| |

Received: 6 September 2016 Revised: 11 November 2016 Accepted: 19 December 2016

DOI: 10.1111/myc.12598

ORIGINAL ARTICLE

Comparative efficacy of topical application of tacrolimus and

clotrimazole in the treatment of pityriasis versicolor: A single
blind, randomised clinical trial

Mozhdeh Sepaskhah1 |Maryam Sadat Sadat1|Keyvan Pakshir2 |Zahra Bagheri3

1
Molecular Dermatology Research Center,
Shiraz University of Medical Sciences, Summary
Shiraz, Iran Background: Pityriasis versicolor (PV) is a common superficial fungal disease. Possibility
2
Basic Sciences in Infectious Diseases
of emergence of resistant strains to azoles, and difficulty in differentiation of hypopig-
Research Center,Department of Parasitology
and Mycology,School of Medicine,Shiraz mented PV and early vitiligo, encouraged us to evaluate the efficacy of topical tacroli-
University of Medical Sciences, Shiraz, Iran
mus (a calcineurin inhibitor agent with proven in vitro anti-Malassezia effect) for PV
3
Department of Biostatistics,Faculty of
treatment generally and its effect on PV-induced hypopigmentation specifically.
Medicine,Shiraz University of Medical
Sciences, Shiraz, Iran Objectives: To evaluate the efficacy of topical tacrolimus on pityriasis versicolor.
Patients/Methods: Fifty PV patients were randomly allocated into two equal groups
Correspondence
Mozhdeh Sepaskhah, Molecular Dermatology applying either topical clotrimazol or tacrolimus twice daily for 3weeks. They were
Research Center, Shiraz University of Medical
evaluated at the beginning of study, in the third and fifth weeks clinically and mycologi-
Sciences, Shiraz, Iran.
Email: sepaskhah_m@yahoo.com cally (direct smear).
Results: Although both treatments resulted in global, clinical, and mycological cure of
Funding information
Research deputy of Shiraz University of PV, there was no significant difference regarding the mentioned aspects of cure be-
Medical Sciences, Grant/Award Number:
tween tacrolimus and clotrimazole treated patients. (P-value: .63, .45, and .26, respec-
91-01-01-5510.
tively) Tacrolimus had no significant effect on hypopigmentation in the fifth week
follow-up. (P-value: .62).
Conclusions: In spite of the lack of efficacy of tacrolimus on PV-induced hypopigmen-
tation, the therapeutic effect on PV introduces tacrolimus as a therapeutic option for
PV, especially when early vitiligo is among the differential diagnoses without concern-
ing the aggravating effect of topical corticosteroids on PV.

KEYWORDS
antifungal agents, clotrimazole, pityriasis versicolor, skin infection, tacrolimus, treatment, yeast

1| INTRODUCTION dapaconazole, clotrimazole, miconazole, flutrimazole), ciclopirox

Malassezia species are involved in the pathogenesis of several skin
disorders.1 In addition to direct fungal infections like pityriasis versi-
color and pityrosporum folliculitis, Malassezia species are considered
(although controversially in some instances) in the pathogenesis of
some inflammatory skin diseases; especially, atopic dermatitis, sebor-
2
rhoeic dermatitis and psoriasis.
Besides many topical and systemic medications tried with vari-
able efficacies to treat Malassezia-associated diseases, including
azole agents (ketoconazole, fluconazole, itraconazole, pramiconazole,
olamine, selenium sulphide, adapalene, zinc pyrithione, propylene
glycol and terbinafine,314 in vitro anti-Malassezia effect of calcineurin
inhibitors (tacrolimus and pimecrolimus) has been evaluated.15,16
Tacrolimus is a macrolide antibiotic discovered as a metabolite of
fungus Streptomyces tsukubaensis. It is a prodrug that after intracellu-
lar activation and combining with FK506-binding protein 12 (FKBP12)
eventually targets calcineurin phosphatase. Calcineurin phospha-
tase dephosphorylates the calcineurin-dependent transcription fac-
tor (Crz1) and enables it to be translocated into the nucleus where
it activates the transcription of genes involved in the regulation of

Mycoses 2017; 15 wileyonlinelibrary.com/journal/myc 2017 Blackwell Verlag GmbH | 1

 |
2 SEPASKHAH etal.
T A B L E 1 Characteristics of pityriasis versicolor patients in
clotrimazole and tacrolimus treatment groups
Clotrimazole Tacrolimus
Variant group group
Mean age SD (years) 309.6 308.9
History of recurrence; no (%) 12 (48) 8 (32)
% of BSA involvement; no (%)
<5% 20 (80) 17 (68)
5-10% 4 (16) 7 (28)
10-15% 1 (4) 1 (4)
BSA, body surface area.
fungal stress response, cell wall integrity, growth and drug resistance.17
Juvvadi etal. [17] also reviewed the role of calcineurin in the men-
tioned functions in several yeast (other than Malassezia) and filamen-
tous fungi including Candida, Cryptococcus and Aspergillus fumigatus.
Considering in vitro efficacy of tacrolimus against Malassezia
strains and in spite of the proven efficacy of tacrolimus in the treat-
ment of Malassezia-associated inflammatory skin diseases,17 to the
best of our knowledge, there is no clinical trial regarding the efficacy
of this agent in a disease directly linked to Malassezia infection.
So, we conducted this double-blind, randomised, controlled clin-
ical trial to compare the efficacy of topically applied tacrolimus and
clotrimazole in the treatment of pityriasis versicolor.
2| PATIENTS AND METHODS
The study was designed as a double-blind, randomised, controlled par-
allel trial in the dermatology clinic of a referral hospital in Shiraz, south
of Iran from April 2014 till June 2015. The study protocol was regis-
tered in Iranian Registry of Clinical Trials (IRCT2014021216557N1).
The study protocol followed guidelines of the 1975 Declaration of
Helsinki and was approved by Shiraz University of Medical Sciences
ethics committee. Written informed consent was obtained prior to
enrolment. Fifty patients with clinical impression of pityriasis versi-
color were enrolled. The clinical diagnosis was confirmed by Woods
lamp examination (yellow fluorescence of the skin lesions) and direct
Scotch tape smear. The patients were advised to avoid bathing and
using detergents on the skin lesions for 3days before direct examina-
tion for fungal infection. Samples were taken by tape adhesion (sili-
paste, China) on the skin lesions and stocking the tape on a glass slide.
The samples were investigated for fungal elements (clusters of the
yeast, short pseudohyphae) and the results were expressed as signifi-
cant, mild, few and no fungal elements.
Inclusion criteria were the age of 10years and over (according to
the epidemiological study in Iran that showed 20.6% of PV patients
18
between 10 and 19years of age), involvement of <15% of body sur-
face area (to make less likely the risk of systemic absorption of tacroli-
mus by limitation of area of involvement) and confirmation of pityriasis
versicolor by the mentioned methods.
Pregnancy, lactation, history of hypersensitivity to main agents
or preservatives of tacrolimus ointment or clotrimazole cream, any
serious dermatological or systemic disease and consumption of any
topical or systemic antifungal medication in the last 1 month before
enrolment in the study were considered exclusion criteria.
After signing written informed consent, the patients were ran-
domly assigned by permuted-block randomisation (four in each block)
to one of the two treatment groups. The patients received either
clotrimazole 1% cream (Najo pharmaceutical company, Tehran, Iran)
or tacrolimus 0.03% ointment (Moduproc, Aburaihan pharmaceuti-
cal company, Tehran, Iran), which were packed in similar containers
and were labelled randomly as A and B by a technician who decoded
the groups after statistical analysis. This technician was not involved
in the assessment of the patients. Due to the different appearance
of the tacrolimus and clotrimazole (ointment vs cream), the study is
only investigator blinded. However, participants were discouraged to
discuss anything about the treatment with the investigators, and the
evaluated outcomes were based on the investigators assessment; so
we expect the unblinded participants would not interfere with the
results.
The patients applied medication on the skin lesions twice daily for
3weeks (a median of the 2 to 4weeks treatment period considered in
the previous studies evaluating topical treatments for PV9,10) and were
assessed at the beginning of the treatment (week 0), after completion
of the treatment (week 3) and 2weeks after cessation of treatment
(week 5). In every visit, clinical features (erythema/hyperpigmentation,
hypopigmentation, scale and pruritus), Woods lamp examination and
direct smear were assessed. Pruritus severity was assessed as being
present or absent. The assessment was done by one of the researchers
who was not involved in the randomisation and allocation.
Complete clinical cure was defined as disappearance of erythema/
hyperpigmentation and scale. Significant decrease or localisation of
these two features was defined as partial clinical cure and absence of
any changes was considered failure of clinical cure.
Complete global cure would be accepted if there were complete
clinical cure, negative Woods lamp examination (absence of yellow
fluorescence) and negative direct smear (absence of fungal elements);
but if clinical cure was partial along the negative other two criteria
(Woods lamp examination and direct smear), partial global cure would
be applied. Lack of any of the criteria (clinical cure, negative Woods
lamp examination and negative direct smear) was considered global
cure failure. However, lack of changes in hypopigmentation was not
considered failure.
2.1|Statistics
The data were analysed by spss software version 18 (Chicago, IL,
United states) and medcalc version 8 (Ostend, Belgium). Data of two
groups were compared using Chi-squared test and data in each group
before and after treatment were compared by Wilcoxon test and
McNemars test.
For direct smear results, Wilcoxon test was used to compare
pretreatment and week 5 results due to positive direct smears in all
SEPASKHAH etal. |
3

T A B L E 2 Comparison of the therapeutic efficacy of clotrimazole T A B L E 3 Comparing effects of clotrimazole and tacrolimus on
and tacrolimus on pityriasis versicolor patients at the end of study global and clinical cure and pruritus of pityriasis versicolor patients
(fifth week) between the follow-ups

Therapeutic Clotrimazole Tacrolimus Clotrimazole Tacrolimus

efficacy group no (%) group no (%) P-value Therapeutic efficacy group no (%) group no (%)

Week 5 global cure Week 3 global cure

Complete 14 (56) 14 (56) .63 Complete 12 (48) 9 (36)
Partial 1 (4) 3 (12) Partial 3 (12) 2 (8)
Failure 10 (40) 8 (32) Failure 10 (40) 14 (56)
Week 5 clinical cure Week 5 global cure
Complete 21 (84) 21 (84) .45 Complete 14 (56) 14 (56)
Partial 1 (4) 3 (12) Partial 1 (4) 3 (12)
Failure 3 (12) 1 (4) Failure 10 (40) 8 (32)
Week 5 P-value .74 .14
Pruritus 6 (24) 3 (12) .46 Week 3 clinical cure
No pruritus 19 (76) 22 (88) Complete 20 (80) 19 (76)
Partial 4 (16) 4 (16)
Failure 1 (4) 2 (8)
participants of clotrimazole-treated group and absence of any other Week 5 clinical cure
possible load of fungi in the baseline visit in this group. Complete 21 (84) 21 (84)
P-value of <.05 was considered statistically significant.
Partial 1 (4) 3 (12)
Failure 3 (12) 1 (4)
P-value .70 .08
3|RESULTS Baseline pruritus
Pruritus 9 (36) 12 (48)
Fifty patients completed the study. Twenty-five patients applied
No pruritus 16 (64) 13 (52)
clotrimazole cream and the other 25 were treated with tacrolimus
Week 5 pruritus
ointment. The characteristics of the patients in treatment groups are
Pruritus 6 (24) 3 (12)
presented in Table1.
No pruritus 19 (76) 22 (88)
Both treatments were effective. McNemars test was used to com-
pare global and clinical pretreatment status with cured cases at the P-value .45 .01

end of the study (the fifth week).

At the end of the study, 15 clotrimazole-treated patients were glob-
ally cured (completely or partially) and 10 patients failed to get cured
(P-value<.001). At the same time, 22 clotrimazole-treated patients
experienced complete or partial clinical cure and three patients failed
to respond clinically (P-value<.001).
17 patients among the tacrolimus-treated ones were cured glob-
ally (completely or partially) and eight patients did not get cured glob-
ally at the end of the study (P-value<.001). Complete or partial clinical
cure was gained in 24 tacrolimus-treated patients and one patient in
this group did not respond clinically at the end of study (P-value<.001).

80 P = .54 P = 1.00 P = .043 P = .001

70

60
% of patients

50

40 Few fungal elements

30 Mild load of fungal elements

20 Significant load of fungal elements

F I G U R E 1 Effects of topical tacrolimus No fungal elements
and clotrimazole on mycological cure. 10
Fungal burden of clotrimazole and 0
tacrolimus-treated skin lesions in pityriasis Clotrimazole Tacrolimus Clotrimazole Tacrolimus
versicolor patients in the third and fifth wk 3 wk 3 wk 5 wk 5
weeks of treatment and P-value in
comparison with pretreatment fungal load Fungal load
 |
4 SEPASKHAH etal.
However, global cure and clinical cure were not significantly differ-
ent in tacrolimus and clotrimazole-treated patients (P-values .63 and
.45 respectively); also, no significant difference was found between
tacrolimus and clotrimazole effects on pruritus (P-value: .46) (Table2).
In addition, global cure and clinical cure were not different between
the third and fifth week follow-ups in each treatment group. (Table3).
Tacrolimus was the exclusive treatment that improved pruritus sig-
nificantly at the end of the study (P-value: .01) (Table3).
There was no difference in mycological cure between two groups
(P-value: .26). The details of the effects of treatments on the fungal
burden and P-values of the difference of fungal load in each group in
the third and fifth weeks of follow-up in comparison with the pretreat-
ment time are shown in Figure1.
Significant fading of hypopigmentation at the end of the study was
not observed in tacrolimus-treated patients (P-value: .62).
Woods lamp examination showed fluorescence in 60% of patients
in clotrimazole group and 84% of patients in tacrolimus group before
treatment and was negative in all of the patients of both groups at the
end of study.
No side effect was noted during treatment with either clotrimazole
or tacrolimus.
4| DISCUSSION
Topical application of both tacrolimus and clotrimazole cured pityriasis
versicolor patients. Actually, tacrolimus ointment was found to be as
effective as clotrimazole cream in the treatment of pityriasis versicolor
and more than half of the patients (56%) were cured globally (clinically
and mycologically); clinical cure was even higher (84%) in both groups.
Despite lack of mycological cure at the end of treatment in either
group, both medications resulted in mycological cure at 2 weeks of fol-
low-up. This finding may indicate the continuous antifungal effect of both
agents in tissue after stopping treatment. Rad and colleagues also reported
improved mycological cure 2 weeks after discontinuing clotrimazole.19
Although, to the best of our knowledge, there is no clinical study
regarding efficacy of tacrolimus for the treatment of pityriasis versicolor, its
anti-Malassezia effect has been proven in vitro in spite of higher minimum
inhibitory concentration (MIC) than ketoconazole and itraconazole.15 The
same study demonstrated in vitro synergistic effect of tacrolimus with
ketoconazole and itraconazole against Malassezia species.15 In addition,
another calcineurin inhibitor -pimecrolimus- has been effective against
16
Malassezia species in vitro with similar MIC to tacrolimus.
IgE sensitisation to Malassezia species is considered an important
factor in the pathogenesis of atopic dermatitis and colonisation with
these organisms are shown to be associated with both higher levels of
total IgE and more severe disease.1,20 So, efficacy of tacrolimus as an
accepted effective treatment for atopic dermatitis17 could be at least
partly due to anti-Malassezia effect that we also showed in our study.
21
Pruritus is a well-known symptom of pityriasis versicolor. Although
tacrolimus and clotrimazole were not different in anti-itching property
(P-value: .46), only tacrolimus significantly improved pruritus of pityri-
asis versicolor lesions 2 weeks after treatment cessation (P-value: .01).
Antipruritic effect of calcineurin inhibitors has been evaluated in the
previous studies22,23 and is explained with both anti-inflammatory and
direct effects on the cutaneous non-myelinated nerve fibres.22,24
The effects of topical application of tacrolimus on cytokines in the
epidermis are controversial. In Homey etal. study,25 tacrolimus sup-
pressed elevated tumour necrosis factor alpha (TNF-), Interleukin 1
beta (IL-1), Interleukin 1 alpha (IL-1), Interferon gamma (INF-), mac-
rophage inflammatory protein-2 (MIP-2) and granulocyte-macrophage
CSF (GM-CSF), but Balato etal. [26] failed to show any effect by tac-
rolimus on the production of IL-1, Interleukin 6 (IL-6), Interleukin 8
(IL-8), Interleukin 10 (IL-10) and tumour necrosis factor beta (TNF-)
by Malassezia-infected keratinocytes.
Tacrolimus is an effective treatment for vitiligo.27 Although in
the previous studies, disturbance of melanogenesis and/or destruc-
tion of melanocytes by fungal metabolites were considered the main
pathogeneses of hypopigmented pityriasis versicolor,28 a recent study
shows similar changes in the cutaneous microenvironment of hypopig-
mented pityriasis versicolor and vitiligo and demonstrated increased
TNF- and decreased basic fibroblast growth factor (bFGF) mRNA in
both conditions.29 According to these findings, tacrolimus is expected
to restore the normal pigmentation of pityriasis alba skin lesion; but, in
our study, tacrolimus did not affect the hypopigmentation. This lack of
effect may be explained by short course of drug application (3weeks),
or low concentration of tacrolimus in the topical medication.
The only available tacrolimus formulation has greasy base which
could be worrisome in hyperhidrotic patients. The results of this study
may encourage the production of more convenient for use products in
hairy and hyperhidrotic cases (eg lotions or gels), if technically possible.
There may be concern about the possibility of systemic absorption
of tacrolimus. According to the previous studies assessing systemic
absorption after repeated topical application of tacrolimus in atopic
dermatitis adult patients, the risk was negligible especially in limited
areas of exposure (like in our study).30,31 Moreover, it should be noted
that these studies were conducted on atopic dermatitis patients with
disrupted skin barrier that increases the risk of systemic absorption,
but is unlikely according to the pathogenesis of PV. So, we did not
monitor the tacrolimus blood level in our study.
Although it is claimed that there is no evidence in humans that
combination of topical calcineurin inhibitors and ultraviolet (UV) light
is more carcinogenic than UV alone, until further evidence is available,
adequate UV protection to all patients using topical calcineurin inhibi-
tors even in short periods, like in our study, should be advised.32
Overall, limitations of our study were short follow-up period, relatively
low concentration of medication and also relatively small number of cases.
In conclusion, topical application of tacrolimus 0.03% was effec-
tive and at least as effective as clotrimazole 1% cream in the global,
clinical and mycological cure of pityriasis versicolor. In spite of the
expensiveness and lack of efficacy of tacrolimus on fading PV-induced
hypopigmentation during this study, the therapeutic effect on PV
introduces tacrolimus as a therapeutic option for PV, especially in PV
patients refractory to other treatments and also when early vitiligo is
among the differential diagnoses without concerning the aggravating
effect of topical corticosteroids on PV.
SEPASKHAH etal. |
5

ACKNOWLE DG ME NTS 16. Sugita T, Tajima M, Tsubuku H, Tsuboi R, Nishikawa A. A new calci-
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a part of the requirements for the degree of specialty in dermatology, 17. Cury Martins J, Martins C, Aoki V, Gois AF, Ishii HA, da Silva EM.
Topical tacrolimus for atopic dermatitis. Cochrane Database Syst Rev.
and was financially supported by a grant (No. 91-01-01-5510) from
2015;7:Cd009864.
Research deputy of Shiraz University of Medical Sciences. The authors
18. Zeinali E, Sadeghi G, Yazdinia F, Shams-Ghahfarokhi M, Razzaghi-
are grateful to Ms. Saeedeh Alipour for her assistance in preparation Abyaneh M. Clinical and epidemiological features of the genus
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Sadeghi for coding and presenting the medications to the patients. 19. Rad F, Aala F, Reshadmanesh N, Yaghmaie R. Randomized compar-
ative clinical trial of Artemisia sieberi 5% lotion and clotrimazole 1%
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CO NFLI CT OF I NTE RE S T
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2013;93:340345.
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