DOI: 10.1111/jdv.

12989 JEADV

REVIEW ARTICLE

Topical acne treatments in Europe and the issue of

antimicrobial resistance
M.T. Leccia,1 N. Auffret,2 F. Poli,2 J.-P. Claudel,3 S. Corvec,4 B. Dreno5,*
1
Clinique de Dermatologie, Allergologie et Photobiologie, CHU A Michallon, Grenoble, France
2
Ho^pital Europeen Georges Pompidou, Paris, France
3
Private Practice, Tours, France
4
Institut de Biologie des Ho^pitaux de Nantes, Service de Bacteriologie-Hygie
ne, CHU de Nantes, Nantes, France
5
Clinique de Dermatologie, University Hospital, Nantes, France
*Correspondence: B. Dre no. E-mail: brigitte.dreno@wanadoo.fr

Abstract
Acne vulgaris (acne) is a chronic inflammatory disease of the sebaceous gland, characterized by follicular hyperkeratini-
zation, excessive colonization by Propionibacterium acnes (P. acnes) as well as immune reactions and inflammation.
Despite an armamentarium of topical treatments available including benzoyl peroxide, retinoids and azelaic acid, topical
antibiotics in monotherapies, especially erythromycin and clindamycin, are still used in Europe to treat acne. This inten-
sive use led to antimicrobial-resistant P. acnes and staphylococci strains becoming one of the main health issues world-
wide. This is an update on the current topical acne treatments available in Europe, their mechanism of action, their
potential to induce antimicrobial resistance and their clinical efficacy and safety.
Received: 13 November 2014; Accepted: 6 January 2015

Conflicts of interest
This Expert Board was organised by Galderma Laboratories, France. The authors have no financial interest to disclose
in any of the drug products cited in this work.

Funding sources
None.

Introduction
Acne vulgaris (acne) is a chronic inflammatory skin disease. Its
pathogenesis is complex, involving the sebaceous gland, follicu-
lar hyperkeratinization, excessive bacterial colonization, immune
reactions and inflammation.1,2 The anaerobic bacteria Propioni-
bacterium acnes (P. acnes) predominant in sebaceous sites pre-
senting 20–70% of the permanent resident group of the skin
microbiome plays a major role.3
Propionibacterium acnes activates the innate immunity by
stimulating Toll-Like Receptors (TLRs) and Protease-Activated
Receptors (PARs) on the follicle’s cells (mainly keratinocytes,
Langerhans cells), inducing the secretion of antimicrobial pep-
tides (AMPs) by these cells and sebocytes, resulting in a chronic
inflammation of the follicle.4
An update on the role of P. acnes in the pathogenesis of acne
was published in 2014.4 The present objective is to provide an
update on topical acne treatments available in Europe taking
into consideration the increasing problem of antimicrobial resis-
tance (AMR) of P. acnes.
Methods
PubMed data base was searched for topical acne treatments
using: antibiotic, erythromycin, dapsone, disulone, clindamycin,
nadifloxacin, antimicrobial peptides, azelaic acid, benzoyl perox-
ide, retinoids, adapalene, tretinoin, tazarotene, combined treat-
ment, peroxisome proliferator-activated receptors, alone or
combined with acne or P. acnes, antimicrobial resistance, innate
immunity and microbiome.
A total of 120 articles published between 1970 and June 2014
were reviewed, analysed and discussed; data from randomized
double-blinded clinical studies were considered for efficacy and
safety.
The review was completed with treatment recommendations
based on the guidelines from the American Academy of Derma-
tology and the European Dermatology Forum.5,6 Both are
derived from a treatment algorithm proposed by an interna-
tional expert board on acne.7,8 Recently, the same expert group
enforced these recommendations in the light of the increasing
worldwide resistance to antibiotics.9,10

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1486
Current topical treatments and their role in the
process of antimicrobial resistance
The involvement of P. acnes in acne remains controversial
because of its presence as normal flora on the human skin and its
incompletely understood pathogenic potential making its mana-
ging a challenge.11 Propionibacterium acnes is a main actor in the
pathophysiology of acne and a commensal bacteria of the pilose-
baceous follicle. The balance between its infectious and inflam-
matory role in acne remains controversial.
Four different classes of topical acne treatments are available
in Europe: antibiotics, benzoyl peroxide, which are both consid-
ered as antibacterials, 1st and 2nd generation retinoids and aze-
laic acid (AA). Fixed combination treatments combining two
classes of topical treatments have recently been introduced.
Topical antibacterials
They include macrolides, lincosamides, fluoroquinolones, disu-
lone and benzoyl peroxide (BPO).
Antibiotics
Macrolides such as erythromycin, and lincosamides such as clin-
damycin inhibit bacterial protein synthesis. Erythromycin is bac-
teriostatic, while clindamycin is bactericidal.12 Both act
primarily by stimulating the dissociation of peptidyl-tRNA from
ribosomes during translocation.12 Their anti-inflammatory
activity with the modulation of innate immunity is not well
established, mainly related to an inhibition of the chemotaxis of
polymorphonuclear leucocytes.13
The fluoroquinolone nadifloxacin interacts with two bacterial
targets, the related enzymes DNA gyrase and topoisomerase
IV.14 Its efficacy in inflammatory acne lesions may be attributed
to its inhibitory effect on pro-inflammatory cytokines such as
interleukin (ILL)-1a, ILL-6 and ILL-8.15
Disulone (4,4’-diaminodiphenylsulfone, dapsone) is an ani-
line derivative. In vitro, it acts on inflammatory effector cells,
cytokines and/or mediators such as cellular toxic oxygen metab-
olism, myeloperoxidase/halogenid system, adhesion molecules,
chemotaxis, membrane-associated phospholipids, prostaglan-
dins, leukotrienes, interleukin-8, tumour necrosis factor a, lym-
phocyte functions and tumour growth.16
Erythromycin at 2–4% and clindamycin at 1% are available in
various topical vehicles; nadifloxacin as a 1% cream and disu-
lone as a 5% gel.
Clinical data show that erythromycin reduced the inflamma-
tory lesion count by between 40–60%.17–19 Clindamycin applied
for 12 weeks provided similar results.20–25 Disulone 5% was
effective in mild-to-moderate acne reducing non-inflammatory,
inflammatory and total lesion count by 19, 58 and 49% respec-
tively, all were well tolerated.26–29
AMR of P. acnes was reported for the first time in the 70’s by
Leyden.30 Data collected between 1976 and 1997 estimated that
the global incidence rate of P. acnes’ resistance to antibiotics
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Leccia et al.
increased from 20% in 1978 to 62% in 1996.31 Resistance to
erythromycin was the most common.32 Prevalence of combined
resistance to clindamycin and erythromycin in 2003 was up to
91% in Spain and in France 75%; over the same period AMR to
erythromycin and clindamycin by pressure of selection on the
microbiome was described for the coagulase-negative staphylo-
cocci.33–36 AMR is related to the cutaneous microbiome and
not, as hypothesized, to the transfer of a resistant gene from
P. acnes to a staphylococcus or streptococcus; AMR of P. acnes
is chromosomal.
Antibiotics work by killing or inhibiting the growth of bacte-
ria.37 One or more of the bacterial targets may be able to neu-
tralize the topical antibiotic or to escape from its effect, while
elimination of sensitive strains induces a qualitative and quanti-
tative modification of the cutaneous microbiome.37,38 As a con-
sequence, the surviving bacteria are more likely to develop
AMR.34
Post-transcriptional methylation of an adenine residue of 23S
ribosomal RNA leads to co-resistance to macrolides, lincosa-
mides and streptogramins type B (the so-called MLSB pheno-
type).39 Resistance to fluoroquinolones occurs as a result of
mutational amino acid substitutions in the subunits of the more
sensitive (or primary-target) enzyme within the cell.14 AMR to
disulone has been observed for Mycobacterium leprae.
AMR of P. acnes can lead to dangerous and difficult-to-treat
bloodstream infections as well as deep infections.40–44
Benzoyl peroxide
BPO was introduced in 1934.45,46 It is available in various topical
preparations and is equally effective at concentrations of 2.5, 5.0
and 10%.47,48 It is lipophilic and capable of penetrating into the
pilosebaceous follicle. Within the skin, BPO releases free radical
oxygen and benzoic acid oxidizing bacterial proteins. Micromo-
lar drug concentrations of BPO inhibit the release of reactive
oxygen species but induce cytotoxicity in neutrophils.49
BPO has anti-inflammatory and comedolytic effects50–52 and
reduces the number of P. acnes strains on the skin surface and in
the follicle.53–55
Not much recent data about the clinical efficacy of BPO in
monotherapy are available. After 3 months of treatment, BPO
was similar to clindamycin in reducing the number of inflamma-
tory lesions and reduced the non-inflammatory lesion count by
30% compared to 9% with clindamycin.56 Similar results were
obtained when compared to erythromycin and adapalene.57,58
Side-effects comprise erythema, irritation and desquamation,
worsening with higher concentrations.47 Rare cases of hypersen-
sitivity have been reported.59,60
BPO does not induce AMR.55
Retinoids
Retinoids are classified into first and second generation. Topical
retinol, tretinoin (retinoic acid, retin-A) and isotretinoin belong
© 2015 European Academy of Dermatology and Venereology

Topical acne treatments
to the first generation, tazarotene and adapalene to the second
generation.
All target comedones and microcomedones, in addition sec-
ond generation retinoids exert anti-inflammatory activity on the
innate immunity.61,62
Tretinoin exerts an anti-inflammatory effect on monocytes
via two pathways, one specifically affecting TLR2/1 and CD14
expression and one independent of TLR expression.63 Through-
out the inhibition of TLR2/1, tretinoin modulates MMP and
TIMP expression, shifting from a matrix-degrading phenotype
to a matrix-preserving phenotype.64
Second generation retinoids such as adapalene bind to gamma
and beta retinoic acid nuclear and retinoid X receptors. They
exert their activities by interacting with RARs or RXRs on cells
and by activating genes that contain or RXRE in their promot-
ers. Moreover, they regulate gene expression by inhibiting the
activity of other transcription factors, such as AP-1.65
Adapalene is the only second generation retinoid available in
Europe. It modulates the epidermal immune system by increas-
ing the CD1d expression and by decreasing the ILL-10 expres-
sion by keratinocytes. It was hypothesized that these
modulations increase the interactions between dendritic cells
and T lymphocytes and strengthen the antimicrobial activity
against P. acnes. The associated decreased expression of TLR-2
by keratinocytes may contribute to the anti-inflammatory activ-
ity of adapalene.66,67
Tretinoin is available in different concentrations and for-
mulations. An initial response to tretinoin may be observed
within 2–3 weeks.68 Overall, application of tretinoin for
12 weeks resulted in a reduction in lesion count ranging
from 32% to 81% for non-inflammatory lesions and from
17% to 71% for inflammatory lesions.69 The use of topical
tretinoin is limited by cutaneous irritation, including ery-
thema, desquamation, burning and pruritus, especially in
patients with sensitive skin grade I, II. Novel formulations
tend to limit these side-effects.70–72
Adapalene
In Europe, adapalene is available in a 0.1% gel.
A meta-analysis showed that adapalene 0.1% gel and tretinoin
0.025% gel applied for 12 weeks were similar in efficacy with a
mean reduction in total lesions of 57% in patients receiving
adapalene and 53% in patients receiving tretinoin.
It is generally admitted that adapalene 0.1% gel is significantly
better tolerated than tretinoin formulations.73–77 Side-effects
reported include erythema, scaling, dryness, pruritus and burn-
ing. They are mostly mild (grade I OMS) in intensity.
Retinoids do not induce AMR. Some authors suggest that
topical retinoids may have the potential of indirectly reducing
the risk of antibiotic resistance by controlling and maintaining
remission of inflammatory and non-inflammatory lesions.78,79
This has not yet been demonstrated.
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1487
Azelaic acid
Azelaic acid is a dicarboxylic acid found naturally in wheat, rye
and barley.80 AA 15% gel is approved in several European coun-
tries to treat mild-to-moderate inflammatory acne.
It is suggested that AA inhibits the synthesis of cellular protein
in aerobic and anaerobic microorganisms, especially P. acnes
and S. epidermidis.81–83 Within aerobic microorganisms, AA
reversibly inhibits a variety of oxido-reductive enzymes includ-
ing tyrosinase, mitochondrial enzymes of the respiratory chain,
thioredoxin reductase, 5-a-reductase and DNA polymerases.84–
87
AA 15% gel was clinically tested over 4 months vs. BPO 5%
and clindamycin 1%, in two independent, randomized, blinded
comparative trials.88,89 AA 15% gel was as effective as BPO and
clindamycin with a median percentage reduction in the superfi-
cial inflammatory lesions of 70 and 71%, compared with a 77%
reduction with BPO 5% gel and a 63% reduction with clindamy-
cin respectively.
AA gel is well tolerated and side-effects (local burning and
irritation) were distinctly less than with BPO but more pro-
nounced than with clindamycin.90
AA does not induce bacterial resistance.91,92
Topical fixed combination treatments
In the past, combined use of antibacterials and retinoids was
tested with an increased treatment success compared to mon-
ades. More recently, fixed dose combination products have been
introduced providing similar efficacy and safety and an
improved treatment compliance. These fixed combinations have
a quicker onset of action and limit AMR.93
Four types of fixed combinations are available in Europe:
BPO and a topical antibiotic, topical antibiotic and a topical ret-
inoid, topical antibiotic and zinc and BPO and a topical reti-
noid.
BPO and topical antibiotics
Few data have been published about the combined use of BPO
and erythromycin. One study showed a reduction of more than
70% of inflammatory lesions after 3 months.57
Combining BPO and clindamycin reduced inflammation and
acne severity (on average 56%) to either product alone.56,94–96
The use of BPO-clindamycin resulted in an onset of action 2–
4 weeks after treatment was initiated.97,98
Due to the good local tolerance of topical antibiotics,
adverse events were limited to those generally reported for
BPO.95,99
Combinations of BPO and topical antibiotics reduce the
development of antibacterial resistance of P. acnes and of eryth-
romycin-resistant S. epidermidis.46,100,101 Furthermore, the con-
comitant use of BPO reduces the amount of erythromycin
required to inhibit propionibacteria strains by up to 50% com-
pared to erythromycin alone.102
© 2015 European Academy of Dermatology and Venereology
 14683083, 2015, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.12989 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [02/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1488 Leccia et al.

Topical antibiotics and zinc
Zinc has anti-inflammatory and bactericide properties against P. ac-
nes.103, modulates innate immunity and type I 5-areductase expres-
sion.104–108
An in vitro study showed that addition of zinc salts in the cul-
ture media of P. acnes reduces the resistance to erythromycin.103
This finding was not confirmed in vivo.97,109
One fixed combination of erythromycin 4% and zinc ace-
tate 0.8% in an alcoholic solution is available in Europe. No
recent clinical data have been published. After 12 weeks of
fixed combination of erythromycin and zinc acetate, after
12 weeks. Non-inflammatory lesions had improved by 58%,
inflammatory lesions by 73%.97 One topical gel formulation
containing clindamycin at 1% and zinc acetate is available

Table 1 Properties of molecules to treat acne available in Europe

Molecule(s) Bacteriostatic/bactericidal Induces Lesion type targeted Side-effects
mechanism AMR
Erythromycin Bactericidal Yes Inflammatory lesions Well tolerated
Stimulation of the dissociation of +++
peptidyl-tRNA from ribosomes
during translocation
Clindamycin Bacteriostatic at very high Yes Inflammatory lesions Well tolerated
concentrations +++
Stimulation of the dissociation of
peptidyl-tRNA from ribosomes
during translocation
Nadifloxacin Bactericidal Yes Inflammatory lesions Well tolerated
Interaction with DNA gyrase and ++
topoisomerase
Disulone Bactericidal Yes, but not Inflammatory lesions Well tolerated
Inhibition of the synthesis of reported for
dihydrofolic acid by competing P. acnes
with para-aminobenzoic acid for ++
the active site of dihydropteroate
synthase
Benzoyl Peroxide (BPO) Bactericidal No Inflammatory lesions Irritation, erythema and
Oxidization of bacterial proteins – desquamation
throughout radicals
Marginal inhibition of protein
kinase C
Tretinoin Not applicable No Inflammatory Erythema, desquamation,
– and non-inflammatory burning and pruritus
lesions, comedones
and microcomedos
Adapalene Not applicable No Inflammatory and Mostly mild erythema,
– non-inflammatory scaling, dryness, pruritus
lesions, comedones and burning
and microcomedos
Azelaic acid Bactericidal No Inflammatory lesions Well tolerated
Inhibition of cellular protein in –
aerobic and anaerobic
microorganisms
Erythromycin/BPO Bactericidal Yes Inflammatory lesions Mild irritation, erythema
++
Clindamycin/BPO Bactericidal/bacteriostatic Yes Inflammatory lesions Mild irritation, erythema
++
Eythromycin/Zinc Bactericidal Yes Inflammatory lesions Well tolerated
++
Tretinoin/Erythromycin Bactericidal Yes Inflammatory and Mild irritation, erythema
++ non-inflammatory
lesions, comedones
and microcomedos
Adapalene/BPO Bactericidal No Inflammatory and Mild irritation, erythema
– non-inflammatory
lesions, comedones
and microcomedos

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Topical acne treatments
Table 2 Three easy-to-follow recommendations to limit antimicro-
bial resistance of Propionibacterium acnes and other pathologic
strains
1. Overall, avoid the use of topical antibiotics in monotherapies
2. If the use of topical antibiotics is indicated, add Benzoyl Peroxide or
a topical retinoid
This is a rational choice because of the complementary modes of
action that have been shown clinically to result in
Increased speed of response
Greater clearing
Enhanced efficacy against comedones and inflammatory lesions
Better adherence
3. Never use topical antibiotics over a long period. Prefer topical
retinoids for maintenance therapy, with Benzoyl Peroxide added for an
antimicrobial effect, if needed
Adapted from Thiboutot et al. 20097.
in Europe. It was tested in one study with no superior effi-
cacy clindamycin.110
For both combinations, side-effects reported were minimal
and consisted predominantly of mild irritant dermatitis (grade
I).97,110,111
No data have been found about zinc inducing AMR in P. ac-
nes.
Topical retinoids and antibacterials
Topical retinoids may be combined with any topical antibacte-
rial. They have the advantage of targeting different acne triggers.
Two fixed topical gel combinations containing either tretinoin
0.025% and erythromycin 4% or adapalene 0.1% and BPO 2.5%
are available in Europe.
Clinical studies demonstrated that an association of a topical
antibacterial and a topical retinoid increased the clinical efficacy
compared to that of the monades.
Erythromycin and tretinoin
A gel containing tretinoin 0.025% and erythromycin 4% applied
for up to 14 weeks eliminated or improved non-inflammatory
lesions by more than 40%, inflammatory lesions were reduced
by 58% and pustules by 74%.112
The combination was well tolerated and caused only few or
no local side-effects.112,113
It is believed to reduce AMR of P. acnes to the erythromycin.
BPO and adapalene
One fixed combination of adapalene 0.1% and BPO 2.5% is
available in Europe.
Several randomized, double-blind studies showed a significant
improvement with the combination compared with monothera-
py and vehicle arms after 3 months of treatment: inflammatory
lesion count was reduced by 55%, and that of non-inflammatory
lesions by 52%.114–116
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1489
Long-term studies have shown that this combination is also
efficacious as maintenance therapy after topical or oral acne
treatments.117–119
Overall, local tolerability of the combination and adapalene
were almost similar. Mean symptom scores were mild or
less.114,120
Combinations of adapalene and BPO do not induce AMR of
P. acnes.
Table 1 summarizes the mechanisms of action, potential for
inducing AMR, target lesions and local side-effects of the differ-
ent molecules.
How treating topically acne?
Modifying current prescribing practice patterns to reduce AMR of
P. Acnes is inevitable until new molecules such as PPARs and
AMPs become available. To avoid the abuse of topical antibiotics,
BPO may be the most appropriate antibacterial to limit over-colo-
nization by P. acnes. Other molecules, including AA and retinoids
alone or associated with BPO, which target the majority of trig-
gering factors of acne, are available in Europe. Thus, three easy-
to-follow recommendations on the use of topical acne treatments
limiting the use of topical antibiotics are proposed in Table 2.
Acknowledgement
The authors acknowledge the writing support of Patrick G€
oritz,
SMWS-Scientific and Medical Writing Services, France.
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