RE VI EW A R T I CL E

British Journal of Dermatology

BJD

Efcacy and safety of to ical antifungals in the treatment of dermatomycosis! a systematic re"ie#
I$ Rotta% A$ &anche'% ($R$ )onc*al"es% +$,$ -tu.i and C$J$ Correr/
Pharmaceutical Sciences Postgraduate Program, and *Department of Pharmacy, Federal University of Parana, Av. Pref. othario !eissner "#$, %uriti&a, Parana '($)()*(, Bra+il

&ummary
Corres ondence
%assyano Janua,rio %orrer. -.mail/ cassyano0ufpr.&r

Acce ted for u0lication

$( Decem&er $())

,unding sources
1one.

Con1icts of interest
1one declared. D23 )(.))))45.)#"6.$)##.$()$.)(')6.7

8he analysis of comparative efficacy and safety of topical antifungals in the litera. ture is restricted to the treatment of tinea pedis and onychomycosis. 8herefore our o&5ective 9as to evaluate and compare the efficacy and safety of topical anti. fungals used in the treatment of dermatomycosis, 9e performed a comprehensive search for randomi+ed controlled trials :;%8s< in the follo9ing data&ases/ !ed. line, %ochrane %entral ;egister of %ontrolled 8rials, -!BAS-, ilacs and 3nterna. tional Pharmaceutical A&stracts, 9e identified studies that compared the use of topical antifungals 9ith other antifungals or 9ith place&o pu&lished up to July $()( in -nglish, Spanish or Portuguese. 8he =uality of reporting 9as assessed according to the Jadad scale> only studies 9ith a score of # or more 9ere included. 8he outcomes evaluated 9ere mycological cure at the end of treatment, sustained cure, occurrence of adverse events and tolera&ility, including 9ithdra9. als due to adverse events. A total of )(? ;%8s satisfied the inclusion criteria, con. taining a total of )#6 comparisons, 9ith 66 out of )$( possi&le comparisons among the )" drugs evaluated. Pooled data on efficacy sho9ed that all the anti. fungals 9ere &etter than place&o. 8here 9ere no significant differences among antifungal classes. 1o differences 9ere found in safety or tolera&ility in any direct comparison. Sensitivity analysis indicated the ro&ustness of the findings. 2ur results indicate the clear superiority of topical antifungals over place&o &ut that there is no consistent difference among classes. !i7ed treatment comparisons are necessary to ran@ antifungals, as direct comparisons among many of them are lac@ing.
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Dermatomycosis are fungal infections that are 9idespread throughout the 9orld, and they are an important cause of mor&idity. Dermatophytosis, caused &y different species of dermatophytes, is one of the more common infections. Ao9ever, commensal yeasts such as !alasse+ia furfur and %andida spp., are also important causative agents of dermato. mycosis. Diagnosis depends on a com&ination of clinical and la&ora. tory data, including physical e7amination of the lesions and microscopic visuali+ation of microorganisms in potassium hydro7ide and their gro9th in culture. 8reatment consists of the use of topical or oral antifungals or a com&ination of these, depending on the site, e7tent of infection and the caus. ative organism. 3n most antifungals is places and allylamines.
6* ? )#

cause minimal adverse effects.

episodes of infection, management 9ith topical effective> these are availa&le over the counter in most are divided in t9o main classes/ a+oles and 8hese are cheaper than oral formulations and

2nly t9o =uantitative systematic revie9s relating to the treatment of dermatomycosis 9ith topical antifungals have &een pu&lished to date, &oth limited to the management of tinea pedis. For this reason, 9e performed a comprehen. sive systematic revie9 and meta.analysis to determine the efficacy and safety of topical antifungals in the treatment of any dermatomycosis.
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&earch strategy and selection criteria A systematic revie9 9as conducted according to the %ochrane %olla&oration guidelines. Ce performed a comprehensive search for randomi+ed controlled trials :;%8s< using as descriptors the names of the antifungals of interest :amorol. fine, &ifona+ole, &utenafine, ciclopiro7olamine, clotrima+ole, econa+ole, fenticona+ole, flutrima+ole, isocona+ole, @etocona+. ole, micona+ole, naftifine, o7icona+ole, sertacona+ole, ter&ina.
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+ethods
$()$ 8he Authors BJD $()$ British Association of Dermatologists $()$ )"", ppB$*B##

234

567 To ical antifungals in the treatment of dermatomycosis% I$ Rotta et al$

fine and tiocona+ole< com&ined 9ith the terms DrandomE, Dcontrolled trialE and Dcontrolled clinical trialE. 8he terms Dvagi. nalE, DvulvovaginalE and DoropharyngealE 9ere included in the search preceded &y the Boolean operator D128E, so as to include only studies assessing the topical use of interventions. 8he search strategies used for each data&ase are descri&ed in Appendi7 S) :see Supporting information<. 8he follo9ing data&ases 9ere included in the search/ !ed. line, %ochrane %entral ;egister of %ontrolled 8rials, -!BAS-, ilacs and the 3nternational Pharmaceutical A&stracts. Studies pu&lished up to July $()( in -nglish, Spanish or Portuguese, that compared the use of topical antifungals in the treatment of dermatomycosis 9ith the use of other antifungals or 9ith place&o 9ere included. 89o revie9ers :3.;. and A.S.< independently selected studies &ased initially on their title and a&stract. 2nly ;%8s that evalu. ated the treatment of any dermatomycosis, including cutane. ous candidiasis and that of tinea pedis, corporis, cruris and versicolor 9ere included. Ce e7cluded onychomycosis from the study as its treatment duration is much longer 9hen com. pared 9ith other dermatomycosis. 8inea capitis 9as also e7cluded as it is not treated 9ith topical antifungals. 2nly trials that evaluated mycological cure &ased on micro. scopy and or culture to esta&lish the presence of fungal spe. cies 9ere included. 8he intervention consisted of any topical antifungal regardless of pharmaceutical dosage form, concen. tration, drug regimen, duration of therapy or pharmacological class. Ce e7cluded studies that used a crossover methodology. Data e8traction and assessment of trial 9uality Data e7traction 9as performed &y t9o revie9ers :3.;. and A.S.< independently and included study design, &aseline char. acteristics, health intervention, drug regimen, efficacy, safety and tolera&ility. Any discrepancies in data collection 9ere resolved through consensus and a third revie9er :%.J.%.< 9as consulted 9hen necessary. 8he efficacy outcomes evaluated 9ere mycological cure at the end of treatment, defined as cure o&tained until * days follo9ing the end of treatment, and sustained cure, defined as cure maintained for at least )? days after the conclusion of treatment. Chen more than one sustained cure result 9as descri&ed, 9e prioriti+ed those for 9hich the time interval of monitoring 9as greater. For &oth outcomes, the cure had to &e confirmed &y culture and or microscopy. 8he clinical cure rate 9as not evaluated as this is a su&5ective outcome. 8rials that only sho9ed this rate 9ere e7cluded. 8he safety outcomes evaluated 9ere the occurrence of adverse events and tolera&ility, including 9ithdra9als due to adverse events. 8he methodological =uality of each ;%8 included 9as eval. uated using a method assessment tool pu&lished &y Jadad
BJD

et al., descri&ed in Appendi7 S$ :see Supporting informa. tion<. 2nly studies 9ith a score of # or more 9ere included. 8o assess the ris@ of &ias in the included studies, 9e used the %ochrane %olla&oration tool, an evaluation in 9hich critical

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$()$ 8he Authors $()$ British Association of Dermatologists $()$ )"", ppB$*B##

To ical antifungals in the treatment of dermatomycosis% I$ Rotta et al$ 565

assessments are separated into different domains in order to consider the follo9ing types of &ias/ selection, performance, detection, attrition, reporting and other &iases. &tatistical analysis For the efficacy outcome, 9e used the random.effects model and inverse variance method to pool the odds ratios :2;s< from individual studies. For the safety and tolera&ility out. comes, 9e employed the statistical method of Peto, 9hich is appropriate 9hen the num&er of o&served events is small and similar in &oth e7perimental and control groups, as e7pected 9hen evaluating adverse events associated 9ith topical therapy 9ith antifungal agents. 8he 2; and the corresponding B6F confidence interval :%3< 9ere calculated and pooled using a fi7ed.effects model. 8he heterogeneity of treatment effects 9as evaluated &y the inconsistency inde7 :3 <. Galues of 3 lo9er than $6F 9ere con. sidered to sho9 lo9 heterogeneity, 9hereas values &et9een $6 and 6(F 9ere considered moderate to high. 3n meta.analyses 9ith 3 H 6(F :high heterogeneity<, sensitivity analyses 9ere performed to determine 9hether the study characteristics and statistical methods could have influenced the results. A sensitiv. ity analysis 9as conducted &y the hypothetical removal of each study from the meta.analysis and evaluation of its impact on the overall result. !oreover, the studies 9ere pooled into su&groups &ased on the dermatomycosis evaluated. All analyses 9ere car. ried out using ;evie9 !anager v. 6I) statistical soft9are :http/44ims.cochrane.org4revman4do9nload<.
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information allocation

such

as

se=uence

generation

and

Results
&ystematic re"ie# of the literature 2f the ???# articles initially identified, ?)'# 9ere e7cluded after title a&stract revie9 and another 6B after full.te7t analy. sis &ecause they did not meet the inclusion criteria. 3n add. ition, B* articles 9ere e7cluded for &eing duplicates. 8hus, )(? ;%8s satisfied the inclusion criteria and 9ere included in the meta.analysis. As some articles reported more than one study, 9e included a total of )#6 studies. 2f these, *# com. pared antifungals 9ith place&o and "$ compared antifungals 9ith each other :Fig. )<. 8he studies included )6 *B6 partici. pants, of 9hich ""F 9ere men, and the 9eighted mean age 9as #'I? years. Ce found 66 of the )$( possi&le comparisons among the )" drugs evaluated :Fig. $<. For details a&out the characteristics of the studies, see Appendi7 S# :see Supporting information<. +ethodological 9uality 2nly studies of medium or high =uality according to the Jadad scale 9ere included in the meta.analysis, 9ith an average score of #I". 2f the 6B trials e7cluded after full revie9, #6 did not $()$ meet8he the =uality criteria proposed &y Jadad et al. Authors
BJD
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;elevant

$()$ British Association of Dermatologists $()$ )"", ppB$*B##

Potentially relevant articles identified from search strategy (n = 4443) Title and abstract review Duplicates excluded (n = !)

&xcluded because of failure to meet inclusion criteria (n = 4#'3) "rticles retrieved for detailed assessment (n = #$3) %ull text review

&xcluded because of failure to meet inclusion criteria (n = ( )

Fig ). Flo9chart of the selection of randomi+ed controlled trials included in the systematic revie9.

"rticles included in meta+analysis (n = #,4)

)$ comparisons among allylamines and placebo 33 comparisons among a*oles and placebo #4 comparisons among others antifungals and placebo # comparisons among a*oles and allylamines #3 comparisons among a*oles and other antifungals 3, comparisons among different a*oles

+icona'ole

(lace0o

Amorolfine

Isocona'ole

-8icona'ole

Bifona'ole

Tiocona'ole

,enticona'ole

,lutrima'ole

Ciclo iro8

Butenafine

Ter0inafine :aftifine

Clotrima'ole

Econa'ole

&ertacona'ole

;etocona'ole

Fig $. 1et9or@ of eligi&le comparisons &et9een topical antifungals and place&o and among them for the treatment of dermatomycosis. 8his net9or@ represents all relationships for &oth efficacy outcomes evaluated. 8he 9idth of the line connecting t9o elements is proportional to the num&er of comparisons &et9een them. 8hrough the net9or@, it is clear that there is an a&sence of several head to head comparisons, 9ith only 66 found among the )$( possi&le comparisons.

concealment 9ere insufficient in the ma5ority of the studies included. Ao9ever, the &aseline characteristics of patients included in each group 9ere homogeneous, indicating that the a&sence of information a&out the allocation should not have af. fected the confidence of the results o&tained. Blinding 9as reported as satisfactory in almost 6#F of the studies included,

although 9e &elieve that the mycological cure outcome 9as not li@ely to &e influenced &y lac@ of &linding.

Efcacy A'oles "s$ lace0o 89enty.eight studies, comprising a total of #(?? patients, compared the a+oles &ifona+ole, clotrima+ole, econa+ole, @etocona+ole, micona+ole, o7icona+ole, sertacona+ole and tio. cona+ole 9ith place&o. 8he concentration of these drugs 9as

(a)
OCZ 1% (1) STZ 2% (2) ECZ 1% (3) BFZ 1% (3) CTZ 1% (7) TCZ 2% (1) KTL 2% (1) MCZ 1-2% (8) ZOLES (2!) TBF 1-3% (1%) &FT 1% (!) LL'L MI&ES (2") C() "#77-1% (!) BTF 1% (!) OT*E+S (12)

Odds ratio (95% CI)

<=62 >5=4?@4=6?A <=42 >3=67@B=B<A D=?< >5=64@5<=22A 6=2B ><=?D@53=B?A 57=72 >D=52@3D=<7A 5D=54 ><=75@66=4BA 52=76 >6=2B@B3=3BA 3D=65 >?=53@4D=B4A 1"#25 (!#88$15#27) B=B< >3=67@55=4DA 4=2B ><=5B@37=72A !#15 (3#%7$1"#91) D=2B ><=B7@4=77A 55=5D ><=?<@<3=D7A !#!3 (%#12$1"#!7)

:$A$ 7C 67C 7C 4BC :$A$ :$A$ 42C 71% 44C 4DC 75% 7C ?<C !7%

"

1"

2"

3"

Odds ratio (95%CI) (,)

CTZ 1% (2) STZ 2% (1) OCZ 1% (1) ECZ 1% (2) BFZ 1% (2) KTL 2% (1) MCZ 1-2% (%) ZOLES (13) &FT 1% (!) TBF 1-3% (17) LL'L MI&ES (23) C() "#77-1% (!) BTF 1% (!) OT*E+S (12)

Odds ratio (95% CI)

D=<B >5=B5@53=B<A 6=D7 >D=74@57=74A 6=B4 ><=7B@5D=5BA ?=37 >3=<?@3?=34A 53=?5 >3=?2@B6=43A 5?=B7 >5=6D@37?=D6A 37=55 >3=?7@5DD=36A 7#25 (5#15$1"#2") 2=62 ><=6B@3B=4?A 5<=<3 >2=?B@5?=7<A 12#!7 ( 8#99$17#8%) 6=24 ><=32@5D=4DA 56=?B >?=27@<5=2<A 1"#!1 (!#38$17#!%)

7C :$A$ :$A$ 7C 7C :$A$ 4<C 5% 4BC 4C %2% ?3C B3C 7%%

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1"

2"

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Odds ratio (95%CI) Fig #. Forest plots comparing the efficacy of antifungals vs. place&o for mycological cure at the end of treatment :a< and sustained cure :&< outcomes. 8he sym&ols represent the measure of effect :odds ratio< o&tained 9ith each drug, the hori+ontal line indicating the B6F confidence interval :%3< found. 8he concentrations of drugs reported in the randomi+ed controlled trials are descri&ed. 8he num&er of studies found for each drug is indicated in parentheses. 3 , inconsistency inde7, representing the degree of heterogeneity among the studies included in the meta.analysis> 1.A., 3 is not applica&le, as only one study for the drug in =uestion 9as found> BFJ, &ifona+ole> B8F, &utenafine> %PK, ciclopiro7olamine> %8J, clotrima+ole> -%J, econa+ole> L8 , @etocona+ole> !%J, micona+ole> 1F8, naftifine> 2%J, o7icona+ole> S8J, sertacona+ole> 8BF, ter&inafine> 8%J, tiocona+ole.
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)F or $F and they 9ere used for $" 9ee@s. 3n terms of mycological cure at the end of treatment, meta.analysis of data from $" ;%8s estimated the pooled 2; as )(I$6 :B6F %3 "I'')6I$*<, favouring a+oles. 8here 9as a high degree of heterogeneity :3 M *)F< among the studies selected for the meta.analysis. Sensitivity analyses 9ere carried out &y pooling the studies into su&groups &ased on the dermatomycosis evaluated. Chen the heterogeneity remained high, a hypothet. ical removal of the studies responsi&le for that heterogeneity 9as performed. By the sensitivity analyses performed, the 3 decreased, &ecoming lo9 or moderate, and the 2; value remained statistically significant, favouring treatment 9ith a+oles.
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3nterpolation of the data from )# ;%8s comparing the sus. tained cure rate among a+oles and place&o gave an 2; of *I$6 :B6F %3 6I)6)(I$(<. 8here 9as a lo9 degree of heterogene. ity :3 M 6F< among the studies selected, indicating consist. ency in the results. 8he follo9.up period lasted from $ to " 9ee@s after the cessation of treatment. Allylamines "s$ lace0o 1aftifine and ter&inafine 9ere evaluated in $6 place&o. controlled trials, 9hich included $(() participants. 8he con. centration of these drugs 9as )F or #F and they 9ere used for )? 9ee@s. 3n terms of mycological cure at the end of
$

treatment, meta.analysis of data from $( ;%8s estimated the pooled 2; as "I)6 :B6F %3 #I?*)(IB)<, favouring allylam. ines. 8he interpolated results of the individual studies sho9ed considera&le variation &et9een studies :3 M *6F<. Sensitivity analyses 9ere carried out &y pooling the studies into su&groups &ased on the dermatomycosis evaluated. Chen the heterogeneity remained high, a hypothetical removal of the studies responsi&le for that heterogeneity 9as performed. By the sensitivity analyses performed, the 3 decreased, &ecoming lo9 or moderate, and the 2; value remained statistically sig. nificant, favouring the treatment 9ith allylamines. 2f the $6 ;%8s found, $# sho9ed a sustained cure. %om. &ined data from these studies sho9ed a statistically significant difference favouring allylamines :2; )$I"*, B6F %3 'IBB $ )*I'?<. 8he 3 value of ?$F reflects the moderate heterogene. ity &et9een studies. 8he follo9.up period lasted from $ to ?? 9ee@s after the cessation of treatment. -ther antifungals "s$ lace0o Fourteen ;%8s compared other antifungals 9ith place&o. 8he )$ place&o.controlled trials of &utenafine and ciclopiro7ol. amine yielded a pooled 2; of "I"# :B6F %3 ?I)$)(I"*< for mycological cure at the end of treatment. 8he concentration of these drugs 9as (I**F or )F and they 9ere used for ) ? 9ee@s. 8here 9as a high degree of heterogeneity :3 M "*F< among the selected studies. 8he results of )$ ;%8s 9ere interpolated for the sustained cure outcome, giving an 2; of )(I") :B6F %3 "I#')*I"?<, in favour of the other antifungals. Again, there 9as a high degree of heterogeneity :3 M *?F< among the studies. 8he follo9.up period lasted from $ to ?? 9ee@s after the cessation of treatment. 8he results of the studies on topical antifungals vs. place&o are presented in Figure #. A'oles "s$ allylamines 8he meta.analysis included )* ;%8s, 9ith )*') participants, comparing the allylamines, naftifine and ter&inafine :)F or $F<, used for )" 9ee@s 9ith the a+oles, &ifona+ole, clotri. ma+ole, econa+ole, fenticona+ole, micona+ole and o7icona+ole :)F or $F<, used for $" 9ee@s. 3n terms of mycological cure at the end of treatment, )6 trials sho9ed a small and not statistically significant difference in favour of allylamines :(I*', B6F %3 (I?')I$?<. 8he same efficacy rate :')F< 9as o&tained for &oth classes. 8here 9as moderate heterogeneity in the results of the individual trials :3 M ?6F<, indicating that high.=uality evidence 9as o&tained. Although the meta.analysis of )6 trials comparing the sus. tained cure o&tained follo9ing the use of a+oles and allylam. ines sho9ed a significant result in favour of allylamines :(I66,
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B6F %3 (I##(I'B<, there 9as evidence of inconsistency, due to the high heterogeneity among trials :3 M "(F<. 8his inconsistency may &e attri&uted to one study in particular :A&lon et al. )BBB<. decreased the 3
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8he hypothetical removal of this study

to 6(F and changed the results of the

analysis, such that there 9as no difference in efficacy among classes. A'oles "s$ other antifungals Ce identified )) studies, containing a total of B6$ patients, comparing the a+oles, &ifona+ole, clotrima+ole and fenticona+. ole :)F or $F<, 9ith antifungals other than allylamines, &oth used for $6 9ee@s. 3n terms of mycological cure at the end of treatment, )( ;%8s produced a pooled 2; of (I"? :B6F %3 (I?()I()<, favouring the other antifungals, although the difference 9as not significant. 8here 9as consistency among the studies selected :3 M *F<. 3n terms of sustained cure, the com&ined data from )( ;%8s sho9ed an 2; of (I*B :B6F %3 (I6()I$"<, again not reaching statistical significance. 8he 3 9as (F. For details a&out the sensitivity analysis performed for each meta. analysis 9ith an 3 H 6(F, see Appendi7 S? :see Sup. porting information<. &afety and tolera0ility 1o differences 9ere found in safety or tolera&ility in all direct comparisons made &et9een antifungals and place&o or among antifungals. 8a&le ) presents the results o&tained regarding comparisons among antifungals and place&o for safety out. come. As e7pected, fe9 serious adverse events 9ere reported 9ith the
$ $ $

use of any topical antifungal. 8he adverse events most commonly reported &y patients 9ere &urning, stinging and itching, all confined to the site of application.

Discussion
2ur systematic revie9 and meta.analysis indicate that a+oles, allylamines and other antifungals, such as &utenafine and ciclopiro7olamine, are all efficacious in the management of any dermatomycosis 9hen compared 9ith place&o. 8he t9o other pu&lished systematic revie9s 9ith meta.analysis per. formed &y Aart et al. :)BBB< and %ra9ford and Aollis :$((*< found similar results for the management of tinea pedis. 8he duration of treatment 9ith a+oles lasted from $ to " 9ee@s and the efficacy of this class seemed to improve over time. !icona+ole sho9ed the &est success rate for &oth efficacy outcomes evaluated. Short treatments in the range of )$ 9ee@s 9ith naftifine and ter&inafine demonstrated the superiority of allylamines in relation to place&o for &oth outcomes. Niven the strength of evidence o&tained from the large num&er of studies :n M )#6< and participants :n M )6 *B6<, place&o.controlled trials evaluating topical antifungals in the treatment of dermatomycosis can no longer &e 5ustified, and only clinical trials comparing t9o active treatments are recom. mended. 3n $((', %ra9ford et al. pu&lished a paper confirm. ing that there is enough evidence to recommend the a&andonment of vehicle.controlled trials assessing topical treatments for athleteEs foot.
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8a&le ) Antifungals vs. place&o/ safety 1um&er of studies # $ " ? * ) $ ) $? " )6 $) " " )$ 1um&er of participants $66 ?$# )6$B $B) ?6" $"" B'' 6' ?$#( 6$" )$(? )*#( ''$ *BB )"') Adverse events in intervention :F< ) 6 # # ( 6 ' # ? B 6 " ) )) " Adverse events in control :F< $ # # ) ( B )( ( ? )6 " B $ ? # 2dds ratio :B6F %3< (I#( )I?' (IB) )I6) & 1(I?' (I*' ?I"( (I'6 (I6' (I*$ (I"6 (I6( (I"6 (I6' :(I(##I$?< :(I6)?I$'< :(I6()I"*< :(I$B*IB'< :(I)")I#'< :(I?B)I$#< :(I(*$'?I$6< :(I"$)I)*< :(I#?)I($< :(I?))I$6< :(I??(IB"< :(I)")I6"< :(I$")I"#< :(I$')I$(<

Antifungal Bifona+ole Letocona+ole %lotrima+ole -cona+ole !icona+ole 27icona+ole Sertacona+ole 8iocona+ole A+oles 1aftifine 8er&inafine Allylamines Butenafine %iclopiro7 2thers
a

P.value (I#$ (I?* (I** (I"$ & 1(I)* (I$' (I?* (I#) (I(" (I$? (I(# (I$# (I#6 (I)?

3 :F< ( a 1)? ( a 1c 1A ( c 1A ( ( ( ( $B ( (

1- indicates heterogeneity could not &e estimated, as, in most studies included, the num&er of adverse events found in &oth treatment and control
& c $

groups 9as +ero> it 9as not possi&le to calculate the odds ratio for micona+ole, as the num&er of adverse events found in &oth treatment and control groups 9as +ero in all studies included> 1A indicates 3 is not applica&le, &ecause only one study 9as found for the compared pairs.

%ra9ford and Aollis reported that direct comparisons of allyl. amines and a+oles sho9ed allylamines to &e more efficacious than a+oles. 8his difference among classes 9as detected in out. comes assessed " 9ee@s after treatment &egan and appeared to remain over longer periods. A result favouring the use of allyl. amines 9as also o&tained &y Aart et al., although some language &ias 9as detected. 8hus eight studies reported in -nglish favoured allylamines, 9hile four foreign language reports sho9ed no difference among a+oles and allylamines. 2ur meta.analysis of ;%8s comparing the mycological cure rate o&tained 9ith a+oles and allylamines sho9 no significant difference among classes, the same efficacy rate :')F< &eing found for &oth. For the sustained cure outcome, ho9ever, al. lylamines 9ere found to &e superior to a+oles, &ut the result 9as inconsistent, due to the high degree of heterogeneity :3 M "(F< among the selected studies. Follo9ing the sensitiv. ity analysis and hypothetical removal from the meta.analysis of the study &y A&lon et al., the heterogeneity &ecame mod. erate and the difference among classes &ecame nonsignificant. 8his study 9as also e7cluded from the systematic revie9 con. ducted &y Aart et al., &ecause of an inade=uate period of treatment 9ith a+oles. Ce detected no difference in efficacy among a+oles and other antifungals, such as amorolfine, &utenafine and cic. lopiro7olamine. Ao9ever, although not significant, the out. come of mycological cure favoured the DnonallylamineE antifungals. 8he difference 9as less o&vious 9hen considering sustained cure as the outcome. 1o differences 9ere found in the safety or tolera&ility 9ith any of the antifungal classes. All treatments are generally 9ell
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tolerated> most of the symptoms reported &y patients 9ere mild to moderate and limited to the site of application. 3t is

important to mention that the num&er of adverse events men. tioned in selected studies may &e overestimated or underesti. mated, as the adverse events associated 9ith the use of topical antifungals are also signs and symptoms of the fungal disease, and it is therefore difficult to determine 9hether these reac. tions 9ere due to disease or caused &y the drug. Allylamines are considered safe and tolera&le. Ao9ever, the efficacy results sho9ed no conclusive evidence of their superior. ity compared 9ith a+oles. 3n addition, allylamine treatment is more e7pensive. As a cost.effective strategy, a+oles are recommended as the first.line therapy, follo9ed &y allylamines if these are not effective. Ao9ever, to confirm this recommen. dation, pharmacoeconomic studies are re=uired to evaluate the real cost.effectiveness ratio of each therapeutic option. 2ur study has some limitations. Due to the difficulty of interpolation, the results of the studies 9ere not pooled in the
)6

meta.analysis according to the dermatomycosis evaluated. 8he difficulty of su&group formation 9as attri&uted to the scarce. ness of studies evaluating the same drug, or antifungals &elonging to the same pharmacological class, to treat a specific dermatomycosis. 3n addition, several studies did not restrict their assessment to a single form of dermatomycosis, as the treatment is similar for all. $ Several meta.analysis sho9ed high values of 3 :H 6(F<, indicating inconsistency in the results of the included studies. Ao9ever, after conducting sensitivity analysis, involving the hypothetical removal of the studies considered responsi&le for the high heterogeneity reported, and pooling the studies into su&groups &ased on the dermatomycosis evaluated, the results remained similar to those found prior to performing such analysis, maintaining their statistical significance. 8his demon. strates that the 9ide range of effects in the data collected from

many primary studies did not affect the outcomes considered in this study. 8hese findings 9ere similar to those reported in the systematic revie9 conducted &y %ra9ford and Aollis, 9hose meta.analysis also sho9ed high heterogeneity among the studies selected. Furthermore, o9ing to the a&sence of a sufficient num&er of good.=uality clinical trials that directly compared the antifungal drugs of interest, only 66 comparisons among the )$( possi&le 9ere found, ma@ing the performance of mi7ed.treatment com. parisons necessary in order to esta&lish indirect comparisons among those treatment pairs 9ith common comparators. 3n the presence of direct and indirect comparisons, these can &e inter. polated, giving mi7ed results. 3n conclusion, our results sho9ed consistent evidence that all topical antifungals are &etter than place&o. 1o consistent differ. ences in efficacy 9ere found among classes. Aead.to.head clini. cal trials comparing a+oles 9ith allylamines should &e conducted to determine the real difference in efficacy among these classes. 1o differences 9ere found in safety or tolera&ility in any direct comparisons, allo9ing us to conclude that topical therapy 9ith antifungal agents is safe and tolera&le. Due to the a&sence of a sufficient num&er of direct compar. isons among the antifungals, mi7ed.treatment comparisons 9ere necessary. Finally, given the difference in cost among the antifungals, pharmacoeconomic analysis is re=uired to determine the most cost.effective therapeutic strategy for each condition.
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) Borgers !, Degreef A, %au9en&ergh N. Fungal infections of the s@in/ infection process and antimycotic therapy. %urr Drug 8argets $((6> "/'?B"$.

WhatEs already .no#n a0out this to icF

Dermatomycosis are 9idespread and often the first.line management strategy is the use of topical antifungals. A+oles, allylamines, &utenafine, ciclopiro7olamine, tolcic. late and tolnaftate are all efficacious relative to place&o in the management of tinea pedis. Direct comparisons of allylamines vs. a+oles in the treat. ment of tinea pedis sho9 allylamines generally to &e more efficacious than a+oles.

What does this study addF

All topical antifungals are &etter than place&o in the treatment of any dermatomycosis. 1o statistical difference in efficacy 9as detected among classes :a+oles, allylamines and others<. 1o differences 9ere found in safety and tolera&ility in all direct comparisons esta&lished &et9een antifungals and place&o and among them.

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orting information

Additional supporting information may &e found in the online version of this article. Appendi7 S) Search strategies for each electronic data&ase. Appendi7 S$ Assessment of methodological =uality accord. ing to JadadEs criteria. Appendi7 S# %haracteristics of randomi+ed controlled trials included in meta.analysis. Appendi7 S? :a< Sensitivity analysis for meta.analysis 9ith 3 H 6(F comparing a+oles or allylamines 9ith place&o for mycological cure at the end of treatment outcome. :&< Sensi. tivity analysis for meta.analysis 9ith 3 H 6(F comparing other antifungals 9ith place&o for &oth efficacy outcomes. :c< Sensitivity analysis for meta.analysis 9ith 3 H 6(F comparing a+oles 9ith allylamines for sustained cure outcome.
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