Acne vulgaris medical resident chief

BMJ 2013;346:f2634 doi: 10.1136/bmj.f2634 (Published 8 May 2013)
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Clinical Review
Acne vulgaris
Annelise L Dawson medical resident , Robert P Dellavalle chief
Department of Internal Medicine, Brigham and Women’s Hospital, Boston, MA, USA; 2Department of Dermatology, University of Colorado Denver,
Aurora, Colorado, USA; 3Dermatology Service, Department of Veterans’ Affairs Medical Center, Denver, CO 80220, USA ; 4Department of
Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA
Acne vulgaris is a common inflammatory skin condition.
Although often perceived as a self limited disease of
adolescence, its prevalence remains high into adulthood. Nearly
90% of teenagers have acne, and half of them continue to
experience symptoms as adults.1-3 By age 40 years, 1% of men
and 5% of women still have lesions.4 Recent analyses show an
increasing prevalence of acne in children, perhaps because of
pubertal onset.5
Given that acne may persist for decades and require long term
therapy, there has been a recent effort to reclassify acne as a
chronic disease.2 6 Acne has clear detrimental psychosocial
effects and may lead to permanent scarring.7 It is therefore not
surprising that patients are motivated to seek medical care. In
the United Kingdom, acne accounts for more than 3.5 million
annual visits to general practitioners,3 8 who must therefore be
equipped to treat acne. Several prominent groups—including
the Global Alliance to Improve Outcomes in Acne, the European
Dermatology Forum, and the American Academy of
Dermatology—have published comprehensive treatment
recommendations detailing comparable therapeutic strategies.9-11
Here we provide a streamlined outline of treatment intended for
the non-specialist.
What are the clinical characteristics of
A spectrum of lesions may be present, including
non-inflammatory open and closed comedones (blackheads and
whiteheads, respectively) and inflammatory papules, pustules,
nodules, and cysts. Lesions may be present on the face, neck,
chest, or back—areas with the greatest density of pilosebaceous
units.12 Comedone formation is intrinsic to the diagnosis of acne
vulgaris—when not clinically apparent, consider alternative
diagnoses. Diseases that mimic acne include rosacea, folliculitis,
angiofibromas, perioral dermatitis, and keratosis pilaris.5 13 14
The patient’s age may also help to distinguish these disorders
from acne. Keratosis pilaris and perioral dermatitis, for example,
tend to present in childhood, whereas rosacea tends to affect
older adults. In cases of diagnostic uncertainty, referral to
specialist care is warranted.
Several groups have proposed standardized measures for
classifying acne, although none has been universally
accepted.10 13 15 Classification is important because it helps to
inform treatment strategies.3 11 Acne is categorized broadly into
mild, moderate, and severe forms. Mild acne is typically limited
to the face and is characterized by the presence of
non-inflammatory closed and open comedones with few
inflammatory lesions. Moderate acne is characterized by an
increased number of inflammatory papules and pustules on the
face and often mild truncal disease. Finally, acne is considered
to be severe when nodules and cysts are present. In these cases,
facial lesions are often accompanied by widespread truncal
What causes acne?
Acne is an inflammatory disease of the pilosebaceous duct that
results from four primary pathophysiologic processes:
• Abnormal keratinocyte proliferation and desquamation that
leads to ductal obstruction
• Androgen driven increase in sebum production
• Proliferation of Propionibacterium acnes
• Inflammation.2 9 13 16 17
Increased androgen production causes abnormal epithelial
desquamation and follicular obstruction, which lead to the
primary precursor lesion in acne—the microcomedone.
Microcomedones are pathological structures not visible to the
naked eye that evolve into visible lesions.18 An increase in
circulating androgens also promotes sebum production, causing
these obstructed follicles to fill with lipid rich material and form
visible open and closed comedones.12 19 Sebum serves as a
substrate for bacterial growth, leading to proliferation of P acnes.
Finally, P acnes releases chemical mediators that promote
inflammation, which is propagated by traumatic rupture of
comedones into the surrounding dermis.2 17 This inflammation
manifests through the development of inflammatory papules,
pustules, nodules, and cysts.
Correspondence to: R P Dellavalle, Dermatology Service, Department of Veteran Affairs Medical Center, Denver, CO, USA
[email protected]
For personal use only: See rights and reprints
BMJ 2013;346:f2634 doi: 10.1136/bmj.f2634 (Published 8 May 2013)
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Summary points
Do not underestimate the impact of acne on patient quality of life and mental health
Topical retinoids are now a mainstay of treatment
Avoid prolonged antibiotic courses and antibiotic monotherapy because of the risk of bacterial resistance
For women with refractory acne or lesions confined to the lower half of the face, consider the addition of combined oral contraceptives
Oral isotretinoin is the most effective treatment for severe acne
Assess treatment adherence, which may be limited by irritation or regimen complexity
Sources and selection criteria
We performed a Medline database search using the term “acne” together with “antibiotic resistance”, “antibiotics”, “azelaic acid”, “benzoyl
peroxide”, “classification”, “depression”, “diet”, “epidemiology”, “isotretinoin”, “oral contraceptives”, “pathogenesis”, “retinoids”, “scarring”,
“smoking”, “treatment”, “treatment guidelines”, and “vulgaris.” We also searched the Cochrane Database of Systematic Reviews using the
term “acne”.
The successful management of acne requires an understanding
of these four facets of the pathophysiology of acne. Clinicians
should select mechanistically driven treatment regimens that
target each patient’s predominant lesion types.
Can acne be prevented?
Myths about the causes of acne abound. The central
discoloration in blackheads is not dirt, but oxidized melanin.20
A comprehensive systematic review found little evidence for
an association between acne and poor facial hygiene and
provided minimal support for frequent face washing.21
Aggressive cleansing may cause irritation, thereby exacerbating
active lesions or limiting the patient’s tolerance of therapy.21 22
Basic care with twice daily washing and use of a moisturizer
that does not contribute to comedone formation
(noncomedogenic) is an accepted standard.9 Although
misconceptions about dietary triggers have been largely
dispelled, recent reports—including a systematic review of
dietary influences on acne and a randomized investigator masked
controlled trial of glycemic load and acne severity—suggest
that acne is associated with high dairy diets and those with a
high glycemic load.23-27 Finally, a cross sectional analysis found
a significant dose dependent association between smoking and
acne severity.20 28
How is acne treated?
Careful assessment of the morphology and severity of acne is
an important first step in management, because lesion
morphology largely dictates the optimal treatment approach.
Treatment should be designed to target precursor lesions
(microcomedones) and active inflammatory lesions. Milder
cases are best managed with topical regimens, whereas systemic
drugs are indicated in more severe cases. The box summarises
the mechanisms of action of the most commonly used agents.
The table⇓ provides a treatment framework based on disease
Topical agents
Retinoids are vitamin A derivatives that normalize keratinocyte
desquamation and adhesion, leading to comedolysis and
preventing formation of new microcomedones. Some retinoids
also display anti-inflammatory properties.11 15 29-32 Perhaps the
most notable recent development in the treatment of acne is the
increased use of topical retinoids.29 Many randomized trials
show the efficacy of these drugs relative to vehicle, and they
For personal use only: See rights and reprints
are recommended for all cases of acne, except when oral
retinoids are used.9 11 Studies show improvements within weeks,
with maximal benefit after three to four months.13 15 18 Mild
non-inflammatory comedonal acne may be treated with retinoid
monotherapy. When inflammatory lesions are present, retinoids
should be combined with antimicrobial therapy or benzoyl
peroxide.9 16 Because retinoids prevent the development of
microcomedones, they can also be used for maintenance
Several topical retinoid products exist, including tretinoin,
isotretinoin (not available in the United States), adapalene, and
tazarotene (not licensed for treatment of acne in the United
Kingdom).18 These products are available in cream, gel, liquid,
and microsphere formulations, each at multiple concentrations.
Formulations vary by country.9 18 Use of retinoids is limited by
transient skin irritation, which may be prevented by selecting
lower concentration or cream based formulations.18 29 31 A
meta-analysis of five randomized controlled trials suggests that
adapalene is the best tolerated retinoid, whereas several
moderately sized randomized studies found tazarotene to be
most efficacious at the expense of irritation.13 18 29 31-38 In addition,
anecdotal evidence suggests that some patients experience an
initial “flare” in acne lesions, which subsides with continued
use.2 18 31 Lastly, pregnant and breastfeeding women should
avoid topical retinoids.18 Women of child bearing age should
be counselled about the need for contraception.17
Topical antibiotics
The primary topical antibiotics used for acne are clindamycin
and erythromycin.30 These agents have bacteriostatic and
anti-inflammatory properties.11 30 32 Topical antibiotics are used
for mild to moderate acne when inflammatory lesions are
Antibiotic resistance is a growing concern and has prompted
efforts to limit the duration of antibiotic courses and to
emphasize combined regimens.2 Patterns of P acnes resistance
correspond to trends in antibiotic use.2 39 Treatment outcomes
worsen when resistance is present—systematic reviews show
decreasing antibiotic efficacy over time, particularly for
erythromycin and clindamycin.2 32 40 41 P acnes resistance is not
the only concern—Staphylococcus and Streptococcus resistance
may also develop.39 42 In practice, this means avoiding antibiotic
monotherapy and maintenance therapy.19 20 Instead, topical
antibiotics should always be used with retinoids, and possibly
benzoyl peroxide. Several double blind randomized controlled
trials have found that the addition of retinoid or benzoyl peroxide
therapy to topical antibiotics improves treatment
outcomes.9 10 17 39 43 44 Retinoids do not decrease resistance but
BMJ 2013;346:f2634 doi: 10.1136/bmj.f2634 (Published 8 May 2013)
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Effects of the different agents used to treat acne
Topical retinoids: Comedolytic and sometimes anti-inflammatory
Antibiotics: Antimicrobial and anti-inflammatory
Benzoyl peroxide: Antimicrobial plus weakly anti-inflammatory and comedolytic
Hormonal agents: Sebosuppressive
Oral retinoids: Comedolytic, sebosuppressive, antimicrobial, and anti-inflammatory
promote antibiotic efficacy by improving penetration and
providing synergistic comedolytic and anti-inflammatory
effects.18 45 Benzoyl peroxide has bactericidal properties, thereby
minimizing bacterial resistance.39 45 Topical antibiotic courses
should be limited to 12 weeks’ duration when possible.9 16 46
Finally, combined topical and oral antibiotics should be
avoided.15 47
Administration, although it has been approved in many European
countries, so receives greater emphasis in the European
literature.10 55 A small double blind randomized trial
demonstrated efficacy of azelaic acid relative to placebo.56
Studies comparing azelaic acid with other topical agents are
limited. Azelaic acid is well tolerated but poses a risk of
hypopigmentation in darker skinned patients.17
Benzoyl peroxide
Salicylic acid
Benzoyl peroxide is a non-antibiotic antimicrobial agent that
has bactericidal effects by generating reactive oxygen species
within the follicle.15 32 48 49 It also has weak comedolytic and
anti-inflammatory properties.32 Owing to its bactericidal
properties, benzoyl peroxide produces rapid improvement in
inflammatory lesions and prevents the development of antibiotic
resistance.15 32 39 45 48-52 Although data on the comparative efficacy
and tolerability of benzoyl peroxide and topical retinoid
monotherapy are conflicting, most guidelines recommend a
mechanistically driven approach, with the addition of benzoyl
peroxide mainly when inflammatory lesions are present.9 10 17
Some studies, including a small double blind randomized trial,
show that inflammatory lesions improve more rapidly with
benzoyl peroxide than with topical retinoids.53
Benzoyl peroxide is available in numerous formulations, in
concentrations ranging from 2.5% to 10%,29 none of which show
clear superiority in systematic reviews, although irritation
increased with higher concentrations.27 32 48 52 Irritation typically
resolves with continued use. In addition, patients should be
warned that benzoyl peroxide may bleach clothing, bedding,
and hair.13 32 Finally, because all retinoids except adapalene are
unstable with benzoyl peroxide, these agents should be applied
separately.18 31 32
Combination products
The benefits of combined regimens include complementary
mechanisms of action, reduced risk of antibiotic resistance, and
improved treatment outcomes.2 9 10 13 15 17 18 30 47 48 An increasing
number of antibiotic-retinoid and antibiotic-benzoyl peroxide
combinations are now available. Retinoid-benzoyl peroxide
combinations are limited by retinoid instability in the presence
of benzoyl peroxide.
The biggest drawback to combined products is cost. Individual
generic components are typically less expensive and can be
applied simultaneously with equivalent effects.32 46 Nevertheless,
a small investigator blinded randomized controlled trial found
that combined products improve patient adherence by
simplifying daily regimens.54 For many clinicians and patients,
this improved ease of application and corresponding increase
in adherence justifies the cost of combined therapies.
Other topical treatments
Azelaic acid
Azelaic acid is an alternative to retinoids that has comedolytic,
antimicrobial, and anti-inflammatory properties.9 13 17 This agent
has not been approved for acne by the US Food and Drug
For personal use only: See rights and reprints
Salicylic acid is an over-the-counter agent with desquamating
and comedolytic properties that is less potent than retinoids.48
Few studies of salicylic acid exist, although available studies
show that it is less effective but better tolerated than other
agents.17 29 48 Salicylic acid may be used when patients cannot
tolerate standard agents.
Systemic agents
Systemic agents should be considered for patients with moderate
to severe acne. These therapies are useful in patients with truncal
disease in whom application of topical agents would be difficult.
Hormonal therapies
Hormonal therapies are a useful adjunct to treatment in women
with moderate to severe acne, especially those who desire oral
contraception or in whom traditional therapy has failed.27
Anecdotal evidence suggests that women with lesions confined
to the lower face and jaw are most likely to benefit.15 57
Hormonal agents are available in two primary forms: combined
oral contraceptives, which suppress ovarian androgen
production, and androgen receptor blockers, such as cyproterone
acetate, spironolactone, and flutamide. In the UK, a combined
oral contraceptive containing cyproterone acetate and
ethinylestradiol is licensed for the treatment of acne.13 57 58 These
agents decrease androgen mediated effects on the sebaceous
follicle.57 Although hyperandrogenic states such as polycystic
ovarian syndrome are associated with acne, most women with
acne have normal androgen levels but still benefit from
antiandrogen therapy.57 Full benefit is seen after three to six
months of treatment.15
A recent Cochrane review confirmed the efficacy of combined
oral contraceptives in treating inflammatory and
non-inflammatory acne but found few differences in efficacy
between the different types, including cyproterone acetate, which
is often recommended.59 60 It is therefore not clear whether
formulations containing cyproterone acetate should be favored,
especially because this agent may increase the risk of venous
thromboembolism.27 57 59 Progesterin only contraceptives may
worsen acne.9
Oral antibiotics
Systemic antibiotics are indicated for moderate to severe
inflammatory acne.9 Like topical antibiotics, oral antibiotics
have antimicrobial and anti-inflammatory effects.13 39 50
Doxycycline, minocycline, lymecycline, tetracycline, and
BMJ 2013;346:f2634 doi: 10.1136/bmj.f2634 (Published 8 May 2013)
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A patient’s story
I first developed acne in high school. My family encouraged me to wash my face often with several over-the-counter products, which mostly
exacerbated my symptoms. I was so embarrassed about my skin that I started to avoid spending time with friends. When my mother noticed
this change, she agreed to take me to a dermatologist, who suggested topical antibiotics and benzoyl peroxide. These treatments caused
substantial irritation, so I stopped using them promptly. I was sure that my acne was incurable, so I learned to live with it.
When I reached adulthood, I began taking oral contraceptive pills, not knowing that they could affect the acne. Within a month of starting
treatment, my acne improved dramatically. After six months, my lesions had nearly disappeared. I was thrilled to be disease free for the first
time in nearly a decade but felt sad that this therapy had not been offered to me years earlier. I suspect this would have substantially improved
my teenage confidence and self esteem.
erythromycin are most commonly used. Few comparative studies
exist, although a systematic review of systemic therapy with
tetracyclines found no antibiotic to be more effective than
another.17 41 46 Although minocycline was previously favored by
clinicians, a recent Cochrane review found no clear evidence
of superiority.61 62 Given the lack of comparative data, antibiotic
selection may be driven by side effect profiles and patterns of
P acnes resistance. Tetracyclines must be avoided in pregnant
women and children given the associated risk of tooth
discoloration. Women of childbearing age should be advised to
use contraception when taking these agents. Doxycyline causes
photosensitivity. In rare cases minocycline leads to skin
hyperpigmentation and drug induced systemic lupus
erythematosus. Limecycline has gained popularity in Europe
but is not available in the US.63 Increasing P acnes resistance
has decreased reliance on erythromycin and tetracycline.11 42 49 50
As with topical antibiotics, oral antibiotics should be combined
with other agents to minimize the development of bacterial
resistance and improve treatment efficacy. Always use oral
antibiotics in conjunction with a topical retinoid or benzoyl
peroxide16 50—several small to moderate sized randomized
controlled trials have shown that this increases efficacy.64-66
Assess treatment response at six to eight weeks, at which point
a decision to continue or change antibiotics may be made.50
When possible, limit antibiotic courses to 12 weeks’
duration.2 16 46
Isotretinoin is remarkably efficacious in the treatment of severe
acne, as well as treatment resistant moderate disease, and is now
the first line treatment in such cases.10 13 Isotretinoin is thought
to target all four components involved in the development of
acne by normalizing follicular desquamation, decreasing sebum
secretion, inhibiting the growth of P acnes, and exerting
anti-inflammatory effects.13 31 49 Given these broad effects and
the potential for adjunctive therapy to compound adverse effects,
isotretinoin is prescribed as monotherapy.
Patients typically complete a 16-24 week course of isotretinoin,
taking 0.5-1 mg per kg per day to target a cumulative dose of
120-150 mg per kg.11 16 49 The dose is slowly increased as
tolerated. Effects are not usually seen for the first one or two
months.67 Meta-analyses show that at least half of patients are
permanently cured after a single course, and only 20% of
patients require repeat treatment.15 17 31 49 68 69 Relapse is most
common in younger patients, in women with hormonally driven
acne, and when goal cumulative dosing is not achieved.31 57 70 71
Use of oral isotretinoin is tightly regulated because of its well
known teratogenic effects and is available through specialist
care only in many countries.42 Female patients must demonstrate
a negative pregnancy test and use contraception.49 Although
charged with having detrimental psychological effects, there is
no clear evidence that isotretinoin leads to depression or
suicidality.72-74 Other adverse reactions include chapped skin,
dry eyes, epistaxis, myalgias, and alterations in serum lipid and
For personal use only: See rights and reprints
transaminase concentrations, most of which resolve after
treatment is stopped.11 13 31 49
What are the consequences of acne?
Although many people dismiss acne vulgaris as an
inconsequential disease of adolescence, it has clear long lasting
psychosocial and physical effects. Many studies have shown an
association between acne and depression and anxiety,
independent of disease severity.7 75 Psychological effects
improve with treatment.76 Furthermore, acne may cause
permanent scarring that is difficult to correct. Finally, because
of its frequency and chronicity, the economic burden of acne is
substantial, with associated expenditure in the US alone
exceeding $2.5bn (£1.64bn; €1.93bn) annually.20 To reduce
these effects, patients with acne should receive early, aggressive,
mechanistically driven therapy.
Contributors: Both authors had full access to the content of this review
and are guarantors. ALD searched the literature, compiled the
references, and drafted the manuscript. RPD critically revised the
manuscript for intellectual content.
Competing interests: We have read and understood the BMJ Group
policy on declaration of interests and declare the following interests:
Provenance and peer review: Commissioned; externally peer reviewed.
Patient consent obtained.
Yentzer BA, Hick J, Reese EL, Uhas A, Feldman SR, Balkrishnan R. Acne vulgaris in the
United States: a descriptive epidemiology. Cutis 2010;86:94-9.
Thiboutot D, Gollnick H, Bettoli V, Dreno B, Kang S, Leyden JJ, et al. New insights into
the management of acne: an update from the global alliance to improve outcomes in acne
group. J Am Acad Dermatol 2009;60(5 suppl):S1-50.
Purdy S, de Berker D. Acne. BMJ 2006;333:949-53.
Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad
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an age-based approach to therapy. Semin Cutan Med Surg 2011;30(3 suppl):S6-11.
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and when? Am J Clin Dermatol 2008;9:279-84.
Barnes LE, Levender MM, Fleischer AB Jr, Feldman SR. Quality of life measures for acne
patients. Dermatol Clin 2012;30:293-300, ix.
Newton JN. How cost-effective is oral isotretinoin? Dermatology 1997;195(suppl 1):10-4;
discussion 38-40.
Gollnick H, Cunliffe W, Berson D, Dreno B, Finlay A, Leyden JJ, et al. Management of
acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol
2003;49(1 suppl):S1-37.
Nast A, Dreno B, Bettoli V, Degitz K, Erdmann R, Finlay AY, et al. European
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Strauss JS, Krowchuk DP, Leyden JJ, Lucky AW, Shalita AR, Siegfried EC, et al.
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Brown SK, Shalita AR. Acne vulgaris. Lancet 1998;351:1871-6.
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BMJ 2013;346:f2634 doi: 10.1136/bmj.f2634 (Published 8 May 2013)
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Areas for future research
Large randomized controlled trials on the treatment of acne are needed
Comparative effectiveness research should be prioritized, as cited by the Institute of Medicine77
Study of the cutaneous microbiome, including disease associations with Propionibacterium acnes strains, may improve our understanding
of the pathogenesis of acne and open up new therapeutic approaches78
Additional educational resources
Resources for healthcare professionals
American Academy of Dermatology: Strauss JS, Krowchuk DP, Leyden JJ, Lucky AW, Shalita AR, Siegfried EC, et al. Guidelines of
care for acne vulgaris management. J Am Acad Dermatol 2007;56:651-63
European Dermatology Forum: Nast A, Dreno B, Bettoli V, Degitz K, Erdmann R, Finlay AY, et al. European evidence-based (S3)
guidelines for the treatment of acne. J Eur Acad Dermatol Venereol 2012;26(suppl 1):1-29
Global Alliance to Improve Oucomes in Acne: Gollnick H, Cunliffe W, Berson D, Dreno B, Finlay A, Leyden JJ, et al. Management of
acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol 2003;49(1 suppl):S1-37
National Institute of Health and Care Excellence (—Clinical knowledge summary on acne vulgaris
Resources for patients
American Academy of Dermatology (—Basic patient information regarding acne
treatment with particular emphasis on adult acne
British Association of Dermatologists (—General overview of acne treatment
National Institute of Health and Care Excellence (—Clinical knowledge summary on acne vulgaris
UpToDate Patient Information (—Patient oriented guide to the pathophysiology
and treatment of acne
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gel versus once-daily tretinoin 0.1% microsponge gel for the treatment of facial acne
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tazarotene 0.1% gel and adapalene 0.1% gel for the treatment of facial acne vulgaris.
Cutis 2002;69(2 suppl):4-11.
Tanghetti E, Dhawan S, Green L, Del Rosso J, Draelos Z, Leyden J, et al. Randomized
comparison of the safety and efficacy of tazarotene 0.1% cream and adapalene 0.3% gel
in the treatment of patients with at least moderate facial acne vulgaris. J Drugs Dermatol
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vulgaris and other inflammatory skin disorders: a status report. Dermatol Clin 2009;27:1-15.
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Treatment of acne with a combination clindamycin/benzoyl peroxide gel compared with
For personal use only: See rights and reprints
clindamycin gel, benzoyl peroxide gel and vehicle gel: combined results of two double-blind
investigations. J Am Acad Dermatol 1997;37:590-5.
Leyden JJ, Krochmal L, Yaroshinsky A. Two randomized, double-blind, controlled trials
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BMJ 2013;346:f2634 doi: 10.1136/bmj.f2634 (Published 8 May 2013)
Page 7 of 7
Table 1| General treatment algorithm according to acne severity
Topical retinoid
Benzoyl peroxide
Oral antibiotic
Hormonal agent*
Possible treatment
Possible treatment
Possible treatment
Possible treatment
Possible treatment
Recommended Possible treatment
Recommended treatment‡
Azelaic acid
Oral retinoid†
*Female patients only.
†Oral retinoids are prescribed as monotherapy.
‡Select oral or topical antibiotic only.
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