1as

repo

rted

inthearticle)

Adverse

eventsin

grou

pA

(erythem

a,stinging

,oedema,

itchinessand

burning)

andin

grou

pB

(transient

erythema)

Hantschke

and

Reichenberger,27do

uble-

blind(Essen,Germany)

20men,10

wom

en(age

rang

e9–

81years)

Upto

clinicalcure,maxim

um12

weeks

A:clotrimazole1%

cream

twice

daily

B:tolnaftate

1%cream

twicedaily

C:naftifine

1%cream

twicedaily

Mycologicalcure:3/

3in

grou

pA,3/

3in

grou

pB,

5/5in

grou

pC

Clin

icalcure:Com

parablebu

tdelayed

Relapse:grou

pA=1andgrou

pC=1

AEs:0in

grou

pA,1/

5in

grou

pB,

1/3in

grou

pC(‘abu

rningsensation’)

Treatmentwas

continued

untilclinicalcure

was

achieved

Sevenparticipantswith

tineacorporiswere

includ

ed,sixwithtinea

cruris;other

derm

atom

ycoses

werealso

includ

edMachado

-Pinto

andLabo

rne4

1

(Brazil)

13men,15

wom

en(age

rang

e

10–7

0years)

withdifferenttinea

infections,includ

ingtinea

corporis/cruris

6weeks

A:oxicon

azole1%

cream

twice

daily

B:tolnaftate

1%cream

twicedaily

Mycologicalcure

(tinea

cruris):

4/4in

grou

pA

comparedwith4/

5in

grou

pB(RR1�2

0,95

%CI

0�72–

1�39)

Mycologicalcure

(tinea

corporis):

6/6in

grou

pA

comparedwith4/

4in

grou

pB(RR1�0

0,95

%CI

0�70–

1�43)

Clin

icalcure:identicalto

theabovemycological

cure

AEs:no

separate

data


ris

Thisstud

yno

ton

lyinclud

ed

participantswithtinea

crurisandcorporis,bu

talso

includ

edparticipantswith

tineapedisandtinea

manuu

m

(con

tinu

ed)



Table

2(con

tinu

ed)

Stud

yParticipants

Intervention

sSummaryou

tcom

esCom

ments

Tho

mas,58do

uble-blin

d

(Cardiff,U.K.)

30men

(meanage43

years)

with

tineacrurisor

pedis

4weeks

A:clotrimazole1%

cream

twice

daily

B:tolnaftate

1%cream

twicedaily

Clin

icalcure:6/

6in

grou

pAcomparedwith10

/

10in

grou

pB(RR1�0

0,95

%CI0�7

8–1�2

7)Noseparate

data

fortineacrurisregarding

mycologicalcure

andAEs

Relapse:0/

6in

grou

pAcomparedwith1/

10in

grou

pB(RR0�0

7,95

%CI0�0

1–1�0

8)

Stud

yalso

includ

edpatients

withtineapedis

Thu

linandØsterbye,60op

en

stud

y(Aarhu

s,Denmark)

94(sex

andageun

repo

rted)with

differenttineainfections,includ

ing

tineacorporis/cruris

4weeks

A:micon

azole2%

cream

twice

daily

B:tolnaftate

2%lotion

twicedaily

Mycologicalcure

(tinea

cruris):

7/8in

grou

pA

comparedwith6/

7in

grou

pB(RR1�0

2,95

%CI

0�68–

1�52)

Mycologicalcure

(tinea

corporis):

3/3in

grou

pA

comparedwith3/

4in

grou

pB(RR1�2

5,95

%CI

0�63–

2�47)

Clin

icalcure

(tinea

cruris):

6/8in

grou

pA

comparedwith5/

7in

grou

pB(RR1�0

5,95

%CI

0�57–

1�94)

Clin

icalcure

(tinea

corporis):

2/3in

grou

pA

comparedwith2/

4in

grou

pB(RR1�3

3,95

%CI

0�38–

4�72)

AEs:repo

rtingun

clear

Alsoparticipantswithother

tineainfections

includ

ed8/

94(30%

),un

clearfrom

which

grou

psexclud

edin

theanalysis,reason

s

unrepo

rted.Per-protocol

analysisandtherefore

assessed

asbeingat

high

risk

ofbias

VanDersarlandSheppard,62

doub

le-blin

d(Keesler

AirForceBase,Biloxi,

MS,

U.S.A.

80men

(meanageun

repo

rted)with

tineacruris

2weeks

A:clotrimazole1%

lotion

twice

daily

B:haloprogin

1%lotion

twicedaily

Mycologicalcure

(KOH

andcultu

re):

29/3

4in

grou

pAcomparedwith20

/32in

grou

pB(RR

1�36,

95%

CI1�0

1–1�8

5;P=0�0

4)Clin

icalcure:22

/34in

grou

pAcomparedwith

18/3

2in

grou

pB(RR1�1

5,95

%CI0�7

8–1�7

1)AEs:0/

40in

grou

pAcomparedwith15

/40in

grou

pB(RR0�0

3,95

%CI0�0

0–0�5

2;P=0�0

2)

Highdrop

outrate

owingto

noncom

pliance(18%

).

Stud

yassessed

asbeingat

high

risk

ofbias.AEs

in

haloprogin

grou

pwere

mainlystinging

Voravutinon

,65do

uble-blin

d

(Hatyai,Thailand

)

n=96

(45men,41

wom

en,10

sex

unrepo

rted;meanage34

years)


4weeks

A:Whitfield’sointmentfour

times

daily

B:micon

azole2%

four

times

daily

Mycologicalcure

(KOH):

41/4

4in

grou

pA

comparedwith40

/42in

grou

pB(RR0�9

8,95

%CI0�8

8–1�0

9)

Relapse:2/

39in

grou

pAcomparedwith1/

39in

grou

pB(RR2�0

0,95

%CI0�1

9–21

�16)

AEs:3/

48in

grou

pAcomparedwith0/

48in

grou

pB(RR7�0

0,95

%CI0�3

7–13

1�96)

(con

tinu

ed)



Table

2(con

tinu

ed)

Stud

yParticipants

Intervention

sSummaryou

tcom

esCom

ments

Weitgasser,69do

uble-blin

d(G

raz,

Austria;tw

ostud

ies)

154men,12

3wom

en(age

rang

e16

–59years)

withdifferenttinea

infections,includ

ingtinea

corporis/cruris

4weeks

Stud

y1

A:haloprogin

1%solution

twice

daily

B:clotrimazole1%

solution

twice

daily

Stud

y2

A:haloprogin

1%ointmenttw

ice

daily

B:clotrimazole1%

cream

twice

daily

Mycologicalcure

forbo

thstud

ies;no

separate

data


ris

Clin

icalcure

both

stud

ies:18

/22in

grou

pA

comparedwith16

/20in

grou

pB(RR1�0

2,95

%

CI0�7

6–1�3

7)

These

stud

iesalso

includ

edothertypesof

tinea

infections

Azolesvs.benzylam

ines

Lietal.,3

9do

uble-blin

d,multicentre

(China)

n=23

4(sex

unrepo

rted;meanage

34years)

withtineacruris/

corporis/p

edis

2weeks

A:bu

tenafine

1%cream

once

daily

B:bifonazole

1%cream

once

daily

Mycologicalcure

(KOH

+cultu

re):

54/5

8in

grou

pAcomparedwith56

/59in

grou

pB(RR0�9

8,

95%

CI0�9

0–1�0

8)Clin

icalcure:19

/58in

grou

pAcomparedwith

23/5

9in

grou

pB(RR0�8

4,95

%CI0�5

2–1�3

7)

Relapse:no

recurrencesin

either

grou

pAEs:6/

58in

grou

pAcomparedwith5/

59in

grou

pB(RR1�2

2,95

%CI0�3

9–3�7

8)Ram

ametal.,4

8do

uble-blin

d

(New

Delhi,India)

n=75

(20men,22

wom

en,33

sex

unrepo

rted;meanage30

years)


4weeks

A:bu

tenafine

1%on

cedaily

and

vehicleon

cedaily

for2weeks

follo

wed

by2weeks

vehicletw

ice

daily

B:clotrimazole1%

twicedaily

Mycologicalcure

(KOH):

20/2

2in

grou

pA

comparedwith27

/28in

grou

pB(RR0�9

4,95

%CI0�8

1–1�1

0)

Relapse:1/

22in

grou

pAcomparedwith2/

28in

grou

pB(RR0�6

4,95

%CI0�0

6–6�5

7)

AEs:6/

37in

grou

pAcomparedwith5/

38in

grou

pB(RR1�2

3,95

%CI0�4

1–3�6

9)

Stud

yassessed

asbeingat

high

risk

ofbias;25

/75

(33%

)wereno

tinclud

edin

theanalysis;per-protocol

analysis.There

wereno

assessmentsof

clinicalcure

Sing

aletal.,5

3do

uble-blin

d(D

elhi,India)

n=80

(53men/2

7wom

en;mean

age29

years)

withtineacorporis/

cruris

2–4weeks

A:bu

tenafine

1%on

cedaily

and

vehicleon

cedaily

for2weeks

follo

wed

by2weeks

vehicletw

ice

daily

B:clotrimazole1%

twicedaily

Mycologicalcure

(culture):

27/2

7in

grou

pA

comparedwith24

/25in

grou

pB(RR1�0

4,95

%

CI0�9

4–1�1

6)Clin

icalcure:26

/27in

grou

pAcomparedwith

24/2

5in

grou

pB(RR1�0

0,95

%CI0�9

0–1�1

2)Relapse:0/

20in

grou

pAcomparedwith3/

21in

grou

pB

AEs:2/

37in

grou

pAcomparedwith3/

34in

grou

pB(RR0�6

1,95

%CI0�1

1–3�4

5)

Stud

yassessed

asbeingat

high

risk

ofbias;28

/80

(35%

)werelostto

follo

w-

updu

ring

treatm

entand

39/8

0(49%

)at

endof

follo

w-up;

per-protocol

analysis

(con

tinu

ed)



Table

2(con

tinu

ed)

Stud

yParticipants

Intervention

sSummaryou

tcom

esCom

ments

Other

topicalantifung

alscomparisons

Dinkelaetal.,1

6do

uble-blin

d,tw

oprim

aryscho

ols

(Tanzania)

124men,12

0wom

en(age

rang

e6–

19years)

differenttinea

infections,includ

ingtineacorporis

2mon

ths

A:triclosansoap

once

daily

B:plainsoap

once

daily

Mycologicalcure

(KOH):

6/7grou

pAcompared

with3/

7in

grou

pB(RR2�0

0,95

%CI0�8

1–4�9

6)

Clin

icalcure:no

precisedata

couldbe

extracted

forparticipantswithon

lytineacorporis

Missing

outcom

edata

45/

224(20%

)combinedwith

per-protocol

analysisjudged

asbeingat

ahigh

risk

ofbias

Fanetal.,2

1do

uble-blin

dRCT

(Guang

zhou

,China)

n=18

3(77men,93

wom

en,13

sexun

repo

rted;agerang

e15

–68

years)

withtineacrurisor

vulvovaginalcand

idiasis

3weeks

A:xianglianlotion

wash+xiangliancream

once

daily

B:po

tassium

perm

anganate

wash+clotrimazole3%

cream

twicedaily

Mycologicalcure

(KOH

+culture):42

/52in

grou

pAcomparedwith27

/45in

grou

pB(RR0�8

4,

95%

CI0�7

2–0�9

7;P=0�0

3)Clin

icalcure:no

separate

data

(datacombined

withmycologicalcure)

FanandYang,

22do

uble-blin

d,multicentre

(China)

n=85

(58men/2

7wom

en;mean

age37

years)

withtineacruris/

corporis

4weeks

A:xianglianlotion

wash+xiangliancream

once

daily

B:po

tassium

perm

anganate

wash+clotrimazole3%

cream

twicedaily

Mycologicalcure

(KOH

+culture)

oftinea

corporis:14

/15in

grou

pAcomparedwith2/

4

ingrou

pB(RR1�8

7,95

%CI0�6

9–5�0

2)Mycologicalcure

(KOH

+culture)

oftineacruris:

10/3

5in

grou

pAcomparedwith4/

12in

grou

pB(RR3�2

1,95

%CI0�3

3–2�2

3)

Clin

icalcure

tineacorporis:11

/15in

grou

pA

comparedwith2/

4in

grou

pB(RR1�4

7,95

%CI

0�53–

4�09)

Clin

icalcure

tineacruris:10

/35in

grou

pA

comparedwith4/

12in

grou

pB(RR0�8

6,95

%CI0�3

3–2�2

3)

Relapse

tineacruris:threein

grou

pA,grou

pB

notrepo

rted

Relapse

tineacorporis:0in

grou

pA;grou

pBno

trepo

rted

Greer

etal.,2

5do

uble-blin

d,multicentre

(U.S.A.)

n=91

(sex

andmeanage

unrepo

rted)withtineacorporis

2weeks

A:bu

tenafin

e1%

cream

once

daily

B:vehicleon

cedaily

Mycologicalcure

(KOH

+culture):37

/42in

grou

pAcomparedwith10

/36in

grou

pB(RR3�1

7,

95%

CI1�8

5–5�4

3;P<0�0

1)Clin

icalcure:24

/42in

grou

pAcomparedwith

9/36

ingrou

pB(RR2�2

9,95

%CI1�2

3–4�2

6;P=0�0

1)

AEs:no

neParticipant-judged

improvem

ent:39

/42in

grou

p

Acomparedwith10

/36(RR3�3

4,95

%CI1�9

6–5�7

0;P<0�0

1)

(con

tinu

ed)



Table

2(con

tinu

ed)

Stud

yParticipants

Intervention

sSummaryou

tcom

esCom

ments

Holti,29do

uble-blin

d

(New

castle,U.K.)

n=14

(sex

andageun

repo

rted)


includ

ingtineacorporis

8weeks

A:Whitfield’sointmenton

cedaily

B:pecilocinon

ceaday

Mycologicalcure:on

lyforgrou

pB(2/2

)

Clin

icalcure:on

lyforgrou

pB(2/2

)Norelapsein

either

grou

p

Twoparticipantswithtinea

corporis(the

remaind

erof

patientsin

thisstud

ywere

diagno

sedwithtineapedis)

Ledezm

aetal.,3

6(Venezuela)

60men

(meanage20

years)

with

tineacorporis

1week

A:ajoene

0�6%

geltw

icedaily

B:terbinafine

1%cream

twicedaily

Mycologicalcure

(KOH

+culture):19

/25in

grou

p

Acomparedwith13

/17in

grou

pB(RR0�9

9,95

%CI0�7

0–1�4

0)

Clin

icalcure:no

tassessed

only

clinicalscore

Relapse:1/

19in

grou

pAcomparedwith1/

13in

grou

pB

Stud

yassessed

asbeingat

high

risk

ofbias.High

numberof

drop

outs(30%

).

Twiceas

manydrop

outsin

theterbinafine

grou

p.Per-

protocol

analysis

Lesher

etal.,3

7do

uble-blin

d,

multicentre

(U.S.A.)

n=93

(75men,on

ewom

an,17

sexun

repo

rted;meanage

37years)

withtineacruris

2weeks

A:bu

tenafin

e1%

cream

once

daily

B:vehiclecream

once

daily

Mycologicalcure

(KOH

+culture):29

/37in

grou

p

Acomparedwith4/

38in

grou

pB(RR7�4

5,95

%CI2�2

0–19

�11;P<0�0

1)

Clin

icalcure:23

/37in

grou

pAcomparedwith

6/38

ingrou

pB(RR3�9

4,95

%CI1�8

1–8�5

5;

P<0�0

1)

Relapse:no

nein

either

grou

p.AEs:on

ein

thebu

tenafin

egrou

p(burning

)

Participant-judged

cure:25

/37in

grou

pA

comparedwith9/

39in

grou

pB(RR2�9

3,95

%

CI1�5

8–5�4

2;P<0�0

1)

Participant-judged

cure

increasedat

6weeks

after

treatm

ent–even

morein

favour

ofbu

tenafine

MacasaetandPert,40do

uble-

blind(M

anila,Philipp

ines)

33men,20

wom

en(m

eanage

30years)

withtineacorporis

2weeks

A:griseofulvin

1%solution

once

daily

B:vehiclesolution

once

daily

Mycologicalcure

(culture):

21/2

6in

grou

pA

comparedwith3/

27in

grou

pB(RR7�2

7,95

%CI2�4

6–21

�47;P<0�0

1)

Clin

icalcure:19

/26in

grou

pAcomparedwith

2/27

ingrou

pB(RR9�8

7,95

%CI2�5

5–38

�20;

P<0�0

1)AEs:1/

26in

grou

pAcomparedwith3/

27in

grou

pB(RR0�3

5,95

%CI0�0

4–3�1

2)Oladele

etal.,4

5do

uble-blin

d

(Nigeria)

33men

(age

rang

e20

–60years)

withdifferentskin

infections,

includ

ingtineacorporis/cruris

4weeks

A:Senn

aAlata

soap

twicedaily

B:placebosoap

twicedaily

Clin

icalcure:5/

5in

grou

pAcomparedwith0/

1

ingrou

pB

Durationof

treatm

entun

tilcure:ittook

4weeks

forthefive

participantsin

grou

pAto

becured

Onlysixparticipantshad

tineacorporisandmatched

ourinclusioncriteria;five

werein

theSenn

aAlata

soap

grou

pandon

ein

the

placebosoap

grou

p

(con

tinu

ed)



data for clinical cure could not be pooled owing to substantial

heterogeneity, but did confirm no difference in effectiveness

between the groups, and the same held true for the number

of adverse events (Table S2; see Supporting Information).

In the comparison of azoles vs. azoles in combination with

corticosteroids there was no difference in mycological cure

between the two treatment arms. In the azole-only group 245

of 313 participants were cured based on negative mycology

compared with 248 of 312 in the azole combined with

moderate potent corticosteroids group (RR 0�99, 95% CI

0�93–1�05).34,38,46,51,68,70 However, based on four stud-

ies,46,51,68,70 the combined treatment appeared to be more

effective with respect to clinical cure than azole monotherapy

(RR 0�67, 95% CI 0�53–0�84; P < 0�01). The number of

adverse events was similar in both groups (RR 1�36, 95% CI

0�68–2�69) (Table S3; see Supporting Informa-

tion).34,38,46,51,70

As in the former comparisons, based on mycological cure

rate, there was no difference in effectiveness between azoles

and benzylamines from three pooled studies: 107 of 112 in

the azole group compared with 101 of 107 in the benzylam-

ines group (RR 1�01, 95% CI 0�94–1�07).38,48,53 Although

the data could not be pooled for clinical cure (significant het-

erogeneity), these results were in concordance with the data

on mycological cure rates. Rates of adverse events were com-

parable for both treatment arms (RR 0�85, 95% CI 0�41–1�76)(Table S4; see Supporting Information).

The final comparison in the review evaluated azoles vs. pla-

cebo,6,44,55,57 but pooling of data was not possible in view of

considerable heterogeneity between the studies, albeit with

the exception of adverse events. With the exception of one

study, mycological and clinical cure rates favoured azoles

(Table S5; see Supporting Information).6

Discussion

One hundred and twenty-nine studies with 18 086 partici-

pants were included in the review; many of the studies were

more than 20 years old.1 Most studies demonstrated some evi-

dence to support the effectiveness and safety of currently used

or prescribed topical antifungal therapies for tinea cruris and

tinea corporis. Only data for some outcomes from studies

comparing terbinafine vs. placebo and naftifine vs. placebo

could be pooled, although the quality of the evidence was

considered to be low. Several studies compared frequency of

application; for those studies that compared once- vs. twice-

daily application there was no statistically significant difference

in any of the outcomes while taking into account that once-

daily application might be expected to lead to improved com-

pliance. Pooling of different classes of antifungals was possible

for topical azoles, benzylamines and allylamines, as well as

azoles combined with corticosteroids. All of the antifungals

appeared to be effective, but this was based on low- to very

low-quality evidence as most studies were assessed as having

an ‘unclear’ to ‘high’ risk of bias. The combined treatment of

azoles and corticosteroids achieved higher clinical (but not

Table

2(con

tinu

ed)

Stud

yParticipants

Intervention

sSummaryou

tcom

esCom

ments

Shietal.,5

2do

uble-blin

d,

multicentre

(China)

n=12

0(74men,23

wom

en,23

sexun

repo

rted;meanage

27years)

withdifferenttinea

infections,includ

ingtinea

corporis/cruris

2–4weeks

A:tetrandine

2%+ketoconazole

2%cream

twicedaily

B:ketoconazole

2%cream

twice

daily

C:tetrandine

2%cream

twicedaily

Mycologicalcure

(KOH

+culture):14

/16in

grou

p

Acomparedwith7/

15in

grou

pBand0/

12in

grou

pC

Clin

icalcure:12

/16in

grou

pAcomparedwith

5/15

ingrou

pBand0/

12in

grou

pC

Relapse:no

nein

grou

pA,tw

oin

grou

pBand

notapplicable

forgrou

pC

AEs:no

nein

anygrou

p

Stud

yassessed

asbeingat

high

risk

ofbias;19

%were

notinclud

edin

theanalysis

–un

clearfrom

which

grou

ps;per-protocol

analysis

KOH,po

tassium

hydroxidepreparation;

RR,risk

ratio;

CI,confi

denceinterval;AE,

adverseevent.Inconsistencyandincompletenessof

data

repo

rtingin

manyof

theolderstud

iesdidno

tallow

usto

undertakeconfi

dently

anystud

yotherthan

theavailablecase

analysisforefficacy

relatedto

cure,whereas

foradverseeffectswere-analysedandrepo

rted

thedata,whereverpo

ssible,accordingto

the

intention-to-treat

principle.



mycological) cure rates than with azole monotherapy, but the

quality of the evidence was also rated as very low. A possible

explanation for this treatment effect is that the azole compo-

nent was responsible for the mycological cure, while the cor-

ticosteroid component had a greater effect on diminishing the

redness of the inflamed skin. A few included studies provided

contradictory results on the effectiveness of Whitfield’s cream,

bearing in mind that this is still a widely used treatment in

many rural areas in developing countries.

The adverse events reported in all of the studies were con-

sidered to be mild and transient, and were balanced between

treatment arms – whether active or placebo controlled.

The quality of the studies (all studies were assessed as being

at unclear to high risk of bias) was mainly influenced by limi-

tations in study design and imprecision due to low sample

size. An important limitation in trial conduct in several studies

was the postrandomization exclusion of participants based on

subsequent negative mycological culture. In the general prac-

tice setting patients will usually receive initial treatment based

solely on a clinical diagnosis pending the results of potassium

hydroxide preparation or culture. This shortcoming in study

conduct and subsequent reporting and analysis could have

been overcome by the investigators undertaking a primary

analysis according to the intention-to-treat principle, followed

by a secondary analysis of those patients that fulfilled the eligi-

bility criteria of a confirmed diagnosis.

Several literature reviews have been published over the last

10–15 years, which, although lacking a systematic search and

critical appraisal of the literature, were broadly in agreement

with our findings that most topical antifungal treatments are

effective.2,136,137,139 No specific preference for an individual

topical antifungal was expressed, with the exception of two

reviews in which allylamines were recommended as the first-

line treatment, which appears to have been based mainly upon

a recognition of their rapid mode of action and shorter treat-

ment duration.2,138 Combined therapy of an antifungal with a

corticosteroid was suggested in two reviews but more

specifically if the tinea infection was accompanied by severe

inflammation.137,139 This treatment approach is still consid-

ered controversial and subject to debate, and some clinicians

even consider this a form of ‘mistreatment’ and that it might

lead to tinea incognito.136,140 Nondermatologists tend to

prescribe these combined agents far more frequently than

dermatologists, which is reportedly owing to a lesser degree

of accuracy in making the correct diagnosis.141 The adverse

events associated with protracted use of topical corticosteroids

are fairly well recognized, but the overall duration of the

included studies was too short for any assessment and, in any

event, these were not reported.

Three similar systematic reviews have been published on

this topic,142–144 and while we are in broad agreement that

their conclusions reflect the findings, we express a degree of

concern about the methodological rigour of these reviews.145

Applying similar language restrictions, i.e. only including

studies in English, Spanish or Portuguese, would have reduced

the number of included studies in our review by 20%, most

of which were in German. The effect of this form of study

selection and its relevance to language bias and the consequent

gap in evidence is well recognized.146 Although the authors of

these reviews indicated they had used the Cochrane ‘risk of

bias’ tool, these assessments and corresponding judgements

for the different domains of this tool were not reported. The

methodological quality of the studies included in these

reviews was assessed using the Jadad scale, which has well-

recognized and acknowledged limitations, specifically in plac-

ing greater emphasis on the reporting of a trial rather than on

its conduct.145

We examined several other clinical references and sources

for guidelines and systematic reviews, for example Agency for

Healthcare Research and Quality; DynaMed; National Guide-

lines Clearinghouse; National Institute for Health and Clinical

Excellence; Scottish Intercollegiate Guideline Network; U.K.

Database of Uncertainties about the Effects of Treatments; and

UpToDate.147–153 With the exception of DynaMed, the major-

ity of these clinical references either did not address tinea

corporis or tinea cruris, or provided very limited current

information that could aid clinical decision making.148

The inadequate reporting in some of the studies and our

inability to obtain missing trial details from the principal

investigators may have contributed to some bias in the assess-

ment of these studies, but it has been clearly stated in our

review when these conditions occurred. The limited data pro-

vided in these studies did not enable fair and reliable compari-

sons to be made for any one single intervention against

another for a specific outcome, with the exception of terbina-

fine and naftifine.

Fig 2. Risk of bias summary: our judgements

about each risk of bias item for each included

study.



Table 3 Summary of findings of terbinafine vs. placebo10,14,18,24,43,63,71

Terbinafine 1% cream/gel compared with placebo cream/gel for tinea cruris and tinea corporisPatient or population: patients with tinea cruris and tinea corporisSettings: hospital and primary care clinicsIntervention: terbinafine 1% cream/gelComparison: placebo cream/gel

Outcomes

Illustrative comparative risks(95% CI)a

Relativeeffect(95% CI)

Participants,n(studies, n)

Quality ofthe evidence(GRADE)b Comments

Assumed risk Corresponding riskPlacebocream/gel

Terbinafine 1%cream/gel

Mycological cure:Negative KOH microscopy,culture or both. Treatmentduration 1–2 weeks

See comment See comment Notestimable

330 (7) ⊕⊕⊖⊖Lowc,d

Unexplainedstatisticalheterogeneity; datanot pooled

Clinical cure:resolution of clinical signsand symptoms. Treatmentduration 1–2 weeksFollow-up: 2–4 weeks

Study population RR 4�51(3�1–6�56)

273 (5) ⊕⊕⊖⊖Lowe–g165 per

1000746 per 1000(513–1000)

Moderate133 per1000

600 per 1000(412–872)

Adverse effects:reported by investigatorsand/or participantsFollow-up: 0–8 weeks


469 (7) ⊕⊝⊝⊝Very lowc,h

Contact dermatitis-type symptoms,no systemicadverseeffects reported

97 per 1000 42 per 1000(19–89)

Moderate29 per 1000 12 per 1000

(6–27)Relapse or recurrence:evidence of clinical ormycological infection inpreviously curedparticipantsFollow-up: 1–8 weeks

See comment See comment Notestimable

168 (3) ⊕⊕⊖⊖Lowi,j

Only Budimulja9

allowed anaccurateassessment ofrelapse – nonewere seen ineithergroup (n = 101)

Participant-judged cure:judgement of treatment as‘good’ or ‘very good’


253 (2) ⊕⊕⊖⊖Lowk–m198 per

1000885 per 1000(627–1000)

Duration oftreatment untilclinical cure:not assessed

Study population Notestimable

0 (0) Seecomment

Outcome notassessed by studyauthors

See comment See comment

CI, confidence interval; GRADE, Grading of Recommendations Assessment, Development and Evaluation; KOH, potassium hydroxide prepara-

tion; RR, risk ratio;⊕, low risk of bias;⊖, high risk of bias. aThe basis for the assumed risk (e.g. the median control group risk across studies) is

provided as follows. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the inter-

vention (and its 95% CI). bGRADE Working Group grades of evidence: ‘high’ quality – further research is very unlikely to change our confidence

in the estimate of effect; ‘moderate’ quality – further research is likely to have an important impact on our confidence in the estimate of effect

and may change the estimate; ‘low’ quality – further research is very likely to have an important impact on our confidence in the estimate of

effect and is likely to change the estimate; ‘very low’ quality – we are very uncertain about the estimate. cRandom sequence generation, allocation

concealment and blinding at unclear risk of bias across studies, with two studies (Lebwohl et al.35 and Millikan43) judged overall to be at high risk

of bias. In both of these studies, there was a high dropout rate (20–25%) in already underpowered studies. dSubstantial unexplained heterogene-

ity. eThree studies (Lebwohl et al.,35 Millikan43 and Zaias et al.71) judged to be at high risk of bias overall. fSmall sample size – optimal informa-

tion size would be 2790 participants. gAlthough there is a large effect (RR 4�51; in all studies RR > 4�00), there are threats to validity (see risk of

bias). hCI includes the threshold for appreciable benefit and nearly no effect, very low number of events and low sample size (optimal informa-

tion size would be 4238 participants). iMillikan43 judged to be at high risk of bias overall – high dropout rate in an underpowered study;

sequence generation, allocation concealment and blinding judged to be at unclear risk of bias in the remaining studies. jLow number of events

and sample size is lower than optimal information size. kBlinding for both studies judged to be at unclear risk of bias; Zaias et al.71 judged overall

to be at high risk of bias – details on total number of randomized participants not given. lNumber of events < 300; optimal information size

would be 2210 participants. mAlthough there is a large effect (RR > 4), there are threats to validity (see risk of bias).



A major limitation of our review was reflected in our

inability to use some of the data reported in the included

studies. In some this was due to the absence of separate data

for different tinea infections or because of the very limited

data available in abstracts to conference proceedings, which

did not permit adequate data extraction in almost half of the

included studies (n = 63).

In conclusion, most of the commonly used topical antifun-

gal treatments are effective and safe. However, no conclusions

could be drawn regarding the superiority of one class of topi-

cal antifungal over another. Pooled outcome data suggested

that the individual treatments terbinafine and naftifine are

effective, but the evidence was rated as low.

Combined treatments of azoles with a corticosteroid

achieved slightly better clinical cure rates based on very low-

quality evidence, but could be justified for a short duration of

use in the presence of inflammation. In resource-poor coun-

tries some of the more expensive treatments may not be avail-

able to everyone, with the possibility that only Whitfield’s

cream and the older azole creams are treatment options.

As all evidence was based on studies assessed as at an

‘unclear’ to ‘high risk’ of bias, the Cochrane review highlights

the need for high-quality, well-designed, adequately powered

and rigorously reported studies that can ultimately provide

reliable evidence to help inform clinical decision making.

Acknowledgments

We are grateful to Hana Burgess, Liz Doney, Beth Stuart and

Michael Moore for their contribution to the original review.

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Supporting Information

Additional Supporting Information may be found in the online

version of this article at the publisher’s website:

Fig S1. Studies was assessed for risk of bias. ⊕, low risk of

bias; ⊖, high risk of bias; (?), unclear risk of bias.

Table S1. Included studies with unusable or irretrievable

data.

Table S2. Summary of findings of azoles compared with al-

lylamines.

Table S3. Summary of findings of azoles compared with az-

oles/moderately potent corticosteroid combinations.

Table S4. Summary of findings of azoles compared with

benzylamines.

Table S5. Summary of findings of azoles compared with

placebo.



http://www.guideline.gov/

http://www.nice.org.uk/

http://www.sign.ac.uk/index.html

http://www.library.nhs.uk/duets/

http://www.uptodate.com/home

http://www.uptodate.com/home

Evidence based topical treatments for tinea cruris and tinea corporis: A summary of a Cochrane...

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