doi: 10.1111/1346-8138.

15113 Journal of Dermatology 2019; : 1–6

ORIGINAL ARTICLE
Topical 2% ketoconazole cream monotherapy significantly
improves adult female acne: A double-blind, randomized
placebo-controlled trial
Natcha CHOTTAWORNSAK,1,2 Yuda CHONGPISON,3 Pravit ASAWANONDA,1,2 Chanat
KUMTORNRUT1,2
1
Division of Dermatology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, 2The Thai Red Cross Society of
Thailand, King Chulalongkorn Memorial Hospital, 3Research Affairs, Center for Excellence in Biostatistics, Faculty of Medicine,
Chulalongkorn University, Bangkok, Thailand

ABSTRACT
The emergence of bacterial resistance is a global crisis. Prolonged use of antibiotics especially in acne is one
issue of concern among dermatologists. Ketoconazole (KTZ) cream, a topical antifungal with anti-inflammatory
and antiandrogenic actions, can decrease lipase activity of Cutibacterium acnes in vitro. We evaluated the effi-
cacy and safety of KTZ cream in mild adult female acne (AFA) by conducting a randomized, double-blind, pla-
cebo-controlled trial using KTZ 2% and placebo cream twice daily for 10 weeks. We assessed the improvement
of clinical severity, measured by AFA score graded by investigators and participants, and the change of acne
count. Forty-one participants enrolled in our study. The proportion of participants with acne improvement from
baseline (42.9% vs 9.5%, P = 0.015) and the success rate (45.0% vs 14.3%, P = 0.043) in the KTZ group were sig-
nificantly higher than that of the placebo group. The most common adverse events were dryness and itching. The
percentage change of acne count decreased significantly compared with baseline but did not differ statistically
between the two groups (P = 0.268). We concluded that the KTZ monotherapy showed a plausible effect in
improving AFA with excellent safety profile. It should be considered as a viable option for mild AFA treatment.

Key words: acne vulgaris, adult female acne, ketoconazole, post-adolescent acne, topical acne treatment.

INTRODUCTION Currently, treatment of AFA often includes adapalene with ben-

The increasing evidence of antibiotic resistance is a major con-
cern around the world.1 Dermatologists are among the physi-
cians most commonly prescribing antibiotics in the USA, and
acne vulgaris (AV) is the most common indication.2,3 As a
result, antibiotic stewardship has been strongly encouraged in
several guidelines during the last few years.4–7
Together with Cutibacterium acnes colonization, microbial
dysbiosis, particularly Malassezia spp., has been acknowl-
edged as an important factor in acne pathogenesis in AV.8,9
Studies showed that the number of Malassezia spp. is related
to AV, particularly the inflammatory type.8,9
The prevalence of adult female acne (AFA), which predomi-
nantly affects women older than 25 years, has recently
increased.10 The chronicity and recurrent nature of AFA con-
tribute to the increased risk of antibiotic resistance given the
long-term and continuous treatment often required.
zoyl peroxide,11 which is associated with skin irritation and does
not address the Malassesia dysbiosis. Ketoconazole (KTZ) cream,
one of the commonly used imidazole antifungal drugs, with anti-in-
flammatory effect12 and antiandrogenic activity,13 is an effective
treatment for Malassezia-related skin disorders such as seborrheic
dermatitis which is a frequent comorbidity with acne.14 Moreover,
the in vitro study showed that KTZ inhibited the growth of C. acnes
and worked against antibiotic-resistant isolates.15 This could result
from its antilipase activity.16
To demonstrate the efficacy and safety of KTZ on AFA, we con-
ducted a randomized placebo-controlled clinical trial among Thai
participants with mild AFA.
METHODS
This was a randomized, double-blind, placebo-controlled, par-
allel study conducted at a single tertiary-care center, King

Correspondence: Chanat Kumtornrut, M.D., M.Sc., Division of Dermatology, Department of Medicine, Faculty of Medicine, Chulalongkorn
University and King Chulalongkorn Memorial Hospital, The Thai Red Cross Society of Thailand, 1873, Rama IV Road, Patumwan, Bangkok
10330, Thailand. Email: chanat_1@yahoo.com
Received 2 August 2019; accepted 10 September 2019.

© 2019 Japanese Dermatological Association 1

N. Chottawornsak et al.
Chulalongkorn Memorial Hospital, Thailand, from August 2017
to December 2018. This study was performed in agreement
with the principles of the Declaration of Helsinki and approved
by the Institutional Review Board of the Faculty of Medicine,
Chulalongkorn University, Thailand (protocol no. 317/60). All
participants provided written informed consent before their
enrollment in the study. Additional informed consent was
obtained from a subject whose photographs are included in
this article. The clinical trials registration number is
NCT03178994. The Consolidated Standards of Reporting Trials
checklist was followed for this manuscript.
The sample size calculation was performed with at least
80% power and a significance level of 0.05 to detect the mean
difference in total acne count of 40 between the two groups,
adjusting for 15% loss to follow up. Eligible participants were
women aged above 25 years who had mild acne with an AFA
score of 2 on the face based on the Global Acne Severity
Scale.17 The exclusion criteria were: (i) 2-week use of topical
and/or 4-week use of systemic acne medication prior to the
study; (ii) other special types of acne or conditions presenting
with acne/acneiform eruptions (e.g. SAPHO syndrome); (iii)
irregular menstrual cycles or clinically suspected polycystic
ovarian syndrome; (iv) other facial rashes preventing the accu-
rate assessment; (v) known or suspected allergy to the ingredi-
ents; and (vi) pregnancy or lactation.
After enrollment, the participants entered a washout period
for 2 weeks to standardize the daily skincare routine and cos-
metic products used. The baseline assessment was per-
formed 14 days after the last menstrual period to decrease
hormonal variation. Randomized with a 1:1 allocation and ran-
dom block of four by Stata version 14 software (StataCorp,
College Station, TX, USA), participants were given either KTZ
2% (Nizoral Creamâ; Janssen Cilag, High Wycombe, UK) or
placebo from the in-house preparation which were packed in
identical tubes. The placebo contained cetyl alcohol, stearic
acid, glyceryl monostearate, propylene glycol, sodium lauryl
sulfate, propyl paraben and purified water. The participants
were instructed to apply the cream on their entire face twice
daily for 8 weeks. At the end of week 8, the participants dis-
continued using the cream while maintaining other routine
skincare and entered the post-treatment period for 2 weeks
more (a 10-week study period in total) to evaluate the lasting
KTZ effect. Throughout the study period, all participants were
required to use the provided cleansing gels with non-medi-
cated ingredients (i.e. water, cetyl alcohol, propylene glycol,
sodium lauryl sulfate and stearyl alcohol; in-house preparation)
and avoid changing to other skincare or cosmetic products.
The outcome assessments were at baseline and weeks 2, 4,
6, 8 and 10. In addition, well-trained research assistants were
responsible for explaining how to apply the medications at
every visit.
The primary outcome was the percent change of acne count
compared between baseline and the end of the study (week 8)
among groups. Two certified dermatologists performed the
acne counts of both inflammatory and non-inflammatory
lesions under an appropriate room light at every visit. We
chose the Adult Female Acne Scoring Tool (AFAST),18 which
2 © 2019 Japanese Dermatological Association
evaluates two separate areas, the face (AFAST-F) and sub-
mandibular area (AFAST-S), to measure the clinical acne sever-
ity. “Acne improvement” was defined as the proportion of
participants who had achieved at least 1 AFAST grade reduc-
tion from baseline and “success rate” of treatment as those
who achieved 0 (clear) and 1 (almost clear) AFAST scores at
the end of the treatment period (week 8) and post-treatment
period (week 10). Other secondary outcomes included the
Patient Global Assessment (PGA) score of acne severity and
quality of life, which were assessed by the validated Thai ver-
sion of the Dermatology Life Quality Index (DLQI) question-
naire, and the self-reported skin tolerability (burning sensation,
itching, scale, dryness and skin tightness).
All data were examined using mean and standard deviation
(SD) or counts and percentages for continuous and categorical
variables, respectively. The paired t-test was used to compare
the percent change of acne count and DLQI score between
baseline and the end of treatment (week 8). The independent-
sample t-test and v2-test were performed to compare the out-
comes between the groups. All statistical analyses were per-
formed with Stata version 14 software (StataCorp).
RESULTS
Demographic data and clinical characteristics
Forty-one females with mild AFA were enrolled and random-
ized. Thirty-nine participants (95.1%) completed the study pro-
tocol (Fig. 1) and had maintained good compliance throughout
the study period. Those two dropouts were in the placebo
group and occurred at weeks 4 and 6, respectively, due to the
change of workplace to other provinces.
Participants were aged between 25 and 49 years old, with a
mean age of 35.2 and 34.1 years in KTZ and placebo groups,
respectively. Approximately 93% of the participants had per-
sistent AFA. The total numbers of lesion counts or acne sever-
ity grading assessment at baseline and other factors related to
Figure 1. Subject disposition. ITT, intention to treat; KTZ,
ketoconazole; PP, per protocol.
 Ketoconazole cream for adult female acne

acne conditions, including frequency of acne flare-up, family Efficacy

history of first-degree relatives, cosmetic use, alcohol use and The mean acne counts at week 8 in the KTZ and placebo
smoking status, were similar between groups (Table 1). groups statistically significantly declined from baseline
(P < 0.001 and 0.002, respectively). In the KTZ group, the
mean inflammatory counts were 6.3 (baseline) and 7.0 (week
8), and the mean comedones were 23.3 (baseline) and 18.7
Table 1. Demographic, clinical characteristics and baseline (week 8). In the placebo group, the mean inflammatory counts
Dermatology Life Quality Index of participants with adult were 7.6 (baseline) and 9.7 (week 8), and the mean comedones
female acne (n = 41) were 21.3 (baseline) and 18.1 (week 8). However, the mean
percent change of acne counts did not demonstrate a signifi-
KTZ 2% Placebo
cant difference between groups (P = 0.268) (Fig. 2a). We
(n = 20) (n = 21)
observed that the efficacy of KTZ in acne count reduction
Mean age (SD), years 35.1 (6.4) 34.0 (6.4) including both inflammatory lesions and comedones was lar-
Mean age of onset (SD), years 15.3 (3.5) 16.9 (5.1) gest at week 6. Greater decrease in the number of comedonal
Mean duration (SD), years 19.8 (7.7) 17.1 (7.1)
lesions than inflammatory lesions was demonstrated along the
Past history
study (Fig. 2b,c). The acnes counts in both groups changed
History of AFA
FH of AFA, 1st degree, n (%) 9 (45.0) 8 (38.1) slightly during the post-treatment period with no statistically
Type of AFA significant changes detected.
Persistent acne, n (%) 20 (100.0) 18 (85.7) Interestingly, the proportion of participants in the KTZ group
Late-onset acne, n (%) 0 (0.0) 3 (14.3) showing a 1-grade reduction by AFAST-F compared with
Aggravating factors, n (%) baseline was significantly higher than in the placebo group
Menstruation 17 (85.0) 18 (85.7) (42.9% vs 9.5%, P = 0.015). There was also a three-times
Stress 7 (35.0) 6 (28.6) higher success rate, again defined as those who achieved
Sunlight 2 (10.0) 0 (0.0) AFAST-0/1 at week 8, in the KTZ group compared with pla-
Smoking 0 (0.0) 1(4.8)
cebo (45.0% vs 14.3%, P = 0.043) (Fig. 3). The representative
Cosmetics 7 (35.0) 9 (42.9)
photographs of acne improvement in a participant using KTZ
Sleep deprivation 2 (10.0) 2 (9.5)
Frequency of flaring per month, n (%) 2% at baseline and at week 8 are shown in Figure 4. However,
Once 12 (60.0) 10 (47.6) there was no difference between treatment and control groups
Twice 3 (15.0) 4 (19.0) in the AFAST-F scores in the post-treatment period (week 10)
Three times 1 (5.0) 2 (9.5) and in the AFAST-S scores at weeks 8 and 10 (Fig. 3).
All month 4 (20.0) 5 (23.8) Apart from investigator-based assessment, KTZ resulted in
Baseline characteristics a significantly higher proportion of participants with acne
Cosmetic use, n (%) improvement compared with placebo as evaluated by subjects
Foundation 10 (50.0) 7 (33.3) (PGA) (66.7% vs 28.6%, P = 0.008) (Fig. 3). This result was
Powder 18 (90.0) 18 (85.7)
similar to AFAST score. Although there were no significant dif-
Alcohol use, n (%) 1 (5.0) 3 (14.3)
ferences in the change of mean DLQI between baseline and
Smoking status, n (%) 0 (0.0) 0 (0.0)
Acne counts week 8 among KTZ 2% and placebo groups, the mean DLQI
Mean total lesions (SD) 29.9 (17.0) 28.9 (14.1) scores from both groups gradually decreased throughout the
Mean comedonal lesions (SD) 23.3 (15.0) 21.3 (11.8) study period.
Mean inflammatory lesions (SD) 6.3 (4.7) 7.6 (5.7)
Severity of facial acne (GEA Scale score) at baseline Safety and skin tolerability
Mean severity score (SD) 2.1 (0.5) 1.9 (0.5) No serious or major adverse effects were reported. There
Severity of facial acne (AFAST-F score) at baseline, n (%) were a few similar treatment-related side-effects in both
Almost clear 4 (20.0) 4 (19.0) groups. The common side-effects found in the KTZ group
Mild 14 (70.0) 17 (81.0)
were itching (25%) and dryness (15%) which spontaneously
Moderate 2 (10.0) 0 (0.0)
resolved without discontinuation of the treatment or additional
Mean severity score (SD) 1.9 (0.5) 1.8 (0.4)
Severity of submandibular acne (AFAST-S score) at baseline, medications.
n (%)
Clear 7 (35.0) 7 (33.3) DISCUSSION
Almost clear 11 (55.0) 11 (52.4)
Mild 2 (10.0) 3 (14.3) The present randomized controlled trial evaluated the efficacy
Mean severity score (SD) 0.7 (0.6) 0.8 (0.6) and safety of KTZ 2% cream in healthy women with mild AFA.
Mean of DLQI (SD) 6.7 (5.0) 8.6 (4.6) As a monotherapy, KTZ showed significant overall improve-
ment in clinical severity, with the maximal effect at week 6 after
AFA, adult female acne; AFAST-F, Adult Female Acne Scoring Tool from
initiation. This aligned with the efficacy of miconazole 2%
face; AFAST-S, Adult Female Acne Scoring Tool from submandibular
area; DLQI, Dermatology Life Quality Index; FH, family history; GEA Scale, which showed the highest accumulative effect on acne reduc-
Global Acne Severity Scale; KTZ, ketoconazole; SD, standard deviation. tion at the end of the study (day 45).19

© 2019 Japanese Dermatological Association 3

N. Chottawornsak et al.
Figure 2. Mean percentage change and standard error of mean (SEM) of lesion counts from baseline by visit. (a) Total lesions, (b)
comedones, (c) inflammatory lesions. KTZ, ketoconazole.
We chose AFAST as it is a novel objective tool for assess-
ment of clinical severity for AFA.18,20 Subjective evaluation by
participants also showed significant results. The positive
results from two different evaluators of clinical assessment
Figure 3. Percentage of participants with acne improvement
defined by AFAST-F, AFAST-S, PGA and treatment success at
the end of treatment (week 8). AFAST-F, Adult Female Acne
Scoring Tool from face; AFAST-S, Adult Female Acne Scoring
Tool from submandibular area; KTZ, ketoconazole; PGA,
Patient Global Assessment. *P < 0.05 from Chi-squared-test.
4 © 2019 Japanese Dermatological Association
implied the expected benefit of KTZ when being used in clini-
cal practise for AFA.
In our study, only a few participants reported treatment-re-
lated adverse effects which were transient and spontaneously
resolved without further management. This could be a crucial
benefit of KTZ when compared with available standard topical
treatments, such as topical retinoid and benzoyl peroxide, in
which skin irritation is extremely common and often leads to
discontinuation of treatment.
Together with antifungal properties and anti-inflammatory
effects, other possible mechanisms of KTZ in acne treatment
may be through its antilipase activity and antiandrogenic
effect. Lipase is one of the pivotal enzymes and virulence
factors of C. acnes to stimulate inflammation and follicular
hyperkeratosis.21 KTZ inhibits the lipase activity in both
antibiotic-susceptible and -resistant C. acnes,15,16 resulting in
a decreased free-fatty acid component in sebum and sup-
pression of comedo formation. We speculated that this may
be the explanation for the observed effect of KTZ on come-
dones and onset of action. Also, systemic KTZ can suppress
androgen production through inhibition of cytochrome P450-
dependent enzymes in the testes, ovaries and adrenal
glands.13 It is conceivable that topical KTZ may possess a
similar effect on the steroidogenesis function of the piloseba-
ceous units.22
 Ketoconazole cream for adult female acne

Figure 4. Acne improvement in a representative subject treated with KTZ 2% (a) at baseline and (b) the end of the treatment. Pho-
tographs taken by Visiaâ (Canfield Scientific, Parsippany, NJ, USA). KTZ, ketoconazole.

At the same time, KTZ could also affect lipase activity of
Malassezia spp.,16 which has a higher lipase activity than
C. acnes.23 Some authors believed that Malassezia spp. is
related to refractory acne and other concurrent inflamma-
tory facial dermatoses such as seborrheic dermatosis.
Because KTZ treatment markedly improved acne lesions24
and is one of the most effective treatments in seborrheic
dermatosis,25 one could propose an additional benefit of
treating two commonly found skin disorders by employing
this monotherapy.
Since the increase in antibiotic resistance became a major
public concern, many acne treatment guidelines have encour-
aged the stewardship of antibiotic use.4–7 Topical antibiotics
should be used in a limited setting and for a restricted dura-
tion. Thus, using KTZ with an effect on AV comparable with
topical clindamycin26 but causing no risk of antibiotic resis-
tance should be encouraged in the current practice.
There were limitations in our study. First, selecting mild
AFA, with few lesions presented at baseline, could limit the
power to detect the difference in acne counts. Second, our trial

© 2019 Japanese Dermatological Association 5

N. Chottawornsak et al.
had a shorter study period than other acne treatment studies.
Third, we would not be able to generalize our results to moder-
ate and severe AFA, adolescent acne or acne in male subjects.
We also excluded participants with clinically definite or sus-
pected underlying medical problems, mainly polycystic ovarian
syndrome. Future studies of topical KTZ or other antifungals
are required to confirm the promising efficacy including larger
sample size, longer follow-up period and more varied clinical
settings. At the same time, the mechanism of action of KTZ on
acne should particularly be explored.
Based on our study, we recommend the use of topical KTZ
in any healthy women with mild AFA, especially those con-
cerned with irritation from other topical anti-acne treatments.
We also support topical KTZ to be an additional treatment in
clinical practice guidelines for AFA. Furthermore, the combina-
tion of treatments may result in optimal acne management in
real-life practice.
In conclusion, given the significant efficacy and excellent
safety profile, our study revealed a potential role of KTZ
monotherapy as a viable acne treatment without concern of
antibiotic resistance. It should be considered as an alternative
therapy to the standard treatments for mild AFA patients.
ACKNOWLEDGMENTS: The study was supported by the
Division of Dermatology, Department of Medicine, Faculty of Medicine,
Chulalongkorn University, and was funded by the Ratchadapisek Som-
poch Endowment Fund (2017), Chulalongkorn University (grant
no. RA61/023) and the Dermatological Society of Thailand. The authors
would like to thank Ms Ruangrong Glinhom, Ms Porntenpin Champa-
phan and Mr Anukorn Sriaram for technical assistance, and Mrs Kan-
jana Yuttaviboon and Ms Kittima Leklad for secretarial support.
CONFLICT OF INTEREST: None declared.
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