Clinics in Dermatology (2017) 35, 173–178

Topical treatments for acne

Marita Kosmadaki, MD, PhD ⁎, Andreas Katsambas, MD, PhD
Andreas Sygros Hospital, 5, University of Athens, Greece, Ionos Dragoumi Street, Athens 11528, Greece

Abstract Topical drugs have been used successfully to treat acne for decades. This review discusses the use,
efficacy, and safety of options available via prescription. Topical antibiotics, dapsone, benzyl peroxide, aze-
laic acid, and topical retinoids are included. Topical antibiotics should not be used as monotherapy but rather
be combined with other agents to avoid resistant Propionibacterium acnes strains. Benzoyl peroxide is ef-
fective in preventing bacteria resistance. Topical retinoids address primarily the comedonal but also the in-
flammatory lesions of acne. Azelaic acid is useful in treating acne lesions and for lightening
postinflammatory hyperpigmentation that may accompany inflammatory acne lesions. Combinations of
agents that address different aspects of acne pathogenesis may offer higher benefit to acne patients.
© 2017 Elsevier Inc. All rights reserved.

Acne presents in different ages and in different severity.
Topical antiacne drugs include antimicrobials, benzoyl perox-
ide, azelaic acid, and retinoids. They are effective for mild to
moderate acne and may supplement the systemic treatment re-
quired in moderate to severe acne. Consensus guidelines rec-
ommend their use alone or in combination to target different
aspects of acne pathogenesis.1
Topical antibiotics
Topical antibiotics are used in acne due to their antibacterial
and antiinflammatory actions. They offer limited benefit for
the treatment of comedonal acne. The main antimicrobials
employed are erythromycin and clindamycin. Tetracycline is
less commonly used. Their antimicrobial effect is attributed
to inhibition of bacterial protein synthesis. Their antiinflam-
matory activity possibly relates to the inhibition of the chemo-
taxis of polymorphonuclear leucocytes.2
⁎ Corresponding author.
E-mail address: Kosmadaki@gmail.com (M. Kosmadaki).
Erythromycin at 2-4% and clindamycin at 1% are available
in various topical formulations. No significant differences in
efficacy are known between 2% and 4% erythromycin. Eryth-
romycin appears to be the most effective topical antibiotic on
inflammatory acne lesions in past decades (94% improvement
with erythromycin, 82% for clindamycin, and 70% for tetracy-
cline)3,4; however, its effectiveness appears to be decreasing in
more recent studies, probably due to the emergence to
antibiotic-resistant bacteria.5 As monotherapy, topical clinda-
mycin may be equally as effective as or superior to oral tetra-
cycline in treating inflammatory lesions.6–8 Twice-daily
application of 1% clindamycin is as effective as oral minocy-
cline 50 mg twice daily.9
Topical antibiotics have been a mainstay of acne treatment
for many decades, although antibiotic resistance of Propioni-
bacterium acnes was reported for the first time almost 40 years
ago.10 More than 50% of P acnes strains are reported to be re-
sistant, particularly to topical macrolides.11 Resistance appears
to emerge through either selection of preexisting resistant bac-
terial strains or through de novo acquisition of a resistant phe-
notype. There is a cross resistance between erythromycin and
clindamycin. Such resistant strains may appear about 2 weeks
after starting topical antibiotics, and after only 4 weeks of

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174
topical erythromycin use, the aerobic flora of the face is
dominated by erythromycin-resistant, coagulase-negative
staphylococci.12 By week 12, erythromycin-resistant Staphy-
lococcus epidermidis becomes the dominant species of staph-
ylococci. There is a possible link of P acnes resistance to poor
acne treatment outcomes with topical antibiotics.13
The issue of antibiotic resistance is broader because other
normal microbiome members are affected and changes in the
microbiome may increase the risk of colonization by patho-
genic organisms.14 Patients who have received topical antibi-
otics for acne are more often colonized by tetracycline-
resistant Streptococcus pyogenes in the oropharynx than acne
patients not treated with antibiotics.15 In addition, the risk of
an upper respiratory tract infection in individuals who use an-
tibiotics to treat acne is reported to be about two times higher
than in those not using antibiotics.16
The development of bacterial resistance is less likely in pa-
tients who are treated with a combination of benzoyl peroxide
and erythromycin or clindamycin.17 The European guidelines
for treatment of acne suggest that topical monotherapy with
antibiotics is not recommended.1
Combination of topical antibiotics with topical retinoids is
more efficient than when each drug is used alone.18 Topical ret-
inoids increase the penetration of antibiotics in the piloseba-
ceous, as well as the anticomedogenic and comedolytic
activity19; however, they do not offer protection against develop-
ment of resistant bacterial strains, as reported for the benzoyl per-
oxide and antibiotic combinations. Topical antibiotics are well
tolerated; rarely, they may cause allergic contact dermatitis.20
Azelaic acid
Azelaic acid (AzA) is a naturally occurring dicarboxylic ac-
id. It has antimicrobial, antiinflammatory, and comedolytic ac-
tion with a well-established role in acne treatment. The
antibacterial action affects different cutaneous microorgan-
isms, including P acnes and S epidermidis. Azelaic acid re-
duces the concentration of P acnes on the skin surface and
follicles. The exact mechanism remains unclear, but it may in-
terfere with the transmembrane pH gradient that mainly in-
hibits protein synthesis of the susceptible microorganism.21
The reduction of the intrafollicular P acnes population possi-
bly further produces a reduction of free fatty acids arising from
triglycerides due to the action of bacterial lipases.22
The antiinflammatory activity of azelaic acid has been re-
ported in several clinical studies, with diminution of inflam-
matory acne lesions being partially attributed to the findings
that azelaic acid, in vitro, is a scavenger of reactive oxygen
species and capable of inhibiting reactive oxygen species gen-
eration by neutrophils.23 Azelaic acid may also reduce the in-
flammatory response through inhibition of proinflammatory
cytokines and the induction of peroxisome proliferator-
activated receptor γ.24–26 Another study found that azelaic ac-
id promotes the downregulation of kallikrein 5 in epidermal
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M. Kosmadaki, A. Katsambas
keratinocytes, which subsequently downregulates cathelici-
dins and leads to a decreased inflammatory processes26; how-
ever, speculated antiinflammatory modes of action were
correlated to rosacea rather than to acne.
Azelaic acid further decreases the size and number of com-
edones by altering follicular hyperkeratosis. This is achieved
by interfering with the synthesis of proteins involved in final
keratinocytic differentiation.27,28 The effect of azelaic acid
on sebum production remains unclear, with patients reporting
a gradual reduction in skin greasiness29,30 and authors publish-
ing controversial data.22,28,31
Azelaic acid 20% cream is comparable to 5% benzoyl per-
oxide gel32 and 0.05% tretinoin cream33 at 6 months, with a
significant reduction of inflamed lesions at 1 month, whereas
2 months were necessary for comedodimunition.22 Similarly,
azelaic acid 15% gel is as effective as benzoyl peroxide
(BPO) 5% or clindamycin 1% at reducing superficial inflam-
matory acne lesions, at 4 months, with a twice-daily regi-
men.34 Azelaic acid 15% gel twice daily was found to be
comparable to once-daily adapalene 0.1% gel after 12 weeks
of treatment of women with acne.35
The efficacy of the azelaic acid 15% gel is comparable to
the combination of 5% benzoyl peroxide plus 1% clindamy-
cin, with a similar reduction of inflamed lesions at 4 months.36
A recent randomized, single-blind, parallel-group study re-
ported a greater efficacy of BPO 3% plus clindamycin 1% over
azelaic acid 20% cream at 4 weeks of treatment of mild to
moderate acne vulgaris,37 with the superiority of BPO 3% plus
clindamycin 1% sustained through week 12, suggesting that
azelaic acid may have a slower onset of action. The combina-
tion of a gel containing azelaic acid 5% and erythromycin 2%
was more effective than placebo, erythromycin 2% alone, or
azelaic acid 20% alone.38
No bacterial resistance has been associated with azelaic ac-
id treatment. A further benefit of its use as an antiacne drug is
that it reduces postinflammatory hyperpigmentation due to its
antityrosinase activity.
Side effects of azelaic acid include itching, burning, and
dysesthesia.33 Local reactions may be better tolerated with
gradual initiation of application (once-daily application) and
contemporaneous application of soothing creams. To our
knowledge, no cases of allergic contact dermatitis have been
reported. After topical application of the 15% or 20% formula-
tions, approximately 3-8% of the drug is absorbed systemical-
ly. Azelaic acid is neither toxic nor phototoxic, and it is not
known to interact with other drugs.
Benzoyl peroxide
BPO is a powerful nonspecific antimicrobial agent. Its lipo-
philic nature allows it to penetrate the stratum corneum and to
enter the pilosebaceous duct. It is rapidly degraded to benzoic
acid and hydrogen peroxide, generating oxidative free radicals
that result in bacteria death. It is also toxic to yeasts. Small
Topical treatments
concentrations of BPO can also harm neutrophils, inhibiting
their release of reactive oxygen species and thus possibly pre-
venting the release of proinflammation signals that have a role
in acne. Benzoyl peroxide has been reported to reduce the
P acnes population, including antibiotic-resistant strains, and
to limit development of new resistant strains when used with
antibiotics.34,35 No bacterial resistance to BPO has been re-
ported. BPO has a mild comedolytic activity but does not to
significantly affect sebum production. It is available in differ-
ent formulations and concentrations (2.5%, 5%, and 10%).
BPO is viewed as an effective topical treatment for acne.36
Its action on inflammatory lesions is reported to be similar to
topical antibiotics,37,38 but it is more effective on noninflamed
lesions. Benzyl peroxide and topical tretinoin similarly reduce
total acne lesions, but benzyl peroxide is probably superior to
tretinoin in reducing inflammatory lesions.39 BPO 4% gel is
also comparable to adapalene 0.1% gel in reducing both in-
flammatory and noninflammatory lesions at 11 weeks.40 A lat-
er study suggests a slight superiority of adapalene 0.1% gel to
BPO 2.5% gel once daily for 2 months.41
BPO is also available in combination with other acne treat-
ments with different mechanism of action, in an effort to in-
crease efficacy and to minimize bacteria resistance from
topical antibiotics.
A combination of BPO 5% and erythromycin 3%42 or clin-
damycin38,43 is more effective than either drug alone. Impor-
tantly, clindamycin 1%–benzyl peroxide 5% gel reduces
clindamycin- and erythromycin-resistant strains of P acnes.44
Gel formulations of clindamycin and lower concentrations of
BPO—2.5%,42,45 3%,46 3.75%47,48—are thought to be better
tolerated and effective in moderate to severe acne, but compar-
ison studies have not yet been published. The combination of
BPO 3% and clindamycin 1% once daily is more effective that
azelaic acid 20% twice daily after 12 weeks of treatment.49
Combinations of BPO and topical retinoids are also avail-
able. Adapalene 0.1%–BPO 2.5% gel is more effective than
either drug used alone and has a faster onset of action.50,51
Combination treatment with BPO and topical tretinoin is supe-
rior to monotherapy with either drug.17 This product combines
the two drugs in an optimized aqueous gel formulation that
protects tretinoin from fast peroxide-induced oxidation.52
Side effects include a formulation- and concentration-
dependent irritant dermatitis with redness, desquamation, and
a burning sensation. These usually subside after several days
of continued use.53 BPO can cause bleaching of hair, as well
as bedding, clothes, and towels, so that patients should be ad-
vised to use white fabric. Rarely, BPO can cause sensitization
and allergic dermatitis in acne patients, although the exact in-
cidence of allergic contact dermatitis remains unknown.20
Topical retinoids
Topical retinoids used for acne include tretinoin, adapalene,
tazarotene, and isotretinoin. They inhibit keratinocyte proliferation,
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175
improve differentiation, and, importantly, increase the follic-
ular epithelial turnover, suppressing the formation of micro-
comedones,54 the earliest precursor of the acne lesion. Topical
retinoids do not directly inhibit P acnes but rather create an in-
hospitable environment.55 Their action on sebum production
is very limited compared with systemic retinoids.
Tretinoin
Is the first retinoid used for acne and has been used broadly
for more than four decades. It is effective in comedonal and in-
flammatory mild to moderate acne,56 particularly when ap-
plied at night due to its photolability. Tretinoin is
commercially available in several strengths and formula-
tions.57 Recently, a short-contact regimen has also been re-
ported to diminish irritant dermatitis often observed with
tretinoin treatment.58
Isotretinoin
Is readily isomerized to tretinoin and vice versa. Used in a
concentration of 0.05%, it is considered to have similar effica-
cy to tretinoin 0.05% cream59,60 and probably slightly inferior
to adapalene 0.1% gel in reducing both inflammatory and non-
inflammatory lesions.61 A combination of isotretinoin 0.05%
and erythromycin 2% is superior to isotretinoin alone.62
Adapalene
Is a synthetic retinoid that has been developed for treatment
of acne vulgaris. Compared with tretinoin, it is less photolabile
and more lipophilic, which enables it to penetrate follicles
quickly. A meta-analysis of five well-controlled trials63 report-
ed similar efficacy of adapalene 0.1% and tretinoin 0.025% af-
ter 12 weeks of treatment; however, adapalene has a more
rapid onset of therapeutic action and produces less local skin
irritation. A combination of adapalene 0.1% and BPO 2.5%
is more effective than monotherapies.51,64 Similarly, a combi-
nation of adapalene 0.1% and clindamycin 1% is more effec-
tive than each of the drugs used alone.18 Adapalene in 0.3%
concentration is also available, well tolerated,65 and probably
comparable in efficacy to tretinoin 0.05%.66
Tazarotene
0.1% gel is effective in treating comedonal and inflamma-
tory lesions in mild to moderate acne and is probably superior
to tretinoin 0.025%67 and 0.05%,68 with a similar tolerability.
Tazarotene 0.1% is more effective than adapalene 0.1%69 and
176
0.3%,70 but it is also more irritating. A short-contact regimen
of tazarotene gel 0.1% is also effective.71 The combination
of tazarotene with clindamycin increases efficacy.72 Triple
combinations of tazarotene 0.1% gel with a clindamycin
1%–BPO 5% gel and erythromycin–benzoyl peroxide prepa-
rations72,73 have been reported to enhance efficacy versus
monotherapy. The combination of tazarotene and BPO 4%
does not result in a better therapeutic outcome.
All retinoids can be contact irritants, with alcohol-based gels
and solutions having the greatest irritancy potential. Patients
should be advised to avoid harsh soaps and other potentially ir-
ritating agents that traumatize the epidermis and to regularly
apply sunscreen. Alternate-day application (especially early in
therapy), reduction of retinoid concentration, and combinations
with less irritating agents should be suggested for several
weeks if skin irritation is problematic. Improved delivery sys-
tems have been developed to decrease irritancy, primarily
through controlled slow release. Rarely, all retinoids may cause
allergic contact dermatitis.20 All topical retinoids should be
avoided during pregnancy, with tazarotene carrying the stron-
gest warning (Food and Drug Administration Category X).
Topical dapsone
Dapsone is a sulfone classified as an antimicrobial due to its
inhibition of bacterial DNA synthesis and is also an effective
antiinflammatory agent. Dapsone 5% gel is approved at a
twice-daily application in the United States for the treatment
of acne. An almost 30% reduction of inflammatory lesions
count may be observed at 1 month74 and 50% at 3 months of
treatment.75 A dapsone 7.5% gel applied once daily is equally
effective,76,77 with a N50% reduction in inflammatory and
N40% reduction in noninflammatory lesions at 12 weeks. Top-
ical dapsone appears to benefit adult women more than adoles-
cent girls or men.78,79 It has been reported safe and effective
for long-term acne treatment74 or maintenance treatment after
systemic medication81; however, the effect of dapsone use on
bacterial resistance is unknown. No comparison studies to oth-
er topical agents have been published.
Topical dapsone may cause mild irritation and dryness. Ap-
plication of topical dapsone and BPO may result in an orange-
brown coloration of the skin due to dapsone oxidation. This is
easily washed off. Topical dapsone gel is pregnancy category
C and is approved for patients 12 years or older. Glucose-6-
phosphate dehydrogenase testing is not required before start-
ing topical application.
Conclusions
Dermatologists have different options for the topical treat-
ment of acne. BPO, topical retinoids, and azelaic acid may
be used alone or in combination. Topical antibiotics are not
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M. Kosmadaki, A. Katsambas
recommended as monotherapy but may be part of acne treat-
ment solely in combination with other agents to prevent further
propagation of resistant P acnes strains. The precise role of
topical dapsone remains to be determined, as we gain more ex-
perience with the agent, but it appears to be a good therapeutic
option, particularly for adult women with acne.
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