Acne vulgaris can have a substantial impact on a patient’s quality of life; there can be significant psychosocial consequences and it can leave permanent physical scarring. Early and effective acne treatment is important
See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/281845863 Acne Vulgaris Article · September 2015 DOI: 10.1038/nrdp.2015.29 CITATIONS READS 33 10,360 authors, including: Sara moradi tuchayi Eugenia Makrantonaki Massachusetts General Hospital Ulm University 56 PUBLICATIONS 172 CITATIONS 153 PUBLICATIONS 1,985 CITATIONS SEE PROFILE SEE PROFILE Ruta Ganceviciene Clio Dessinioti Vilnius University Hospital Santariškių Klinikos National and Kapodistrian University of Athens 16 PUBLICATIONS 1,018 CITATIONS 103 PUBLICATIONS 1,282 CITATIONS SEE PROFILE Some of the authors of this publication are also working on these related projects: Pathogenesis and Treatment of Acne and Rosacea View project Hidradenitis suppurativa View project All content following this page was uploaded by Eugenia Makrantonaki on 04 July 2016 The user has requested enhancement of the downloaded file SEE PROFILE PRIMER Acne vulgaris Sara Moradi Tuchayi1, Evgenia Makrantonaki2–4, Ruta Ganceviciene2,5, Clio Dessinioti2,6, Steven R. Feldman1,7,8 and Christos C. Zouboulis2 Abstract | Acne vulgaris is a chronic inflammatory disease — rather than a natural part of the life cycle as colloquially viewed — of the pilosebaceous unit (comprising the hair follicle, hair shaft and sebaceous gland) and is among the most common dermatological conditions worldwide Some of the key mechanisms involved in the development of acne include disturbed sebaceous gland activity associated with hyperseborrhoea (that is, increased sebum production) and alterations in sebum fatty acid composition, dysregulation of the hormone microenvironment, interaction with neuropeptides, follicular hyperkeratin ization, induction of inflammation and dysfunction of the innate and adaptive immunity Grading of acne involves lesion counting and photographic methods However, there is a lack of consensus on the exact grading criteria, which hampers the conduction and comparison of randomized controlled clinical trials evaluating treatments Prevention of acne relies on the successful management of modifiable risk factors, such as underlying systemic diseases and lifestyle factors Several treatments are available, but guidelines suffer from a lack of data to make evidence-based recommendations In addition, the complex combination treatment regimens required to target different aspects of acne pathophysiology lead to poor adherence, which undermines treatment success Acne commonly causes scarring and reduces the quality of life of patients New treatment options with a shift towards targeting the early processes involved in acne development instead of suppressing the effects of end products will enhance our ability to improve the outcomes for patients with acne Correspondence to S.R.F e-mail: sfeldman@ wakehealth.edu Center for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine, 4618 Country Club Road, Winston-Salem, North Carolina 27104, USA Article number: 15029 doi:10.1038/nrdp.2015.29 Published online 17 September 2015 Acne vulgaris is a chronic inflammatory disease of the pilosebaceous unit (comprising the hair follicle, hair shaft and sebaceous gland; FIG. 1) and is among the most common dermatological conditions worldwide, with an estimated 650 million people affected1,2 Acne is considered a chronic disease owing to its prolonged course, pattern of recurrence and relapse, and manifestations such as acute outbreaks or slow onset Moreover, acne causes profound negative psychological and social effects on the quality of life of patients3 Although progress has been made in understanding the pathophysiology of acne and the mechanisms of actions of available drugs to treat the disease, many unanswered questions remain The lack of a consensus grading system also slows efforts to compare efficacies of different medications in clinical studies, which is impeding the formulation of a globally approved consensus guideline Given that abnormalities in several processes (sebum production and sebocyte differentiation, proliferation and inflammation) can contribute to the development of acne, a multipronged treatment regimen is needed in most patients This complex regimen impairs adherence, which is key for treatment success Acne commonly results in scarring and post-inflammatory hyperpigmentation, which has a subsequent impact on quality of life; hence, early and aggressive therapy is crucial Novel delivery strategies for and modifications of existing drugs are recent changes in acne treatment, in addition to the development of new medications that target regulatory pathways involved in acne pathophysiology instead of suppressing the effects of the end products of these pathways With myriad treatment options available, including oral isotretinoin (an agent that blocks all the pathophysiological pathways of acne and has excellent adherence but is associated with severe teratogeni city), and several new therapies in development, better treatment options may be available for patients soon In this Primer, we describe the following aspects of acne vulgaris: epidemiology, pathophysiology, diagnostic methods, available medications and new treatments, patient quality of life and adherence to treatment Epidemiology Most people experience acne during adolescence, with >95% of teenage boys and 85% of teenage girls affected4,5 Almost 20% of these young people have moderate-tosevere acne6 (TABLE 1), and as many as 50% continue to suffer from acne in adulthood6,7 A systematic analysis for the Global Burden of Disease study indicated that acne was the eighth most prevalent disease globally in 2010, following only two other skin disease categories on the list (FIG. 2) NATURE REVIEWS | DISEASE PRIMERS VOLUME | 2015 | © 2015 Macmillan Publishers Limited All rights reserved PRIMER Author addresses Center for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine, 4618 Country Club Road, Winston-Salem, North Carolina 27104, USA Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany Department of Dermatology and Allergology, Ulm University, Ulm, Germany Research Group Geriatrics, Charité Universitaetsmedizin Berlin, Berlin, Germany Clinic of Infectious, Chest Diseases, Dermatovenereology and Allergology, Vilnius University, Lithuania Andreas Syngros Hospital, National and Capodistrian University of Athens, Athens, Greece Department of Pathology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA Acne is the most commonly diagnosed skin condition in the United States according to the 2010 National Ambulatory Medical Care Survey (NAMCS) factsheet for dermatology8, and accounts for more than million visits to physicians each year Acne was the most common condition seen by dermatologists in the United States and the thirteenth most common condition by nondermatologists, resulting in the second most common reason for referrals to dermatologists10; corresponding data from other countries is lacking Approximately twothirds of dermatology visits for acne are made by women11 The mean age of patients with acne seeking treatment is 24 years12, and one-third of total consultations for acne are made by patients >25 years of age13 When NAMCS data were analysed according to specific age groups per diagnosis by dermatologists and by general practitioners during skin disease-related appointments (1993–2010), acne was the most frequent diagnosis for patients 5–44 years of age14 The mean age of children (age range: 6–18 years) seeking treatment for acne has decreased from 15.8 years in 1979 to 15.0 years in 2007 This observation might be indicative of an earlier onset of acne, which is in line with the observation that puberty is also progressively starting at an earlier age; however, the availability of better treatment options may also have a role15 Currently, children as young as 6–8 years of age are seeking treatment15 Not only is acne the most common dermatological diagnosis in the overall population but it is also the most common dermatological diagnosis in patients with skin of colour In the United States, acne is the most commonly diagnosed condition in African-American, Asian and Hispanic patients presenting to the dermatologist, whereas the top dermatological diagnosis in white patients is actinic keratosis16 Acne has been reported to be more prevalent among black and Hispanic women than in white, Asian and Continental Indian women17 Given that acne is so prevalent, it has a high associated cost — estimated in 2004 in the United States at >US$3 billion of total direct and indirect cost and approximately US$12 billion of intangible cost because of the quality of life impact (estimated using willingness to pay)18 Mechanisms/pathophysiology Acne develops in the pilosebaceous unit (FIG. 1) and involves many processes (FIG. 3) Some of the key features underlying acne development include disturbed sebaceous gland activity associated with hyperseborrhoea (excessive sebum) and alterations in sebum fatty acid composition, dysregulation of the hormone micro environment, interaction with neuropeptides, follicular hyperkeratinization, induction of inflammation and dysfunction of the innate and adaptive immunity These processes impair functioning of the pilos ebaceous unit, which leads to the transition of a normal pore to microcomedones, and further to comedones and inflammatory lesions Bacterial antigens can potentiate the inflammatory process19–21 Genetic studies of heterozygous and homozygous twins and family studies have produced a growing body of evidence for the role of hereditary factors in the risk of acne development 22–24 Acne can also be triggered or worsened by, for example, ultraviolet radiation and other environmental factors25,26, dietary factors27,28, smoking 29, stress and the modern lifestyle30 Sebum Sebum is secreted by the sebaceous gland and comprises an oily mixture of triglycerides, wax esters, squalene, free fatty acids and small amounts of cholesterol, cholesterol esters and diglycerides Sebum production is regulated by many factors that activate pathways involved in cell proliferation and differentiation, lipogenesis, hormone metabolism, and cytokine and chemokine release31 (FIG. 4) Sebaceous lipogenesis is more complex than previously thought, as ligand-independent, MYCNmediated hyperactivation of epidermal growth factor receptor and induction of perilipins — a major group of proteins that coat lipid droplets — may also regulate sebocyte differentiation and lipid production32–34 Excessive sebum is thought to be a key contributor to acne development However, not all patients with acne experience hyperseborrhoea In fact, the correlation between sebum production and acne severity depends on age and sex 35–37; in men, acne is more dependent on sebum production35 Acne is also associated with alterations in the free fatty acid composition of sebum Sebum of patients with acne contains less essential (that is, fatty acids that cannot be synthesized by the body and can only be acquired from the diet) free fatty acids (including linoleic acid) than that of people without acne38,39 Pro-inflammatory sebum lipid fractions (monounsaturated fatty acids (MUFAs) and lipoperoxides; see below) have been associated with the development of acne lesions, and the skin surface lipid oxidant to antioxidant ratio is another acne stimulus40 Specifically, sebum of patients with acne contains lipoperoxides resulting from the peroxidation of the lipid squalene41 Both lipoperoxides and MUFAs influence keratinocyte proliferation and differentiation, contributing to follicular hyperkeratinization41,42 Different ethnic groups have different lipid profiles; for example, specific wax ester lipid fractions differ in quantity between white and African Americans43 | 2015 | VOLUME www.nature.com/nrdp © 2015 Macmillan Publishers Limited All rights reserved PRIMER a Normal hair follicle Hair b Whitehead Follicular orifice Skin surface Whitehead comedone Enlargement of follicle opening Sebaceous gland Bacteria Follicle c Blackhead comedone Blackhead d Papule Inflammation White blood cells e g f Pustule h Nodule or cyst i Nature Reviews | Disease Primers Systemic and local hormonal imbalance Whether the primary abnormality causing acne is in the level of circulating hormones or in the processing of hormones in the peripheral tissue is debated Typically, acne starts during puberty when the hormone balance starts to change dramatically In a cross-sectional, retrospective study, the androgenic hormone profile of 835 female patients with acne >15 years of age was analysed In the 54.6% of participants with signs of hyperandrogenism, the levels of dehydroepiandrosterone (DHEA) were most frequently elevated44 In a recent cross-sectional study, androstenedione and testosterone levels were higher (P 0.9)144 Digital photography provides various advantages, such as supervised or automatic image analysis and ease of storage of large numbers of photographs 145 Advanced imaging techniques include parallel polarization and orthogonal polarization imaging, stereoimage optical topometer imaging to construct three-dimensional stereoimages, and fluorescence photography Parallel polarization imaging enhances the visualization of skin surface features, such as papules, pore size, skin oiliness and acne scars145 Orthogonal polarization (or cross-polarization) photo graphy enhances the visualization of inflammatory acne lesions, erythema and skin brightness Parallelpolarized and cross-polarized photography with video microscopy and sebum production measurement can be combined Fluorescence photography using short wavelengths (long ultraviolet A or blue-range light) can be used to visualize P. acnes density based on the porphyrin production and the corresponding orange– red fluorescence intensity Multispectral images use Fisher linear discriminant functions to classify acne NATURE REVIEWS | DISEASE PRIMERS VOLUME | 2015 | © 2015 Macmillan Publishers Limited All rights reserved PRIMER Figure | Clinical presentation of acne vulgaris. Acne Nature Reviews | Disease Primers lesions, including comedones (white arrows), papule (yellow arrow) and pustule (black arrow) on the facial skin and capture image data at specific wavelengths across the electromagnetic spectrum136,145 Differentiation from other dermatological conditions Acne is clinically heterogeneous and differential diagnosis is based on the type of lesion, age at disease onset and persistence of acne in adulthood The differential diagnosis is usually possible on clinical grounds and the patient’s medical history; however, when in doubt, laboratory tests, imaging or histopathological examination of a skin biopsy may need to be performed to exclude other conditions to establish a correct diagnosis146 (TABLE 2) In all cases, the presence of comedones is a prerequisite for establishing diagnosis of acne147 On the basis of the age of presentation, neonatal acne should be differentiated from skin infections (bacterial, viral or fungal), transient benign pustular eruptions (neonatal cephalic pustulosis, erythema toxicum neonatorum and transient neonatal pustular melanosis), milia, sebaceous gland hyperplasia, miliaria, infantile acne, acne induced by topical oils and ointments (acne venenata infantum), drug-induced acneiform eruptions and congenital adrenal hyperplasia19 The differential diagnosis of childhood acne includes perioral dermatitis and childhood rosacea146 More complex conditions that may need to be differentiated from acne vulgaris include the synovitis acne pustulosis hyperostosis osteitis (SAPHO) syndrome, and pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome19,148 Prevention The prevention of acne relies on the successful management of modifiable risk factors implicated in its development, including underlying systemic diseases and lifestyle factors Acne may be the cutaneous manifestation of an underlying systemic disease such as congenital adrenal hyperplasia or polycystic ovary syndrome; in these cases, the timely and successful management of the underlying disease will prevent the presentation or persistence of acne19,148 Various lifestyle factors, such as dietary habits, obesity and smoking, may influence the development of acne149 However, the effect of lifestyle interventions on acne remains a largely debated issue, as epidemiological studies have produced contradictory results, and well-designed trials that are able to produce evidencebased results are largely lacking A case–control study that investigated the association of dietary habits in people with acne (n = 205) and without acne (n = 358) reported an increased risk of acne development only with the increased consumption of milk (in particular, skimmed milk) but not with the consumption of cheese or chocolate117 Similarly, self-reported history of acne was positively associated with intake of skimmed milk in a prospective cohort study of 4,273 boys Milk might influence comedogenesis through hormonal pathways, as milk contains androgens (precursors of dihydro testosterone and other non-steroidal growth factors), or through higher levels of IGF1, which might affect the pilosebaceous unit 150 A community-based study of high school pupils in Tehran, Iran (n = 933) reported that the regular consumption of sweets, nuts, chocolates and oily foods was associated with increased acne severity A cross-sectional study in 1,871 patients with acne reported that frequent fat and sugar intake were associated with increased risk of acne151 However, other studies have failed to show an association between diet and acne152 Considering these controversies, more studies are warranted Very few randomized controlled studies have been conducted to assess the role of dietary interventions on acne A low-glycaemic-load diet for 12 weeks was associated with a greater reduction in the total number of acne lesions compared with the patients on a conventional high-glycaemic-load diet (−21.9 (95% CI: 26.8 to −19.0) versus −13.8 (95% CI: −19.1 to −8.5); P = 0.01) in one small trial (n = 43; all participants had acne and were male) The low-glycaemic-load diet was also associated with weight reduction, decreased free androgen index, increased IGF-binding protein (IGFBP1) levels (mean increase in log(IGFBP1): 0.14 ng per ml) and improved insulin sensitivity 153 Similar results were obtained in a small number of patients (n = 17) when the low-glycaemic-load diet was given for 10 weeks154 Another randomized, blind, controlled study showed that omega-3 fatty acids or γ‑linolenic acid (a omega-6 fatty acid) supplementation for 10 weeks in 45 patients with acne resulted in a significant improvement in the acne severity grade and in inflammatory acne lesion counts155 Omega-3 fatty acids may reduce inflammation by inhibiting pro-inflammatory cytokines, and | 2015 | VOLUME www.nature.com/nrdp © 2015 Macmillan Publishers Limited All rights reserved PRIMER γ‑linolenic acid can have anti-inflammatory actions via inhibition of leukot riene B4 (REF. 155) Finally, a case–control study reported that individuals with a body mass index of >18.5 had an increased risk of acne117 Obesity may be accompanied by peripheral hyperandrogenism, which may be associated with increased sebum production and the development of acne117 No association was found between smoking and acne in this study, but another study has shown a correlation between smoking and comedonal post-adolescent acne156 Box | Commonly used acne grading scales Leeds grading technique* • 0.25–1: physiological acne • 1.5–10: clinical acne Revised Leeds grading technique‡ • 1–3: non-inflamed acne on the face • 1–12: acne on the face • 1–8: acne on the chest • 1–8: acne on the back Plewig and Kligman numerical grading of comedonal acneĐ ã I: 50 comedones Plewig and Kligman numerical grading of papulopustular acneĐ ã I: 30 inflammatory lesions Global Evaluation Acne scale|| • 0: no acne lesions; residual pigmentation and erythema may be seen • 1: almost no lesions, with a few scattered open or closed comedones and very few papules • 2: mild acne, in which 50% of the face is involved with many papules, pustules, comedones and a maximum of one nodule • 4: severe acne, in which the entire face is involved, covered with many papules, pustules, comedones and rare nodules • 5: Very severe acne with highly inflammatory lesions covering the whole face with the presence of nodules US FDA’s Investigator’s Global Assessment for acne vulgarisả ã 0: no acne lesions ã 1: almost clear skin with rare non-inflammatory lesions and no more than one papule • 2: mild acne with some non-inflammatory lesions and no more than a few papules or pustules • 3: moderate acne with many non-inflammatory lesions, some inflammatory lesions, and no more than one nodule • 4: severe acne with many non-inflammatory lesions and inflammatory lesions, but no more than a few nodular lesions *Overall assessment of acne severity in different body areas (face, back and chest) based on reference greyscale facial photographs135 ‡Revision of the Leeds grading to include reference colour photographs and the introduction of grade 1–3 for non-inflammatory acne139 §On one side of the face ||In Europe240 ¶In the United States241 Management A large number of acne treatment products are available, and a wide range of combination products have been introduced, which offer numerous treatment options to various patients with different preferences However, large, well-designed, randomized controlled trials to assess and compare the effectiveness of acne treatment options are either lacking or have used different designs and methodologies, resulting in a scarcity of strong evidence to support many of the recommendations in acne treatment guidelines Hence, current guidelines rely on the opinions of experts Furthermore, for acne associated with systemic diseases, therapeutic information is mostly at the level of case reports19,148 Current guidelines for acne treatment include those from the Global Alliance to Improve Outcomes in Acne6,157, the American Academy of Dermatology/ American Academy of Dermatology Association158, the European Dermatology Forum Evidence-based (S3) guidelines for the treatment of acne159, the European expert group on oral antibiotics in acne160, and the Forum for the Improvement of Clinical Trials in Acne position on isotretinoin161 Some general principles that form the foundation of these guidelines are as follows Acne is no longer considered a natural part of the life cycle, and to prevent its psychological and physical sequelae, early and aggressive treatment is necessary Longitudinal studies of the natural history of acne focusing on the role of early treatment in preventing persistent disease are yet to be conducted162 As a multifactorial disease, combination therapy seems to be the most reasonable approach in most cases6 Guideline recommendations are categorized according to acne severity and the presence or absence of inflammation (TABLE 3) Combination of a topical retinoid plus an antimicrobial agent is recommended as first-line therapy for most patients with acne, targeting multiple pathological factors in both inflammatory and non-inflammatory acne lesions Two key exceptions for this general rule are severe acne and mild comedogenic or non-inflammatory acne For mild comedogenic or non-inflammatory acne, treatment usually starts solely with a topical retinoid, whereas in the case of severe acne, oral isotretinoin therapy should be considered early To limit antibiotic resistance, antibiotic monotherapy should be avoided In mild-to-moderate acne, topical antibiotics should be used with benzoyl peroxide (BPO) and a topical retinoid, and oral antibiotics are better reserved for moderate-to-moderately severe acne; the duration of antibiotic use should be limited163 Isotretinoin remains the treatment of choice for severe acne, but several precautionary measures have to be taken during an isotretinoin course149,161 Topical retinoids Topical retinoids are vitamin A derivatives The binding of retinoids to their receptors — the retinoic acid receptors and the retinoid X receptors — in keratinocytes reduces follicular hyperkeratinization and decreases adhesion164 This effect not only results in inhibition of comedogenesis but also might enhance the penetration of other topical acne medications Furthermore, NATURE REVIEWS | DISEASE PRIMERS VOLUME | 2015 | © 2015 Macmillan Publishers Limited All rights reserved PRIMER Table | Differential diagnosis of acne vulgaris Condition Patient history Clinical presentation Drug-induced acneiform eruptions History of drug intake, including halogenated compounds (iodides, radiopaque contrast materials and bromides), anti-epileptic drugs (phenytoin and carbamazepine), antidepressant drugs (lithium), anti-tubercular drugs (isoniazid), growth hormone, cyclosporine, vitamins (B1, B6 and B12) and EGFR inhibitors Monomorphous papules or pustules; localization on the trunk and upper extremities Diagnostic methods Laboratory test Skin biopsy Imaging N/A Degeneration of the follicular epithelium, with a localized intrafollicular and perifollicular neutrophilic inflammatory reaction N/A Papulopustular More common in women rosacea 30–40 years of age; chronic course No comedones; mild N/A flushing or erythema at the convexities of the face Not diagnostic N/A Gram-negative Long-term oral antibiotic treatment folliculitis for acne Papules and pustules Bacterial culture and Gram staining Infiltrate of inflammatory cells (mainly neutrophils, later mixed with lymphocytes) in the follicular ostium and upper regions of the follicle N/A Acne fulminans Sudden onset of haemorrhagic ulcerative acne mainly on the trunk; fever, myalgias and arthralgias Anaemia or leukocytosis Haemorrhagic epidermal necrosis and granulocytes in the dermis Focal lytic bone lesions or sacroiliitis might be present Affects adolescent boys; can be precipitated by oral isotretinoin intake EGFR, epidermal growth factor receptor; N/A, not applicable retinoids have anti-inflammatory effects by inhibiting the activation of the transcription factor AP1 (REF. 165), and by downregulating the expression of TLR2 (REF. 166) Owing to these comedolytic (that is, agents that break up comedones and open up clogged pores) and anti- inflammatory effects, topical retinoids are strongly recommended in the treatment regimen of both com edogenic and inflammatory acne as an initial and maintenance treatment and to avoid relapses6 Topical retinoids for the treatment of acne include tretinoin, adapalene, tazarotene (which is not available in Europe), retinaldehyde and topical isotretinoin (the latter two are not available in the United States), which are all available in various formulations and concentrations167 To prevent acne development or maintain improvement and avoid acne relapses, the application of appropriate topical treatment is recommended159 The fact that the micro comedone is the initial microscopic acne lesion highlights the need for applying topical acne therapies not only on clinically apparent lesions but also on the whole face to prevent the development of visible lesions159 However, because they should be applied to the whole affected area, topical treatments often cause irritation and dryness In addition, use of topical retinoids is not recommended during pregnancy; tazarotene is classified as a pregnancy category X drug (that is, fetal risk has been proven in investigational or marketing studies in humans) and is contraindicated, whereas adapalene and topical tretinoin are classified as pregnancy category C drugs (that is, adverse effects have been shown in animal studies, but controlled studies in humans are still lacking) Several randomized trials have compared different topical retinoids, but more studies are needed Adapalene products tend to be the most tolerable of treatments Topical retinoids are also reasonable choices for maintenance therapy after initial successful treatment Topical antimicrobials BPO BPO, an organic peroxide derived from a byproduct of coal tar, has become the most widely used topical acne medication in dermatology 168 BPO treatment alone improves inflammatory acne157, and its mechanisms of action include antimicrobial, antiinflammatory and keratolytic effects and wound-healing activity 168 Although more potent than any prescription antibiotic against P. acnes, BPO remains safe for human use168 Low-strength (2.5% or 5%) BPO is recommended, as it is less irritating than and as effective as higher concentration preparations169 For BPO, as with adapalene, the time to achieve a 25% reduction in the mean number of inflammatory lesions does not change for different concentrations in patients with mild-to-moderate papulopustular acne However, BPO seemed to act faster than topical adapalene, tretinoin and isotretinoin170 Some authors have suggested starting treatment with BPO alone for mild inflammatory acne, owing to the cost of retinoids, safety and good results162 BPO is also available as a fixed-dose combination product with adapalene that can help to reduce the complexity of treatment Topical antibiotics Erythromycin and clindamycin are the most commonly used topical antibiotics in acne treatment, both of which are available in different formulations Antibiotics (either topical or oral) are not intended to be a monotherapy for acne For example, 10 | 2015 | VOLUME www.nature.com/nrdp © 2015 Macmillan Publishers Limited All rights reserved PRIMER topical antibiotics should only be used in combination with BPO to help prevent the development of antibioticresistant bacteria Fixed-dose combination gels of topical antibiotics with BPO are also available171, as well as a combined gel formulation of clindamycin with tretinoin172,173 The clindamycin and BPO combination seems to act more rapidly than adapalene; this combination might be faster than BPO alone, but more studies are needed to confirm this result 170 A combination of adapalene and BPO and that of clindamycin and BPO have comparable times to achieve a 25% reduction in lesion count 170,171 Dapsone gel is a newer topical antibiotic choice Although the mechanism of action of dapson is not yet clear, it has shown good results in studies and various new options are in development 174 Other topical agents Salicylic acid is a topical medication present in many over-the-counter products, which has comedolytic effects but may be less effective than retinoids Another topical agent, azelaic acid, has antibacterial, comedolytic and anti-inflammatory properties and is considered as a potential first-line monotherapy for female adult patients with acne, and a good choice for maintenance therapy owing to its good tolerability and safety 175 A potential adverse effect of azelaic acid is hypopigmentation, which might be helpful in treating post-inflammatory hyperpigmentation Although most publications have investigated the 20% azelaic acid cream formulation, the 15% gel was as efficient as BPO and topical clindamycin for patients with mild-tomoderate acne176 A novel study using the cyanoacrylate technique — a precise method for microcomedone assessment — in patients with mild-to-moderate acne has shown an equivalent effect for azelaic acid 15% gel compared with 0.1% adapalene 177 Oral antibiotics Doxycycline and minocycline have replaced tetra cycline and erythromycin in most cases of acne therapy Tetracycline, doxycycline and minocycline are contra indicated in pregnancy and in children