Guidelines of care for the management of acne vulgaris

Open AccessPublished:February 17, 2016DOI:https://doi.org/10.1016/j.jaad.2015.12.037
      Acne is one of the most common disorders treated by dermatologists and other health care providers. While it most often affects adolescents, it is not uncommon in adults and can also be seen in children. This evidence-based guideline addresses important clinical questions that arise in its management. Issues from grading of acne to the topical and systemic management of the disease are reviewed. Suggestions on use are provided based on available evidence.

      Key words

      Disclaimer

      Adherence to these guidelines will not ensure successful treatment in every situation. Furthermore, these guidelines should not be interpreted as setting a standard of care, or be deemed inclusive of all proper methods of care, nor exclusive of other methods of care reasonably directed to obtaining the same results. The ultimate judgment regarding the propriety of any specific therapy or technique must be made by the physician and the patient in light of all the circumstances presented by the individual patient, and the known variability and biologic behavior of the disease. This guideline reflects the best available data at the time the guideline was prepared. The results of future studies may require revisions to the recommendations in this guideline to reflect new data.

      Scope

      This guideline addresses the management of adolescent and adult patients who present with acne vulgaris (AV). This document will discuss various acne treatments, including topical therapies, systemic agents, and physical modalities, including lasers and photodynamic therapy. In addition, grading/classification system, microbiology and endocrinology testing, complementary/alternative therapies, and the role of diet will be reviewed. This guideline does not examine the treatment of acne sequelae (eg, scarring or postinflammatory dyschromia).

      Methods

      A work group of 17 recognized acne experts, 1 general practitioner, 1 pediatrician, and 1 patient was convened to determine the scope of the guideline and identify clinical questions (Table I) in the diagnosis and management of AV. Work group members completed a disclosure of interests, which was periodically updated and reviewed throughout guideline development. If a potential conflict was noted, the work group member recused him or herself from discussion and drafting of recommendations pertinent to the topic area of the disclosed interest.
      Table IClinical questions used to structure the evidence review
      What systems are most commonly used for the grading and classification of adult acne and acne vulgaris in adolescents (11-21 years of age) to adults?
      What is the role of microbiologic and endocrine testing in evaluating patients with adult acne and acne vulgaris in adolescents to adults?
      • What is the effectiveness and what are the potential side effects of topical agents in the treatment of adult acne and acne vulgaris in adolescents to adults, including:
        • Retinoids and retinoid-like drugs
        • Benzoyl peroxide
        • Topical antibiotics
        • Salicylic/azelaic acids
        • Sulfur and resorcinol
        • Aluminum chloride
        • Zinc
        • Combinations of topical agents
      • What is the effectiveness and what are the potential side effects of the following systemic antibacterial agents in the treatment of adult acne and acne vulgaris in adolescents to adults, including:
        • Tetracyclines: doxycycline and minocycline
        • Macrolides: erythromycin and azithromycin
        • Clindamycin
        • Trimethoprim (with or without sulfamethoxazole)
        • Ampicillin/amoxicillin
      • What is the effectiveness and what are the potential side effects of hormonal agents in the treatment of adult acne and acne vulgaris in adolescents to adults, including:
        • Contraceptive agents
        • Spironolactone
        • Antiandrogens
        • Oral corticosteroids
      What is the effectiveness and what are the potential side effects of isotretinoin in the treatment of adult acne and acne vulgaris in adolescents to adults?
      • What is the effectiveness and potential side effects of physical modalities for the treatment of acne vulgaris in adolescents to adults, including:
        • Intralesional steroids
        • Chemical peels
        • Comedo removal
        • Lasers and photodynamic therapy
          Indicates a new clinical question for this guideline.
      • What is the effectiveness and what are the potential side effects of complementary/alternative therapies in the treatment of adult acne and acne vulgaris in adolescents to adults, including:
        • Herbal agents
        • Homeopathy
        • Psychological approaches
        • Massage therapy
        • Hypnosis/biofeedback
      What is the role of diet in adult acne in adolescents to adults?
      Indicates a new clinical question for this guideline.
      An evidence-based model was used and evidence was obtained for the clinical questions (Table I) using a systematic search of PubMed and the Cochrane Library database from May 2006 through September 2014 for clinical questions addressed in the previous version of this guideline published in 2007, and 1964 to 2014 for all newly identified clinical questions. Searches were prospectively limited to publications in the English language. MeSH terms and strings used in various combinations in the literature search included: acne or acne vulgaris combined with treatment, therapy, prevention, prophylaxis, grading, classification, scoring, microbiology, endocrinology, hormone, topical, retinoid, benzoyl peroxide (BP), antibiotic, doxycycline, minocycline, tetracycline, macrolide, erythromycin, azithromycin, trimethoprim (with or without sulfamethoxazole), oral contraceptives, antiandrogen, corticosteroid, isotretinoin, peel, complementary, alternative, herbal, diet, glycemic index, milk, antioxidants, probiotics, and fish oil. Additional studies were identified by hand-searching bibliographies of publications, including reviews and metaanalyses.
      A total of 1145 abstracts were initially assessed for possible inclusion; 242 were retained for final review based on relevancy and the highest level of available evidence for the outlined clinical questions. Evidence tables were generated for these studies and used by the work group in developing recommendations. In addition, the evidence tables generated for the Academy's previous acne guideline were also used by the work group. The Academy's previous published guidelines on acne were also evaluated, as were other current published guidelines on acne.
      • Strauss J.S.
      • Krowchuk D.P.
      • Leyden J.J.
      • et al.
      Guidelines of care for acne vulgaris management.
      • Eichenfield L.F.
      • Krakowski A.C.
      • Piggott C.
      • et al.
      Evidence-based recommendations for the diagnosis and treatment of pediatric acne.
      Relevant references published after September 2014 are provided solely as supplemental supporting text information for recommendations as derived from the systematic search, and to address comments received during the guideline review and approval process.
      The available evidence was evaluated using a unified system called the Strength of Recommendation Taxonomy (SORT) developed by editors of the US family medicine and primary care journals (ie, American Family Physician, Family Medicine, Journal of Family Practice, and BMJ USA).
      • Ebell M.H.
      • Siwek J.
      • Weiss B.D.
      • et al.
      Simplifying the language of evidence to improve patient care: Strength of recommendation taxonomy (SORT): a patient-centered approach to grading evidence in medical literature.
      Evidence was graded using a 3-point scale based on the quality of methodology (eg, randomized control trial, case control, prospective/retrospective cohort, case series, etc) and the overall focus of the study (ie, diagnosis, treatment/prevention/screening, or prognosis) as follows:
      • I.
        Good-quality patient-oriented evidence (ie, evidence measuring outcomes that matter to patients: morbidity, mortality, symptom improvement, cost reduction, and quality of life).
      • II.
        Limited-quality patient-oriented evidence.
      • III.
        Other evidence, including consensus guidelines, opinion, case studies, or disease-oriented evidence (ie, evidence measuring intermediate, physiologic, or surrogate end points that may or may not reflect improvements in patient outcomes).
      Clinical recommendations were developed on the best available evidence tabled in the guideline. The strength of recommendation was ranked as follows:
      • A.
        Recommendation based on consistent and good-quality patient-oriented evidence.
      • B.
        Recommendation based on inconsistent or limited-quality patient-oriented evidence.
      • C.
        Recommendation based on consensus, opinion, case studies, or disease-oriented evidence.
      In those situations where documented evidence-based data were not available or were showing inconsistent or limited conclusions, expert opinion and medical consensus was used to generate clinical recommendations.
      This guideline has been developed in accordance with the American Academy of Dermatology/American Academy of Dermatology Association “Administrative Regulations for Evidence-Based Clinical Practice Guidelines” (version approved August 2012), which include the opportunity for review and comment by the entire AAD membership and final review and approval by the AAD Board of Directors.

      American Academy of Dermatology website. Guideline development process. Available at: https://www.aad.org/practice-tools/quality-care/clinical-guidelines/guideline-development-process. Accessed January 4, 2016.

      This guideline will be considered current for a period of 5 years from the date of publication, unless reaffirmed, updated, or retired at or before that time.

      Definition

      AV is a chronic inflammatory dermatosis notable for open or closed comedones (blackheads and whiteheads) and inflammatory lesions, including papules, pustules, or nodules (also known as cysts).

      Introduction

      Acne is a common skin disease, especially in adolescents and young adults. Approximately 50 million people in the United States have AV.
      • White G.M.
      Recent findings in the epidemiologic evidence, classification, and subtypes of acne vulgaris.
      Acne affects approximately 85% of teenagers, but can occur in most age groups
      • Bhate K.
      • Williams H.C.
      Epidemiology of acne vulgaris.
      and can persist into adulthood. The prevalence of acne in adult women is about 12%.
      • Goulden V.
      • Stables G.I.
      • Cunliffe W.J.
      Prevalence of facial acne in adults.
      There is no mortality associated with acne, but there is often significant physical and psychological morbidity, such as permanent scarring, poor self-image, depression, and anxiety. The direct cost of the disease is estimated to exceed $3 billion per year.
      • Bhate K.
      • Williams H.C.
      Epidemiology of acne vulgaris.
      Acne is a multifactorial inflammatory disease affecting the pilosebaceous follicles of the skin. The current understanding of acne pathogenesis is continuously evolving. Key pathogenic factors that play an important role in the development of acne are follicular hyperkeratinization, microbial colonization with Propionibacterium acnes, sebum production, and complex inflammatory mechanisms involving both innate and acquired immunity. In addition, studies have suggested that neuroendocrine regulatory mechanisms, diet, and genetic and nongenetic factors all may contribute to the multifactorial process of acne pathogenesis. An algorithm for the treatment and management of acne in adolescents and young adults is shown in Fig 1.
      Figure thumbnail gr1
      Fig 1Treatment algorithm for the management of acne vulgaris in adolescents and young adults. The double asterisks (∗∗) indicate that the drug may be prescribed as a fixed combination product or as separate component. BP, Benzoyl peroxide.

      Systems for the grading and classification of acne

      Acne grading systems may be useful in patient care. Such systems can assist in more specific classification of disease, help determine appropriate treatment options, and monitor improvement during the treatment course. Recommendations for grading and classifying acne are shown in Table II, and the strength of recommendations for grading and classifying acne is shown in Table III.
      Table IIRecommendations for grading and classification of acne
      Clinicians may find it helpful to use a consistent grading/classification scale (encompassing the numbers and types of acne lesions as well as disease severity, anatomic sites, and scarring) to facilitate therapeutic decisions and assess response to treatment.
      Currently, no universal acne grading/classifying system can be recommended.
      Table IIIStrength of recommendations for the management and treatment of acne vulgaris
      RecommendationStrength of recommendationLevel of evidenceReferences
      Grading/classification systemBII, III
      • Tan J.K.
      • Tang J.
      • Fung K.
      • et al.
      Development and validation of a comprehensive acne severity scale.
      ,
      • Mallon E.
      • Newton J.N.
      • Klassen A.
      • et al.
      The quality of life in acne: a comparison with general medical conditions using generic questionnaires.
      ,
      • Gupta M.A.
      • Johnson A.M.
      • Gupta A.K.
      The development of an Acne Quality of Life scale: reliability, validity, and relation to subjective acne severity in mild to moderate acne vulgaris.
      ,
      • Lasek R.J.
      • Chren M.M.
      Acne vulgaris and the quality of life of adult dermatology patients.
      ,
      • Martin A.R.
      • Lookingbill D.P.
      • Botek A.
      • et al.
      Health-related quality of life among patients with facial acne—assessment of a new acne-specific questionnaire.
      ,
      • Rapp S.R.
      • Feldman S.R.
      • Graham G.
      • et al.
      The Acne Quality of Life Index (Acne-QOLI): development and validation of a brief instrument.
      ,
      • Dreno B.
      • Khammari A.
      • Orain N.
      • et al.
      ECCA grading scale: an original validated acne scar grading scale for clinical practice in dermatology.
      ,
      • Pochi P.E.
      • Shalita A.R.
      • Strauss J.S.
      • et al.
      Report of the Consensus Conference on Acne Classification. Washington, D.C., March 24 and 25, 1990.
      ,
      • Doshi A.
      • Zaheer A.
      • Stiller M.J.
      A comparison of current acne grading systems and proposal of a novel system.
      ,
      • Lucky A.W.
      • Barber B.L.
      • Girman C.J.
      • et al.
      A multirater validation study to assess the reliability of acne lesion counting.
      ,
      • Cook C.H.
      • Centner R.L.
      • Michaels S.E.
      An acne grading method using photographic standards.
      ,
      • Burke B.M.
      • Cunliffe W.J.
      The assessment of acne vulgaris–the Leeds technique.
      ,
      • Allen B.S.
      • Smith Jr., J.G.
      Various parameters for grading acne vulgaris.
      ,
      • Dreno B.
      • Poli F.
      • Pawin H.
      • et al.
      Development and evaluation of a Global Acne Severity Scale (GEA Scale) suitable for France and Europe.
      ,
      • Hayashi N.
      • Akamatsu H.
      • Kawashima M.
      Acne Study Group. Establishment of grading criteria for acne severity.
      ,
      • Hayashi N.
      • Suh D.H.
      • Akamatsu H.
      • Kawashima M.
      Acne Study Group
      Evaluation of the newly established acne severity classification among Japanese and Korean dermatologists.
      ,
      • Tan J.
      • Wolfe B.
      • Weiss J.
      • et al.
      Acne severity grading: determining essential clinical components and features using a Delphi consensus.
      ,
      • Tan J.K.
      • Jones E.
      • Allen E.
      • et al.
      Evaluation of essential clinical components and features of current acne global grading scales.
      ,
      • Beylot C.
      • Chivot M.
      • Faure M.
      • et al.
      Inter-observer agreement on acne severity based on facial photographs.
      ,
      • Tan J.K.
      • Fung K.
      • Bulger L.
      Reliability of dermatologists in acne lesion counts and global assessments.
      ,
      • Bergman H.
      • Tsai K.Y.
      • Seo S.J.
      • Kvedar J.C.
      • Watson A.J.
      Remote assessment of acne: the use of acne grading tools to evaluate digital skin images.
      ,
      • Min S.
      • Kong H.J.
      • Yoon C.
      • Kim H.C.
      • Suh D.H.
      Development and evaluation of an automatic acne lesion detection program using digital image processing.
      ,
      • Qureshi A.A.
      • Brandling-Bennett H.A.
      • Giberti S.
      • et al.
      Evaluation of digital skin images submitted by patients who received practical training or an online tutorial.
      ,
      • Choi C.W.
      • Choi J.W.
      • Park K.C.
      • Youn S.W.
      Ultraviolet-induced red fluorescence of patients with acne reflects regional casual sebum level and acne lesion distribution: qualitative and quantitative analyses of facial fluorescence.
      ,
      • Choi C.W.
      • Lee D.H.
      • Kim H.S.
      • et al.
      The clinical features of late onset acne compared with early onset acne in women.
      ,
      • Dobrev H.
      Fluorescence diagnostic imaging in patients with acne.
      ,
      • Choi C.W.
      • Choi J.W.
      • Youn S.W.
      Subjective facial skin type, based on the sebum related symptoms, can reflect the objective casual sebum level in acne patients.
      ,
      • Kim M.K.
      • Choi S.Y.
      • Byun H.J.
      • et al.
      Comparison of sebum secretion, skin type, pH in humans with and without acne.
      ,
      • Xhauflaire-Uhoda E.
      • Pierard G.E.
      Skin capacitance imaging of acne lesions.
      ,
      • Youn S.H.
      • Choi C.W.
      • Choi J.W.
      • Youn S.W.
      The skin surface pH and its different influence on the development of acne lesion according to gender and age.
      ,
      • Youn S.W.
      • Kim J.H.
      • Lee J.E.
      • Kim S.O.
      • Park K.C.
      The facial red fluorescence of ultraviolet photography: is this color due to Propionibacterium acnes or the unknown content of secreted sebum?.
      ,
      • Zane C.
      • Capezzera R.
      • Pedretti A.
      • Facchinetti E.
      • Calzavara-Pinton P.
      Non-invasive diagnostic evaluation of phototherapeutic effects of red light phototherapy of acne vulgaris.
      Microbiologic testingBII, III
      • Cove J.H.
      • Cunliffe W.J.
      • Holland K.T.
      Acne vulgaris: is the bacterial population size significant?.
      ,
      • Mourelatos K.
      • Eady E.A.
      • Cunliffe W.J.
      • Clark S.M.
      • Cove J.H.
      Temporal changes in sebum excretion and propionibacterial colonization in preadolescent children with and without acne.
      ,
      • Shaheen B.
      • Gonzalez M.
      A microbial aetiology of acne: what is the evidence?.
      ,
      • Fitz-Gibbon S.
      • Tomida S.
      • Chiu B.H.
      • et al.
      Propionibacterium acnes strain populations in the human skin microbiome associated with acne.
      ,
      • Holland C.
      • Mak T.N.
      • Zimny-Arndt U.
      • et al.
      Proteomic identification of secreted proteins of Propionibacterium acnes.
      ,
      • Lomholt H.B.
      • Kilian M.
      Population genetic analysis of Propionibacterium acnes identifies a subpopulation and epidemic clones associated with acne.
      ,
      • Miura Y.
      • Ishige I.
      • Soejima N.
      • et al.
      Quantitative PCR of Propionibacterium acnes DNA in samples aspirated from sebaceous follicles on the normal skin of subjects with or without acne.
      ,
      • Tochio T.
      • Tanaka H.
      • Nakata S.
      • Ikeno H.
      Accumulation of lipid peroxide in the content of comedones may be involved in the progression of comedogenesis and inflammatory changes in comedones.
      ,
      • Tomida S.
      • Nguyen L.
      • Chiu B.H.
      • et al.
      Pan-genome and comparative genome analyses of propionibacterium acnes reveal its genomic diversity in the healthy and diseased human skin microbiome.
      Endocrinologic testingBI, II
      • Lucky A.W.
      • Biro F.M.
      • Simbartl L.A.
      • Morrison J.A.
      • Sorg N.W.
      Predictors of severity of acne vulgaris in young adolescent girls: results of a five-year longitudinal study.
      ,
      • Bunker C.B.
      • Newton J.A.
      • Kilborn J.
      • et al.
      Most women with acne have polycystic ovaries.
      ,
      • Lawrence D.M.
      • Katz M.
      • Robinson T.W.
      • et al.
      Reduced sex hormone binding globulin and derived free testosterone levels in women with severe acne.
      ,
      • Timpatanapong P.
      • Rojanasakul A.
      Hormonal profiles and prevalence of polycystic ovary syndrome in women with acne.
      ,
      • Lucky A.W.
      Endocrine aspects of acne.
      ,
      • Lucky A.W.
      • McGuire J.
      • Rosenfield R.L.
      • Lucky P.A.
      • Rich B.H.
      Plasma androgens in women with acne vulgaris.
      ,
      • Abulnaja K.O.
      Changes in the hormone and lipid profile of obese adolescent Saudi females with acne vulgaris.
      ,
      • Arora M.K.
      • Seth S.
      • Dayal S.
      The relationship of lipid profile and menstrual cycle with acne vulgaris.
      Topical therapies
       Benzoyl peroxideAI, II
      • Fyrand O.
      • Jakobsen H.B.
      Water-based versus alcohol-based benzoyl peroxide preparations in the treatment of acne vulgaris.
      ,
      • Mills Jr., O.H.
      • Kligman A.M.
      • Pochi P.
      • Comite H.
      Comparing 2.5%, 5%, and 10% benzoyl peroxide on inflammatory acne vulgaris.
      ,
      • Schutte H.
      • Cunliffe W.J.
      • Forster R.A.
      The short-term effects of benzoyl peroxide lotion on the resolution of inflamed acne lesions.
       Topical antibiotics (eg, clindamycin and erythromycin)AI, II
      • Mills Jr., O.
      • Thornsberry C.
      • Cardin C.W.
      • Smiles K.A.
      • Leyden J.J.
      Bacterial resistance and therapeutic outcome following three months of topical acne therapy with 2% erythromycin gel versus its vehicle.
      ,
      • Bernstein J.E.
      • Shalita A.R.
      Topically applied erythromycin in inflammatory acne vulgaris.
      ,
      • Jones E.L.
      • Crumley A.F.
      Topical erythromycin vs blank vehicle in a multiclinic acne study.
      ,
      • Shalita A.R.
      • Smith E.B.
      • Bauer E.
      Topical erythromycin v clindamycin therapy for acne. A multicenter, double-blind comparison.
      ,
      • Leyden J.J.
      • Shalita A.R.
      • Saatjian G.D.
      • Sefton J.
      Erythromycin 2% gel in comparison with clindamycin phosphate 1% solution in acne vulgaris.
      ,
      • Kuhlman D.S.
      • Callen J.P.
      A comparison of clindamycin phosphate 1 percent topical lotion and placebo in the treatment of acne vulgaris.
      ,
      • Becker L.E.
      • Bergstresser P.R.
      • Whiting D.A.
      • et al.
      Topical clindamycin therapy for acne vulgaris. A cooperative clinical study.
       Combination of topical antibiotics and benzoyl peroxideAI
      • Leyden J.J.
      • Hickman J.G.
      • Jarratt M.T.
      • Stewart D.M.
      • Levy S.F.
      The efficacy and safety of a combination benzoyl peroxide/clindamycin topical gel compared with benzoyl peroxide alone and a benzoyl peroxide/erythromycin combination product.
      ,
      • Lookingbill D.P.
      • Chalker D.K.
      • Lindholm J.S.
      • et al.
      Treatment of acne with a combination clindamycin/benzoyl peroxide gel compared with clindamycin gel, benzoyl peroxide gel and vehicle gel: combined results of two double-blind investigations.
      ,
      • Tschen E.H.
      • Katz H.I.
      • Jones T.M.
      • et al.
      A combination benzoyl peroxide and clindamycin topical gel compared with benzoyl peroxide, clindamycin phosphate, and vehicle in the treatment of acne vulgaris.
       Topical retinoids (eg, tretinoin, adapalene, and tazarotene)AI, II
      • Krishnan G.
      Comparison of two concentrations of tretinoin solution in the topical treatment of acne vulgaris.
      ,
      • Bradford L.G.
      • Montes L.F.
      Topical application of vitamin A acid in acne vulgaris.
      ,
      • Shalita A.R.
      • Chalker D.K.
      • Griffith R.F.
      • et al.
      Tazarotene gel is safe and effective in the treatment of acne vulgaris: a multicenter, double-blind, vehicle-controlled study.
      ,
      • Shalita A.
      • Weiss J.S.
      • Chalker D.K.
      • et al.
      A comparison of the efficacy and safety of adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris: a multicenter trial.
      ,
      • Cunliffe W.J.
      • Caputo R.
      • Dreno B.
      • et al.
      Clinical efficacy and safety comparison of adapalene gel and tretinoin gel in the treatment of acne vulgaris: Europe and U.S. multicenter trials.
      ,
      • Richter J.R.
      • Bousema M.T.
      • De Boulle K.L.V.
      • Degreef H.J.
      • Poli F.
      Efficacy of a fixed clindamycin phosphate 1.2%, tretinoin 0.025% gel formulation (Velac) in the topical control of facial acne lesions.
      ,
      • Zouboulis C.C.
      • Derumeaux L.
      • Decroix J.
      • Maciejewska-Udziela B.
      • Cambazard F.
      • Stuhlert A.
      A multicentre, single-blind, randomized comparison of a fixed clindamycin phosphate/tretinoin gel formulation (Velac) applied once daily and a clindamycin lotion formulation (Dalacin T) applied twice daily in the topical treatment of acne vulgaris.
      ,
      • Christiansen J.V.
      • Gadborg E.
      • Ludvigsen K.
      • et al.
      Topical tretinoin, vitamin A acid (Airol) in acne vulgaris. A controlled clinical trial.
      ,
      • Dunlap F.E.
      • Mills O.H.
      • Tuley M.R.
      • Baker M.D.
      • Plott R.T.
      Adapalene 0.1% gel for the treatment of acne vulgaris: its superiority compared to tretinoin 0.025% cream in skin tolerance and patient preference.
      ,
      • Kakita L.
      Tazarotene versus tretinoin or adapalene in the treatment of acne vulgaris.
      ,
      • Webster G.F.
      • Berson D.
      • Stein L.F.
      • Fivenson D.P.
      • Tanghetti E.A.
      • Ling M.
      Efficacy and tolerability of once-daily tazarotene 0.1% gel versus once-daily tretinoin 0.025% gel in the treatment of facial acne vulgaris: a randomized trial.
      ,
      • Galvin S.A.
      • Gilbert R.
      • Baker M.
      • Guibal F.
      • Tuley M.R.
      Comparative tolerance of adapalene 0.1% gel and six different tretinoin formulations.
       Combination of topical retinoids and benzoyl peroxide/topical antibioticAI, II
      • Richter J.R.
      • Bousema M.T.
      • De Boulle K.L.V.
      • Degreef H.J.
      • Poli F.
      Efficacy of a fixed clindamycin phosphate 1.2%, tretinoin 0.025% gel formulation (Velac) in the topical control of facial acne lesions.
      ,
      • Zouboulis C.C.
      • Derumeaux L.
      • Decroix J.
      • Maciejewska-Udziela B.
      • Cambazard F.
      • Stuhlert A.
      A multicentre, single-blind, randomized comparison of a fixed clindamycin phosphate/tretinoin gel formulation (Velac) applied once daily and a clindamycin lotion formulation (Dalacin T) applied twice daily in the topical treatment of acne vulgaris.
       Azelaic acidAI
      • Cunliffe W.J.
      • Holland K.T.
      Clinical and laboratory studies on treatment with 20% azelaic acid cream for acne.
      ,
      • Katsambas A.
      • Graupe K.
      • Stratigos J.
      Clinical studies of 20% azelaic acid cream in the treatment of acne vulgaris. Comparison with vehicle and topical tretinoin.
       DapsoneAI, II
      • Draelos Z.D.
      • Carter E.
      • Maloney J.M.
      • et al.
      Two randomized studies demonstrate the efficacy and safety of dapsone gel, 5% for the treatment of acne vulgaris.
      ,
      • Lucky A.W.
      • Maloney J.M.
      • Roberts J.
      • et al.
      Dapsone gel 5% for the treatment of acne vulgaris: safety and efficacy of long-term (1 year) treatment.
      ,
      • Tanghetti E.
      • Harper J.C.
      • Oefelein M.G.
      The efficacy and tolerability of dapsone 5% gel in female vs male patients with facial acne vulgaris: gender as a clinically relevant outcome variable.
       Salicylic acidBII
      • Shalita A.R.
      Treatment of mild and moderate acne vulgaris with salicylic acid in an alcohol-detergent vehicle.
      Systemic antibiotics
       Tetracyclines (eg, tetracycline, doxycycline, and minocycline)AI, II
      • Garner S.E.
      • Eady A.
      • Bennett C.
      • Newton J.N.
      • Thomas K.
      • Popescu C.M.
      Minocycline for acne vulgaris: efficacy and safety.
      ,
      • Leyden J.J.
      • Bruce S.
      • Lee C.S.
      • et al.
      A randomized, phase 2, dose-ranging study in the treatment of moderate to severe inflammatory facial acne vulgaris with doxycycline calcium.
      ,
      • Lebrun-Vignes B.
      • Kreft-Jais C.
      • Castot A.
      • Chosidow O.
      French Network of Regional Centers of Pharmacovigilance
      Comparative analysis of adverse drug reactions to tetracyclines: results of a French national survey and review of the literature.
      ,
      • Kermani T.A.
      • Ham E.K.
      • Camilleri M.J.
      • Warrington K.J.
      Polyarteritis nodosa-like vasculitis in association with minocycline use: a single-center case series.
       Macrolides (eg, azithromycin and erythromycin)AI
      • Rafiei R.
      • Yaghoobi R.
      Azithromycin versus tetracycline in the treatment of acne vulgaris.
       Trimethoprim (with or without sulfamethoxazole)BII
      • Jen I.
      A comparison of low dosage trimethoprim/sulfamethoxazole with oxytetracycline in acne vulgaris.
      ,
      • Fenner J.A.
      • Wiss K.
      • Levin N.A.
      Oral cephalexin for acne vulgaris: clinical experience with 93 patients.
       Limiting treatment duration and concomitant/maintenance topical therapyAI, II
      • Gold L.S.
      • Cruz A.
      • Eichenfield L.
      • et al.
      Effective and safe combination therapy for severe acne vulgaris: a randomized, vehicle-controlled, double-blind study of adapalene 0.1%-benzoyl peroxide 2.5% fixed-dose combination gel with doxycycline hyclate 100 mg.
      ,
      • Leyden J.
      • Thiboutot D.M.
      • Shalita A.R.
      • et al.
      Comparison of tazarotene and minocycline maintenance therapies in acne vulgaris: a multicenter, double-blind, randomized, parallel-group study.
      ,
      • Margolis D.J.
      • Fanelli M.
      • Hoffstad O.
      • Lewis J.D.
      Potential association between the oral tetracycline class of antimicrobials used to treat acne and inflammatory bowel disease.
      Hormonal agents
       Combined oral contraceptivesAI
      • Lucky A.W.
      • Koltun W.
      • Thiboutot D.
      • et al.
      A combined oral contraceptive containing 3-mg drospirenone/20-microg ethinyl estradiol in the treatment of acne vulgaris: a randomized, double-blind, placebo-controlled study evaluating lesion counts and participant self-assessment.
      ,
      • Maloney J.M.
      • Dietze Jr., P.
      • Watson D.
      • et al.
      Treatment of acne using a 3-milligram drospirenone/20-microgram ethinyl estradiol oral contraceptive administered in a 24/4 regimen: a randomized controlled trial.
      ,
      • Maloney J.M.
      • Dietze Jr., P.
      • Watson D.
      • et al.
      A randomized controlled trial of a low-dose combined oral contraceptive containing 3 mg drospirenone plus 20 microg ethinylestradiol in the treatment of acne vulgaris: lesion counts, investigator ratings and subject self-assessment.
      ,
      • Plewig G.
      • Cunliffe W.J.
      • Binder N.
      • Hoschen K.
      Efficacy of an oral contraceptive containing EE 0.03 mg and CMA 2 mg (Belara) in moderate acne resolution: a randomized, double-blind, placebo-controlled phase III trial.
       SpironolactoneBII, III
      • Shaw J.C.
      Low-dose adjunctive spironolactone in the treatment of acne in women: a retrospective analysis of 85 consecutively treated patients.
      ,
      • Sato K.
      • Matsumoto D.
      • Iizuka F.
      • et al.
      Anti-androgenic therapy using oral spironolactone for acne vulgaris in Asians.
       FlutamideCIII
      • Wang H.S.
      • Wang T.H.
      • Soong Y.K.
      Low dose flutamide in the treatment of acne vulgaris in women with or without oligomenorrhea or amenorrhea.
      ,
      • Castelo-Branco C.
      • Moyano D.
      • Gomez O.
      • Balasch J.
      Long-term safety and tolerability of flutamide for the treatment of hirsutism.
       Oral corticosteroidsBII
      • Nader S.
      • Rodriguez-Rigau L.J.
      • Smith K.D.
      • Steinberger E.
      Acne and hyperandrogenism: impact of lowering androgen levels with glucocorticoid treatment.
      Isotretinoin
       Conventional dosingAI, II
      • Amichai B.
      • Shemer A.
      • Grunwald M.H.
      Low-dose isotretinoin in the treatment of acne vulgaris.
      ,
      • Goldstein J.A.
      • Socha-Szott A.
      • Thomsen R.J.
      • Pochi P.E.
      • Shalita A.R.
      • Strauss J.S.
      Comparative effect of isotretinoin and etretinate on acne and sebaceous gland secretion.
      ,
      • Jones D.H.
      • King K.
      • Miller A.J.
      • Cunliffe W.J.
      A dose-response study of I3-cis-retinoic acid in acne vulgaris.
      ,
      • Layton A.M.
      • Knaggs H.
      • Taylor J.
      • Cunliffe W.J.
      Isotretinoin for acne vulgaris–10 years later: a safe and successful treatment.
      ,
      • Lehucher-Ceyrac D.
      • Weber-Buisset M.J.
      Isotretinoin and acne in practice: a prospective analysis of 188 cases over 9 years.
      ,
      • Peck G.L.
      • Olsen T.G.
      • Butkus D.
      • et al.
      Isotretinoin versus placebo in the treatment of cystic acne. A randomized double-blind study.
      ,
      • Rubinow D.R.
      • Peck G.L.
      • Squillace K.M.
      • Gantt G.G.
      Reduced anxiety and depression in cystic acne patients after successful treatment with oral isotretinoin.
      ,
      • Stainforth J.M.
      • Layton A.M.
      • Taylor J.P.
      • Cunliffe W.J.
      Isotretinoin for the treatment of acne vulgaris: which factors may predict the need for more than one course?.
      ,
      • Strauss J.S.
      • Leyden J.J.
      • Lucky A.W.
      • et al.
      A randomized trial of the efficacy of a new micronized formulation versus a standard formulation of isotretinoin in patients with severe recalcitrant nodular acne.
      ,
      • Strauss J.S.
      • Rapini R.P.
      • Shalita A.R.
      • et al.
      Isotretinoin therapy for acne: results of a multicenter dose-response study.
      ,
      • Strauss J.S.
      • Stranieri A.M.
      Changes in long-term sebum production from isotretinoin therapy.
      ,
      • Goldsmith L.A.
      • Bolognia J.L.
      • Callen J.P.
      • et al.
      American Academy of Dermatology Consensus Conference on the safe and optimal use of isotretinoin: summary and recommendations.
      ,
      • Lehucher-Ceyrac D.
      • de La Salmoniere P.
      • Chastang C.
      • Morel P.
      Predictive factors for failure of isotretinoin treatment in acne patients: results from a cohort of 237 patients.
      ,
      • Strauss J.S.
      • Leyden J.J.
      • Lucky A.W.
      • et al.
      Safety of a new micronized formulation of isotretinoin in patients with severe recalcitrant nodular acne: a randomized trial comparing micronized isotretinoin with standard isotretinoin.
      ,
      • Webster G.F.
      • Leyden J.J.
      • Gross J.A.
      Comparative pharmacokinetic profiles of a novel isotretinoin formulation (isotretinoin-Lidose) and the innovator isotretinoin formulation: a randomized, 4-treatment, crossover study.
      ,
      • Alhusayen R.O.
      • Juurlink D.N.
      • Mamdani M.M.
      • Morrow R.L.
      • Shear N.H.
      • Dormuth C.R.
      Isotretinoin use and the risk of inflammatory bowel disease: a population-based cohort study.
      ,
      • Crockett S.D.
      • Gulati A.
      • Sandler R.S.
      • Kappelman M.D.
      A causal association between isotretinoin and inflammatory bowel disease has yet to be established.
      ,
      • Crockett S.D.
      • Porter C.Q.
      • Martin C.F.
      • Sandler R.S.
      • Kappelman M.D.
      Isotretinoin use and the risk of inflammatory bowel disease: a case-control study.
      ,
      • Etminan M.
      • Bird S.T.
      • Delaney J.A.
      • Bressler B.
      • Brophy J.M.
      Isotretinoin and risk for inflammatory bowel disease: a nested case-control study and meta-analysis of published and unpublished data.
      ,
      • Reddy D.
      • Siegel C.A.
      • Sands B.E.
      • Kane S.
      Possible association between isotretinoin and inflammatory bowel disease.
      ,
      • Sundstrom A.
      • Alfredsson L.
      • Sjolin-Forsberg G.
      • Gerden B.
      • Bergman U.
      • Jokinen J.
      Association of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study.
      ,
      • Bozdag K.E.
      • Gulseren S.
      • Guven F.
      • Cam B.
      Evaluation of depressive symptoms in acne patients treated with isotretinoin.
      ,
      • Chia C.Y.
      • Lane W.
      • Chibnall J.
      • Allen A.
      • Siegfried E.
      Isotretinoin therapy and mood changes in adolescents with moderate to severe acne: a cohort study.
      ,
      • Cohen J.
      • Adams S.
      • Patten S.
      No association found between patients receiving isotretinoin for acne and the development of depression in a Canadian prospective cohort.
      ,
      • Jick S.S.
      • Kremers H.M.
      • Vasilakis-Scaramozza C.
      Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide.
      ,
      • Nevoralova Z.
      • Dvorakova D.
      Mood changes, depression and suicide risk during isotretinoin treatment: a prospective study.
      ,
      • Rehn L.M.
      • Meririnne E.
      • Hook-Nikanne J.
      • Isometsa E.
      • Henriksson M.
      Depressive symptoms and suicidal ideation during isotretinoin treatment: a 12-week follow-up study of male Finnish military conscripts.
       Low-dose treatment for moderate acneAI, II
      • Agarwal U.S.
      • Besarwal R.K.
      • Bhola K.
      Oral isotretinoin in different dose regimens for acne vulgaris: a randomized comparative trial.
      ,
      • Akman A.
      • Durusoy C.
      • Senturk M.
      • Koc C.K.
      • Soyturk D.
      • Alpsoy E.
      Treatment of acne with intermittent and conventional isotretinoin: a randomized, controlled multicenter study.
      ,
      • Borghi A.
      • Mantovani L.
      • Minghetti S.
      • Giari S.
      • Virgili A.
      • Bettoli V.
      Low-cumulative dose isotretinoin treatment in mild-to-moderate acne: efficacy in achieving stable remission.
      ,
      • Kaymak Y.
      • Ilter N.
      The effectiveness of intermittent isotretinoin treatment in mild or moderate acne.
      ,
      • Lee J.W.
      • Yoo K.H.
      • Park K.Y.
      • et al.
      Effectiveness of conventional, low-dose and intermittent oral isotretinoin in the treatment of acne: a randomized, controlled comparative study.
       MonitoringBII
      • Leachman S.A.
      • Insogna K.L.
      • Katz L.
      • Ellison A.
      • Milstone L.M.
      Bone densities in patients receiving isotretinoin for cystic acne.
      ,
      • Bershad S.
      • Rubinstein A.
      • Paterniti J.R.
      • et al.
      Changes in plasma lipids and lipoproteins during isotretinoin therapy for acne.
      ,
      • De Marchi M.A.
      • Maranhao R.C.
      • Brandizzi L.I.
      • Souza D.R.
      Effects of isotretinoin on the metabolism of triglyceride-rich lipoproteins and on the lipid profile in patients with acne.
      ,
      • Zech L.A.
      • Gross E.G.
      • Peck G.L.
      • Brewer H.B.
      Changes in plasma cholesterol and triglyceride levels after treatment with oral isotretinoin. A prospective study.
       iPLEDGE and contraceptionAII
      • Shin J.
      • Cheetham T.C.
      • Wong L.
      • et al.
      The impact of the iPLEDGE program on isotretinoin fetal exposure in an integrated health care system.
      ,
      • Collins M.K.
      • Moreau J.F.
      • Opel D.
      • et al.
      Compliance with pregnancy prevention measures during isotretinoin therapy.
      Miscellaneous therapies and physical modalities
       Chemical peelsBII, III
      • Grover C.
      • Reddu B.S.
      The therapeutic value of glycolic acid peels in dermatology.
      ,
      • Dreno B.
      • Fischer T.C.
      • Perosino E.
      • et al.
      Expert opinion: efficacy of superficial chemical peels in active acne management—what can we learn from the literature today? Evidence-based recommendations.
      ,
      • Ilknur T.
      • Demirtasoglu M.
      • Bicak M.U.
      • Ozkan S.
      Glycolic acid peels versus amino fruit acid peels for acne.
       Intralesional steroidsCIII
      • Levine R.M.
      • Rasmussen J.E.
      Intralesional corticosteroids in the treatment of nodulocystic acne.
      ,
      • Potter R.A.
      Intralesional triamcinolone and adrenal suppression in acne vulgaris.
      Complementary and alternative therapies (eg, tea tree oil, herbal, and biofeedback)BII
      • Bassett I.B.
      • Pannowitz D.L.
      • Barnetson R.S.
      A comparative study of tea-tree oil versus benzoylperoxide in the treatment of acne.
      ,
      • Enshaieh S.
      • Jooya A.
      • Siadat A.H.
      • Iraji F.
      The efficacy of 5% topical tea tree oil gel in mild to moderate acne vulgaris: a randomized, double-blind placebo-controlled study.
      ,
      • Fouladi R.F.
      Aqueous extract of dried fruit of Berberis vulgaris L. in acne vulgaris, a clinical trial.
      ,
      • Hunt M.J.
      • Barnetson R.S.
      A comparative study of gluconolactone versus benzoyl peroxide in the treatment of acne.
      ,
      • Lalla J.K.
      • Nandedkar S.Y.
      • Paranjape M.H.
      • Talreja N.B.
      Clinical trials of ayurvedic formulations in the treatment of acne vulgaris.
      ,
      • Paranjpe P.
      • Kulkarni P.H.
      Comparative efficacy of four Ayurvedic formulations in the treatment of acne vulgaris: a double-blind randomised placebo-controlled clinical evaluation.
      ,
      • Hughes H.
      • Brown B.W.
      • Lawlis G.F.
      • Fulton Jr., J.E.
      Treatment of acne vulgaris by biofeedback relaxation and cognitive imagery.
      Role of diet in acne
       Effect of glycemic indexBII
      • Smith R.N.
      • Mann N.J.
      • Braue A.
      • Makelainen H.
      • Varigos G.A.
      The effect of a high-protein, low glycemic-load diet versus a conventional, high glycemic-load diet on biochemical parameters associated with acne vulgaris: a randomized, investigator-masked, controlled trial.
      ,
      • Kwon H.H.
      • Yoon J.Y.
      • Hong J.S.
      • Jung J.Y.
      • Park M.S.
      • Suh D.H.
      Clinical and histological effect of a low glycaemic load diet in treatment of acne vulgaris in Korean patients: a randomized, controlled trial.
      ,
      • Smith R.
      • Mann N.
      • Makelainen H.
      • Roper J.
      • Braue A.
      • Varigos G.
      A pilot study to determine the short-term effects of a low glycemic load diet on hormonal markers of acne: a nonrandomized, parallel, controlled feeding trial.
      ,
      • Preneau S.
      • Dessinioti C.
      • Nguyen J.M.
      • Katsambas A.
      • Dreno B.
      Predictive markers of response to isotretinoin in female acne.
      ,
      • Ismail N.H.
      • Manaf Z.A.
      • Azizan N.Z.
      High glycemic load diet, milk and ice cream consumption are related to acne vulgaris in Malaysian young adults: a case control study.
       Dairy consumptionBII
      • Adebamowo C.A.
      • Spiegelman D.
      • Berkey C.S.
      • et al.
      Milk consumption and acne in adolescent girls.
      ,
      • Adebamowo C.A.
      • Spiegelman D.
      • Berkey C.S.
      • et al.
      Milk consumption and acne in teenaged boys.
      ,
      • Di Landro A.
      • Cazzaniga S.
      • Parazzini F.
      • et al.
      Family history, body mass index, selected dietary factors, menstrual history, and risk of moderate to severe acne in adolescents and young adults.
      Numerous acne assessment tools have been described, taking into account various factors, such as type of acne, severity of acne, number of acne lesions, anatomic location/extent of acne,
      • Tan J.K.
      • Tang J.
      • Fung K.
      • et al.
      Development and validation of a comprehensive acne severity scale.
      quality of life and other psychosocial metrics,
      • Mallon E.
      • Newton J.N.
      • Klassen A.
      • et al.
      The quality of life in acne: a comparison with general medical conditions using generic questionnaires.
      • Gupta M.A.
      • Johnson A.M.
      • Gupta A.K.
      The development of an Acne Quality of Life scale: reliability, validity, and relation to subjective acne severity in mild to moderate acne vulgaris.
      • Lasek R.J.
      • Chren M.M.
      Acne vulgaris and the quality of life of adult dermatology patients.
      • Martin A.R.
      • Lookingbill D.P.
      • Botek A.
      • et al.
      Health-related quality of life among patients with facial acne—assessment of a new acne-specific questionnaire.
      • Rapp S.R.
      • Feldman S.R.
      • Graham G.
      • et al.
      The Acne Quality of Life Index (Acne-QOLI): development and validation of a brief instrument.
      and scarring,
      • Dreno B.
      • Khammari A.
      • Orain N.
      • et al.
      ECCA grading scale: an original validated acne scar grading scale for clinical practice in dermatology.
      among other measures.
      • Pochi P.E.
      • Shalita A.R.
      • Strauss J.S.
      • et al.
      Report of the Consensus Conference on Acne Classification. Washington, D.C., March 24 and 25, 1990.
      • Doshi A.
      • Zaheer A.
      • Stiller M.J.
      A comparison of current acne grading systems and proposal of a novel system.
      • Lucky A.W.
      • Barber B.L.
      • Girman C.J.
      • et al.
      A multirater validation study to assess the reliability of acne lesion counting.
      • Cook C.H.
      • Centner R.L.
      • Michaels S.E.
      An acne grading method using photographic standards.
      • Burke B.M.
      • Cunliffe W.J.
      The assessment of acne vulgaris–the Leeds technique.
      • Allen B.S.
      • Smith Jr., J.G.
      Various parameters for grading acne vulgaris.
      • Dreno B.
      • Poli F.
      • Pawin H.
      • et al.
      Development and evaluation of a Global Acne Severity Scale (GEA Scale) suitable for France and Europe.
      • Hayashi N.
      • Akamatsu H.
      • Kawashima M.
      Acne Study Group. Establishment of grading criteria for acne severity.
      • Hayashi N.
      • Suh D.H.
      • Akamatsu H.
      • Kawashima M.
      Acne Study Group
      Evaluation of the newly established acne severity classification among Japanese and Korean dermatologists.
      • Tan J.
      • Wolfe B.
      • Weiss J.
      • et al.
      Acne severity grading: determining essential clinical components and features using a Delphi consensus.
      Recently, 18 of these grading scales were ranked based on a variety of characteristics.
      • Tan J.K.
      • Jones E.
      • Allen E.
      • et al.
      Evaluation of essential clinical components and features of current acne global grading scales.
      To date, there is no universally agreed-upon grading system, and systems can differ greatly between studies. In addition, interobserver reliability of these scales varies, but has been poor in some studies.
      • Lucky A.W.
      • Barber B.L.
      • Girman C.J.
      • et al.
      A multirater validation study to assess the reliability of acne lesion counting.
      • Beylot C.
      • Chivot M.
      • Faure M.
      • et al.
      Inter-observer agreement on acne severity based on facial photographs.
      • Tan J.K.
      • Fung K.
      • Bulger L.
      Reliability of dermatologists in acne lesion counts and global assessments.
      Methods such as photographic standards have been used to improve reproducibility.
      Improvements in digital technology, photographic equipment, and teledermatology may allow for accurate, remote assessment of acne in the near future.
      • Bergman H.
      • Tsai K.Y.
      • Seo S.J.
      • Kvedar J.C.
      • Watson A.J.
      Remote assessment of acne: the use of acne grading tools to evaluate digital skin images.
      • Min S.
      • Kong H.J.
      • Yoon C.
      • Kim H.C.
      • Suh D.H.
      Development and evaluation of an automatic acne lesion detection program using digital image processing.
      • Qureshi A.A.
      • Brandling-Bennett H.A.
      • Giberti S.
      • et al.
      Evaluation of digital skin images submitted by patients who received practical training or an online tutorial.
      Scientific measures, such as ultraviolet-induced red fluorescence,
      • Choi C.W.
      • Choi J.W.
      • Park K.C.
      • Youn S.W.
      Ultraviolet-induced red fluorescence of patients with acne reflects regional casual sebum level and acne lesion distribution: qualitative and quantitative analyses of facial fluorescence.
      • Choi C.W.
      • Lee D.H.
      • Kim H.S.
      • et al.
      The clinical features of late onset acne compared with early onset acne in women.
      • Dobrev H.
      Fluorescence diagnostic imaging in patients with acne.
      casual sebum level,
      • Choi C.W.
      • Choi J.W.
      • Youn S.W.
      Subjective facial skin type, based on the sebum related symptoms, can reflect the objective casual sebum level in acne patients.
      • Kim M.K.
      • Choi S.Y.
      • Byun H.J.
      • et al.
      Comparison of sebum secretion, skin type, pH in humans with and without acne.
      skin capacitance imaging,
      • Xhauflaire-Uhoda E.
      • Pierard G.E.
      Skin capacitance imaging of acne lesions.
      skin surface pH,
      • Youn S.H.
      • Choi C.W.
      • Choi J.W.
      • Youn S.W.
      The skin surface pH and its different influence on the development of acne lesion according to gender and age.
      • Youn S.W.
      • Kim J.H.
      • Lee J.E.
      • Kim S.O.
      • Park K.C.
      The facial red fluorescence of ultraviolet photography: is this color due to Propionibacterium acnes or the unknown content of secreted sebum?.
      and transepidermal water loss
      • Zane C.
      • Capezzera R.
      • Pedretti A.
      • Facchinetti E.
      • Calzavara-Pinton P.
      Non-invasive diagnostic evaluation of phototherapeutic effects of red light phototherapy of acne vulgaris.
      may also help to more objectively classify and rate acne in the future. Reproducibility, as well as ease of use and acceptance by dermatologists, will be essential for the success of any grading system.

      Microbiologic testing

      P acnes, a Gram-positive anaerobic rod, is the primary bacterium implicated in acne.
      • Cove J.H.
      • Cunliffe W.J.
      • Holland K.T.
      Acne vulgaris: is the bacterial population size significant?.
      • Mourelatos K.
      • Eady E.A.
      • Cunliffe W.J.
      • Clark S.M.
      • Cove J.H.
      Temporal changes in sebum excretion and propionibacterial colonization in preadolescent children with and without acne.
      • Shaheen B.
      • Gonzalez M.
      A microbial aetiology of acne: what is the evidence?.
      It has specific, nonstandard culture requirements that prohibit routine culture. Currently, microbiologic testing of acne lesions is largely unnecessary because it does not affect management, and successful antibiotic treatment may not result from a reduction of bacterial numbers.
      • Cove J.H.
      • Cunliffe W.J.
      • Holland K.T.
      Acne vulgaris: is the bacterial population size significant?.
      The antibiotics typically used in the management of acne, tetracyclines, have additional antiinflammatory actions independent of microbial killing. As additional information is learned about P acnes from a molecular and genetic perspective, and its role in inciting inflammation in acne,
      • Fitz-Gibbon S.
      • Tomida S.
      • Chiu B.H.
      • et al.
      Propionibacterium acnes strain populations in the human skin microbiome associated with acne.
      • Holland C.
      • Mak T.N.
      • Zimny-Arndt U.
      • et al.
      Proteomic identification of secreted proteins of Propionibacterium acnes.
      • Lomholt H.B.
      • Kilian M.
      Population genetic analysis of Propionibacterium acnes identifies a subpopulation and epidemic clones associated with acne.
      • Miura Y.
      • Ishige I.
      • Soejima N.
      • et al.
      Quantitative PCR of Propionibacterium acnes DNA in samples aspirated from sebaceous follicles on the normal skin of subjects with or without acne.
      • Tochio T.
      • Tanaka H.
      • Nakata S.
      • Ikeno H.
      Accumulation of lipid peroxide in the content of comedones may be involved in the progression of comedogenesis and inflammatory changes in comedones.
      • Tomida S.
      • Nguyen L.
      • Chiu B.H.
      • et al.
      Pan-genome and comparative genome analyses of propionibacterium acnes reveal its genomic diversity in the healthy and diseased human skin microbiome.
      more targeted therapeutic interventions in the future may result. Recommendations for microbiologic testing of acne are shown in Table IV and the strength of recommendations for microbiologic testing is shown in Table III.
      Table IVRecommendations for microbiologic and endocrinologic testing
      Routine microbiologic testing is not recommended in the evaluation and management of patients with acne
      Those who exhibit acne-like lesions suggestive of Gram-negative folliculitis may benefit from microbiologic testing
      Routine endocrinologic evaluation (eg, for androgen excess) is not recommended for the majority of patients with acne
      Laboratory evaluation is recommended for patients who have acne and additional signs of androgen excess
      The prime situation where microbiologic testing is useful in patients with acne is in evaluating for Gram-negative folliculitis. This uncommon disorder presents as uniform and eruptive pustules, with rare nodules, in the perioral and perinasal regions, typically in the setting of prolonged tetracycline use. It is caused by various bacteria, such as Klebsiella and Serratia, and is unresponsive to many conventional acne treatments. Gram-negative folliculitis is typically diagnosed via culture of the lesions, and is generally treated with isotretinoin or an antibiotic to which the bacteria are sensitive. In cases of acne unresponsive to typical treatments—particularly with prominent truncal involvement or monomorphic appearance—pityrosporum folliculitis should be considered. Staphylococcus aureus cutaneous infections may appear similar to acne, and should be considered in the differential, particularly in cases of acute eruptions; a swab culture may be helpful in these cases.

      Endocrinologic testing

      While the role of androgens in acne pathogenesis is well known, endocrinologic evaluation is only warranted in certain cases, because most acne patients will have normal hormone levels. Testing is primarily indicated for patients with clinical features or a history of hyperandrogenism. In prepubertal children, these features include: acne, early-onset body odor, axillary or pubic hair, accelerated growth, advanced bone age, and genital maturation. Growth charts and a hand film for bone age are good screening tools before specific hormonal testing.
      • Strauss J.S.
      • Krowchuk D.P.
      • Leyden J.J.
      • et al.
      Guidelines of care for acne vulgaris management.
      • Lucky A.W.
      • Biro F.M.
      • Simbartl L.A.
      • Morrison J.A.
      • Sorg N.W.
      Predictors of severity of acne vulgaris in young adolescent girls: results of a five-year longitudinal study.
      In postpubertal females, clinical signs, such as infrequent menses, hirsutism, androgenetic alopecia, infertility, polycystic ovaries, clitoromegaly, and truncal obesity warrant further hormonal testing.
      • Strauss J.S.
      • Krowchuk D.P.
      • Leyden J.J.
      • et al.
      Guidelines of care for acne vulgaris management.
      • Eichenfield L.F.
      • Krakowski A.C.
      • Piggott C.
      • et al.
      Evidence-based recommendations for the diagnosis and treatment of pediatric acne.
      • Bunker C.B.
      • Newton J.A.
      • Kilborn J.
      • et al.
      Most women with acne have polycystic ovaries.
      • Lawrence D.M.
      • Katz M.
      • Robinson T.W.
      • et al.
      Reduced sex hormone binding globulin and derived free testosterone levels in women with severe acne.
      • Timpatanapong P.
      • Rojanasakul A.
      Hormonal profiles and prevalence of polycystic ovary syndrome in women with acne.
      • Seirafi H.
      • Farnaghi F.
      • Vasheghani-Farahani A.
      • et al.
      Assessment of androgens in women with adult-onset acne.
      Recalcitrant acne caused by androgen excess can also be seen in both men and women with nonclassical congenital adrenal hyperplasia (eg, 21-hydroxylase deficiency).
      • Degitz K.
      • Placzek M.
      • Arnold B.
      • Schmidt H.
      • Plewig G.
      Congenital adrenal hyperplasia and acne in male patients.
      • Trapp C.M.
      • Oberfield S.E.
      Recommendations for treatment of nonclassic congenital adrenal hyperplasia (NCCAH): an update.
      Recommendations for endocrinologic testing of acne are shown in Table IV, and the strength of recommendations for endocrinologic testing is shown in Table III.
      The most common cause of elevated androgens of ovarian origin is polycystic ovarian syndrome (PCOS).
      • Lucky A.W.
      Endocrine aspects of acne.
      It has recently been proposed that diagnosis of PCOS in adult females requires 2 of the 3 following criteria: androgen excess (clinical or biochemical), ovulatory dysfunction (oligo- or anovulation), or polycystic ovaries (based on ultrasonographic findings). In adolescent females, the diagnosis of PCOS can be made based on hyperandrogenism (clinical or biochemical) in the presence of persistent oligomenorrhea.
      • Legro R.S.
      • Arslanian S.A.
      • Ehrmann D.A.
      • et al.
      Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline.
      The differential diagnosis of PCOS includes thyroid disease, prolactin excess, and nonclassical congenital adrenal hyperplasia, among others.
      • Legro R.S.
      • Arslanian S.A.
      • Ehrmann D.A.
      • et al.
      Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline.
      Hormonal testing and interpretation of testing is complex. A typical hormone-screening panel includes free and total testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, luteinizing hormone, and follicle-stimulating hormone.
      • Lucky A.W.
      • Biro F.M.
      • Simbartl L.A.
      • Morrison J.A.
      • Sorg N.W.
      Predictors of severity of acne vulgaris in young adolescent girls: results of a five-year longitudinal study.
      • Lawrence D.M.
      • Katz M.
      • Robinson T.W.
      • et al.
      Reduced sex hormone binding globulin and derived free testosterone levels in women with severe acne.
      • Timpatanapong P.
      • Rojanasakul A.
      Hormonal profiles and prevalence of polycystic ovary syndrome in women with acne.
      • Lucky A.W.
      Endocrine aspects of acne.
      • Lucky A.W.
      • McGuire J.
      • Rosenfield R.L.
      • Lucky P.A.
      • Rich B.H.
      Plasma androgens in women with acne vulgaris.
      • Seirafi H.
      • Farnaghi F.
      • Vasheghani-Farahani A.
      • et al.
      Assessment of androgens in women with adult-onset acne.
      Growth hormone, insulin-like growth factor, lipid levels, insulin, sex hormone–binding globulin, free 17-β-hydroxysteroids, free androgen index, prolactin, estrogen, and progesterone may also be abnormal in those with severe acne.
      • Timpatanapong P.
      • Rojanasakul A.
      Hormonal profiles and prevalence of polycystic ovary syndrome in women with acne.
      • Lucky A.W.
      • McGuire J.
      • Rosenfield R.L.
      • Lucky P.A.
      • Rich B.H.
      Plasma androgens in women with acne vulgaris.
      • Abulnaja K.O.
      Changes in the hormone and lipid profile of obese adolescent Saudi females with acne vulgaris.
      • Arora M.K.
      • Seth S.
      • Dayal S.
      The relationship of lipid profile and menstrual cycle with acne vulgaris.
      • Seirafi H.
      • Farnaghi F.
      • Vasheghani-Farahani A.
      • et al.
      Assessment of androgens in women with adult-onset acne.
      • Saleh B.O.
      Role of growth hormone and insulin-like growth factor-I in hyperandrogenism and the severity of acne vulgaris in young males.
      Insulin resistance may also represent a risk factor for acne in certain patients.
      • Del Prete M.
      • Mauriello M.C.
      • Faggiano A.
      • et al.
      Insulin resistance and acne: a new risk factor for men?.
      Patients with abnormal test results, or in whom there is a persistent concern for a hormonal disorder, should be further evaluated by an endocrinologist.

      Topical therapies

      The topical therapy of AV includes the usage of agents that are available over the counter or via prescription. Therapy choice may be influenced by age of the patient, site of involvement, extent and severity of disease, and patient preference. Topical therapies may be used as monotherapy, in combination with other topical agents or in combination with oral agents in both initial control and maintenance. Recommendations for use of topical therapies are shown in Table V, and the strength of recommendations for treatment of acne with topical therapies is shown in Table III. Prescribing information for all topical therapies is located in Supplemental Table I, Supplemental Table X, Supplemental Table XI, Supplemental Table XII, Supplemental Table XIII, Supplemental Table II, Supplemental Table III, Supplemental Table IV, Supplemental Table V, Supplemental Table VI, Supplemental Table VII, Supplemental Table VIII, Supplemental Table IX.(Please note all Supplemental Tables can be found at www.jaad.org.)
      Table VRecommendations for topical therapies
      Benzoyl peroxide or combinations with erythromycin or clindamycin are effective acne treatments and are recommended as monotherapy for mild acne, or in conjunction with a topical retinoid, or systemic antibiotic therapy for moderate to severe acne
      Benzoyl peroxide is effective in the prevention of bacterial resistance and is recommended for patients on topical or systemic antibiotic therapy
      Topical antibiotics (eg, erythromycin and clindamycin) are effective acne treatments, but are not recommended as monotherapy because of the risk of bacterial resistance
      Topical retinoids are important in addressing the development and maintenance of acne and are recommended as monotherapy in primarily comedonal acne, or in combination with topical or oral antimicrobials in patients with mixed or primarily inflammatory acne lesions
      Using multiple topical agents that affect different aspects of acne pathogenesis can be useful. Combination therapy should be used in the majority of patients with acne
      Topical adapalene, tretinoin, and benzoyl peroxide can be safely used in the management of preadolescent acne in children
      Azelaic acid is a useful adjunctive acne treatment and is recommended in the treatment of postinflammatory dyspigmentation
      Topical dapsone 5% gel is recommended for inflammatory acne, particularly in adult females with acne
      There is limited evidence to support recommendations for sulfur, nicotinamide, resorcinol, sodium sulfacetamide, aluminum chloride, and zinc in the treatment of acne
      Commonly used topical acne therapies include BP, salicylic acid, antibiotics, combination antibiotics with BP, retinoids, retinoid with BP, retinoid with antibiotic, azelaic acid, and sulfone agents. Although most physicians have anecdotal regimens they find beneficial, agents reviewed here are limited to those approved by the US Food and Drug Administration (FDA) for use in the United States, and for which peer-reviewed literature has been published.
      BP is an antibacterial agent that kills P acnes through the release of free oxygen radicals and is also mildly comedolytic.
      • Cunliffe W.J.
      • Dodman B.
      • Ead R.
      Benzoyl peroxide in acne.
      • Fulton Jr., J.E.
      • Farzad-Bakshandeh A.
      • Bradley S.
      Studies on the mechanism of action to topical benzoyl peroxide and vitamin A acid in acne vulgaris.
      No resistance to this agent has been reported, and the addition of BP to regimens of antibiotic therapy enhances results and may reduce resistance development. BP is available as topical washes, foams, creams, or gels, and can used as leave-on or wash-off agents. Strengths available for acne therapy range from 2.5% to 10%. BP therapy is limited by concentration-dependent irritation, staining and bleaching of fabric, and uncommon contact allergy. Total skin contact time and formulation can also affect efficacy. Lower concentrations (eg, 2.5-5%), water-based, and wash-off agents may be better tolerated in patients with more sensitive skin.
      • Fyrand O.
      • Jakobsen H.B.
      Water-based versus alcohol-based benzoyl peroxide preparations in the treatment of acne vulgaris.
      • Mills Jr., O.H.
      • Kligman A.M.
      • Pochi P.
      • Comite H.
      Comparing 2.5%, 5%, and 10% benzoyl peroxide on inflammatory acne vulgaris.
      Results can be noted in as soon as 5 days.
      • Schutte H.
      • Cunliffe W.J.
      • Forster R.A.
      The short-term effects of benzoyl peroxide lotion on the resolution of inflamed acne lesions.
      Topical antibiotics for acne accumulate in the follicle and have been postulated to work through antiinflammatory mechanisms and via antibacterial effects.
      • Mills Jr., O.
      • Thornsberry C.
      • Cardin C.W.
      • Smiles K.A.
      • Leyden J.J.
      Bacterial resistance and therapeutic outcome following three months of topical acne therapy with 2% erythromycin gel versus its vehicle.
      These agents are best used in combination with BP (wash-off or leave-on), which increases efficacy and decreases the development of resistant bacterial strains. Monotherapy with topical antibiotics in the management of acne is not recommended because of the development of antibiotic resistance. Clindamycin 1% solution or gel is currently the preferred topical antibiotic for acne therapy.
      • Padilla R.S.
      • McCabe J.M.
      • Becker L.E.
      Topical tetracycline hydrochloride vs. topical clindamycin phosphate in the treatment of acne: a comparative study.
      Topical erythromycin in 2% concentration is available as a cream, gel, lotion, or pledget,
      • Bernstein J.E.
      • Shalita A.R.
      Topically applied erythromycin in inflammatory acne vulgaris.
      • Jones E.L.
      • Crumley A.F.
      Topical erythromycin vs blank vehicle in a multiclinic acne study.
      but has reduced efficacy in comparison with clindamycin because of resistance of cutaneous Staphylococci and P acnes.
      • Mills Jr., O.
      • Thornsberry C.
      • Cardin C.W.
      • Smiles K.A.
      • Leyden J.J.
      Bacterial resistance and therapeutic outcome following three months of topical acne therapy with 2% erythromycin gel versus its vehicle.
      • Shalita A.R.
      • Smith E.B.
      • Bauer E.
      Topical erythromycin v clindamycin therapy for acne. A multicenter, double-blind comparison.
      • Leyden J.J.
      • Shalita A.R.
      • Saatjian G.D.
      • Sefton J.
      Erythromycin 2% gel in comparison with clindamycin phosphate 1% solution in acne vulgaris.
      • Kuhlman D.S.
      • Callen J.P.
      A comparison of clindamycin phosphate 1 percent topical lotion and placebo in the treatment of acne vulgaris.
      • Becker L.E.
      • Bergstresser P.R.
      • Whiting D.A.
      • et al.
      Topical clindamycin therapy for acne vulgaris. A cooperative clinical study.
      Stable, fixed-combination agents are available with erythromycin 3%/BP 5%, clindamycin 1%/BP 5%, and clindamycin 1%/BP 3.75%.
      • Leyden J.J.
      • Hickman J.G.
      • Jarratt M.T.
      • Stewart D.M.
      • Levy S.F.
      The efficacy and safety of a combination benzoyl peroxide/clindamycin topical gel compared with benzoyl peroxide alone and a benzoyl peroxide/erythromycin combination product.
      • Lookingbill D.P.
      • Chalker D.K.
      • Lindholm J.S.
      • et al.
      Treatment of acne with a combination clindamycin/benzoyl peroxide gel compared with clindamycin gel, benzoyl peroxide gel and vehicle gel: combined results of two double-blind investigations.
      • Tschen E.H.
      • Katz H.I.
      • Jones T.M.
      • et al.
      A combination benzoyl peroxide and clindamycin topical gel compared with benzoyl peroxide, clindamycin phosphate, and vehicle in the treatment of acne vulgaris.
      • Pariser D.M.
      • Rich P.
      • Cook-Bolden F.E.
      • Korotzer A.
      An aqueous gel fixed combination of clindamycin phosphate 1.2% and benzoyl peroxide 3.75% for the once-daily treatment of moderate to severe acne vulgaris.
      Combination agents may enhance compliance with treatment regimens. Rare reports of diarrhea or Clostridium difficile–related colitis with clindamycin topically have appeared in the literature, but the risk appears low.
      • Becker L.E.
      • Bergstresser P.R.
      • Whiting D.A.
      • et al.
      Topical clindamycin therapy for acne vulgaris. A cooperative clinical study.
      Tolerance of these agents is excellent; clindamycin alone is pregnancy category B.
      Topical retinoids are vitamin A derivatives that are prescription agents with randomized, double-blind, placebo-controlled trials supporting their use for acne treatment.
      • Krishnan G.
      Comparison of two concentrations of tretinoin solution in the topical treatment of acne vulgaris.
      • Bradford L.G.
      • Montes L.F.
      Topical application of vitamin A acid in acne vulgaris.
      • Shalita A.R.
      • Chalker D.K.
      • Griffith R.F.
      • et al.
      Tazarotene gel is safe and effective in the treatment of acne vulgaris: a multicenter, double-blind, vehicle-controlled study.
      • Lucky A.W.
      • Cullen S.I.
      • Funicella T.
      • et al.
      Double-blind, vehicle-controlled, multicenter comparison of two 0.025% tretinoin creams in patients with acne vulgaris.
      Three active agents are available: tretinoin (0.025-0.1% in cream, gel, or microsphere gel vehicles), adapalene (0.1%, 0.3% cream, or 0.1% lotion
      • Shalita A.
      • Weiss J.S.
      • Chalker D.K.
      • et al.
      A comparison of the efficacy and safety of adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris: a multicenter trial.
      • Cunliffe W.J.
      • Caputo R.
      • Dreno B.
      • et al.
      Clinical efficacy and safety comparison of adapalene gel and tretinoin gel in the treatment of acne vulgaris: Europe and U.S. multicenter trials.
      ), and tazarotene (0.05%, 0.1% cream, gel or foam). Each retinoid binds to a different set of retinoic acid receptors: tretinoin to alpha, beta, and gamma, and tazarotene and adapalene, selectively, to beta and gamma—thereby conferring slight differences in activity, tolerability, and efficacy. Retinoids are the core of topical therapy for acne because they are comedolytic, resolve the precursor microcomedone lesion, and are antiinflammatory.
      These agents enhance any topical acne regimen and allow for maintenance of clearance after discontinuation of oral therapy. Retinoids are ideal for comedonal acne and, when used in combination with other agents, for all acne variants. Three topical agents are available that contain retinoids in combination with other products: adapalene 0.1%/BP 2.5%, approved for use in patients ≥9 years of age, and 2 agents with fixed combination clindamycin phosphate 1.2%/tretinoin 0.025% gel, approved for patients ≥12 years of age.
      • Richter J.R.
      • Bousema M.T.
      • De Boulle K.L.V.
      • Degreef H.J.
      • Poli F.
      Efficacy of a fixed clindamycin phosphate 1.2%, tretinoin 0.025% gel formulation (Velac) in the topical control of facial acne lesions.
      • Zouboulis C.C.
      • Derumeaux L.
      • Decroix J.
      • Maciejewska-Udziela B.
      • Cambazard F.
      • Stuhlert A.
      A multicentre, single-blind, randomized comparison of a fixed clindamycin phosphate/tretinoin gel formulation (Velac) applied once daily and a clindamycin lotion formulation (Dalacin T) applied twice daily in the topical treatment of acne vulgaris.
      • Dreno B.
      • Bettoli V.
      • Ochsendorf F.
      • et al.
      Efficacy and safety of clindamycin phosphate 1.2%/tretinoin 0.025% formulation for the treatment of acne vulgaris: pooled analysis of data from three randomised, double-blind, parallel-group, phase III studies.
      Retinoid use may be limited by side effects, including dryness, peeling, erythema, and irritation, which can be mitigated by reduced frequency of application.
      • Pedace F.J.
      • Stoughton R.
      Topical retinoic acid in acne vulgaris.
      Given any single agent, higher concentrations may be more efficacious, but with greater side effects.
      • Krishnan G.
      Comparison of two concentrations of tretinoin solution in the topical treatment of acne vulgaris.
      • Cunliffe W.J.
      • Caputo R.
      • Dreno B.
      • et al.
      Clinical efficacy and safety comparison of adapalene gel and tretinoin gel in the treatment of acne vulgaris: Europe and U.S. multicenter trials.
      • Christiansen J.V.
      • Gadborg E.
      • Ludvigsen K.
      • et al.
      Topical tretinoin, vitamin A acid (Airol) in acne vulgaris. A controlled clinical trial.
      Some formulations of tretinoin (primarily generic products) are not photostable and should be applied in the evening. Tretinoin also may be oxidized and inactivated by the coadministration of BP. It is recommended that the 2 agents be applied at different times. Tretinoin microsphere formulation, adapalene, and tazarotene do not have similar restrictions. Topical retinoids have been associated with an increased risk of photosensitivity; concurrent daily sunscreen can be used to reduce the risk of sunburn.
      There are several head-to-head studies with retinoid products. Some support greater efficacy of tazarotene over adapalene and tretinoin, and adapalene over tretinoin, but the concentrations and formulations used were varied.
      • Shalita A.
      • Weiss J.S.
      • Chalker D.K.
      • et al.
      A comparison of the efficacy and safety of adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris: a multicenter trial.
      • Dunlap F.E.
      • Mills O.H.
      • Tuley M.R.
      • Baker M.D.
      • Plott R.T.
      Adapalene 0.1% gel for the treatment of acne vulgaris: its superiority compared to tretinoin 0.025% cream in skin tolerance and patient preference.
      • Kakita L.
      Tazarotene versus tretinoin or adapalene in the treatment of acne vulgaris.
      • Webster G.F.
      • Berson D.
      • Stein L.F.
      • Fivenson D.P.
      • Tanghetti E.A.
      • Ling M.
      Efficacy and tolerability of once-daily tazarotene 0.1% gel versus once-daily tretinoin 0.025% gel in the treatment of facial acne vulgaris: a randomized trial.
      Data suggest that adapalene is better tolerated than multiple concentrations of tretinoin, but this is based on older formulations.
      • Galvin S.A.
      • Gilbert R.
      • Baker M.
      • Guibal F.
      • Tuley M.R.
      Comparative tolerance of adapalene 0.1% gel and six different tretinoin formulations.
      Overall, the limitations of the existing studies prohibit direct efficacy comparisons of topical retinoids.
      Tretinoin and adapalene are pregnancy category C, while tazarotene is category X; therefore, patients should be counseled on these pregnancy risks when starting a retinoid or if a woman patient desires pregnancy.
      The therapy of acne in children <12 years of age with products approved by the FDA has expanded. Fixed combination BP 2.5%/adapalene 1% gel is approved for patients ≥9 years of age, and tretinoin 0.05% micronized tretinoin gel for patients ≥10 years of age. All other retinoids are approved by the FDA for patients ≥12 years of age. Current data show that retinoids in younger patients are effective and are not associated with increased irritation or risk.
      Azelaic acid 20% is mildly effective as a comedolytic, antibacterial, and antiinflammatory agent. The agent has use in patients with sensitive skin or of Fitzpatrick skin types IV or greater because of the lightening effect of the product on dyspigmentation.
      • Cunliffe W.J.
      • Holland K.T.
      Clinical and laboratory studies on treatment with 20% azelaic acid cream for acne.
      • Katsambas A.
      • Graupe K.
      • Stratigos J.
      Clinical studies of 20% azelaic acid cream in the treatment of acne vulgaris. Comparison with vehicle and topical tretinoin.
      • Kircik L.H.
      Efficacy and safety of azelaic acid (AzA) gel 15% in the treatment of post-inflammatory hyperpigmentation and acne: a 16-week, baseline-controlled study.
      Azelaic acid is category B in pregnancy.
      The sulfone agent, dapsone 5% gel, is available as a twice-daily agent for the therapy of AV. In clinical trials, topical dapsone showed modest to moderate efficacy, primarily in the reduction of inflammatory lesions.
      • Draelos Z.D.
      • Carter E.
      • Maloney J.M.
      • et al.
      Two randomized studies demonstrate the efficacy and safety of dapsone gel, 5% for the treatment of acne vulgaris.
      • Lucky A.W.
      • Maloney J.M.
      • Roberts J.
      • et al.
      Dapsone gel 5% for the treatment of acne vulgaris: safety and efficacy of long-term (1 year) treatment.
      Combination with topical retinoids may be indicated if comedonal components are present. The mechanism of action is poorly understood, and its ability to kill P acnes has been poorly studied. It is generally thought to work as an antiinflammatory agent. The benefit in women seems to exceed the benefit in male and adolescent patients.
      • Tanghetti E.
      • Harper J.C.
      • Oefelein M.G.
      The efficacy and tolerability of dapsone 5% gel in female vs male patients with facial acne vulgaris: gender as a clinically relevant outcome variable.
      • Del Rosso J.Q.
      • Kircik L.
      • Gallagher C.J.
      Comparative efficacy and tolerability of dapsone 5% gel in adult versus adolescent females with acne vulgaris.
      Topical dapsone may be oxidized by the coapplication of BP, causing orange-brown coloration of the skin which can be brushed or washed off. Topical dapsone 5% gel is pregnancy category C and has efficacy and safety data down to patients 12 years of age. Glucose-6-phosphate dehydrogenase testing is not required before starting topical dapsone.
      Salicylic acid is a comedolytic agent that is available over the counter in 0.5% to 2% strengths for the therapy of AV. Both wash-off and leave-on preparations are well tolerated. Clinical trials demonstrating the efficacy of salicylic acid in acne are limited.
      • Shalita A.R.
      Treatment of mild and moderate acne vulgaris with salicylic acid in an alcohol-detergent vehicle.
      • Shalita A.R.
      Comparison of a salicylic acid cleanser and a benzoyl peroxide wash in the treatment of acne vulgaris.
      Although sulfur and resorcinol have been used for many years in the treatment of acne, evidence from peer-reviewed literature supporting their efficacy is lacking.
      • Elstein W.
      Topical deodorized polysulfides. Broadscope acne therapy.
      Aluminum chloride possesses antibacterial activity and, therefore, has been investigated in the treatment acne. Of 2 peer-reviewed studies, 1 found benefit
      • Hurley H.J.
      • Shelley W.B.
      Special topical approach to the treatment of acne. Suppression of sweating with aluminum chloride in an anhydrous formulation.
      and 1 did not.
      • Hjorth N.
      • Storm D.
      • Dela K.
      Topical anhydrous aluminum chloride formulation in the treatment of acne vulgaris: a double-blind study.
      Topical zinc alone is ineffective.
      • Bojar R.A.
      • Eady E.A.
      • Jones C.E.
      • Cunliffe W.J.
      • Holland K.T.
      Inhibition of erythromycin-resistant propionibacteria on the skin of acne patients by topical erythromycin with and without zinc.
      • Cochran R.J.
      • Tucker S.B.
      • Flannigan S.A.
      Topical zinc therapy for acne vulgaris.
      • Stainforth J.
      • MacDonald-Hull S.
      • Papworth-Smith J.W.
      • Eady E.A.
      • Cunliffe W.J.
      • Norris J.F.B.
      A single-blind comparison of topical erythromycin/zinc lotion and oral minocycline in the treatment of acne vulgaris.
      There is some evidence to suggest the efficacy of sodium sulfacetamide.
      • Lebrun C.M.
      Rosac cream with sunscreens (sodium sulfacetamide 10% and sulfur 5%).
      • Tarimci N.
      • Sener S.
      • Kilinc T.
      Topical sodium sulfacetamide/sulfur lotion.
      • Thiboutot D.
      New treatments and therapeutic strategies for acne.
      Topical niacinamide (nicotinomide) 2% to 4% gel is available over the counter. The limited studies available compare its efficacy to topical clindamycin 1% gel.
      • Shalita A.R.
      • Smith J.G.
      • Parish L.C.
      • Sofman M.S.
      • Chalker D.K.
      Topical nicotinamide compared with clindamycin gel in the treatment of inflammatory acne vulgaris.
      • Khodaeiani E.
      • Fouladi R.F.
      • Amirnia M.
      • Saeidi M.
      • Karimi E.R.
      Topical 4% nicotinamide vs. 1% clindamycin in moderate inflammatory acne vulgaris.

      Systemic antibiotics

      Systemic antibiotics have been a mainstay of acne treatment for years. They are indicated for use in moderate to severe inflammatory acne and should be used in combination with a topical retinoid and BP.
      • Gold L.S.
      • Cruz A.
      • Eichenfield L.
      • et al.
      Effective and safe combination therapy for severe acne vulgaris: a randomized, vehicle-controlled, double-blind study of adapalene 0.1%-benzoyl peroxide 2.5% fixed-dose combination gel with doxycycline hyclate 100 mg.
      • Tan J.
      • Humphrey S.
      • Vender R.
      • et al.
      A treatment for severe nodular acne: a randomized investigator-blinded, controlled, noninferiority trial comparing fixed-dose adapalene/benzoyl peroxide plus doxycycline vs. oral isotretinoin.
      • Zaenglein A.L.
      • Shamban A.
      • Webster G.
      • et al.
      A phase IV, open-label study evaluating the use of triple-combination therapy with minocycline HCl extended-release tablets, a topical antibiotic/retinoid preparation and benzoyl peroxide in patients with moderate to severe acne vulgaris.
      Evidence supports the efficacy of tetracycline, doxycycline, minocycline, trimethoprim/sulfamethoxazole (TMP/SMX), trimethoprim, erythromycin, azithromycin, amoxicillin, and cephalexin. Recommendations for systemic antibiotics are shown in Table VI, and the strength of recommendations for treatment of acne with systemic antibiotics is shown in Table III. Prescribing information for systemic antibiotics is located in the Supplemental Table XIV, Supplemental Table XV, Supplemental Table XVI, Supplemental Table XVII, Supplemental Table XVIII, Supplemental Table XIX, Supplemental Table XX, Supplemental Table XXI, Supplemental Table XXII.
      Table VIRecommendations for systemic antibiotics
      Systemic antibiotics are recommended in the management of moderate and severe acne and forms of inflammatory acne that are resistant to topical treatments
      Doxycycline and minocycline are more effective than tetracycline, but neither is superior to each other
      Although oral erythromycin and azithromycin can be effective in treating acne, its use should be limited to those who cannot use the tetracyclines (ie, pregnant women or children <8 years of age). Erythromycin use should be restricted because of its increased risk of bacterial resistance
      Use of systemic antibiotics, other than the tetracyclines and macrolides, is discouraged because there are limited data for their use in acne. Trimethoprim-sulfamethoxazole and trimethoprim use should be restricted to patients who are unable to tolerate tetracyclines or in treatment-resistant patients
      Systemic antibiotic use should be limited to the shortest possible duration. Re-evaluate at 3-4 months to minimize the development of bacterial resistance. Monotherapy with systemic antibiotics is not recommended
      Concomitant topical therapy with benzoyl peroxide or a retinoid should be used with systemic antibiotics and for maintenance after completion of systemic antibiotic therapy
      The tetracycline class of antibiotics should be considered first-line therapy in moderate to severe acne, except when contraindicated because of other circumstances (ie, pregnancy, ≤8 years of age, or allergy). The antibiotics of the tetracycline class work by inhibiting protein synthesis by binding the 30S subunit of the bacterial ribosome. This class also has notable antiinflammatory effects, including inhibiting chemotaxis and metalloproteinase activity. Previous guidelines recommended minocycline as superior to doxycycline in reducing P acnes.
      • Strauss J.S.
      • Krowchuk D.P.
      • Leyden J.J.
      • et al.
      Guidelines of care for acne vulgaris management.
      However, a recent Cochrane review of clinical trials found minocycline effective but not superior to other antibiotics in the treatment of acne.
      • Garner S.E.
      • Eady A.
      • Bennett C.
      • Newton J.N.
      • Thomas K.
      • Popescu C.M.
      Minocycline for acne vulgaris: efficacy and safety.
      There are few studies addressing dosing of the tetracycline class. Minocycline in an extended release form appears safest (at 1 mg/kg), but no dose response was found for efficacy.
      • Fleischer Jr., A.B.
      • Dinehart S.
      • Stough D.
      • et al.
      Safety and efficacy of a new extended-release formulation of minocycline.
      Doxycycline appears effective in the 1.7 to 2.4 mg/kg dose range.
      • Leyden J.J.
      • Bruce S.
      • Lee C.S.
      • et al.
      A randomized, phase 2, dose-ranging study in the treatment of moderate to severe inflammatory facial acne vulgaris with doxycycline calcium.
      Subantimicrobial dosing of doxycycline (ie, 20 mg twice daily to 40 mg daily) has also shown efficacy in patients with moderate inflammatory acne.
      • Toossi P.
      • Farshchian M.
      • Malekzad F.
      • Mohtasham N.
      • Kimyai-Asadi A.
      Subantimicrobial-dose doxycycline in the treatment of moderate facial acne.
      • Moore A.
      • Ling M.
      • Bucko A.
      • Manna V.
      • Rueda M.J.
      Efficacy and safety of subantimicrobial dose, modified-release doxycycline 40 mg versus doxycycline 100 mg versus placebo for the treatment of inflammatory lesions in moderate and severe acne: a randomized, double-blinded, controlled study.
      Erythromycin and azithromycin have also been used in the treatment of acne. The mechanism of action for the macrolide class of antibiotics is to bind the 50S subunit of the bacterial ribosome. Again, there are some antiinflammatory properties for these medications, but the mechanisms are not well understood. Azithromycin has been primarily studied in the treatment of acne in open label studies with different pulse dosing regimens ranging from 3 times a week to 4 days a month, with azithromycin being an effective treatment in the time span evaluated—usually 2 to 3 months.
      • Rafiei R.
      • Yaghoobi R.
      Azithromycin versus tetracycline in the treatment of acne vulgaris.
      • Maleszka R.
      • Turek-Urasinska K.
      • Oremus M.
      • Vukovic J.
      • Barsic B.
      Pulsed azithromycin treatment is as effective and safe as 2-week-longer daily doxycycline treatment of acne vulgaris: a randomized, double-blind, noninferiority study.
      • Antonio J.R.
      • Pegas J.R.
      • Cestari T.F.
      • Do Nascimento L.V.
      Azithromycin pulses in the treatment of inflammatory and pustular acne: efficacy, tolerability and safety.
      • Innocenzi D.
      • Skroza N.
      • Ruggiero A.
      • et al.
      Moderate acne vulgaris: efficacy, tolerance and compliance of oral azithromycin thrice weekly for.
      • Bardazzi F.
      • Savoia F.
      • Parente G.
      • et al.
      Azithromycin: a new therapeutical strategy for acne in adolescents.
      • Basta-Juzbasic A.
      • Lipozencic J.
      • Oremovic L.
      • et al.
      A dose-finding study of azithromycin in the treatment of acne vulgaris.
      • Kus S.
      • Yucelten D.
      • Aytug A.
      Comparison of efficacy of azithromycin vs. doxycycline in the treatment of acne vulgaris.
      • Parsad D.
      • Pandhi R.
      • Nagpal R.
      • Negi K.S.
      Azithromycin monthly pulse vs daily doxycycline in the treatment of acne vulgaris.
      • Gruber F.
      • Grubisic-Greblo H.
      • Kastelan M.
      • et al.
      Azithromycin compared with minocycline in the treatment of acne comedonica and papulo-pustulosa.
      A recent randomized controlled trial comparing 3 days per month of azithromycin to daily doxycycline did show superiority of doxycycline.
      • Ullah G.
      • Noor S.M.
      • Bhatti Z.
      • Ahmad M.
      • Bangash A.R.
      Comparison of oral azithromycin with oral doxycycline in the treatment of acne vulgaris.
      Macrolides as the penicillin class represent an alternative when traditional antibiotics cannot be used.
      TMP/SMX and trimethoprim have also been used for the treatment of acne. Sulfamethoxazole is bacteriostatic by blocking bacterial synthesis of folic acid, which is necessary for cell division. Trimethoprim is a folic acid analog that inhibits the enzyme dihydrofolate reductase. The 2 agents work together to block nucleotide and amino acid synthesis in the bacteria. Outside of case reports, there is 1 small, double-blind study showing that TMP/SMX is as effective as oxytetracycline.
      • Jen I.
      A comparison of low dosage trimethoprim/sulfamethoxazole with oxytetracycline in acne vulgaris.
      Although data supporting their use are limited, penicillins and cephalosporins are sometimes used in the treatment of acne and can be used as an alternative treatment when circumstances dictate. In particular, these medications represent a useful option in patients who may be pregnant or who have allergies to the other classes of antibiotics. These antibiotics work by binding the penicillin-binding proteins in the bacterial cell membrane and inhibiting bacterial cell wall synthesis. There are few references to support the use of these medications in the treatment of acne outside of case reports. However, there is a small retrospective chart review with cephalexin where the majority of patients showed some clinical improvement on this medication.
      • Fenner J.A.
      • Wiss K.
      • Levin N.A.
      Oral cephalexin for acne vulgaris: clinical experience with 93 patients.
      Adverse events of systemic therapy are often a concern to patients and practitioners. However, severe adverse effects of systemic antibiotics in the treatment of acne are rare. Vaginal candidiasis and drug eruptions can occur with any antibiotic.
      Adverse events with the tetracycline class vary with each medication. Photosensitivity can be seen with the tetracycline class, doxycycline being more photosensitizing than minocycline. Doxycycline is more frequently associated with gastrointestinal disturbances, and higher doses are more likely to cause symptoms.
      • Leyden J.J.
      • Bruce S.
      • Lee C.S.
      • et al.
      A randomized, phase 2, dose-ranging study in the treatment of moderate to severe inflammatory facial acne vulgaris with doxycycline calcium.
      Minocycline has been associated with tinnitus, dizziness, and pigment deposition of the skin, mucous membranes, and teeth. Minocycline pigmentation is more common in patients taking higher doses for longer periods of time. Doxycycline is primarily metabolized by the liver, and can be used safely in most patients with renal impairment. When minocycline is compared to other tetracyclines, more serious adverse events are reported (8.8 cases per 100,000 patient years).
      • Garner S.E.
      • Eady A.
      • Bennett C.
      • Newton J.N.
      • Thomas K.
      • Popescu C.M.
      Minocycline for acne vulgaris: efficacy and safety.
      • Lebrun-Vignes B.
      • Kreft-Jais C.
      • Castot A.
      • Chosidow O.
      French Network of Regional Centers of Pharmacovigilance
      Comparative analysis of adverse drug reactions to tetracyclines: results of a French national survey and review of the literature.
      The rare serious events associated with minocycline include autoimmune disorders, such as drug reaction with eosinophilia and systemic symptoms (DRESS), drug-induced lupus, and other hypersensitivity reactions.
      • Kermani T.A.
      • Ham E.K.
      • Camilleri M.J.
      • Warrington K.J.
      Polyarteritis nodosa-like vasculitis in association with minocycline use: a single-center case series.
      • Shaughnessy K.K.
      • Bouchard S.M.
      • Mohr M.R.
      • Herre J.M.
      • Salkey K.S.
      Minocycline-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome with persistent myocarditis.
      • Smith K.
      • Leyden J.J.
      Safety of doxycycline and minocycline: a systematic review.
      • Tripathi S.V.
      • Gustafson C.J.
      • Huang K.E.
      • Feldman S.R.
      Side effects of common acne treatments.
      • Weinstein M.
      • Laxer R.
      • Debosz J.
      • Somers G.
      Doxycycline-induced cutaneous inflammation with systemic symptoms in a patient with acne vulgaris.
      Finally, pseudotumor cerebri is a rare phenomenon associated with the tetracycline class of antibiotics.
      The adverse events of TMP/SMX include gastrointestinal upset, photosensitivity, and drug eruptions. Multiple cutaneous reactions have been observed with patients on this medication, the most severe eruptions being Stevens–Johnson syndrome and toxic epidermal necrolysis.
      • Firoz B.F.
      • Henning J.S.
      • Zarzabal L.A.
      • Pollock B.H.
      Toxic epidermal necrolysis: five years of treatment experience from a burn unit.
      • Roujeau J.C.
      • Kelly J.P.
      • Naldi L.
      • et al.
      Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis.
      Such severe eruptions are more common in patients with HIV. The relative risk for such a severe reaction varies, but is still a rare event, with studies citing the crude relative risk at 172.
      • Roujeau J.C.
      • Kelly J.P.
      • Naldi L.
      • et al.
      Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis.
      Disorders of the hematopoietic system can also occur with TMP/SMX and can include serious blood dyscrasias, such as neutropenia, agranulocytosis, aplastic anemia, and thrombocytopenia. Although these are rare adverse events, patients on long-term therapy with this medication should be periodically monitored with a complete blood cell count. Cases of fulminant hepatitis necrosis have also occurred in patients taking this medication, as has respiratory hypersensitivity. The concurrent use of TMP/SMX and methotrexate (MTX) can be associated with severe toxicity (Supplementary Table XVII).
      The macrolide class of antibiotics is most commonly associated with gastrointestinal disturbances. Erythromycin is associated with a higher incidence of diarrhea, nausea, and abdominal discomfort than azithromycin. Macrolides have been reported to cause cardiac conduction abnormalities, and rarely hepatotoxicity has been reported. Macrolide antibiotics can also decrease metabolism of cyclosporine. Azithromycin has been associated with cutaneous hypersensitivity reactions.
      Penicillins and cephalosporins are most associated with the adverse events of hypersensitivity reactions ranging from mild drug eruptions to anaphylaxis. Gastrointestinal disturbances are also common and include nausea, diarrhea, and abdominal distention and discomfort.
      When prescribing systemic antibiotics, the issue of bacterial resistance remains a major concern. The Centers for Disease Control and Prevention (CDC) has stressed antibiotic stewardship. This is an initiative to promote the appropriate use of antibiotics where patients receive the right dose of the right antibiotic at the right time for the right duration. Limiting antibiotic use to the shortest possible duration, ideally 3-4 months, can be accomplished with the concomitant use of a retinoid or retinoid/BP.
      • Thiboutot D.M.
      • Shalita A.R.
      • Yamauchi P.S.
      • et al.
      Adapalene gel, 0.1%, as maintenance therapy for acne vulgaris: a randomized, controlled, investigator-blind follow-up of a recent combination study.
      • Poulin Y.
      • Sanchez N.P.
      • Bucko A.
      • et al.
      A 6-month maintenance therapy with adapalene-benzoyl peroxide gel prevents relapse and continuously improves efficacy among patients with severe acne vulgaris: results of a randomized controlled trial.
      While limiting the use of systemic antibiotics is necessary, the work group's consensus agrees there are a subset of patients for whom alternative therapies are inappropriate and who may require a longer course of antibiotics even while taking topical medications. In such patients, consistent follow-up and reevaluation should be used to use the antibiotic for the shortest time necessary. Monotherapy with oral antibiotics is strongly discouraged. The use of topical maintenance regimens cannot be overemphasized. Topical therapies can accomplish continued efficacy months after the discontinuation of systemic antibiotics.
      • Gold L.S.
      • Cruz A.
      • Eichenfield L.
      • et al.
      Effective and safe combination therapy for severe acne vulgaris: a randomized, vehicle-controlled, double-blind study of adapalene 0.1%-benzoyl peroxide 2.5% fixed-dose combination gel with doxycycline hyclate 100 mg.
      • Leyden J.
      • Thiboutot D.M.
      • Shalita A.R.
      • et al.
      Comparison of tazarotene and minocycline maintenance therapies in acne vulgaris: a multicenter, double-blind, randomized, parallel-group study.
      • Thiboutot D.M.
      • Shalita A.R.
      • Yamauchi P.S.
      • et al.
      Adapalene gel, 0.1%, as maintenance therapy for acne vulgaris: a randomized, controlled, investigator-blind follow-up of a recent combination study.
      • Tan J.
      • Stein Gold L.
      • Schlessinger J.
      • et al.
      Short-term combination therapy and long-term relapse prevention in the treatment of severe acne vulgaris.
      The work group's consensus agrees that such maintenance is paramount to reducing antibiotic resistance.
      • Moon S.H.
      • Roh H.S.
      • Kim Y.H.
      • et al.
      Antibiotic resistance of microbial strains isolated from Korean acne patients.
      Other attempts to limit antibiotic use revolve around different dosing recommendations, such as pulse dosing and submicrobial dosing. No alternate dosing routines consistently appear superior to standard dosing.
      Finally, limiting systemic antibiotic use is urged because of the reported associations of inflammatory bowel disease,
      • Margolis D.J.
      • Fanelli M.
      • Hoffstad O.
      • Lewis J.D.
      Potential association between the oral tetracycline class of antimicrobials used to treat acne and inflammatory bowel disease.
      pharyngitis,
      • Margolis D.J.
      • Fanelli M.
      • Kupperman E.
      • et al.
      Association of pharyngitis with oral antibiotic use for the treatment of acne: a cross-sectional and prospective cohort study.
      C difficile infection,
      • Bartlett J.G.
      • Chang T.W.
      • Gurwith M.
      • Gorbach S.L.
      • Onderdonk A.B.
      Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia.
      • Carroll K.C.
      • Bartlett J.G.
      Biology of Clostridium difficile: implications for epidemiology and diagnosis.
      and the induction of Candida vulvovaginitis.

      Hormonal agents

      Combination oral contraceptive pills (COCs) contain both an estrogen and a progestin component. COCs were first approved by the FDA for contraception in the United States in 1960. They prevent ovulation and pregnancy by inhibiting gonadotropin-releasing hormone and, subsequently, follicle-stimulating and luteinizing hormones. These hormones are needed to begin follicular maturation and for ovulation; in their absence, ovulation does not occur. Recommendations for hormonal agents are shown in Table VII, and the strength of recommendations for the treatment of acne with hormonal agents is shown in Table III. World Health Organization (WHO) recommendations for COC usage eligibility are listed in Table VIII. Prescribing information for hormonal therapies is located in Supplemental Table XXIII, Supplemental Table XIV, Supplemental Table XXV, Supplemental Table XXVI, Supplemental Table XXVII, Supplemental Table XXVIII.
      Table VIIRecommendations for hormonal agents
      Estrogen-containing combined oral contraceptives are effective and recommended in the treatment of inflammatory acne in females
      Spironolactone is useful in the treatment of acne in select females
      Oral corticosteroid therapy can be of temporary benefit in patients who have severe inflammatory acne while starting standard acne treatment
      In patients who have well documented adrenal hyperandrogenism, low-dose oral corticosteroids are recommended in treatment of acne
      Table VIIIWorld Health Organization recommendations for combined oral contraceptive usage eligibility
      Data taken from Arrington et al.
      • Arrington E.A.
      • Patel N.S.
      • Gerancher K.
      • Feldman S.R.
      Combined oral contraceptives for the treatment of acne: a practical guide.
      COC use not recommendedCaution or special monitoring
      PregnancyBreastfeeding (6 weeks-6 months postpartum)
      Current breast cancerPostpartum (<21 days)
      Breastfeeding <6 weeks postpartumAge ≥35 years and light smoker (<15 cigarettes per day)
      Age ≥35 years and heavy smoker (≥15 cigarettes per day)History of hypertension (including pregnancy) or if monitoring is not feasible
      Hypertension: systolic, ≥160 mm Hg; diastolic, ≥100 mm HgHypertension: systolic, 140-159 mm Hg; diastolic, 90-99 mm Hg; or controlled and monitored
      Diabetes with end-organ damageHeadaches: migraine without focal neurologic symptoms <35 years
      Diabetes >20 years durationKnown hyperlipidemia should be assessed (eg, type and severity)
      History of or current deep vein thrombosis or pulmonary embolismHistory of breast cancer with ≥5 years of no disease
      Major surgery with prolonged immobilizationBiliary tract disease
      Ischemic heart disease (history or current); valvular heart disease with complicationsMild compensated cirrhosis
      History of cerebrovascular accidentHistory of cholestasis related to COC use
      Headaches (eg, migraine with focal neurologic symptoms at any age, or without aura if ≥35 years)Concurrent use of drugs that affect liver enzymes
      Active viral hepatitis
      Severe decompensated cirrhosis
      Liver tumor (benign or malignant)
      COC, Combined oral contraceptive.
      Data taken from Arrington et al.
      • Arrington E.A.
      • Patel N.S.
      • Gerancher K.
      • Feldman S.R.
      Combined oral contraceptives for the treatment of acne: a practical guide.
      COCs have evolved since 1960. Ethinyl estradiol levels have gradually decreased from around 50 to 150 μg per pill to as low as 10 μg. A variety of different progestational moieties have been used, beginning with the first-generation progestins, the estranes (ie, norethindrone and ethynodiol diacetate). Second-generation progestins include levonorgestrel and norgestimate; these progestins are referred to as the gonanes. Third-generation progestins include less androgenic gonane progestins, such as desogestrel and gestodene. First-, second-, and third-generation progestins are derived from testosterone and alone have androgenic potential. Fourth-generation progestins are not derived from testosterone and include the antiandrogenic progestin drospirenone. While progestins vary in their androgenic potential, evidence suggests that when combined with ethinyl estradiol, the net effect of all COCs is antiandrogenic.
      • Arrington E.A.
      • Patel N.S.
      • Gerancher K.
      • Feldman S.R.
      Combined oral contraceptives for the treatment of acne: a practical guide.
      • Davtyan C.
      Four generations of progestins in oral contraceptives.
      There are currently 4 COCs approved by the FDA for the treatment of acne. They are ethinyl estradiol/norgestimate, ethinyl estradiol/norethindrone acetate/ferrous fumarate, ethinyl estradiol/drospirenone, and ethinyl estradiol/drospirenone/levomefolate. The mechanism of action of COCs in the treatment of acne is based on their antiandrogenic properties. These pills decrease androgen production at the level of the ovary and also increase sex hormone–binding globulin, binding free circulating testosterone and rendering it unavailable to bind and activate the androgen receptor. In addition, COCs reduce 5-alfa-reductase activity and block the androgen receptor.
      • Arrington E.A.
      • Patel N.S.
      • Gerancher K.
      • Feldman S.R.
      Combined oral contraceptives for the treatment of acne: a practical guide.
      • Arowojolu A.O.
      • Gallo M.F.
      • Lopez L.M.
      • Grimes D.A.
      Combined oral contraceptive pills for treatment of acne.
      • Harper J.C.
      Should dermatologists prescribe hormonal contraceptives for acne?.
      • Rabe T.
      • Kowald A.
      • Ortmann J.
      • Rehberger-Schneider S.
      Inhibition of skin 5 alpha-reductase by oral contraceptive progestins in vitro.
      Numerous randomized controlled clinical trials have assessed the efficacy of COCs in the management of acne.
      • Lucky A.W.
      • Koltun W.
      • Thiboutot D.
      • et al.
      A combined oral contraceptive containing 3-mg drospirenone/20-microg ethinyl estradiol in the treatment of acne vulgaris: a randomized, double-blind, placebo-controlled study evaluating lesion counts and participant self-assessment.
      • Maloney J.M.
      • Dietze Jr., P.
      • Watson D.
      • et al.
      Treatment of acne using a 3-milligram drospirenone/20-microgram ethinyl estradiol oral contraceptive administered in a 24/4 regimen: a randomized controlled trial.
      • Maloney J.M.
      • Dietze Jr., P.
      • Watson D.
      • et al.
      A randomized controlled trial of a low-dose combined oral contraceptive containing 3 mg drospirenone plus 20 microg ethinylestradiol in the treatment of acne vulgaris: lesion counts, investigator ratings and subject self-assessment.
      • Plewig G.
      • Cunliffe W.J.
      • Binder N.
      • Hoschen K.
      Efficacy of an oral contraceptive containing EE 0.03 mg and CMA 2 mg (Belara) in moderate acne resolution: a randomized, double-blind, placebo-controlled phase III trial.
      • Arowojolu A.O.
      • Gallo M.F.
      • Lopez L.M.
      • Grimes D.A.
      Combined oral contraceptive pills for treatment of acne.
      • Koltun W.
      • Lucky A.W.
      • Thiboutot D.
      • et al.
      Efficacy and safety of 3 mg drospirenone/20 mcg ethinylestradiol oral contraceptive administered in 24/4 regimen in the treatment of acne vulgaris: a randomized, double-blind, placebo-controlled trial.
      • Koltun W.
      • Maloney J.M.
      • Marr J.
      • Kunz M.
      Treatment of moderate acne vulgaris using a combined oral contraceptive containing ethinylestradiol 20 mug plus drospirenone 3 mg administered in a 24/4 regimen: a pooled analysis.
      • Jaisamrarn U.
      • Chaovisitsaree S.
      • Angsuwathana S.
      • Nerapusee O.
      A comparison of multiphasic oral contraceptives containing norgestimate or desogestrel in acne treatment: a randomized trial.
      It is evident from these trials that COCs reduce acne—both inflammatory and comedonal lesion counts. It is more difficult to determine which, if any, COC is consistently superior in the treatment of acne. A 2012 Cochrane metaanalysis assessed the effect of birth control pills on acne in women and included 31 trials with a total of 12,579 women. Nine trials compared a COC to placebo, and all of these COCs worked well to reduce acne. The progestins included in these 9 trials were levonorgestrel, norethindrone acetate, norgestimate, drospirenone, dienogest, and chlormadinone acetate. Seventeen trials compared 2 COCs, but no consistent differences in acne reduction were appreciated based on formulation or dosage of the COC. Only 1 small study compared a COC to an oral antibiotic; no significant difference in self-assessed acne improvement was identified.
      • Arowojolu A.O.
      • Gallo M.F.
      • Lopez L.M.
      • Grimes D.A.
      Combined oral contraceptive pills for treatment of acne.
      A recent publication evaluated the effectiveness of drospirenone 3 mg/ethinyl estradiol 20 μg in the treatment of moderate truncal AV. The COC showed significant reductions in inflammatory, noninflammatory, and total acne lesions compared to placebo.
      • Palli M.B.
      • Reyes-Habito C.M.
      • Lima X.T.
      • Kimball A.B.
      A single-center, randomized double-blind, parallel-group study to examine the safety and efficacy of 3mg drospirenone/0.02 mg ethinyl estradiol compared with placebo in the treatment of moderate truncal acne vulgaris.
      The risks of COCs must be weighed against the risks of the condition that they are treating or preventing. When COCs are used for contraception, their risks must be compared to the risks of pregnancy. If COCs are used exclusively for acne, their risks must be compared to the risks of acne. It is important to remember that FDA approval of all COCs for acne specifies that they are approved for the treatment of acne in women who also desire contraception.
      COC use is associated with cardiovascular risks. Venous thromboembolic events (VTEs) have been the center of an ongoing debate regarding COCs. Traditionally, higher doses of ethinyl estradiol have been linked to increased risks of VTE. However, in recent years, some progestins have been implicated as risk factors for VTE. A recent Cochrane metaanalysis evaluated 25 publications reporting on 26 studies focused on oral contraceptives and venous thrombosis. The analysis concluded that all COC use increases the risk of VTE compared to nonusers. The relative risk of venous thrombosis for COCs with 30 to 35 μg of ethinyl estradiol and gestodene, desogestrel, cyproterone acetate, or drospirenone was similar and about 50% to 80% higher than for COCs with levonorgestrel.
      • George R.
      • Clarke S.
      • Thiboutot D.
      Hormonal therapy for acne.
      To put this increased risk into perspective, it is important to note that the baseline risk of VTE in nonpregnant, nonusers of COCs is 1 to 5 per 10,000 woman-years. Users of COCs have a VTE risk of 3 to 9 per 10,000 woman-years. Users of drospirenone-containing COCs have a VTE risk of about 10 per 10,000 woman-years. Pregnant women have a VTE risk between 5 and 20 per 10,000 woman-years, and women within 12 weeks postpartum have a VTE risk of between 40 and 65 per 10,000 woman-years.

      The American College of Obstetricians and Gynecologists website. Committee opinion 540. Risk of venous thromboembolism among users of drospirenone-containing oral contraceptive pills. Available at: http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Gynecologic-Practice/Risk-of-Venous-Thromboembolism. Accessed January 6, 2016.

      US Food and Drug Administration website. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular disease endpoints. Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf. Accessed January 6, 2016.

      Myocardial infarction (MI) risks are also increased in COC users. This risk is strongly associated with cigarette smoking and other risk factors, such as diabetes mellitus and hypertension. The WHO reports that COCs are not associated with an increased risk of MI in healthy, normotensive, nondiabetic, nonsmokers at any age.
      Acute myocardial infarction and combined oral contraceptives: results of an international multicentre case-control study. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception.
      There is also an increased risk of both ischemic and hemorrhagic stroke in COC users. Cigarette smoking and hypertension contribute to this increased risk, as do higher doses of ethinyl estradiol and age >35 years. While these are serious potential adverse events, these cardiovascular events are uncommon in women of reproductive age. An increased relative risk still translates to an overall low absolute risk.
      • Arrington E.A.
      • Patel N.S.
      • Gerancher K.
      • Feldman S.R.
      Combined oral contraceptives for the treatment of acne: a practical guide.
      • Harper J.C.
      Should dermatologists prescribe hormonal contraceptives for acne?.
      • Katsambas A.D.
      • Dessinioti C.
      Hormonal therapy for acne: why not as first line therapy? facts and controversies.
      COC use may be associated with an increased risk of breast cancer in some women. A large metaanalysis including data from 53,297 women with breast cancer and 100,239 controls showed an increased risk of breast cancer in current users of COCs. The relative risk of breast cancer in current COC users was 1.24 (95% confidence interval [CI], 1.15-1.33). This increased risk disappeared 10 years after COC discontinuation. Age at first use of a COC was the only factor that was associated with an overall increased risk. Risk did not appear to correlate with the duration of use of the COC or family history of breast cancer.
      Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer.
      A more recent systematic review of cancer risks associated with oral contraceptive use also showed an increased relative risk (1.08; 95% CI, 1.00-1.17) of breast cancer in COC users, and higher risk was associated with more recent use of a COC.
      • Gierisch J.M.
      • Coeytaux R.R.
      • Urrutia R.P.
      • et al.
      Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review.
      Notably, this increased risk of breast cancer is greatest in women <34 years of age, when the overall incidence of breast cancer is at its lowest.
      Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer.
      The risk of cervical cancer may be increased in women who use COCs. An analysis of 24 observational studies found that the risk of cervical cancer increases with an increased duration of COC use. The risk declines after the COC is discontinued and the increase in risk disappears after 10 years of nonuse.
      • Appleby P.
      • Beral V.
      • Berrington de González A.
      • et al.
      International Collaboration of Epidemiological Studies of Cervical Cancer
      Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies.
      Another systematic review found no significant increase in the risk of cervical cancer among ever-users of COCs and never-users from 9 pooled studies. This study did show an increased risk of cervical cancer in women with >5 years of COC use compared with never-users, but the difference was not statistically significant.
      • Gierisch J.M.
      • Coeytaux R.R.
      • Urrutia R.P.
      • et al.
      Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review.
      There is additional concern regarding COC use in younger adolescent populations given the adverse effects of low estrogen on bone mass. Peak bone mass development occurs during adolescence and young adulthood. The addition of low-dose estrogen COCs early in the teen years may undermine the accrual of bone mass.
      • Lloyd T.
      • Rollings N.
      • Andon M.B.
      • et al.
      Determinants of bone density in young women. I. Relationships among pubertal development, total body bone mass, and total body bone density in premenarchal females.
      Osteopenia or decreased bone mineral density with COC use has not been shown.
      • Cromer B.A.
      • Bonny A.E.
      • Stager M.
      • et al.
      Bone mineral density in adolescent females using injectable or oral contraceptives: a 24-month prospective study.
      • Lloyd T.
      • Petit M.A.
      • Lin H.M.
      • Beck T.J.
      Lifestyle factors and the development of bone mass and bone strength in young women.
      However, definitive conclusions are yet to be made. In general, the use of COC for acne should be avoided within 2 years of first starting menses or in patients who are <14 years of age unless it is clinically warranted. The FDA has approved COC use for females 14 years (eg, drospirenone and drosperinone/levomefolate) or 15 years (eg, norgestimate and norethindrone/ferrous fumarate) and older (and desiring use of a COC as mentioned above).
      There are many noncontraceptive benefits of COCs in addition to the improvement of acne. These include regulation of the menstrual cycle, lessening of menorrhagia and associated anemia, and a reduction in the formation of benign ovarian tumors. Decreased risks of colorectal, ovarian, and endometrial cancers have been shown in COC users.
      • Harper J.C.
      Should dermatologists prescribe hormonal contraceptives for acne?.
      • Maguire K.
      • Westhoff C.
      The state of hormonal contraception today: established and emerging noncontraceptive health benefits.
      Oral contraceptives may improve acne for many women. They may be used alone or in combination with other acne treatments. While some women present with signs or symptoms suggestive of a hormonally induced worsening of acne (ie, premenstrual flares or hirsutism), the use of COCs is not limited to these individuals. Any woman with signs or symptoms of hyperandrogenism should be evaluated appropriately for an underlying cause. However, COCs may be beneficial to women with clinical and laboratory findings of hyperandrogenism and in women without these findings.
      COCs may be included as part of a comprehensive acne treatment regimen. Women who desire contraception or who suffer from menorrhagia may choose to begin a COC early in their acne treatment. In other women, COCs may be added to a treatment regimen when results with other agents have been limited. COCs may be used in combination with other oral acne medications, including the tetracycline class of antibiotics and spironolactone. There is much misunderstanding regarding the concomitant use of oral antibiotics and COCs and putative contraceptive failure. Rifampin and griseofulvin are the only antiinfectives that interact with COCs, lessening their effectiveness.
      ACOG Committee on Practice Bulletins-Gynecology
      ACOG practice bulletin. No. 73: Use of hormonal contraception in women with coexisting medical conditions.
      The tetracycline class of antibiotics has not been shown to reduce the effectiveness of COCs when taken concomitantly.
      • Harper J.C.
      Should dermatologists prescribe hormonal contraceptives for acne?.
      • Katsambas A.D.
      • Dessinioti C.
      Hormonal therapy for acne: why not as first line therapy? facts and controversies.
      • Helms S.E.
      • Bredle D.L.
      • Zajic J.
      • Jarjoura D.
      • Brodell R.T.
      • Krishnarao I.
      Oral contraceptive failure rates and oral antibiotics.
      • London B.M.
      • Lookingbill D.P.
      Frequency of pregnancy in acne patients taking oral antibiotics and oral contraceptives.
      Because the progestin drospirenone is an analog of spironolactone, there has been some concern that using a drospirenone-containing COC and spironolactone together might increase the risk of hyperkalemia. In 1 study, 27 women with acne were treated with a COC containing drospirenone 3 mg and ethinyl estradiol 30 μg and spironolactone 100 mg each day. There were no significant elevations of serum potassium and there were no additional side effects significant enough to discontinue treatment.
      • Krunic A.
      • Ciurea A.
      • Scheman A.
      Efficacy and tolerance of acne treatment using both spironolactone and a combined contraceptive containing drospirenone.
      Acne reduction with COC use takes time. Randomized controlled trials consistently show a statistically significant improvement in acne with COCs compared to placebo by the end of cycle 3.
      • Lucky A.W.
      • Koltun W.
      • Thiboutot D.
      • et al.
      A combined oral contraceptive containing 3-mg drospirenone/20-microg ethinyl estradiol in the treatment of acne vulgaris: a randomized, double-blind, placebo-controlled study evaluating lesion counts and participant self-assessment.
      • Maloney J.M.
      • Dietze Jr., P.
      • Watson D.
      • et al.
      Treatment of acne using a 3-milligram drospirenone/20-microgram ethinyl estradiol oral contraceptive administered in a 24/4 regimen: a randomized controlled trial.
      • Maloney J.M.
      • Dietze Jr., P.
      • Watson D.
      • et al.
      A randomized controlled trial of a low-dose combined oral contraceptive containing 3 mg drospirenone plus 20 microg ethinylestradiol in the treatment of acne vulgaris: lesion counts, investigator ratings and subject self-assessment.
      • Plewig G.
      • Cunliffe W.J.
      • Binder N.
      • Hoschen K.
      Efficacy of an oral contraceptive containing EE 0.03 mg and CMA 2 mg (Belara) in moderate acne resolution: a randomized, double-blind, placebo-controlled phase III trial.
      • Koltun W.
      • Lucky A.W.
      • Thiboutot D.
      • et al.
      Efficacy and safety of 3 mg drospirenone/20 mcg ethinylestradiol oral contraceptive administered in 24/4 regimen in the treatment of acne vulgaris: a randomized, double-blind, placebo-controlled trial.
      • Koltun W.
      • Maloney J.M.
      • Marr J.
      • Kunz M.
      Treatment of moderate acne vulgaris using a combined oral contraceptive containing ethinylestradiol 20 mug plus drospirenone 3 mg administered in a 24/4 regimen: a pooled analysis.