New insights into the management of acne: An update from the Global Alliance to Improve Outcomes in Acne Group
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New insights into the management of acne:
An update from the Global Alliance to Improve
Outcomes in Acne Group
Authors and Guest Editors: Diane Thiboutot, MD,a and Harald Gollnick, MDb
Co-Authors and Steering Committee: Vincenzo Bettoli, MD,c Brigitte Dréno, MD, PhD,d Sewon Kang, MD,e
James J. Leyden, MD,f Alan R. Shalita, MD,g and Vicente Torres Lozada, MDh
Co-Authors and Global Alliance Members: Diane Berson, MD,i Andrew Finlay, MBBS, FRCP,j
Chee Leok Goh, MD, MRCP, FRCP, FAMS,k Marı́a Isabel Herane, MD,l Ana Kaminsky, MD, PhD,m
Raj Kubba, MD,n Alison Layton, MB, ChB, FRCP,o Yoshiki Miyachi, MD, PhD,p Montserrat Perez, MD,q
Jaime Piquero Martin, MD,r Marcia Ramos-e-Silva, MD, PhD,s Jo Ann See, MBBS, FACD,t Neil Shear, MD,
FRCPC,u and John Wolf, Jr, MD,v on behalf of the Global Alliance to Improve Outcomes in Acne
Hershey and Philadelphia, Pennsylvania; Magdeburg, Germany; Ferrara, Italy; Nantes, France;
Baltimore, Maryland; Brooklyn and New York, New York; Mexico City, Mexico;
Cardiff and Harrogate, United Kingdom; Singapore; Santiago, Chile; Buenos Aires, Argentina;
New Delhi, India; Kyoto, Japan; Barcelona, Spain; Caracas, Venezuela; Rio de Janeiro, Brazil;
Sydney, Australia; Toronto, Ontario, Canada; and Houston, Texas
The Global Alliance to Improve Outcomes in Acne published recommendations for the management of
acne as a supplement to the Journal of the American Academy of Dermatology in 2003. The recommen-
dations incorporated evidence-based strategies when possible and the collective clinical experience of the
group when evidence was lacking. This update reviews new information about acne pathophysiology and
treatmentesuch as lasers and light therapyeand relevant topics where published data were sparse in 2003
but are now available including combination therapy, revision of acne scarring, and maintenance therapy.
The update also includes a new way of looking at acne as a chronic disease, a discussion of the changing
role of antibiotics in acne management as a result of concerns about microbial resistance, and factors that
affect adherence to acne treatments. Summary statements and recommendations are provided throughout
the update along with an indication of the level of evidence that currently supports each finding. As in the
original supplement, the authors have based recommendations on published evidence as much as
possible. ( J Am Acad Dermatol 2009;60:S1-50.)
Key words: acne; acne scarring; adherence; antibiotic resistance; lasers; maintenance; pathophysiology;
retinoids.
From the Department of Dermatology, Pennsylvania State Univer- Supported by an educational grant from Galderma International.
sity College of Medicine, Hersheya; the Department of Derma- Disclosure: Dr Berson has served on advisory boards for
tology and Venereology, Medical Faculty, Otto-von-Guericke- Galderma, Kao, Stiefel, Dusa, Johnson & Johnson, and Ortho
University, Magdeburgb; Clinical Dermatologica at Arcispedale S. Neutrogena and received honoraria. Dr Bettoli has served as
Anna, University of Ferrarac; Hotel Dieu, Nantesd; Department of an investigator for Galderma, Intendis, Astellas, and La Roche
Dermatology, Johns Hopkins Medicine, Baltimoree; University of Posay and a speaker for Galderma, Intendis, Astellas, Stiefel,
Pennsylvania School of Medicine, Philadelphiaf; Department of and La Roche Posay and received grants in compensation. Dr
Dermatology State University of New York Downstate Medical Dréno has served on advisory boards for Galderma, La Roche
Center, Brooklyng; and Juarez Hospital, Mexico Cityh; the De- Posay, and Expansicone and has been a speaker for Pierre
partment of Dermatology, Weill Medical College, New Yorki; Fabre and an investigator for Biollevis and received honoraria.
Department of Dermatology, Cardiff University School of Med- Dr Finlay has served on advisory boards and as speaker for
icinej; National Skin Center, Singaporek; Department of Derma- Galderma and Pierre Fabre and on advisory boards for York
tology, University of Chilel; Department of Dermatology, School Pharma and has received grants or honoraria. Dr Goh has
of Medicine, University of Buenos Airesm; Delhi Dermatology served as a consultant to Galderma and received travel grants.
Group, New Delhin; Department of Dermatology, Harrogate Dr Gollnick has served as an investigator and speaker for
District Hospitalo; Department of Dermatology, Kyoto University Schering, Stiefel, and Galderma, and on advisory boards for
Graduate School of Medicinep; Hospital de San Pablo, Barcelo- Galderma; in addition, he has been a consultant to Basilea and
naq; Service of Dermatology, Institute of Biomedicine, Hospital IMTM and has received honoraria for these duties. Dr Herane
Vargas, Caracasr; Universidade Federal do Rio de Janeiros; Central has served as an investigator for Bioderma, Vichy, and Isden
Sydney Dermatologyt; Department of Dermatology, Sunnybrook and a speaker for Galderma and Stiefel and has received
and Women’s College Health Sciences Center, Torontou; Depart- honoraria and other financial benefits for this work. Dr Kang
ment of Dermatology, Baylor College of Medicine, Houston.v has served as an investigator and consultant for Galderma and an
S1
S2 Thiboutot et al J AM ACAD DERMATOL
MAY 2009
INTRODUCTION
Abbreviations used:
In 2003, a group of physicians and researchers in
the field of acne, known as the Global Alliance to ALA: aminolevulinic acid
AP-1: activator protein
Improve Outcomes in Acne, published recommen- BPO: benzoyl peroxide
dations for the management of acne.1 The goal was CO2: carbon dioxide
to make recommendations that were evidence based ECCA: échelle d’évaluation Clinique des
cicatrices d’acné
when possible and that included input from numer- ECOB: Elaboration d’un outil d’evaluation de
ous countries. Since the initial meeting of the Global l’observance des traitements
Alliance in 2001, the group has continued to meet medicamenteux
Er:YAG: erbium-doped yttrium-aluminum-garnet
regularly to discuss various aspects of acne manage- FDA: Food and Drug Administration
ment and create educational initiatives for dermatol- HLA-DR: Human leukocyte antigen-DR
ogists around the world. Regional groups in Europe, ICAM: intercellular adhesion molecule
ICG: indocyanine green
Asia, and Latin America have been established. IL: interleukin
Global Alliance members have actively worked IPL: intense pulsed light
with national dermatology societies to formulate MAL: methyl aminolevulinate
MMP: matrix metalloproteinase
guidelines for management of acne that take into PDL: pulsed dye laser
account the individual characteristics of the country PDT: photodynamic therapy
while harmonizing with the international recom- RF: radiofrequency
TCA: trichloroacetic acid
mendations. In addition, the Global Alliance pre- TLR: toll-like receptor
sented a written consensus opinion to the US Food VCAM: vascular cell adhesion molecule
and Drug Administration (FDA) Guidance for
investigator for Stiefel and has received honoraria or grant and speaker for Galderma and Medicis, an advisory board
support. Dr Kubba has served as a consultant to Galderma and member and consultant for QLT, and a speaker for Stiefel and
Schering-Plough and in another capacity for Ranbaxy and Dermik; he has received grants and honoraria and has stock in
Janssen-Cilag and has received grants and honoraria. Dr Layton Medicis. Drs Kaminsky and Perez have no conflicts of interest
has served as an advisor, speaker, and investigator for to declare.
Galderma and received grants and travel grants and has also Preparation of the manuscript was a joint effort as follows. The
been an investigator for Roche, receiving grants. Dr Leyden has manuscript outline, content development and selection of
served as a consultant and on advisory boards for Allergan, references, review of the data, and generation of the first draft
Galderma, Obagi, SkinMedica, Medicis, and Stiefel and received were done in sections, with responsibilities as follows. ‘‘Rec-
grants and honoraria. Dr Miyachi has served on advisory boards ognizing the chronicity of acne’’ section: Drs Shear, Finlay, and
for Galderma, Otsuka, and Sanofi-Aventis and has received Gollnick, and Ms Sanders. ‘‘Update: Pathogenesis of acne’’
grants and honoraria. Dr Piquero Martin has served as a speaker section: Drs Thiboutot, Kang, and Gollnick, and Ms Sanders.
for Galderma and received benefits. Dr Ramos-e-Silva has ‘‘Update: Treatment of acne’’ was further subdivided into the
served on advisory boards for Galderma, Johnson, Stiefel, following sections. ‘‘The changing role of antibiotics in manag-
Novartis, La Roche Posay, and Roche; she has been an inves- ing acne’’ section: Drs Layton, Bettoli, Miyachi, Dréno, Perez, and
tigator for Galderma, Johnson, Stiefel, Novartis, La Roche Posay, Leyden, and Ms Sanders. ‘‘Retinoid-based combination therapy
Biolab, Aventis, and Pfizer, and has been a speaker for for acne’’ section: Drs Thiboutot, Kaminsky, Gollnick, Miyachi,
Galderma, Johnson, Stiefel, Novartis, LaRoche Posay, Vichy, Wolf, Herane, and Piquero Martin, and Ms Sanders. ‘‘Does
and Roche and has received honoraria or grant support. Dr See enough evidence now exist for using lasers and lights to treat
has received honoraria as a speaker for Galderma and L’Oreal. inflammatory acne?’’ section: Drs Leyden, Berson, Kang, See,
Dr Shalita has served as a consultant to Galderma, Stiefel, Shalita, Torres Lozada, and Gollnick, and Ms Sanders. ‘‘The role of
Allergan (including consultancies to companies acquired by topical retinoids in acne maintenance therapy’’ section: Drs
these companies), Baxbier, Quinoa, and Ortho and has been an Gollnick, Bettoli, Thiboutot, and Leyden, and Ms Sanders. ‘‘Man-
investigator for Galderma, Stiefel, and Allergan and has agement of acne scarring’’ section: Drs Dréno, Goh, Kubba,
received grants and honoraria; he has stock options in Medicis. Ramos-e-Silva, and Bettoli, and Ms Sanders. ‘‘Optimizing adher-
Dr Shear has served on advisory boards for Galderma, and as a ence with acne therapy’’ section: Drs Thiboutot, Dréno, Layton,
consultant and other for Galderma and has received honoraria Herane, and Dr Perez, and Ms Sanders. Ms Valerie Sanders is a
and residency or fellowship program funding; Dr Shear has medical writing consultant to Galderma International. Changes
also served as a consultant and other for Dermik and received to the first draft and subsequent drafts were generated by each
honoraria and residency or fellowship program funding. of the authors. All authors reviewed the complete final draft
Dr Thiboutot has been an investigator, consultant, or advisory including all sections.
board member for Allergan, Inc, Arcutis, Inc, Dusa, Inc, Reprint requests: Diane Thiboutot, MD, Department of Dermatol-
Galderma, Inc, Stiefel, Inc, QLT, Inc, and Medicis, Inc and has ogy, The Pennsylvania State University College of Medicine,
received honoraria or grant support. Dr Torres Lozada Hershey, PA. E-mail: dthiboutot@psu.edu.
has been a consultant and investigator for Galderma and has 0190-9622/$36.00
received honoraria. Dr Wolf has been an investigator for ª 2009 by the American Academy of Dermatology, Inc.
Galderma and Medicis, an advisory board member, consultant, doi:10.1016/j.jaad.2009.01.019
J AM ACAD DERMATOL Thiboutot et al S3
VOLUME 60, NUMBER 5
Industry on Acne Vulgaris (Docket No. 2005D-0340) hormones in female patients. Assessment of popu-
regarding development of drugs for acne and design lation differences would be an interesting topic for
of clinical trials in this arena. A subgroup of future studies.
European members of the alliance formulated a In the case of acne, monotherapy is used relatively
response to recent changes in the European Union rarely despite that regulatory bodies require mono-
regulations for use of oral isotretinoin. As new issues therapy studies for drug approval. Because acne is a
come up, the alliance will continue to advocate for multifactorial disease, multiple classes of drugs are
clinicians who treat patients with acne and the typically used in the clinical setting. Indeed, combi-
patients’ rights to optimal treatment. Finally, the nation therapy is now recommended as the first-line
Global Alliance has established a World Wide Web approach for acne.1 In this publication, the Global
site (www.acneglobalalliance.org), which provides Alliance group considered the type and severity of
information about the management of acne and acne in making recommendations. The Global
recent developments in the field. Alliance plans to publish additional articles on the
The first publication in 2003 encompassed current topics of hormonal/antiandrogenic therapy and the
information about acne pathophysiology and current use of oral isotretinoin.
comprehensive treatment recommendations. This The following definitions were used to evaluate
edition includes updates on pathophysiology and the strength of the evidence for recommendations in
treatment, including our research into treatments the supplement:
that have recently emergedesuch as lasers and light
therapyeand areas where published data were d I—Strong evidence from systematic review of mul-
sparse in 2003 but are now available, including tiple well-designed, randomized, controlled trials;
combination therapy, revision of acne scarring, and d II—Strong evidence from at least one properly
maintenance therapy. In addition to an updated designed, randomized, controlled study of appro-
discussion of acne pathophysiology and treatment, priate size;
we share in this supplement a new way of looking at d III—Evidence from well-designed trials without
acne as a chronic disease, a discussion of the randomization, single group pre/post, cohort,
changing role of antibiotics in acne management, time series, or matched case-controlled studies;
and factors that affect adherence to acne treatments. d IV—Evidence from well-designed nonexperimen-
As in the original supplement, we have tried to base tal studies from more than one center or research
recommendations on published evidence as much as group;
possible. However, it should be noted that some d V—Opinions of respected authorities, based on
recommendations are based primarily on our expert clinical evidence, descriptive studies, or reports of
opinion (level V evidence) because of a lack of expert committees.
studies and different designs and methodologies of
existing studies. We have strived to clearly acknowl-
edge in text which recommendations are based RECOGNIZING THE CHRONICITY OF
primarily on opinion, citing them as supported by ACNE
Level V evidence. Editor’s note: This section summarizes ideas that
In addition, a number of the clinical trials included were presented in full in a recent article in the
in our evaluations of data were performed as regis- American Journal of Clinical Dermatology.2
tration trials for regulatory approval. We acknowl- It is important for dermatologists to take the lead
edge that a particular type of patient is selected for in educating other clinicians that acne is often a
study and results may not be generalizable to all chronic disease and not just a self-limiting disorder of
patients; regulatory bodies typically address this in teenagers. For many patients, acne has the following
the package insert. In acne, the registration trial study characteristics that have been used to define chro-
inclusion and exclusion criteria often exclude pa- nicity3,4: a prolonged course, a pattern of recurrence
tients with cystic acne ([2 nodules or cysts), truncal or relapse, manifestation as acute outbreaks or slow
acne is often not evaluated, and minimum and onset, and a psychologic and social impact that
maximum numbers of inflammatory and noninflam- affects the individual’s quality of life. In considering
matory lesions at baseline are specified to give an whether acne is a chronic disease, it is interesting to
objective measure of acne severity. To our knowl- compare it with atopic dermatitis (Table I). The
edge, there are no data suggesting that acne in similarities between the conditions are striking and
various population subgroupseadolescent, adult, range from underlying pathology (inflammation) to
male, femaleeis different in terms of pathophysiol- characteristic manifestation (frequently relapsing
ogy with the exception of a greater effect of and recurrent diseases).
S4 Thiboutot et al J AM ACAD DERMATOL
MAY 2009
Table I. Comparison of chronicity in acne and
CONSENSUS: Acne Should Be Approached atopic dermatitis
as a Chronic Disease
Acne Atopic dermatitis
Level of Evidence: V Basic character Inflammatory Inflammatory
Characteristics of acne that define chronic diseases: Duration [3 mos / [3 mo / 5-40
5-30 years years
d Pattern of recurrence or relapse Genetic Yes, particularly in Yes, thought to
d Prolonged course influence long-term be polygenic
d Manifestation as acute outbreaks or slow onset courses;
d Psychological and social impact thought
to be polygenic
Acne warrants early and aggressive treatment
Age at onset, y ;10 ;1
Maintenance therapy is often needed for optimal
Self-limiting? In ;80% of cases In ;80% of cases
outcomes
by third decade by second
of life decade of life
Counseling? Intervals/years Intervals/years
Medication Continuously/ Continuously/
Why is this important? Because many of our intervals intervals
medical colleagues and a significant proportion of Social impact Yes Yes
the lay public dismiss acne as a natural part of Psychologic Yes Yes
growing up that has few real consequences. Yet impact
considerable evidence shows that acne can be a Postdisease Yes
psychologically damaging condition that lasts sequelae
years.5-11 The members of the Global Alliance believe Physical scarring Yes Yes
that acneeone of the most common skin diseases Psychologic Yes
treated in routine dermatologic careeshould be rec-
Reprinted from Gollnick et al2 with permission from Wolters
ognized and investigated as a chronic disease with Kluwer Health.
psychologic sequelae that do not always correlate
with the clinician’s assessment of severity at one point scars.7,9,10 Physical scars, persistent hyperpigmentation,
in time.5 or both are not uncommon sequelae of acne and are
There are no definitive longitudinal studies of the usually expensive and difficult to treat effectively. The
natural history of acne; however, in the group’s effects of acne can persist for many years, even among
experience approximately 60% of acne cases are individuals who had self-limited adolescent acne.
self-limiting and can be managed with acute treat- Unfortunately, the reason why acne becomes
ment followed by topical maintenance therapy. In chronic in some patients is not well understood
other cases, acne is a disease that requires treatment and it is currently difficult to determine which
for a prolonged period. Oral isotretinoinethe most patients will have a chronic course of the disease.
effective acne treatment developed to dateeis ad- Factors that have been linked to a chronic course
ministered during a 20-week period and sometimes include stress-related production of adrenal andro-
must be given in repeated courses.5 Further, as gens,19 Propionibacterium acnes colonization,20 fa-
reviewed later in this supplement, recent well-con- milial background,7 and specific subtypes of acne
trolled studies have shown that maintenance therapy (conglobata, keloidal, inversa, androgenic, scalp
is an effective strategy to minimize the risk of folliculitis, and chloracne).21,22 The members of the
relapse.12-14 In addition, the members of the Global Global Alliance advocate further study to determine
Alliance believe that limiting the duration of active the link between these and other characteristics and
acne by effective treatment may, in turn, reduce the the development of chronic acne.
likelihood of physical and emotional scarring. For In summary, dermatologists are aware that acne is
these reasons, we encourage early and aggressive a chronic disease with important ramifications. We
treatment of acne. are charged in our role as skin experts with the
How often do negative outcomes occur after acne? mission of helping other health care professionals
That question is difficult to answer definitively. and patients to achieve a better understanding of
However, there is good evidence that acne can persist acne and improve awareness of the highly effective
into adult years in as many as 50% of individuals.7,15-18 treatments that are available. We must also be
Negative psychologic outcomes, including anxiety, vigilant in ensuring that insurers and government
depression, and social withdrawal, have all been regulatory bodies are aware of the impact and
reported among individuals with acne and acne import of acne. Because the physical and emotional
J AM ACAD DERMATOL Thiboutot et al S5
VOLUME 60, NUMBER 5
sequelae associated with acne can last for many study by Jugeau et al27 demonstrated that these
years, insurers need to be encouraged to provide events occur in inflammatory lesions of patients
reimbursement for acute and maintenance acne with facial acne and confirmed the earlier observa-
treatments that have been proven effective in clin- tions of Kim et al25 in acne lesions. This provided
ical trials. additional evidence that inflammatory cytokines,
working via autocrine and paracrine mechanisms
UPDATE: PATHOGENESIS OF ACNE through their respective receptors, amplify the sig-
More detailed information regarding the molecu- naling pathways that activate the activator protein
lar events contributing to the pathogenesis of acne (AP)-1 transcription factor.28 Activation of AP-1 in-
has emerged since 2003. There are 4 primary path- duces MMP genes, whose products degrade and alter
ogenic factors, which interact in complex manner to the dermal matrix.28 Retinoids are known to inhibit
produce acne lesions: (1) sebum production by the AP-1.29 Very recent studies indicate that retinoids can
sebaceous gland; (2) P acnes follicular colonization; induce monocytes to develop into CD2091 macro-
(3) alteration in the keratinization process; and (4) phages that phagocytose P acnes bacteria.30 These
release of inflammatory mediators into the skin. data further substantiate how such currently avail-
Now, cellular culture studies have provided more able treatments as topical retinoids can have anti-
information about the role of sebaceous lipids and inflammatory activity against acne. In addition, they
inflammatory mediators including MMPs. may help to explain why acne can flare after initia-
Jeremy et al23 investigated the initiating events for tion of therapy; for example, disruption of sebocytes
acne lesions, and found that immune changes and may result in release of proinflammatory molecules,
inflammatory responses occur before hyperprolifer- leading to the clinical result of increased inflamma-
ation of keratinocytes, with a pattern similar to a tion in some patients.
type IV delayed hypersensitivity response. The More has been learned about the role of sebor-
immune response is led by CD41 lymphocytes and rhea in acne as well. Sebaceous lipids are at least
macrophages.23 These researchers hypothesize that partly regulated by peroxisome proliferator-acti-
the subsequent production of cytokines activates vated receptors and sterol response element binding
local endothelial cells, up-regulating inflammatory proteins.31,32 Peroxisome proliferator-activated re-
vascular markers (E-selectin, vascular cell adhesion ceptor nuclear receptors act in concert with retinoid
molecule-1 [VCAM-1], intercellular adhesion X receptors to regulate epidermal growth and differ-
molecule-1 [ICAM-1], and human leukocyte anti- entiation and lipid metabolism.31 Sterol response
gen-DR [HLA-DR]) in the vasculature around the element binding proteins mediate the increase in
pilosebaceous follicle.23 They further have postu- sebaceous lipid formation induced by insulin-like
lated that the entire process is initiated by interleukin growth factor-1.32
(IL)-1a up-regulation in response to a relative linoleic In parallel, research into the functions of the
acid deficiency caused by excess sebum and pertur- sebaceous gland has yielded exciting information
bation of barrier function within the follicle.23 about the central role these glands play in regulation
More than a decade ago, an in vitro study by of skin functions.33 The sebaceous gland regulates
Vowels et al24 demonstrated the presence of a independent endocrine functions of the skin and has
soluble factor of P acnes that induced proinflamma- a significant role in hormonally induced aging of
tory cytokine production in human monocytic cell skin.34,35 In addition, the sebaceous gland has both
lines. Although distinct from lipopolysaccharide, this direct and indirect antibacterial activities. Sapienic
soluble factor had similar characteristics, in that its acid, a lipid in sebum, has innate antimicrobial
activity was dependent on the presence of CD14, a activity and is up-regulated by activation of TLR-2
so-called pattern recognition receptor for lipopoly- by skin bacteria.36,37 Further, the sebaceous gland
saccharide and other lipid-containing ligands. This P has ubiquitous expression of antibacterial peptides
acnes product induced the synthesis of tumor ne- and proinflammatory cytokines/chemokines; these
crosis factor-a and IL-1b in the cell lines. Later substances are induced in sebocytes by the pres-
research showed that the cytokine induction by P ence of bacteria.38 The sebaceous gland acts as an
acnes was occurring through TLR-2.25 TLR, a mam- independent endocrine organ in response to
malian homologue of a drosophila protein known as changes in androgens and hormones, and is the
toll, has emerged as a key regulator of host responses control center for a complex regulatory neuropep-
to infection.26 This transmembrane protein has a tide program that acts like the hypothalamus-pitu-
cytoplasmic portion that is homologous to the IL- itary-adrenal axis.33 This aspect of sebaceous gland
1 receptor and thus could trigger a signaling cascade function is primarily influenced by corticotrophin-
that activates nuclear factor-kB. A recent in vivo releasing hormone, its binding protein, and
S6 Thiboutot et al J AM ACAD DERMATOL
MAY 2009
What Is New in Acne Pathophysiology
d Inflammatory events have been found to precede hyperkeratinization
d P acnes contributes to inflammation via activation of toll-like receptor (TLR) on the membranes of inflammatory cells
d Peroxisome proliferator-activated receptors partly regulate sebum production
d The sebaceous gland is a neuroendocrine-inflammatory organ that likely coordinates and executes a local response
to stress and normal functions
d Androgens have influence on follicular corneocytes
d Oxidized lipids in sebum can stimulate production of inflammatory mediators
d Matrix metalloproteinases (MMPs) occur in sebum and diminish with treatment-related resolution of acne lesions
corticotrophin receptors.39-41 corticotrophin-releas- have a prominent role in both inflammatory matrix
ing hormone levels change in response to stress, remodeling and proliferative skin disorders. Sebum
and its role in regulating sebaceous gland function includes several MMPs, which are thought to origi-
is likely a link in the brain-skin connection that is nate in keratinocytes and sebocytes. In addition, oral
thought to explain the relationship between stress isotretinoin can reduce concentrations of MMPs in
and skin disorders with an inflammatory component sebum in parallel with clinical improvement.51
such as acne. Similarly, substance P,42 a-melanocyte- The improved understanding of acne develop-
stimulating hormone,43,44 and corticotrophin- ment on a molecular level suggests that acne is a
releasing hormone-receptor-145 are involved in disease that involves the innate and adaptive im-
regulating sebocyte activity. In addition, an active mune system and inflammatory events. Treatment
role of receptors for highly conserved ectopeptidases that targets both immune system activation and
such as dipeptidylpeptidase IV and aminopeptidase inflammatory pathways is, therefore, desirable. A
N in regulation of sebocytes has been reported.46 full discussion of how antiacne agents work at the
The response of skin to stress is a subject of active molecular level is beyond the scope of this text;
investigation and may soon suggest new targets for however, research indicates that many of the agents
therapeutic interventions. currently used to treat acne have effects on cellular
An additional area of interest that has recently receptors, inflammatory mediators, and other mo-
emerged is the action of vitamin D in the skin. lecular targets. As more becomes known, new targets
Sebocytes are capable of metabolizing and synthe- for treatment may also be identified.
sizing the primary vitamin D metabolite 1,25-dihy-
droxyvitamin D3.47 Several lines of evidence suggest UPDATE: TREATMENT OF ACNE
that the vitamin D endocrine system is involved in Several aspects of acne management have been
regulating sebocyte function and physiology, includ- evolving since the 2003 Global Alliance recommen-
ing production of sebum. Further, vitamin D ana- dations.1 These include the role of antibiotics in
logues may potentially be useful in normalizing treatment, use of lasers and light-based therapies,
sebaceous gland physiology in patients with acne.33 issues regarding maintenance therapy, and treat-
Using a human keratinocyte cell line, Ottaviani ment of acne scars. There is increased evidence
et al48 showed that peroxidation of sebum lipids can supporting the recommendation of a combination
activate inflammatory mediators, including IL-6 and of a topical retinoid plus an antimicrobial agent as
lipoxygenases. Oxidized squalene can also stimulate first-line therapy for most patients with acne as a
hyperproliferative behavior of keratinocytes, suggest- means of targeting multiple pathogenic features and
ing that this lipid may be partly responsible for both inflammatory and noninflammatory acne le-
comedo formation.48 Zouboulis et al49,50 have hypoth- sions. Studies published since 2003 support the
esized that lipoperoxides exert a proinflammatory recommendations outlined in the original algorithm,
effect on the pilosebaceous duct. Lipoperoxides pro- which has undergone minor modification to reflect
duce leukotriene B4, which is a powerful chemo- the addition of new combination products for acne
attractant that can recruit both neutrophils and (Fig 1).
macrophages, and stimulate production of proinflam-
matory cytokines.23,49,51 The changing role of antibiotics in
Papakonstantinou et al52 investigated the role of managing acne
MMPs in acne. These enzymes, which include colla- Antibiotic resistance is a significant public health
genases, gelatinases, stromelysins, and matrilysins, concern in virtually all parts of the world,58 and the
J AM ACAD DERMATOL Thiboutot et al S7
VOLUME 60, NUMBER 5
CONSENSUS: Strategies to Limit Antibiotic Resistance Are Important in Acne Management
Level of Evidence: V
d Treatment regimens that limit, or even reduce, the incidence of bacterial antibiotic resistance are recommended
o Selection pressure can affect other, more pathogenic bacteria in addition to P acnes53,54
o High rates of resistance have been correlated with high outpatient use of antibiotics55
d Use of oral antibiotics can lead to resistance in commensal flora at all body sites; topical antibiotics lead to
resistance largely confined to skin of treated site56
o Oral antibiotics are recommended for moderate to moderately severe acne1
o Topical antibiotics may be used in mild to moderate acne as long as they are combined with benzoyl peroxide
(BPO) and a topical retinoid1
o Limit the duration of antibiotic use1,57 and assess response to antibiotics and continuing need at 6 to 12 weeks
o Some countries have regulatory guidance limiting the duration of use of topical antibiotics (alone and in fixed-
dose combination products) to 11 to 12 weeks
d Use BPO concomitantly as a leave-on or as a wash
o BPO for 5 to 7 days between antibiotic courses may reduce resistant organisms on the skin; however, BPO does
not fully eradicate potential for resistant organisms
d Avoid using antibiotics (either oral or topical) as monotherapy either for acute treatment or maintenance therapy
d Avoid the simultaneous use of oral and topical antibiotics without BPO, particularly if chemically different
Fig 1. Acne treatment algorithm. BPO, benzoyl peroxide. Reprinted from Gollnick et al1 with
permission from the American Academy of Dermatology.
Global Alliance members believe it is appropriate to emphasize the need to limit antibiotic use, both
comment on the role of antibiotic resistance in acne frequency and duration, and to add the nonantibiotic
management. Resistance arises from selective pres- antimicrobial agent BPO when long-term antibiotic
sure on bacteria, and can result from both appropriate use is necessary because BPO is a highly efficient
and inappropriate uses of antibiotics.59 Antibiotics bactericidal agent and will minimize the development
were the first effective treatment for acne; although of resistance at sites of application.57,58,60,61
we acknowledge these agents have an important role Antibiotic resistance in this setting can encompass
in acne management, the Global Alliance members both the effect of antibiotic use on P acnes and
agree with recent guidelines and publications that outcomes of acne and the impact of antibiotics
S8 Thiboutot et al J AM ACAD DERMATOL
MAY 2009
prescribed for acne on other more pathogenic orga- d A significant proportion of patients with acne are
nisms. To date, neither aspect has been extensively colonized with resistant Propionibacterium before
studied; there are some data, as will be discussed treatment is initiated.71 P acnes resistance is dissem-
below. It should be noted that acne does not repre- inated primarily by person-to-person contact; study
sent a classic bacterial infection, where resistance to has shown that the prevalence of resistant P acnes in
an antibiotic translates directly to treatment failures, household contacts of patients with acne ranged
in part because antibiotics exert effects in acne that from 41% in Hungary to 86% in Spain.71 Younger
are independent of their antibacterial actions (eg, siblings and children of patients with acne may be
they have anti-inflammatory actions). Indeed, Eady colonized de novo by resistant strains at an early age.
et al62 state that ‘‘the relationship between resistance Further, dermatologists are highly likely to have
and treatment outcomes is perhaps more complex in resistant strains of P acnes colonizing the face (25
acne than any other microbial disease for which of 39 tested).71 Because the rationale for using anti-
antibiotics are prescribed.’’ The members of the biotics in acne is to target P acnes, harboring resistant
Global Alliance have evaluated the available evi- organisms may be logically expected to have an
dence in acne, reviewed evidence of the effect of impact on treatment outcome.66,67
antibiotic use on P acnes resistance and transmission
of resistance from P acnes to other microbes,59,62,63 Potential effect of antibiotic use in acne on
and incorporated our collective clinical experience other pathogens (level IV evidence). Generally,
to formulate opinions on what actions dermatolo- in medicine, it is agreed that when antibiotics are
gists should take in response to the problem of administered, resistance occurs in both targeted and
antibiotic resistance in acne. nontargeted bacteria. In addition, resident flora has a
Susceptibility breakpoints for P acnes have not ‘‘memory’’ and retains resistant variants long after
been well defined; some researchers have used antibiotic therapy is discontinued. Finally, resistance
general anaerobic bacteria breakpoints63-65 and gene pools are often shared by pathogens and
others have set a level of more than 25 mg/L.62 The nonpathogens.66,72 There is one study of resistant
correlation between reduced susceptibility and out- pathogens arising from antibiotic use in acne.66 Mills
come of antibiotic treatment is complex; however, it et al66 assessed bacterial resistance in a controlled
is clear that propionibacterial growth and multipli- study of 208 patients with acne treated with topical
cation has an important role in acne either through erythromycin for 12 weeks in a double-blind, ran-
direct microbial effects or more indirect effects on domized, parallel-group fashion followed by a sin-
the inflammatory process in skin. Poor outcomes in gle-blind regression phase during which patients
acne may occur when insufficient antibiotic is deliv- were treated with the antibiotic vehicle only. The
ered to the majority of follicles.62 prevalence of erythromycin-resistant coagulase-neg-
Effect of P acnes antibiotic resistance on ative staphylococci on the face increased from 87%
outcome (level IV evidence). Anecdotally, mem- to 98%; in addition, the density of resistant organisms
bers of the Global Alliance have heard dermatologists increased significantly. Similar patterns in both prev-
express the opinion that the problem of antibiotic alence and density were observed on untreated skin
resistance is relevant primarily to pathogenic bacteria of the back and in the nares. In addition, there was an
and antibiotics used in hospital to treat serious increase in carriage rate of Staphylococcus aureus
infections. We list here the reasons why we do not in the anterior nares in patients treated with eryth-
agree. romycin on the face. The majority of the resistant
isolates had high-level resistance, with minimal
d Resistance is a concern for patients with acne and inhibitory concentrations greater than 128 /mL. In
may manifest as a reduced response, no response, addition, there are some studies that show antibiotics
or relapse.66-68 Because no methodology currently commonly used for acne (tetracyclines) can select for
exists to quantify concentrations of topical and/or resistant strains of non-P acnes pathogenic bacte-
systemic antibiotics in sebaceous follicles, out- ria.53,54 Raum et al54 reported that doxycycline used
comes studies correlating clinical response with P to treat febrile infections was associated with an
acnes antibiotic sensitivities are the only way to increase of resistance in Escherichia coli from 29%
establish the relevance of colonization with insen- before treatment to 58% during treatment and for a
sitive strains. These studies are difficult but some short time after treatment. Lesens et al53 reported two
have been done.62,69 A systematic review of the outbreaks of Pantin-Valentine leukocidin-positive S
literature published in 1998 found a ‘‘clear associ- aureus infections among solders in Africa who had
ation between poor therapeutic response and been treated with doxycycline for malaria prophy-
antibiotic-resistant propionibacteria.’’70 laxis. Although the data showing a connection
J AM ACAD DERMATOL Thiboutot et al S9
VOLUME 60, NUMBER 5
Table II. Strategies for limiting antibiotic resistance in Propionibacterium acnes and other bacteria
Level of evidence: V
Combine a topical retinoid plus an antimicrobial (oral or topical); this is a rationale choice because of the
complementary modes of action that have been shown clinically to result in1
o Increased speed of response
o Greater clearing
o Enhanced efficacy against comedones and inflammatory lesions
If the addition of an antibiotic to this regimen is required:
Limit the use of antibiotics to short periods and discontinue when there is no further improvement or the
improvement is only slight
o Oral antibiotics should ideally be used for 3 mo, but 6-8 wk into treatment might be one appropriate time point at
which to assess response to antibiotics57
Co-prescribe a BPO-containing product or use as washout
o BPO reduces the likelihood of antibiotic resistant P acnes emerging and rapidly reduces the number of sensitive and
resistant strains of P acnes at the site of application61
o Use BPO either concomitantly or pulsed as an antiresistance agent
o It may be helpful to use BPO for a minimum of 5-7 days between antibiotic courses
Oral and topical antibiotics should not be used as monotherapy
Concurrent use of oral and topical antibiotics should be avoided, particularly if chemically different
o Increased risk of bacterial resistance
o No synergistic actions
Do not switch antibiotics without adequate justification; when possible, use the original antibiotic for subsequent
courses if patients relapse
Use topical retinoids for maintenance therapy, with BPO added for an antimicrobial effect if needed
Avoid use of antibiotics for maintenance therapy
BPO, Benzoyl peroxide.
between antibiotics used for acne and increased in P acnes occurs with varying frequency among
resistance in bacteria other than P acnes are relatively countries and can be somewhat hard to predict.55,80,81
sparse, it is not illogical to surmise that the antibiotics In addition, susceptibility testing for P acnes is not
are exerting selection pressure on a variety of flora practical on a routine basis and does not necessarily
and not just P acnes. influence therapeutic decisions. Therefore, we rec-
Patients with acne are often treated with multiple ommend taking steps that are known to limit the
antibiotics and their flora is exposed to a significant potential for antimicrobial resistance (Table II).
selective pressure for resistance development. Resistance in P acnes has not been studied as
Margolis et al73 found that patients with acne treated extensively as resistance in organisms considered to
with antibiotics had 2.15 times greater risk of devel- be more pathogenic; however, there are several
oping an upper respiratory tract infection compared factors that suggest there may be cause for concern
with patients with acne who were not treated with in acne. Prescribing practices for acne have been
antibiotics. In addition, there have been an increas- shown to influence the resistance rate.82,83 Data from
ing number of reports of infections caused by P a European surveillance study of P acnes were
acnes, including arthritis,74,75 endocarditis,76 en- correlated with published data on outpatient antibi-
dophthalmitis,77 and adenitis.78 The frequency of P otic sales.55,83 The highest rate of tetracycline resis-
acnes infections is hard to quantify, because it has tance (11.8%) was found in Finland, the country with
long been considered just a contaminant and not a the highest outpatient use of tetracycline. Con-
pathogen so has not been rigorously monitored or versely, no tetracycline resistance was found in Italy,
studied. However, several researchers have termed which had the lowest prescription volume of outpa-
P acnes infections ‘‘an emerging clinical entity’’75 tient tetracycline.55 However, resistance to macro-
and ‘‘an underestimated pathogen.’’79 In addition, lides was high in Italy (erythromycin 42% and
Oprica and Nord,55 on behalf of the European Study clindamycin 21%), correlating with high sales vol-
Group on Antimicrobial Resistance in Anaerobic umes of macrolides. For the 8 countries included in
Bacteria, report that among P acnes isolates from the analysis, the correlation between sales and
systemic infections, blood isolates were encoun- resistance was significant for both clindamycin and
tered most frequently followed by isolates from skin erythromycin. (P \.05).55
and soft-tissue infections and abdominal infections. In addition, new mechanisms of resistance are
The Global Alliance members note that resistance evolving in P acnes.63,83 In 2005, Oprica et al63
S10 Thiboutot et al J AM ACAD DERMATOL
MAY 2009
reported the existence of several novel resistant physicians need to be educated about best practices
genotypes of P acnes that were distributed through- for managing acne using combination therapy in-
out Europe. Data suggest resistance is more common volving a topical retinoid plus an antimicrobial agent
in patients with moderate to severe acne and that and limiting duration of antibiotic therapy/adding
patients have multiple resistance strains with differ- BPO. Much remains to be discovered about bacterial
ent resistance patterns.64 Spread of resistant strains resistance in response to antibiotic use for acne. We
among family and friends occurs frequently; al- believe there is a need to gather data about follicular
though some research suggests that resistant isolates concentrations of antibiotics, because there have
disappear after antibiotic treatment is stopped,59 been no recent attempts to study this. In addition,
other research suggests that resistance persists and studies in larger populations are needed to deter-
can be reactivated rapidly.69,84 Further, it is known mine what is the effect of antibiotic therapy for acne
that cross-resistance and transfer of resistance char- on the frequency of pharyngitis, cystitis, colonization
acteristics is widespread among bacteria. Finally, of the anterior nares, methicillin-resistant S aureus
although it may be argued that resistance to tetracy- colonization, and cutaneous infections.
clines is not clinically relevant with major pathogenic
bacteria, resistance to other antibiotic classes used in Retinoid-based combination therapy for acne
acne (more or less frequently depending on the The current understanding of acne pathophysiol-
region of the world) such as macrolides and less ogy indicates that pairing topical retinoids with
often quinolones and sulfonamides may be very antimicrobials targets the majority of pathogenic
important.85,86 In recognition of the foregoing con- factors more effectively than antimicrobial-focused
cerns, the regulatory bodies in some countries have treatment. As the data reviewed in this article show,
mandated a limited duration of use for topical this combination results in faster and more complete
antibiotics either alone or in fixed-dose combination clearing of acne lesions compared with monother-
products. apy. This means that physicians can now help
Use of subantimicrobial doses of antibiotics may patients navigate acne-prone years with fewer em-
offer promise, but has not been well studied, partic- barrassing acne lesions and, potentially, prevent the
ularly in acne. The theoretical basis is that no long-term problems of relapse, acne scars, and
bacterial killing occurs, so there is no selection of postinflammatory hyperpigmentation.91
resistant strains.87 Instead, the primary mechanisms Since publication of the original Global Alliance
of action of subantimicrobial-dose antibiotics are recommendations,1 numerous clinical studies of
anti-inflammatory mechanisms (in the United States topical retinoids in combination with antimicrobial
low-dose doxycycline has been approved for treat- agents either as single agents or in fixed-dose com-
ment of the inflammation associated with rosacea). bination products have been published; indeed,
This raises the question of how important is bacterial there is now evidence from more than 16,000
killing in acne? Currently, there is no answer to that patients with acne. Because of the large number of
question; however, research continues to illuminate studies in this particular aspect of acne management,
the molecular basis for acne and the role of P acnes this review was performed with the methodology of
in pathophysiology. Miyachi et al88 have found a systematic review. A search of PubMed for clinical
cycline antibiotics that reduce leukocyte recruitment trials with the terms ‘‘acne vulgaris’’ and ‘‘adapa-
by P acnes inhibit release of reactive oxygen lene,’’ ‘‘tazarotene,’’ and ‘‘tretinoin’’ was conducted
species, possibly by altering leukocyte metabolism. including publications in the years 1975 to 2008
Additional studies by Akamatsu et al89,90 have pro- inclusive; a total of 36 studies were identified that
vided supportive evidence about the importance of assessed antimicrobial therapy in combination with a
antioxidant properties with cycline antibiotics. retinoid (11 with adapalene, 4 with tazarotene, and
Notably, antibiotics that do not have antioxidant 21 with tretinoin).
actions, such as penicillin and cephalosporins, are The rationale for combining topical reti-
not clinically effective against acne.88 noids and antimicrobial agents. Historically,
It should also be noted that generally bacterial treatment of acne was directed toward controlling
resistance often diminishes or resolves after selective P acnes and centered on use of antibiotics. Because
pressure from antibiotics is withdrawn. Data regard- acne involves an interplay of 4 major pathogenic
ing resolution of resistance in P acnes are sparse. factors (excess sebum production; bacterial coloni-
Conclusions. As shown in the consensus rec- zation of the pilosebaceous duct and release of
ommendation at the start of this section, the mem- inflammatory mediators; inflammation; and abnor-
bers of the Global Alliance believe that antibiotic use mal keratinization within the follicle), acne treatment
for acne should be limited. Further, we believe that should be directed toward as many pathogenicJ AM ACAD DERMATOL Thiboutot et al S11
VOLUME 60, NUMBER 5
CONSENSUS: Combination Retinoid-based Therapy Is First-line Therapy for Acne
Level of Evidence: I
d The combination of a topical retinoid and antimicrobial agent remains the preferred approach for almost all
patients with acne
o This combination attacks 3 of the 4 major pathogenic factors of acne: abnormal desquamation, P acnes
colonization, and inflammation
o Retinoids are anticomedogenic, comedolytic, and have some anti-inflammatory effects, whereas BPO is
antimicrobial with some keratolytic effects and antibiotics have anti-inflammatory and antimicrobial effects
d The superior efficacy of this combination has been shown in clinical trials involving more than 16,000 patients
(reviewed below)
d Fixed-dose combination products with a topical retinoid and an antimicrobial provide improved patient conve-
nience that may translate to improved adherence; those without an antibiotic in the formulation may minimize the
development of bacterial resistance (level IV evidence); on a theoretical basis, retinoid-BPO combination products
may be the most desirable
factors as possible.92 More specifically, for reasons a retinoid plus antimicrobial therapy was first inves-
explained below, acne management should focus on tigated in the 1970s.96-99 Several early small studies
preventing formation of microcomedones and min- showed that the combination of a retinoid plus an
imizing the potential for visible acne lesions. antimicrobialeBPO, topical antibiotics, and oral
The formation of an acne lesion is thought to antibioticsewas more effective than monotherapy
begin with the microscopic lesion known as the with the antimicrobial.96,99,100 For example, Mills
microcomedo. This lesion, which is not yet clinically et al96 reported that the combination of tretinoin
visible, forms when excess sebum collects in the plus oral tetracycline resulted in a good to excellent
follicle and abnormal epithelial desquamation oc- response in 67% of patients vs 48% of those treated
curs along with proliferation of P acnes. The micro- with tretinoin alone and 41% of those treated with
comedo is the precursor to all acne lesions, both tetracycline alone. Although these early studies are
comedones and papules/pustules. Evaluation of cited as supportive data, this review focuses on the
papules has shown the progression of lesions: results of newer studies because of the change in
microcomedones were found in 52% of papule standards for clinical trial design in dermatology
biopsy specimens; in addition, 22% of papules during the past few decades.
contained an open comedo and 10% contained a Review of combination therapy studies involving
closed comedo.92,93 Clearly, targeting the micro- topical retinoids and antimicrobial agents used to-
comedo will minimize the visible expression of acne. gether shows remarkably consistent results: combi-
Topical retinoids are both comedolytic and anti- nation therapy achieves significantly greater and faster
comedogenic and have been shown to reduce for- acne clearing versus antimicrobial therapy alone.
mation of microcomedones and comedones.94 They Topical retinoids with topical antimicrobials. Top-
also have direct and indirect anti-inflammatory ac- ical retinoids have been studied with topical antibi-
tions. Finally, topical retinoids normalize desquama- otics (clindamycin and erythromycin) and the
tion, which facilitates penetration of other topical antimicrobial BPO, and fixed combination antibiotic/
agents.95 Antibiotics and BPO target P acnes and have BPO products (discussed in section below titled
anti-inflammatory actions; unlike antibiotics, how- ‘‘Fixed-dose combination products’’).98-105 Generally,
ever, BPO has not been associated with the develop- topical combinations are indicated in patients
ment of bacterial resistance. These antimicrobial with mild to moderate acne with an inflammatory
agents also have mild keratolytic effects by mecha- component.91
nisms that are different from those of retinoids (they Adapalene (level II evidence). Wolf et al105
do not regulate the process of hyperkeratinization).95 evaluated the combination of adapalene gel 0.1%
Thus, the mechanism of action of topical retinoids plus clindamycin 1% gel versus clindamycin 1%
and antimicrobials are complementary. This may (plus adapalene vehicle) in a 12-week, randomized
explain why the combination yields superior results study (n = 249) of patients with mild to moderate
compared with either drug class alone. acne. Combination therapy resulted in a more rapid
Clinical studies supporting retinoid-based and significantly greater clearance at all study
combination therapy. The concept of combining visits.105S12 Thiboutot et al J AM ACAD DERMATOL
MAY 2009
Level II evidence supports the use of adapalene
or tretinoin plus topical antimicrobial agents; we
advise against any monotherapy with topical anti-
biotic and recommend limiting the duration of
topical antibiotics, even when used in combination
with retinoids, unless BPO is also used (level V
evidence).
Tretinoin (level III evidence). Similarly, the
combination of tretinoin gel 0.025% plus clindamy-
cin gel 1% provided a numerically superior improve-
ment in acne lesions compared with tretinoin alone
and a significantly superior improvement compared Fig 2. Tazarotene .1% or tretinoin .025% gel plus clinda-
with clindamycin alone in 64 patients at 8 weeks of mycin 1% gel. Percentage of patients with greater than or
therapy.102 Shalita et al104 compared tretinoin 0.1% equal to 50% and greater than or equal to 75% improve-
microsphere with and without BPO 6% cleanser (n = ment at 12 weeks. Reprinted with permission from
56) and found a significantly greater reduction in Tanghetti et al.106
inflammatory acne lesions with combination therapy
versus tretinoin alone, but no difference between
groups in reduction of noninflammatory acne le- Level I evidence supports the use of adapalene
sions. Tolerability in the studies was similar between plus oral antibiotics in treatment of moderate or
groups. moderately severe acne. Level III evidence supports
Comparing retinoids in combination regi- the use of tretinoin and tazarotene plus oral
mens with topical antibiotics (level IV evidence). antibiotics.
There have been few head-to-head comparisons of
different retinoids in combination regimens. However,
Tanghetti et al106,107 reported results from a random- Topical retinoids plus oral antibiotics. As early as
ized, parallel-group, investigator-blinded study of 1972, it was shown that topical tretinoin plus oral
clindamycin 1% gel plus either tazarotene 0.1% cream tetracycline increased efficacy and provided a faster
or tretinoin 0.025% gel in patients with mild to therapeutic response compared with either agent as
moderate acne (135 patients). The tazarotene regimen monotherapy.96,101 Topical retinoids plus oral antibi-
was associated with greater improvements in overall otics are a suitable therapeutic choice for moderate to
disease severity (change on 6-point scale: e1.64 6 severe or persistent acne. It is our opinion that oral and
0.97 with tazarotene vs e1.24 6 0.96 with tretinoin, topical antibiotics should not be used together be-
P = .04), a higher percent of patients with 50% or cause of an increased risk for antibiotic resistance and
greater improvement (Fig 2), and better global assess- low likelihood of additional efficacy. Controlled clin-
ments (67% vs 55% of patients with at least ‘‘marked ical studies have evaluated the combination of topical
improvement’’).107 retinoids with the oral antibiotics tetracycline, doxy-
Generally, combination therapy involving a topical cycline, and lymecycline.96,101,110,111
retinoid and other topical antiacne agents is well Adapalene plus oral antibiotics (level I
tolerated. Cumulative irritancy data suggest that, among evidence). Two well-controlled studies evaluated
the retinoids, adapalene is best tolerated in combina- the combination of adapalene plus an oral tetracy-
tion. Studies have compared the cumulative skin toler- cline (lymecycline and doxycycline).110,111 Both
ance of topical retinoids (adapalene gel 0.1%, tretinoin studies showed that combination therapy was supe-
cream 0.025%, and tretinoin microsphere gel 0.1% and rior in both speed and efficacy versus the antibiotic
0.4%) when applied in combination with topical anti- monotherapy. Significant differences between the
microbial agents (clindamycin 1%, erythromycin 2%, groups in total lesion reductions occurred as early as
BPO 5%, and erythromycin/BPO gel) in 37 patients the first postbaseline visit (week 4, P = .04).111
with irritancy testing on skin of the upper aspect of A large-scale community-based study has also
the back.108,109 Adapalene gel was significantly evaluated adapalene.112 In the MORE (Measuring
less irritating (P \ .001) after repeated application Outcomes in a Real-world Experience) Trial, which
compared with either tretinoin formulation when involved 1662 patients, the most common additional
used in combination with antimicrobial agents.108 acne agents were oral antibiotics, antibiotic/BPOYou can also read
