DOI: 10.1111/jdv.

15782 JEADV

REVIEW ARTICLE

Cutaneous candidiasis – an evidence-based review of

topical and systemic treatments to inform clinical practice
E.H. Taudorf,1,2,* G.B.E. Jemec,1,2 R.J. Hay,3 D.M.L. Saunte1,2
1
Department of Dermato-Venereology, Zealand University Hospital, Roskilde Hospital, Roskilde, Denmark
2
Health Sciences Faculty, University of Copenhagen, Copenhagen, Denmark
3
Department of Dermatology, King’s College London, London, UK
*Correspondence: E.H. Taudorf. E-mail: [email protected]

Abstract
Cutaneous candidiasis is a common skin disease, and several treatments have been investigated within the last fifty
years. Yet, systematic reviews are lacking, and evidence-based topical and systemic treatment strategies remain
unclear. Thus, the aim of this review was to summarize efficacy and adverse effects of topical and oral therapies for cuta-
neous candidiasis in all age groups. Two individual researchers searched PubMed and EMBASE for ‘cutaneous candidi-
asis’ and ‘cutaneous candidiasis treatment’, ‘intertrigo’, ‘diaper dermatitis’ and ‘cheilitis’. Searches were limited to
‘English language’, ‘clinical trials’ and ‘human subjects’, and prospective clinical trials published in abstracts or articles
were included. In total, 149 studies were identified, of which 44 were eligible, comprising 41 studies of 19 topical thera-
pies and four studies of three systemic therapies for cutaneous candidiasis. Topical therapies were investigated in
infants, children, adolescents, adults and elderly, while studies of systemic therapies were limited to adolescents and
adults. Clotrimazole, nystatin and miconazole were the most studied topical drugs and demonstrated similar efficacy
with complete cure rates of 73%–100%. Single-drug therapy was as effective as combinations of antifungal, antibacte-
rial and topical corticosteroid. Four studies investigated systemic therapy, and oral fluconazole demonstrated similar effi-
cacy to oral ketoconazole and topical clotrimazole. Limitations to this review were mainly that heterogeneity of studies
hindered meta-analyses. In conclusions, clotrimazole, nystatin and miconazole were the most studied topical drugs and
demonstrated equal good efficacy and mild adverse effects similar to combinations of antifungal, antibacterial and topi-
cal corticosteroids. Oral fluconazole was as effective as topical clotrimazole and is the only commercially available evi-
dence-based option for systemic treatment of cutaneous candidiasis.
Received: 22 April 2019; Accepted: 27 June 2019

Conflicts of interest
DMLS has received consultant fee for advisory board meeting by AbbVie, Janssen Pharma and Sanofi and as a
speaker for Bayer, Galderma, Astellas, AbbVie and Leo Pharma. RJH has been a consultant for Mayne Pharma,
Polychem and Janssen Pharma. EHT has received consultant fees as a speaker for Leo Pharma. GBE Jemec has
received honoraria from AbbVie, Coloplast, Pierre Fabre, Inflarx, Novartis and UCB for participation on advisory
boards, and grants from AbbVie, Leo Pharma, Janssen-Cilag, Regeneron, Sanofi and Novartis for participation
as an investigator, and received speaker honoraria from AbbVie, Boehringer Ingelheim, Galderma, Leo Pharma
and MSD.

Funding sources
This review has been initiated and conducted on a voluntary basis, and no funding has been involved.

Introduction dermatitis and interdigital candidiasis.1,3 A variety of Candida

Cutaneous candidiasis is a common disease that affects all ages (C.) species may be responsible, of which C. albicans most com-
and accounts for approximately 1% of all outpatient1 and 7% of monly cause human infections.3
all inpatient visits2 to dermatological clinics. Candida can be the Local skin conditions such as increased humidity, occlusion,
primary cause of skin disease or may arise secondary to other broken skin barrier and altered microbial flora often precede
skin diseases as, e.g. atopic dermatitis, psoriasis or existing dia- cutaneous Candida infections. In addition, known risk factors
per dermatitis. All body regions may be involved, but the most include medical or disease-related immunosuppression, endo-
frequent presentations include intertrigo, cheilitis, diaper crine disorders or compromised blood flow.3,4

JEADV 2019, 33, 1863–1873 © 2019 European Academy of Dermatology and Venereology
1864 Taudorf et al.

Candida is a commensal microbiota of human mucosa but AND ‘dermatitis’[All Fields]) OR ‘diaper dermatitis’[All Fields])
not of skin although it may be carried temporarily on, e.g. fin- AND (Clinical Trial[ptyp] AND ‘humans’[MeSH Terms] AND
gers. In cutaneous candidiasis, it is recognized to be pathogenic English[lang]); (‘cheilitis’[MeSH Terms] OR ‘cheilitis’[All
causing skin infection. Traditionally, the diagnosis has mainly Fields]) AND (Clinical Trial[ptyp] AND ‘humans’[MeSH
been established clinically although it ideally should be con- Terms] AND English[lang]).
firmed and specified by microscopy and culture. Today, use of Prospective clinical trials published in articles or abstracts
molecular methods, such as polymerase chain reactions (PCRs) were included, whereas reviews, guidelines, unclear papers and
and matrix-assisted laser desorption ionization time-of-flight reports of <10 patients were excluded.
mass spectrometry (MALDI TOF-MS), has proven rapid, speci- Onychomycoses, mucosal candidiasis and chronic mucocu-
fic and sensitive methods for identification of Candida strains.5,6 taneous candidiasis were beyond the scope of this review.
The distinction between living and dead fungi during review of Data were extracted independently from individual studies by
treatment, however, requires culture. one researcher (EHT), and a narrative review was conducted
National treatment guidelines exist for rare invasive yeast due to heterogeneity of studies; thus, no statistics were
infections as, e.g. Malassezia,7 yet are lacking for the far more applied. A PRISMA flow diagram provides details of the liter-
common cutaneous yeast infections. Current treatments of cuta- ature search (Fig. 1). Level of evidence (LE) was determined
neous candidiasis include a variety of topical and oral therapies based on the Oxford Centre for Evidence-based Medicine
with anti-inflammatory, antibacterial as well as antifungal guidelines from 2009.8 Once included in the review, data
effects. In addition, topical combinations with corticosteroids were registered in a predefined Excel sheet and each study
have been introduced. Yet, it is not clear whether these are was screened for evidence level, year of publication, type and
preferable, and the decision to prescribe combination therapy size of study population, verification method of diagnosis,
depends mainly on the physician’s clinical judgement. In gen- Candida subtype, anatomical region of candidiasis, use of
eral, although several clinical trials involving treatment of cuta- topical or systemic therapy, treatment regimen, follow-up
neous candidiasis have been published within the last sixty years, time, outcome and reported adverse events. Anatomical
systematic evidence-based reviews of treatment strategies are regions were reported as ‘all body areas’ if it included more
lacking. Thus, this review aims to summarize efficacy and than three areas. Outcomes were reported individually as
adverse effects of topical and oral therapies for cutaneous can- clinical cure, mycological cure, complete clinical and myco-
didiasis. logical cure or other descriptions. No risk-of-bias tool was
applied but heterogeneity of studies was reported. The review
Methods was registered in November 2018 at PROSPERO (https://
The databases PubMed and EMBASE were searched for ‘cuta- www.crd.york.ac.uk/prospero/) with registration number:
neous candidiasis’ and ‘cutaneous candidiasis treatment’. In CRD42019117544.
addition, supplementary searches for diagnoses related to can-
didiasis included ‘intertrigo’, ‘diaper dermatitis’ and ‘cheilitis’. Results
Literature searches conducted by two individual researchers
(EHT and DMS) on 15 June 2018 were limited to ‘English lan- Literature search
guage’, ‘clinical trials’ and ‘human subjects’. The following Eighty-one records were identified by searching PubMed and 77
search strings were used: (‘candidiasis, cutaneous’[MeSH Terms] by searching EMBASE, including nine duplicates. In total, 149
OR (‘candidiasis’[All Fields] AND ‘cutaneous’[All Fields]) OR records were screened of which 90 were out of scope, leaving 59
‘cutaneous candidiasis’[All Fields] OR (‘cutaneous’[All Fields] full-text articles for assessment. Finally, 44 studies were included
AND ‘candidiasis’[All Fields])) AND (Clinical Trial[ptyp] AND in qualitative analysis, and 15 articles were excluded (Fig. 1).
‘humans’[MeSH Terms] AND English[lang]); ((‘candidiasis,
cutaneous’[MeSH Terms] OR (‘candidiasis’[All Fields] AND Heterogeneity of studies
‘cutaneous’[All Fields]) OR ‘cutaneous candidiasis’[All Fields] The 44 included study was conducted over a period of 52 years,
OR (‘cutaneous’[All Fields] AND ‘candidiasis’[All Fields])) and a total of 19 drugs were tested (Table 1). Regimens of ther-
AND (‘therapy’[Subheading] OR ‘therapy’[All Fields] OR ‘treat- apy included from 5 days to twelve weeks of treatment repeated
ment’[All Fields] OR ‘therapeutics’[MeSH Terms] OR one to four times daily or once weekly. Study populations were
‘therapeutics’[All Fields])) AND (Clinical Trial[ptyp] AND ‘hu- infants and small children in 20%, children and adults in 23%,
mans’[MeSH Terms] AND English[lang]); (‘intertrigo’[MeSH adolescents and adults in 43%, elderly in 2% and unspecified in
Terms] OR ‘intertrigo’[All Fields]) AND (Clinical Trial[ptyp] 11%. The studies investigated cheilitis in 2%; perineal dermatitis
AND ‘humans’[MeSH Terms] AND English[lang]); (‘diaper in 2%; intertrigo, interdigital, perleche and/or paronychia in
rash’[MeSH Terms] OR (‘diaper’[All Fields] AND ‘rash’[All 16%; diaper dermatitis in 18%; all body areas in 55% and
Fields]) OR ‘diaper rash’[All Fields] OR (‘diaper’[All Fields] unspecified areas in 7%.

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Treatment of cutaneous candidiasis 1865

Records identified through Records identified through

pubmed searching Embase searching Duplicates (n = 9)
(n = 81) (n = 77)

Records screened after Out of Scope after screening

duplicates removed (n = 90)
(n = 149)

Full text articles excluded, n = 15:

Full text articles assessed • More diagnoses, results for cutaneous candidiasis
for eligibility cannot be extracted: n = 5
(n = 59) • Less than ten patients with cutaneous candidiasis
included in the study: n = 4
• Out of scope: n = 4
• Cutaneous Candidiasis diagnosis not verified by
Studies included in
microscopy and/or culture: n = 1
qualitative synthesis
• Quality of study design too low to conclude: n = 1
(n = 44)

Figure 1 Flow diagram demonstrating identification, screening and inclusion of studies.

Of the 41 included studies on topical therapies, information studies and other reported outcome measures in 12 studies. The
regarding outcome was provided as one or more of the follow- four studies on systemic therapy reported one or more of the
ing: clinical cure rates in 10 studies, mycological cure rates in 13 following outcomes: clinical cure rates in 1 study, mycological
studies, complete clinical and mycological cure rates in 12 cure rates in 2 studies, complete cure rate in 1 study and other
outcome measures in 1 study. Information about recurrence of
Table 1 Commercial availability of drugs tested for cutaneous candidiasis after treatment was provided in four of the 44 stud-
candidiasis ies. In total, 16 of the 44 studies investigating topical and sys-
Drug Systemic commercial Topical commercial temic therapies for cutaneous candidiasis did not state statistical
availability availability comparisons.
USA Europe USA Europe
Amphotericin B + + + Topical therapies
Bifonazole + + Overall, 41 articles investigated topical therapy for cutaneous
Ciclopirox + + candidiasis including 2711 patients in 35 RCTs (LE: 1B)9–43 and
Clotrimazole + + seven prospective blinded or open-label trials (LE: 2B),37,44–49 of
Eberconazole + which one article reported two trials in the same article (LE: 1B
Econazole + + and 2B)37 (Table 2). In total, 17 different single-drug and four
Fluconazole + + combination therapies were investigated including clotrimazole
Flucytosine + + (12 studies, LE: 1B or 2B),11,15,21–23,26,27,29,30,33,41,47 nystatin (ten
Flutrimazole +
studies, LE: 1B or 2B),18,23–26,28,36,37,48,49 miconazole (eight
Haloprogin +
studies, LE: 1B),9,10,13,17,22,34,35,43 halcinonide–neomycin–
Ketoconazole* + +
amphotericin B (three studies, LE: 1B),14,16,19 ciclopirox (two
Miconazole + +
studies, LE: 1B and 2B),40,44 haloprogin (two studies, LE:
Mupirocin + +
1B),13,25 halcinonide–neomycin–nystatin (two studies, LE:
Naftifine + +
Nystatin + + 1B),12,20 naftifine (two studies, LE: 1B),31,39 sulconazole (two
Oxiconazole + + studies, LE: 1B),11,43 mupirocin (two studies, LE: 1B or 2B)36,45
Sertaconazole + + and a number of drugs tested in a single study (Table 2). In 50%
Sulconazole + of the studies, the type of Candida was specified by microscopy
Terbinafine + + + + and/or culture and the majority recorded C. albicans, whereas
References: Pharmacompass.com, Drugs.com, Wikipedia.
three studies also found a few patients with C. parapsilosis or
*Withdrawn from systemic use due to serious adverse effects. C. tropicalis.21,42,50 Together, these three studies investigated

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Table 2 Diagnosis, outcome and adverse effects for all tested treatments of cutaneous candidiasis
Study (Year, population Drug Fungal Candida type Study type (Evidence Anatomical region Regimen Follow-up Outcome (% of patients) Reported adverse effects
type and size) verification level) (% patients)
method

Systemic treatments

Nozickova et al.,51 Fluconazole Mic. or cult. NA RCT, open-label (1B) All body areas Oral fluconazole 150 mg Weeks 0, 2, 3–4 and 8 After therapy: mycological cure Fluconazole weekly: 17%
(adults, N = 24) weekly vs. Oral fluconazole (Fluconazole weekly vs. daily): experienced abnormal hepatic
50 mg once daily for up to 82% vs. 100% (no comparison) function, headache or eruption.
4 weeks Fluconazole daily: 25%

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experienced hyperlipidemia,
nausea or headache
Stengel et al.,52 Fluconazole/ Mic. & cult. NA RCT, double-blinded, All body areas 2–4 weeks: fluconazole 150 mg Weekly during treatment After therapy: similar clinical Fluconazole: gastrointestinal
(adolescents and adults, ketoconazole placebo-controlled, weekly plus daily placebo vs. 2– plus 22–47 days after cure with fluconazole vs. (0.01%), urticaria (0.01%),
N = 23) multicenter (1B) 6 weeks: ketoconazole 200 mg cessation ketoconazole (non-sign, headache (0.01%), elevated
daily plus weekly placebo percentages of clearance not basophil count (0.01%),
stated) elevated neutrophil count
(0.01%). Ketoconazole: severe
gastrointestinal symptoms incl.
bloody diarrhoea (0.01%),
vertigo (0.01%), elevated
basophil count (0.01%)

Jung et al.,50 (adults, Terbinafine/ Mic. & cult. C. albicans or RCT, double-blinded, All body areas 4 weeks: Terbinafine 250 mg Weeks 0, 1, 2, 4 and 7 After therapy: clinical and Terbinafine: 5% adverse effects
N = 118) Ketoconazole C. parapsilosis multicenter (1B) twice daily vs. ketoconazole mycological cure in (terbinafine incl. nausea, headache and
200 mg once daily vs. ketoconazole) 65% vs. 57% urticaria. Ketoconazole: 7%
(not compared) adverse effects incl.
gastrointestinal symptoms,
erythema and elevated liver
enzymes.

Systemic and topical treatments

Crevits et al.,29 (adults, Fluconazole/ Mic. & cult. NA RCT, open-label, All body areas Oral fluconazole 150 mg End of treatment and After therapy: clinical cure in Fluconazole: gastrointestinal
N = 14) clotrimazole multicenter (1B) weekly vs. Topical clotrimazole 1 month post-treatment (fluconazole vs. clotrimazole) (2.6%), dermatitis or urticaria
1% cream twice daily for 2– 100% vs. 100%; mycological (1%), bronchospasm (0.5%).
4 weeks cure in 100% vs. 71% (non- Clotrimazole: increased liver
significant) enzymes (1%), headache (1%),
paraesthesia (1%), eczema and
pruritus (1%)

Topical treatments

Stritzler et al.,48 (NA, Amphotericin B/ Mic. & cult. C. albicans Two studies: double- 1) Intertriginous 2) 1) Amphotericin B cream vs. At least 3 months After therapy: clinical and NA
N = 211) nystatin blinded comparative (2B) all body areas nystatin cream 2) Amphotericin mycological cure in 1)
B lotion vs. calamine lotion amphotericin B vs. nystatin 84%
(details not stated) vs. 79% (not compared); 2)
amphotericin B vs. calamine
88% vs. 24% (not compared)
44
Gallup et al., (infants, Ciclopirox Mic. at entry, C. albicans Prospective non- Diaper dermatitis 7 Days: ciclopirox 0.77% twice Days 3, 7,14 Significant reduction of positive In total, 57% experienced one
N = 44) mic. & cult. comparative intervention, daily cultures and severity scores or more mild-to-moderate
at cessation open-label (2B) (P < 0.05); clinical cure at day adverse effects. None were
14 in 66% considered related to treatment.

Bagatell et al.,40 (children Ciclopirox/ Mic. & cult. NA RCT, double-blinded All body areas 4 weeks: twice daily ciclopirox Weeks 0, 1, 2, 3, 4, 5, 6 Week 6: clinical and NA
and adults, N = 240) clotrimazole placebo-controlled/ cream 1% vs placebo/ mycological cure in (ciclopirox
comparative multicenter clotrimazole cream 1% vs. placebo): 74% vs. 12%
(1B) (P < 0.01) or (ciclopirox vs.
clotrimazole) 74% vs. 60%
(non-significant)
33
Sabzghabaee et al., Clotrimazole/ Clinical and mycological NA RCT, placebo-controlled Diaper dermatitis Until cure: twice daily NA Complete clinical cure was NA
(infants, N = 70) menthol identification (1B) clotrimazole 2% and menthol shorter in the menthol group
(method not stated) 5% vs. clotrimazole 2% and than in the placebo group (4.3
placebo vs. 6.9 days, P < 0.0001)
Taudorf et al.

© 2019 European Academy of Dermatology and Venereology

Table 2 Continued
Study (Year, population Drug Fungal Candida type Study type (Evidence Anatomical region Regimen Follow-up Outcome (% of patients) Reported adverse effects
type and size) verification level) (% patients)
method

Desomchoke et al.,30 Clotrimazole Mic. & cult. NA RCT, open-label (1B) Intertrigo 12 weeks: 1% cream vs 1% Weeks 4, 8, 12 and 36 Powder and cream had NA
(adults, N = 32) cream and 1% powder twice significantly higher cure rate
daily than cream, evident at week 4
(P < 0.01); recurrence rates
and patient satisfaction were
similar
15
Zaias et al., (NA, Clotrimazole Mic. & cult. C. albicans Prospective, double- Intertrigo, interdigital 4 weeks: 1% clotrimazole Weeks 0, 4 and 6 Week 6: clinical and No adverse effects

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N = 99) blinded, placebo- solution vs. placebo (no. of mycological cure in
controlled (2B) applications not stated) (clotrimazole vs. placebo) 88%
vs. 33% (no comparison)
Spiekermann et al.,47 Clotrimazole Mic. & cult. NA Prospective, double- NA 2 weeks: twice daily Weeks 0, 1, 2 and 3 Week 3: microscopic cure Burning, stinging, irritation
(NA, N = 149) blinded, comparative, clotrimazole 1% cream vs. (clotrimazole solution vs. (clotrimazole vs. placebo) 3%
multicenter (2B) placebo or clotrimazole 1% placebo/clotrimazole cream vs. vs. 3%
solution vs. placebo placebo) in 92% vs. 46%/82%
Treatment of cutaneous candidiasis

vs 25%; culture cure in 88% vs

40%/78% vs 0%; clinical
improvement in 92% vs 52%/
100% vs 42%. All comparisons:
P < 0.01

Frederiksson et al.,27 Clotrimazole Cult. C. albicans RCT, double-blinded, All body areas 3 weeks: twice daily Weeks 0 and 3 Week 3: clinical cure in 44%; No adverse effects
(children and adults, placebo-controlled (1B) clotrimazole 1% vs. placebo culture cure in 100% vs. no cure
N = 27) in the placebo group (no
comparison)
41
Lalosevic et al., (adults, Clotrimazole/ Mic. & cult. NA RCT, double-blinded All body areas 4 weeks: bifonazole 1% twice Weeks 0, 1, 2, 3, 4 and 6 After therapy: clinical and NA
N = 275) Bifonazole placebo-controlled/ daily/bifonazole 1% once daily/ mycological cure in: bifonazole
comparative, multicenter clotrimazole twice daily/placebo once daily: 66%, bifonazole
(1B) twice daily twice daily: 75%, clotrimazole
twice daily 75%, placebo twice
daily 19% (bifonazole vs.
placebo: P < 0.0001, bifonazole
vs. clotrimazole: P = 0.195)
21
Palacio et al., (adults, Clotrimazole/ Mic. & cult. C. albicans or RCT, double-blinded (1B) All regions 4 weeks: twice daily Weeks 0, 4 and 10 Week 4: clinical and Burning stinging, redness in
N = 24) eberconazole C. parapsilosis eberconazole 1% or mycological cure in (clotrimazole vs. eberconazole)
clotrimazole 1% (clotrimazole vs. eberconazole) 21% vs. 20%
73% vs. 50% (not compared)
Keczkes et al.,23 (adults, Clotrimazole/ Mic. & cult. C. albicans RCT, double-blinded, All body areas 4 weeks: twice daily Weeks 0, 2, 4 and 8 Week 4 (clotrimazole vs. Severe irritation: (clotrimazole
N = 25) nystatin comparative (1B) clotrimazole 1% vs. nystatin nystatin): clinical cure in 55% vs. nystatin) 7% vs. 8%. Mild
(100 000 U/g) vs. 58%, microscopic and irritation: (nystatin) 7%
culture cure in 92% vs 92% (not
compared)

Clayton et al.,26 (adults, Clotrimazole/ Mic. & cult. C. albicans RCT, double-blinded, All body areas 4 weeks: twice daily Weeks 0, 2, 4 and 8 Week 4: clinical and Clotrimazole: no adverse
N = 17) nystatin/Whitfield’s comparative (1B) clotrimazole 1% cream vs. mycological cure achieved in all effects; nystatin: 11% adverse
Ointment nystatin (100 000 U/g) patients, no recurrences at effects (not specified)
week 8
11
Rajan et al., (adults, Clotrimazole/ Mic. NA RCT, double-blinded, Intertrigo, 3 weeks: sulconazole 1% once Weeks 0, 2, 3 and 7 Week 3: microscopic cure in Sulconazole: itching (28%),
N = 57) sulconazole comparative (1B) interdigital, perleche daily vs. clotrimazole 2% twice (sulconazole vs. clotrimazole) Clotrimazole: no adverse
daily 59% vs. 83%; culture cure in effects
63% vs. 33% (not compared)

Alomar et al.,32 (children Flutrimazole/ Mic. or cult. NA RCT, double-blinded, All body areas 4 weeks: 1% flutrimazole cream Days 0, 15, 40 and 60 After therapy: clinical and Mild pruritus and burning
and adults, N = 27) bifonazole multicenter (1B) or 1% bifonazole cream mycological cure in (flutrimazole sensation in (flutrimazole vs.
vs. bifonazole) 75% vs. 91% bifonazole) 7% vs. 4%
(P = 0.588)
13
Clayton et al., (adults, Haloprogin/ Mic. NA RCT, double-blinded (1B) All body areas 4 weeks: twice daily haloprogin Weeks 2, 4 and 8 After therapy: microscopic cure NA
N = 18) miconazole 1% vs. miconazole 2% in (haloprogin vs. miconazole)
100% vs. 81%; culture cure in
87% vs. 100% (not compared)
1867

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Table 2 Continued
Study (Year, population Drug Fungal Candida type Study type (Evidence Anatomical region Regimen Follow-up Outcome (% of patients) Reported adverse effects
type and size) verification level) (% patients)
method

Carter et al.,25 (children Haloprogin/nystatin Mic. & cult. C. albicans RCT, double-blinded, NA 13 days: twice daily haloprogin Weeks 0, 2 and 6 Week 2 (haloprogin vs. No adverse effects
and adults, N = 68) comparative (1B) 1% vs. nystatin (100 000 U/g) nystatin): Clinical improvement
of > 50% in 83% vs. 84%;
microscopic cure in 86% vs.

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88%; culture cure in 83% vs.
88% (all non-significant)
14
Theodoridis et al., HNA Mic. & cult. NA RCT, single-blinded (1B) All body areas Up to 4 weeks: three times daily Weekly intervals until After therapy: clinical cure in No adverse effects
(children and adults, HNA vs. I-HC cure, max. 4 weeks (HNA vs. I-HC) 95% vs. 43%
N = 80) (not compared)
Reyes-Javier et al.,16 HNA Mic. or cult. NA RCT, double-blinded (1B) NA Up to 4 weeks: three times daily Weekly intervals until After therapy: clinical excellent No adverse effects
(children and adults, HNA vs. I-HC cure, max. 4 weeks response in (HNA vs I-HC) 88%
N = 36) vs 26% (P < 0.001)

Abdel-Aal et al.,19 HNA/steroid Mic. & cult. NA RCT, double-blinded, All body areas Up to 4 weeks: three times daily Weekly until cure Week 4: clinical cure (HNA vs. No adverse effects
(infants, children and comparative (1B) HNA vs. I-HC I-HC) in 74% vs. 91% (not
adults, N = 70) compared)
Barba-Rubio et al.,12 one HNN/BGI Mic. & cult. NA RCT, open-label, All body areas Up to 25 days, twice daily HNN Weekly for 4 weeks After therapy: clinical cure in Erythema and itching in (HNN
containing halcinonide, multicenter (1B) (except vulva, vs. BGI (HNN vs. BGI) 85% vs. 71% vs. BGI) 10% vs. 11%
neomycin and nystatin perianal, diaper (not compared)
(NA, N = 67) rash)

Barba-Rubio et al.,20 HNN/steroid Mic. or cult. NA RCT (1B) Intertrigo, Up to 3 weeks: three times daily Weekly until cure Week 3: clinical cure in (HNN HNN: no adverse effects, IH:
(infants, children and interdigital, neck until cure, HNN vs. I-HC vs. IH) 100% vs. 100% 11% erythema or pruritus
adults, N = 30)
46
Greer et al., (adults, Ketoconazole Mic. or cult. C. albicans Prospective, placebo- All body areas Until cleared (up to 2 weeks): Weeks 0 and 2 Week 2: clinical and Ketoconazole: burning (6%)
N = 18) controlled (2B) daily ketoconazole 2% vs. mycological cure in
placebo (ketoconazole vs. placebo) 86%
vs. 20% (P < 0.01)
9
Takahashi et al., Miconazole Mic. NA RCT, double-blinded, Diaper dermatitis 4 weeks: daily wash with Weeks 0, 1, 2, 3 and 4 Week 4 (miconazole vs. (Miconazole vs. placebo):
(elderly, N = 55) placebo-controlled (1B) miconazole 0.75% soap vs placebo): negative conversion erythema: 14% vs 7% (non-
placebo rate (cure): 80% vs. 50% (non- significant), maceration: 5% vs
significant); positive conversion 0% (non-significant)
rate (disease): 17% vs. 44%
(significant)
Spraker et al.,10 Miconazole Mic., cult. NA RCT, double-blinded, Diaper dermatitis 7 days: miconazole 0.25% Day 14 Week 1: microscopic and No adverse effects related to
vehicle-controlle placebo-controlled (1B) ointment vs. placebo several clinical cure in (miconazole vs. treatment
(infants, N = 236) times daily placebo) 23% vs. 10%,
P < 0.001

Concannon et al.,35 Miconazole Clin. & cult. C. albicans RCT, double-blinded, Diaper dermatitis 7 days: miconazole 0.25% Days 0, 1, 3, 5 and 7 Week 1: mycological cure in Mild adverse effects, no
(infants, N = 58) placebo-controlled (1B) ointment vs. placebo after each (miconazole vs. placebo) 96% difference between groups
diaper change vs. 4% (not compared)
34
Mackie et al., (infants Miconazole Clin. & cult. C. albicans or RCT, double-blinded, Diaper dermatitis 2 weeks: miconazole 2% vs. Days 0 and 14 After therapy: clinical and NA
and children, N = 12) C. parapsilosis placebo-controlled (1B) placebo after each diaper culture cure in (miconazole vs.
change placebo) 100% vs. 50%

Cullin et al.,17 (NA, Miconazole Mic. or cult. C. albicans RCT double-blinded, Intertrigo, perleche Phase 1: 2 weeks: twice daily Weeks 0, 1, 2, 3 and 4 Week 2: clinical and No adverse effects
N = 30) comparative (1B) or paronychia miconazole 2% vs placebo. mycological cure in (miconazole
Phase 2: 2 weeks miconazole vs. placebo) 87% vs. 7%
2% for all non-responders
Clayton et al.,22 (adults, Miconazole/ Mic. & cult. C. albicans RCT, double-blinded, All areas 4 weeks: twice daily Weeks 0, 2, 4 and 8 Week 4: mycological cure in Transient burning and irritation
N = 13) clotrimazole comparative (1B) clotrimazole 1% vs. miconazole 100% in both treatment groups (2% miconazole vs. 1%
2% clotrimazole)

Rode et al.,45 (infants and Mupirocin Mic. & cult. NA Prospective, open-label, Perineal region 5 days: 2% mupirocin ointment Days 0, 2 and 5 Complete clinical and NA
children, N = 10) non-comparative (2B) twice daily mycological cure in all patients
within 2–5 days (not compared)
Taudorf et al.

© 2019 European Academy of Dermatology and Venereology

Table 2 Continued
Study (Year, population Drug Fungal Candida type Study type (Evidence Anatomical region Regimen Follow-up Outcome (% of patients) Reported adverse effects
type and size) verification level) (% patients)
method

De Wet et al.,36 (infants Mupirocin/nystatin Clin., Mic. & cult. C. albicans RCT (1B) Diaper dermatitis 7 days: at least three times Days 0, 1, 2, 3, 4, 5, 6 and Week 1: clinical cure in NA
and children, N = 20) daily or after each diaper 7 (mupirocin vs. nystatin) 100%
change: mupirocin 2% vs. vs. 30% (not compared); mean
nystatin (100 000 U/g) time to mycological cure was
similar in both groups
31
Astorga et al., Naftifine Mic. and cult. NA RCT, double-blinded, All body areas 5 weeks: naftifine cream 1% Weeks 0, 1, 2, 3, 5 and 7 Week 5: clinical and Naftifine and placebo: burning,
(adolescents and adults, placebo-controlled (1B) twice daily vs. placebo mycological cure in (naftifine vs. stinging and itching (17% and

JEADV 2019, 33, 1863–1873

N = 59) placebo) 73% vs. 0% 24%, respectively)
(P < 0.001)
Zaias et al.,39 Naftifine Mic. & cult. C. albicans RCT, double-blinded, All body areas 3 weeks: naftifine cream 1% Weeks 0, 1, 2, 3 and 5 Week 5: clinical and Naftifine and placebo: burning,
(adolescents and adults, placebo-controlled (1B) twice daily vs. placebo mycological cure in (naftifine vs. stinging and itching (13% each).
N = 60) placebo) 77% vs. 3% Placebo: contact dermatitis
(P < 0.001) (3%)

Munz et al.,49 (infants, Nystatin Clin. & cult. C. albicans Prospective, double- Diaper dermatitis 10 days: four times daily topical Days 0 10 and after 3– After therapy: all patients NA
Treatment of cutaneous candidiasis

N = 37) blinded, placebo- nystatin (100 000 U/g) 12 months experienced improvement of
controlled (2B) combined with oral (nystatin rash, non-significant differences
100 000 U/mL) or placebo between groups, and one-third
of the patients in both groups
had recurrence within 1 year
37
Ohman et al., (adults, Nystatin Cult. Candida albicans 1) Prospective open-label Cheilitis 4 weeks: four times daily Weeks 0, 2, 4 and 6 Week 4: 1) open-label study NA
N = 26) 2) RCT, double-blinded, nystatin (100 000 U/g) (open- (nystatin) 100% clinical and
placebo-controlled (1B label) or nystatin (100 000 U/g) mycological cure after 4 weeks;
and 2B) vs placebo (RCT) 2) RCT: clinical and mycological
cure in (nystatin vs. placebo)
100% vs. 13% (P < 0.001)
28
Alban et al., (infants, Nystatin Mic. & cult. C. albicans RCT, double-blinded, All body areas 6 days (2–8 days): nystatin Week 0 and end of After therapy: clinical cure in No adverse effects
N = 50) placebo-controlled (1B) (100 000 U/g) vs. placebo 3–4 therapy (nystatin vs. placebo) 76% vs.
times daily 28% (P < 0.01); culture cure in
68% vs. 16% (P < 0.01)
Gissle
n et al.,24 (adults, Nystatin/5- Cult. C. albicans Prospective, single- All body areas 2 weeks: twice daily 5-FC (5- Weeks 0, 1 and 2 Week 2: all patients obtained No adverse effects
N = 30) fluorocytosine blinded, comparative (1B) fluorocytosine 10% cream) vs. mycological cure with both
nystatin to each side of treatments; clinical cure in (5-
symmetrical lesions fluorouracil vs. nystatin) 30%
vs. 37% (non-significant)

Beveridge et al.,18 Nystatin/NTA Mic. & cult. NA RCT, double-blinded, Intertrigo 2 weeks: nystatin vs. NTA three Weeks 0 and 2 After therapy: mycological cure Nystatin: burning 10%; nystatin
(infants, children, adults, comparative, multicenter times daily (nystatin vs. nystatin– –triamcinolone: burning 6%,
elderly, N = 31) (1B) triamcinolone) in 87% vs. 84% pustules 3%
(non-significant)
42
Gip et al., (children and Oxiconazole/ Mic. & cult. C. albicans, RCT, double-blinded, All body areas 3–6 weeks (until 1 week after Weeks 2, 3 and 5–6 After therapy: clinical and Econazole: burning (2.5%)
adults, N = 40) econazole C. tropicalis or comparative (1B) cure): Twice daily oxiconazole mycological cure in
C. parapsilosis 1% cream vs. econazole 1% (oxiconazole vs. econazole)
cream 90% vs. 91% (not compared)

Umbert et al.,38 (adults, Sertaconazole Mic. & cult. C. albicans RCT, double-blinded (1B) All body areas 4 weeks: twice daily Weeks 0, 1, 2, 3, 4 and 6– After therapy: clinical and No adverse effects
N = 20) sertaconazole 1% vs. 8 mycological cure in 95%; no
sertaconazole 2% cream recurrences after treatment (not
compared)
Tanenbaum et al.,43 Sulconazole/ Mic. NA RCT, double-blinded, Intertrigo, 3 weeks: sulconazole 1% once Weeks 0, 2, 3 and 7 After therapy: microscopic cure Erythema, pruritus. No systemic
(adults, N = 96) miconazole comparative (1B) interdigital, perleche daily vs. vehicle/miconazole 2% in (sulconazole vs. miconazole adverse effects
twice daily vs. placebo) 100% vs. 100% vs.
10%; culture cure in 94% vs.
92% vs. 0% (sulconazole vs.
placebo: P < 0.0001 for
microscopy as well as culture)

BGI, betamethasone, gentamicin, iodochlorhydroxyquin, tolnaftate; Clin., clinical; Cult., culture; HNA, halcinonide, neomycin, amphotericin; HNN, halcinonide, neomycin, nystatin; I-HC, iodochlorhydrox-
yquin, hydrocortisone; Mic. , microscopy; NA, not available; NTA, nystatin, triamcinolone; RCT, randomized controlled trial.
1869

© 2019 European Academy of Dermatology and Venereology

1870 Taudorf et al.

infants, children and adults with Candida at various body sites combined with oral nystatin (100 000 U/mL) or oral placebo,
and specific information about the cases of C. parapsilosis and respectively.49
C. tropicalis was not available. Adverse effects to nystatin therapy included skin irritation
and burning (7%–10%)18,23,26 (Table 2).
Topical clotrimazole
Topical clotrimazole 1% twice daily for 2–12 weeks was tested Topical miconazole
in 12 studies including all body sites in In total, eight studies considered topical micona-
adults11,21,23,26,27,29,30,41 and children above the age of five,27 zole.9,10,13,17,22,34,35,43 Four studies (LE: 1B) investigated 1–
infants with diaper dermatitis33 and uncharacterized study 4 weeks of topical miconazole 2% twice daily for all body areas
populations, respectively15,47 (Table 2). In infants, clinical cure in adults13,17,22,43 (Table 2). Three studies (LE: 1B) treated dia-
was obtained at the latest at day 7. In children above the age per dermatitis in infants for 1–2 weeks,10,34,35 while one study
of five, adults or unspecified populations, clinical cure rates (LE: 1B) investigated prophylactic once-daily 0.75% miconazole
alone ranged from 44% to 100%,23,27,47 mycological cure rates soap vs. placebo for 4 weeks in elderly with Candida intertrigo.9
from 78% to 100%23,27,47 and complete cure (clinically as well Miconazole was superior to placebo,10,17,34,35 and efficacy was
as mycologically) from 73% to 100%,15,21,26,41 which was sig- similar to clotrimazole 1%, haloprogin 1% and sulconazole 1%
nificantly higher than placebo (complete cure rates of 0%– (no P-values).13,22,43 Overall, mycological cure ranged from 81%
52% (P < 0.01).15,27,47 Clotrimazole also seemed superior to to 100%13,22,34,35,43; with 96%–100% mycological cure for
eberconazole with complete cure rates of 73% vs. 50% (no infants with diaper dermatitis34,35 and 81%–100% for adults
comparisons).21 Comparisons with sulconazole were inconclu- with Candida at various body sites.13,22 Complete clinical as well
sive (Table 2).11 Clotrimazole was comparable to bifonazole as mycological cure was reported 87% in one study.17 Prophy-
1% twice daily (P = 0.195),41 miconazole 2% twice daily lactic miconazole soap compared to placebo soap for 4 weeks
(complete cure in both groups),22 nystatin 100 000 U/g twice generated significantly fewer pseudohyphae detected by micro-
daily [complete cure/clinical cure in 55% vs. 58%/microscopy scopy (17.9% vs. 44.4%, P < 0.05)9 (Table 2).
and culture cure in 92% vs 92% (no P-values)]23,26 and sys- Adverse effects from miconazole included transient burning,
temic fluconazole 150 mg once weekly (complete clinical cure skin irritation, erythema and pruritus22,43 (Table 2).
in both groups and mycological cure in 71% vs 100%, non-
significant).29 No studies reported therapies superior to clotri- Topical combination therapies
mazole. Adverse effects to clotrimazole included transient Six studies investigated corticosteroid–antimicrobial combina-
burning and irritation (up to 3%),22,29,47 severe skin irritation tions (LE: 1B)12,14,16,18–20 (Table 2). The anti-inflammatory
(1%–7%),23,29 increased liver enzymes (1%),29 headache properties came from topical corticosteroids and the antibacte-
(1%)29 and paraesthesia (1%)29 (Table 2). rial effect from neomycin and gentamycin. Antifungal drugs
included nystatin and amphotericin B in three studies
Topical nystatin each,12,14,16,18–20 iodochlorhydroxyquin (clioquinol) in four
Topical nystatin 100 000 U/g applied 2–4 times daily for 6– studies14,16,19,20 and tolnaftate in one study.12 Infants to elderly
28 days was investigated in 10 studies including cutaneous can- treated at all body sites were included.
didiasis at all body regions in infants to elderly patients (LE: 1B Nystatin combination therapy generated clinical cure rates of
or 2B)18,23–26,28,36,37,48,49 (Table 2). 85%–100% and was similar to nystatin single-drug therapy or
Nystatin demonstrated clinical cure rates compared to pla- combinations of topical nystatin–triamcinolone, topical iodine–
cebo of 76% vs. 28% (P < 0.01), mycological cure rates of 68% iodochlorhydroxyquin–hydrocortisone (I-HC) or topical
vs. 16% (P < 0.01)28 and complete cure rates of 100% vs. 13%.37 betamethasone–gentamicin–iodochlorhydroxyquin–tolnaftate
Nystatin therapy was reported similar in efficacy to topical (BGI) (no P-values).12,18,20 Combination of halcinonide, neomy-
clotrimazole 1%, 5-fluorocytosine 10%, haloprogin 1% and nys- cin and amphotericin B (HNA) was superior or similar to I-HC
tatin–triamcinolone combination therapy18,23–25 and to oral nys- with clinical cure rates of 88%–95% vs. 26%–43%
tatin therapy,49 while it was tested inferior to mupirocin45 (P < 0.001)14,16 or 74% vs. 91% (no P-values),19 respectively
(Table 2). (Table 2).
Infants and adults with Candida at all body regions had clini- Adverse effects in 3%–11% of patients included burning, itch-
cal cure rates of 76% vs. 37%–58% and mycological cure rates of ing, pustules, and erythema12,18,20 (Table 2).
68% vs. 92%–100%.23,24,26,28
Topical nystatin may be used as an oral solution, yet the drug Systemic therapies
is not absorbed from the mucosa or intestine. Accordingly, Four studies concerned systemic treatment of cutaneous can-
infants experienced similar improvement of diaper dermatitis didiasis (LE: 1B)29,49–52 and included 179 (range: 14–118)
after topical nystatin (100 000 U/g) four times daily for 10 days patients treated with fluconazole,29,51,52 ketoconazole50,52 or

JEADV 2019, 33, 1863–1873 © 2019 European Academy of Dermatology and Venereology
Treatment of cutaneous candidiasis 1871

terbinafine50 (Table 2). All studies investigated patients of knowledge increases with the escalation of antifungal resistance
16 years or older with Candida at various body sites. Only one in Candida species.54
study specified the Candida species by microscopy and culture Few evidence-based options exist for systemic treatment of
as C. albicans or C. parapsilosis.50 cutaneous candidiasis. Three out of four studies investigate oral
If stated, exclusion criteria comprised previous antifungal fluconazole and demonstrate similar efficacy to oral ketocona-
therapy of the same fungal infection altogether,29 or at least zole or topical clotrimazole. Meanwhile, oral ketoconazole is no
within 1–2 weeks prior to treatment initiation.50,52 There were longer used for superficial mycoses due to liver adverse effects.53
no data on previous antifungal treatment before study inclusion. It has been questioned whether clearing of the rash in cuta-
Oral fluconazole 150 mg weekly or 50 mg daily for 2–4 weeks neous candidiasis is due to antifungal or simply anti-inflamma-
had clinical cure rates of 82%–100%,29,51 which was similar to tory effect.55,56 However, potent corticosteroid–antimicrobial
ketoconazole 200 mg daily52 or topical clotrimazole twice combination therapies did not prove superior to pure antifungal
daily.29 drugs with a less potent anti-inflammatory effect,55,56 as would
Ketoconazole 200 mg daily vs. terbinafine 500 mg daily for have been suspected if this hypothesis were correct.
4 weeks had complete cure rates of 57% vs. 65%.50 Topical mupirocin was traditionally an antibiotic ointment
Weekly fluconazole 150 mg for 2–4 weeks led to headache, for superficial bacterial skin infections. Later, it was discovered
eruption of rash or abnormal hepatic function in 17% of that mupirocin has a similar mechanism of action against bacte-
patients in one study,51 whereas other studies reported lower ria and Candida which includes inhibition of isoleucyl-transfer
incidences of gastrointestinal complaints (0.01%–3%), urticaria ribonucleic acid synthetase, thus preventing protein synthesis of
(0.01%–1%), headache (0.01%), bronchospasm (0.5%) or ele- the microorganisms.36,57 In support of this, a prospective open-
vated basophil/neutrophil counts (0.01%).29,52 Daily fluconazole label study demonstrated complete cure after 2- to 5-day treat-
50 mg for 2–4 weeks caused hyperlipidemia, nausea or headache ment of children with perineal cutaneous candidiasis.45 In addi-
in 25% of patients.51 Terbinafine 500 mg daily for 4 weeks tion, one RCT investigated a 7-day treatment of infants with
caused nausea, headache and urticaria in 5% of patients,50 while diaper dermatitis due to C. albicans36 and found similar myco-
ketoconazole 200 mg daily for 2–4 weeks led to erythema (2%), logical cure rates, but clinical cure rates of 100% with mupirocin
nausea and vomiting (3%), bloody diarrhoea (0.01%), vertigo vs. 30% with topical nystatin (not compared). Their finding is,
(0.01%), and elevated basophil counts (0.01%) or liver enzymes however, not in accordance with another RCT that presented
(2%)50,52 (Table 2). In 2013, oral ketoconazole was withdrawn clinical cure rates of 76% after nystatin treatment for 6 days of
or restricted globally due to hepatotoxic side-effects53 (Table 1). infants with similar diaper dermatitis due to C. albicans.28
It has also been proposed that combining antifungals with
Discussion either high-strength (e.g. halcinonide, betamethasone valerate)
Despite the common diagnosis of cutaneous candidiasis, evi- or low-strength (e.g. hydrocortisone) topical corticosteroids
dence of topical therapy is inadequate and heterogeneous, while may enhance the effect of topical antifungal treatments. Six stud-
little is known about systemic therapy. ies have evaluated this hypothesis.12,14,16,18–20 With application
Clotrimazole, nystatin and miconazole are the most studied two-three times daily for two-4 weeks, treatments were neither
topical drugs demonstrating similar efficacy with complete clini- shorter nor easier to comply with compared to antifungal ther-
cal and mycological cure rates of 73%–100%. In head-to-head apy alone. Efficacy was proven similar to topical nystatin,18 while
studies against one of these drugs, similar clinically and/or similar or superior to treatment with topical steroids.14,16,19,20
mycologically effects were observed with amphotericin B,48 Adverse effects seemed similar among patients treated with anti-
ciclopirox,40 sulconazole,11,43 haloprogin,13,25 bifonazole,41 fungal and combination therapy (Table 2). Thus, from the pre-
flucytosine24 and mupirocin.36 In addition, oxiconazole,21 eber- sent evidence, pure antifungal therapy is sufficient with less
conazole,21 bifonazole32 and sertaconazole38 demonstrated high long-term side-effects and therefore preferred over combination
complete cure rates of at least 90%, yet, neither of the drugs have therapy, unless there is an underlying disease such a psoriasis.
been tested against clotrimazole, nystatin or miconazole for In total, 44 studies investigated systemic or topical therapies
cutaneous candidiasis. Eberconazole was tested against clotrima- for cutaneous candidiasis, of which only half had a diagnosis
zole in one study and appeared slightly inferior with complete verified by microscopy and/or culture. Of those speciating the
cure rates of 50% vs. 73% (no P-values).21 Adverse effects were organisms, only 18% found species other than C. albicans.
generally mild and similar for all drugs, although comparison Therefore, it is not possible to say whether the species of Can-
was hampered by inconsistent reporting. Thus, overall many dida has an impact on treatment efficacy. Future diagnostic
topical drugs may treat cutaneous candidiasis, while convincing strategies including further utilization of PCR and MALDI TOF-
evidence is lacking for most of them. Testing of the various MS may enable specification of species or even molecular sub-
drugs may be complicated by the limited availability in different types and possibly lead to tailored treatments of cutaneous can-
parts of the world (Table 1). Yet, the need for evidence-based didiasis.

JEADV 2019, 33, 1863–1873 © 2019 European Academy of Dermatology and Venereology
1872 Taudorf et al.

Limitations of this review mainly include heterogeneity of 8 Quality of evidence guidelines from Oxford Centre for Evidence-based
included studies with regard to drug, treatment regimen, age, Medicine [WWW Document]. URL www.cebm.net
9 Takahashi H, Oyama N, Tanaka I et al. Preventive effects of topical wash-
treated body area and outcome measurements. Also, due to ing with miconazole nitrate-containing soap to diaper candidiasis in hos-
altered reporting traditions over the last 52 years, data were not pitalized elderly patients: a prospective, double-blind, placebo-controlled
sufficiently stated and statistical analyses not provided in 36% of study. J Dermatol 2017; 44: 760–766.
10 Spraker MK, Gisoldi EM, Siegfried EC et al. Topical miconazole nitrate
the studies, which hindered meta-analysis of data. Information
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pustular or granulomatous, was sparse and did not allow com- 11 Rajan VS, Thirumoorthy T. Treatment of cutaneous candidiasis: a double
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12 Barba-Rubio J, Calle-Velez G, Dominguez-Soto L, Londo~ no F. Compara-
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this is complicated by different clinical traditions and costs Res 1981; 9: 453–458.
between different countries. 13 Clayton YM, Gange RW, Macdonald DM, Carruthers JA. A clinical dou-
ble-blind trial of topical haloprogin and miconazole against superficial
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