Acne Vulgaris

Acne vulgaris is characterized by noninflammatory, open or closed comedones and by inflammatory papules, pustules, and nodules. Acne vulgaris typically affects the areas of skin with the densest population of sebaceous follicles; these areas include the face, the upper part of the chest, and the back.

Acne vulgaris is the most common skin disease in the United States; it affects an estimated 80% of Americans at some time during their lives.[7] Twenty percent have severe acne, which can result in permanent physical and mental scarring.

Medscape Drugs & Diseases articles on acne include Acne Conglobata,Acne Fulminans,Acne Keloidalis Nuchae, and Acneiform Eruptions. Also see the Medscape Acne Resource Center.

The pathogenesis of acne vulgaris is multifactorial. The key factor is genetics.[3] Acne develops as a result of an interplay of the following four factors[2] :

• Release of inflammatory mediators into the skin

• Follicular hyperkeratinization with subsequent plugging of the follicle

• Cutibacterium acnes (formerly Propionibacterium acnes) follicular colonization

• Excess sebum production

Research has shown that inflammatory responses actually occur before hyperkeratinization. Cytokines produced by CD4+ T cells and macrophages activate local endothelial cells to up-regulate inflammatory mediators such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and human leukocyte antigen (HLA)–DR in the vessels around the pilosebaceous follicle.[8]

Follicular hyperkeratinization involves increased keratinocyte proliferation and decreased desquamation, leading to sebum- and keratin-filled microcomedones.[9]

C acnes (formerly P acnes) is an anaerobic organism present in acne lesions. The presence of C acnes (formerly P acnes) promotes inflammation through a variety of mechanisms. C acnes (formerly P acnes) stimulates inflammation by producing proinflammatory mediators that diffuse through the follicle wall. Studies have shown that C acnes (formerly P acnes) activates the toll-like receptor 2 on monocytes and neutrophils.[10] Activation of the toll-like receptor 2 then leads to the production of multiple proinflammatory cytokines, including interleukins 12 and 8 and tumor necrosis factor. Hypersensitivity to C acnes (formerly P acnes) may also explain why some individuals develop inflammatory acne vulgaris while others do not.[11]

Excess sebum is another key factor in the development of acne vulgaris. Sebum production and excretion are regulated by a number of different hormones and mediators. In particular, androgen hormones promote sebum production and release.[12] The degree of comedonal acne in prepubertal girls correlates with circulating levels of the adrenal androgen dehydroepiandrosterone sulfate (DHEAS).[13, 14]

Numerous other mediators and receptors, including growth hormone and insulinlike growth factor, as well as peroxisome proliferator-activated receptors also regulate the sebaceous gland and may contribute to the development of acne.[15, 16] Furthermore, the sebaceous gland acts a neuroendocrine-inflammatory organ that is activated via corticotrophin-releasing hormones in response to stress and normal functions.[17]

The main underlying cause of acne is a genetic predisposition. In addition, other aggravating factors are recognized.

Cosmetic agents and hair pomades may worsen acne.[18]

Medications that can promote acne development include steroids, lithium, some antiepileptics, and iodides.[19]

Congenital adrenal hyperplasia, polycystic ovary syndrome, and other endocrine disorders associated with excess androgens may trigger the development of acne vulgaris. Even pregnancy may cause a flare-up.[20]

Mechanical occlusion with headbands, shoulder pads, back packs, or under-wire bras can be aggravating factors.[21]

Excessive sunlight may either improve or flare acne. In any case, the ultraviolet exposure ages the skin.

United States

Acne is the most common skin condition in the United States, affecting up to 50 million Americans annually.[22] Acne vulgaris affects 80% of Americans at some time during their lives.[7] Twenty percent have severe acne, which can result in permanent physical and mental scarring.

International

Persons of some races are affected more than others. Cystic acne is prevalent in the Mediterranean region from Spain to Iran.[23]

Race

Acne is common in North American whites. African Americans have a higher prevalence of pomade acne, likely stemming from the use of hair pomades. Ethnicities with darker skin are also more prone to postinflammatory hyperpigmentation.[18]

Sex

During adolescence, acne vulgaris is more common in males than in females. In adulthood, acne vulgaris is more common in women than in men.[22, 24]

Age

Acne or acneform lesions, such as in neonatal cephalic pustulosis, may be present in the first few weeks and months of life, when a newborn is still under the influence of maternal hormones and when the androgen-producing portion of the adrenal gland is disproportionately large.[25] This neonatal acne tends to resolve spontaneously. However, some neonates may require therapy (eg, topical retinoids).[25]

Adolescent acne usually begins with the onset of puberty, when the gonads begin to produce and release more androgen hormone. It affects many adolescents and young adults. Approximately 85% of people between the ages of 12 and 24 years experience at least minor acne.[22]

Acne is not limited to adolescence. It can occur at any stage of life and may continue into one’s 30s and 40s. Acne occurring in adults is increasing, affecting up to 12-15% of women.[22] By age 45 years, 5% of both men and women still have acne.[26]

Acne may cause long-lasting and detrimental psychosocial and physical effects. It is associated with depression and anxiety, regardless of disease severity, although the psychological effects usually improve with treatment. Furthermore, acne may cause permanent scarring that is difficult to correct.[27]

A 2017 Swedish study has added further statistically significant evidence that teenage acne may be a risk factor for the later development of early prostate cancer.[28, 29, 30] Researchers suggest that C acnes (formerly P acnes) may be an associated link.

In male patients, acne generally clears by early adulthood. Five percent of men still have acne at age 25 years. Adult acne is more common in females. Twelve percent of women still have acne at age 25 years. Five percent of women still have acne at age 45 years.[26]

The overall prognosis for patients with acne is good.

Patients should be instructed on their morning and evening treatment programs. Retinoid dermatitis may develop at approximately day 10 of therapy. Patients must be informed of this in advance so they will not consider this exfoliation an allergy. By skipping a day or 2 and restarting the program slowly, the skin can adapt to this irritation.

Prescriptions should be accompanied by a discussion of the potential adverse effects.

For patient education resources, see the Skin Conditions and Beauty Center as well as the patient education article Acne. Also see the Medscape Acne Resource Center.

Local symptoms of acne vulgaris may include pain, tenderness, and/or erythema.

Systemic symptoms are most often absent in acne vulgaris. In rare but severe cases, acne vulgaris could lead to acne conglobata, with highly inflammatory nodulocystic acne and interconnected abscesses. Acne fulminans is even more severe than acne conglobata, with systemic symptoms such as fever, joint pain, and general malaise.

Patients with polycystic ovarian syndrome (PCOS) often first present to dermatologists for acne. With its long-term complications of obesity, infertility, and malignancy, PCOS needs to be considered when female patients present with acne, particularly with moderate-to-severe acne in adulthood that is refractory to conventional therapies. Additionally, a history of oligomenorrhea (< 9 menses a year) or amenorrhea for more than 3 months should raise further suspicion for PCOS.[31]

Acne vulgaris may have a psychological impact on any patient, regardless of the severity or the grade of the disease.[4]

Acne vulgaris is characterized by comedones, papules, pustules, and nodules in a sebaceous distribution (eg, face, upper chest, back). A comedone is a whitehead (closed comedone) or a blackhead (open comedone) without any clinical signs of inflammation. Papules and pustules are raised bumps with inflammation. The face may be the only involved skin surface, but the chest, back, and upper arms are often involved.

In comedonal acne, patients develop open and closed comedones but may not develop inflammatory papules or nodules.

See the image below.

Acne, grade I; multiple open comedones.

Mild acne is characterized by comedones and a few papulopustules. Note the image below.

Acne, grade II; closed comedones.

Moderate acne has comedones, inflammatory papules, and pustules. Greater numbers of lesions are present than in milder inflammatory acne. Note the image below.

Acne, grade III; papulopustules.

Nodulocystic acne is characterized by comedones, inflammatory lesions, and large nodules greater than 5 mm in diameter. Scarring is often evident. Note the image below.

Acne, grade IV; multiple open comedones, closed comedones, and papulopustules, plus cysts.

Studies have found that women with PCOS have slightly increased comedones in the forehead, perioral, or jawline areas, but, otherwise, acne lesion counts, types, and regional burden are largely the same between women with and without PCOS.[32] Other cutaneous manifestations may indicate PCOS, including signs of insulin resistance such as acanthosis nigricans and additional signs of hyperandrogenism such as hirsutism and hair loss.[31] Also see Polycystic Ovarian Syndrome.

The diagnosis of acne vulgaris is clinical. Consider polycystic ovarian syndrome (PCOS) in female patients with oligomenorrhea, hirsutism, and/or acanthosis nigricans in addition acne: These patients should be evaluated with total and free testosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, luteinizing hormone, and follicle-stimulating hormone values, as well as a lipid panel, glucose value, and insulin level.

Also see Polycystic Ovarian Syndrome.

Skin lesion cultures to rule out gram-negative folliculitis are warranted if the patient does not respond to long-term antibiotic treatment or improvement with antibiotics is not maintained.[33]

Also see the Medscape Acne Resource Center.

The microcomedo is characterized by a dilated follicle with a plug of dense keratin. With progression of the disease, the follicular opening becomes dilated, and an open comedo results. The follicular wall thins, and it may rupture. Inflammation and bacteria may be evident, with or without follicular rupture. Follicular rupture is accompanied by dense inflammatory infiltrate throughout the dermis. Later, extensive fibrosis and scarring may develop.[34]

Treatment should be directed toward the known pathogenic factors involved in acne. These include follicular hyperproliferation, excess sebum, Cutibacterium acnes (formerly Propionibacterium acnes) infection, and inflammation. The grade and severity of the acne help in determining which of the following treatments, alone or in combination, is most appropriate.

Current consensus recommends a combination of topical retinoid and antimicrobial therapy as first-line therapy for almost all patients with acne.[2] The superior efficacy of this combination, compared with either monotherapy, results from complementary mechanisms of action targeting different pathogenic factors. Retinoids reduce abnormal desquamation, are comedolytic, and have some anti-inflammatory effects, whereas benzoyl peroxide is antimicrobial with some keratolytic effects and antibiotics have anti-inflammatory and antimicrobial effects.[2]

Note the images below.

Acne with reactive hyperpigmentation; before treatment.

Acne with reactive hyperpigmentation; after treatment.

Topical treatments

Retinoids

Topical retinoids are comedolytic and anti-inflammatory. They normalize follicular hyperproliferation and hyperkeratinization. Topical retinoids reduce the numbers of microcomedones, comedones, and inflammatory lesions.[35] Topical retinoids should be initiated as first-line therapy for both comedonal and inflammatory acne lesions and continued as maintenance therapy to inhibit further microcomedone formation.[35]

The most commonly prescribed topical retinoids for acne vulgaris include adapalene, tazarotene, and tretinoin. These retinoids should be applied once daily to clean, dry skin, but they may need to be applied less frequently if irritation occurs. Skin irritation with peeling and redness may be associated with the early use of topical retinoids and typically resolves within the first few weeks of use.[36] The use of mild, nonirritating cleansers and noncomedogenic moisturizers may help reduce this irritation.[35] Alternate-day dosing may be used if irritation persists.

Topical retinoids thin the stratum corneum, and they have been associated with sun sensitivity.[37] Instruct patients about sun protection. Also see Sunscreens and Photoprotection.

Topical antibiotics

Topical antibiotics are mainly used for their role against C acnes (formerly P acnes). They may also have anti-inflammatory properties. Topical antibiotics are not comedolytic, and bacterial resistance may develop to any of these agents. Commonly prescribed topical antibiotics for acne vulgaris include clindamycin, erythromycin, and, more recently, dapsone and minocycline.

Topical dapsone is a new sulfone antibiotic with anti-inflammatory properties that has been shown to be effective for mild-to-moderate acne, and it has a convenient once-daily application schedule.[38] It is available as 5% twice-daily and 7.5% once-daily formulations.[38] The current American Academy of Dermatology guidelines preceded the FDA approval of the 7.5% formulation. Although no research has compared the efficacy of the 5% formulation with the 7.5% formulation, both have been separately shown to be efficacious and safe. The 7.5% formulation has the additional compliance factor of once-daily application.[33, 38]

Minocycline topical foam 4% was evaluated in three 12-week phase 3 trials (n=2418) in patients aged 9 years or older. Each study demonstrated statistically significant disease improvement with minocycline topical compared with vehicle for the coprimary endpoint of absolute reduction of inflammatory lesions and investigator assessment.[39, 40]

Antibiotic resistance in C acnes (formerly P acnes) is common and is a significant threat to acne treatment.[33] Antimicrobials should be combined with a topical retinoids for greater clearing of lesions and to increase the potential for shortened antibiotic treatment. They should be used with benzoyl peroxide to reduce the likelihood of resistance.[2] Concurrent use of oral and topical antibiotics should be avoided and should not be used as monotherapy. If acne relapses, use the same antibiotic if it was previously effective. It may also be helpful to use benzoyl peroxide for 5-7 days between antibiotic courses to reduce resistance in organisms on the skin.[2]

Benzoyl peroxide products are also effective against C acnes (formerly P acnes), and bacterial resistance to benzoyl peroxide has not been reported.[41] Benzoyl peroxide products are available over the counter and by prescription in a variety of topical forms, including soaps, washes, lotions, creams, and gels. Benzoyl peroxide products may be used once or twice a day. These agents may occasionally cause a true allergic contact dermatitis. More often, an irritant contact dermatitis develops, especially if used with tretinoin or when accompanied by aggressive washing methods.[41] If intensive erythema and pruritus develop, a patch test with benzoyl peroxide is indicated to rule out allergic contact dermatitis.

Androgen receptor antagonists

Clascoterone 1% topical cream is a first-in-class topical androgen receptor inhibitor approved by the FDA for acne vulgaris in patients aged 12 years and older. The exact mechanism is unknown. In vitro studies suggest clascoterone competes with androgens, specifically dihydrotestosterone, for binding to the androgen receptors within the sebaceous gland and hair follicles. 

Approval of clascoterone topical was supported by two phase 3 randomized trials including 1440 patients. At week 12, treatment success rates showed statistically significant improvement for patients receiving clascoterone (18.4% and 20.3%) compared with the vehicle alone (9% and 6.5%) (0.001%).[42]  

Systemic treatments

Oral antibiotics

Systemic antibiotics are a mainstay in the treatment of moderate-to-severe inflammatory acne vulgaris.[33] These agents have anti-inflammatory properties, and they are effective against C acnes (formerly P acnes). The tetracycline group of antibiotics is commonly prescribed for acne. The more lipophilic antibiotics, such as doxycycline and minocycline, are generally more effective than tetracycline.[33]

Sarecycline is a new first-in-class tetracycline-derived antibiotic indicated for adults and children aged 9 years and older with non-nodular moderate-to-severe acne vulgaris. Compared with currently available tetracyclines, it has a narrow spectrum of activity, including less activity against enteric gram-negative bacteria, and it also elicits anti-inflammatory effects. Clinical trials showed efficacy compared with placebo to be statistically significant. Onset of efficacy, observed by improvement of inflammatory lesions, was evident at the first follow-up visit (ie, 3 weeks).[43]

Greater efficacy may also be due to less C acnes (formerly P acnes) resistance to minocycline. However, C acnes (formerly P acnes) resistance is becoming more common with all classes of antibiotics currently used to treat acne vulgaris.[44] C acnes (formerly P acnes) resistance to erythromycin has greatly reduced its usefulness in the treatment of acne.[33]

Subantimicrobial therapy or concurrent treatment with topical benzoyl peroxide may reduce the emergence of resistant strains.[45] Comparing subantimicrobial 40-mg doxycycline, 100-mg doxycycline, and placebo, Moore et al found a comparable percentage of patients clear of acne between at the 40-mg and 100-mg doses, both significantly higher than placebo.[46] Additionally, less drug-related adverse events were found with the 40-mg subantimicrobial dosing. Enteric-coated, delayed-release formulations of doxycycline can further reduce gastrointestinal adverse effects.[47]

Oral antibiotic use can lead to vaginal candidiasis; doxycycline can be associated with photosensitivity; and minocycline has been linked to pigment deposition of the skin, mucous membranes, and teeth.[33]

The emergence of antibiotic-resistant bacteria, other than C acnes (formerly P acnes), is a contentious debate. An early study by Miller et al found increased skin carriage of coagulase-negative staphylococci in not only acne patients with prolonged use of antibiotics, but also in their close contacts.[48] On the contrary, a study by Fanelli et al found that Staphylococcus aureus remained sensitive to tetracycline even after prolonged use of that antibiotic for acne.[49] This has significant ramifications when considering efforts to control the spread of methicillin-resistant S aureus (MRSA), because tetracycline group antibiotics are currently one of the primary options for outpatient treatment of MRSA infection.

Other antibiotics, including trimethoprim alone or in combination with sulfamethoxazole, and azithromycin, reportedly are helpful.[50, 51]

Hormonal therapies

Some hormonal therapies may be effective in the treatment of acne vulgaris. Estrogen can be used to decrease sebum production. Additionally, it reduces ovarian production of androgens by suppressing gonadotrophin release.[35] Oral contraceptives also increase hepatic synthesis of sex hormone–binding globulin, resulting in an overall decrease in circulating free testosterone. Combination birth control pills have shown efficacy in the treatment of acne vulgaris.[52]

Spironolactone may also be used in the treatment of acne vulgaris.[53] Spironolactone binds the androgen receptor and reduces androgen production. Adverse effects include dizziness, breast tenderness, and dysmenorrhea.[35] Dysmenorrhea may be lessened by coadministration with an oral contraceptive. In two 2017 retrospective studies, spironolactone has been shown to be effective in reducing inflammatory lesions in multiple areas of the body with minimal adverse effects.[54, 55] Currently, more high-powered randomized controlled trials are needed to assess the efficacy of spironolactone monotherapy in treating acne, but spironolactone should be considered in recalcitrant acne, in women who do not tolerate or have contraindications to oral contraceptives, and to prevent antibiotic resistance.[35] A 2015 large retrospective study of healthy women aged 18-45 years confirms potassium monitoring is unnecessary for these patients while taking spironolactone.[56] Pregnancy must be avoided while taking spironolactone because of the risk of feminization of the male fetus, and spironolactone is not recommended for males because of the potential for gynecomastia.[35, 54] While a black box warning regarding possible cancer risk was placed on spironolactone many years ago after rats fed high doses of the medication developed both benign and malignant tumors, several large retrospective and longitudinal studies have found no association with cancer.[57]

Isotretinoin

Isotretinoin is a systemic retinoid that is highly effective in the treatment of severe, recalcitrant acne vulgaris.[33] Isotretinoin causes normalization of epidermal differentiation, depresses sebum excretion by 70%, is anti-inflammatory, and even reduces the presence of C acnes (formerly P acnes).[58]

Isotretinoin therapy should be initiated at a dose of 0.5 mg/kg/d for 4 weeks and increased as tolerated until a cumulative dose of 120-150 mg/kg is achieved.[33] Coadministration with steroids at the onset of therapy may be useful in severe cases to prevent initial worsening.[33] Some patients may respond to doses lower than the standard recommendation dosages. A lower dose (0.25-0.4 mg/kg/d) may be as effective in clearing acne as the higher dose given for the same period and with greater patient satisfaction. However, the benefit of prolonged remission is not as great with such therapy as with standard doses.[59] Lower intermittent dosing schedules (1 wk/mo) are not as effective.[59]

Some patients only require one course of oral isotretinoin for complete acne remission, while others require additional courses of isotretinoin therapy. A study found 38% of the patients had no acne during 3-year follow up, and, among the remaining patients, 17% were controlled with further topical therapy, 25% with topical and oral antibiotics, and 20% with second course of isotretinoin.[60] Relapse is more likely in younger or female patients.[60]

Isotretinoin is a teratogen, so pregnancy must be avoided. Contraception counseling is mandatory, and two negative pregnancy test results are required prior to the initiation of therapy in women of childbearing potential. The baseline laboratory examination should also include cholesterol and triglyceride assessment, hepatic transaminase levels, and a CBC count. Pregnancy tests and a lipid panel and liver enzyme examination should be repeated monthly during treatment while dosing is changing. Once a level dose is used and the lipids, liver enzymes, and CBC count are normal, these tests may be discontinued.[35] Other adverse effects include dry skin, lips, and eyes; muscle aches; and headaches. Patients experiencing severe headaches, decreased night vision, or adverse psychiatric events should stop taking isotretinoin immediately.[35]

Acne-associated mood changes and depression have also been reported during treatment, but a 2017 meta-analysis involving 1411 cases found no increased risk of depression with isotretinoin use.[61] Some of the studies that reported a positive causal relationship between isotretinoin and depression included a dose-response relationship with depression of up to 3 mg/kg/day of isotretinoin; however, this high of a dose is not usually prescribed for acne.[62] Other studies have described new-onset depression in both isotretinoin and antibiotic groups, suggesting depression is associated with acne, regardless of treatment.[63] Therefore, it is important to consider the risk of depression among all patients with acne.

Inflammatory bowel diseases (IBDs) have also been controversially linked to isotretinoin use. A number of case reports have linked isotretinoin with the onset of IBD, with a wide variety of severity of acne, dose of isotretinoin, and duration of treatment prior to the development of IBD.[64] Subsequent case-control and cohort studies had conflicting results, with some suggesting no association between isotretinoin and IBD and others suggesting an association between isotretinoin and ulcerative colitis but not Crohn disease[65, 66, 67, 68] Finally, a 2016 large meta-analysis, indexing more than 9 million cases to reduce effects of selection bias and confounding factors, showed isotretinoin is not associated with an increased risk of Crohn disease or ulcerative colitis.[69] A US Food and Drug Administration(FDA)–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.

While using isotretinoin, the patient is considered at high risk for abnormal healing and the development of excessive granulation tissue following procedures.[70] Many dermatologists delay elective procedures, such as dermabrasion or laser resurfacing (eg, with carbon dioxide laser or erbium:YAG laser), for up to 1 year after completion of therapy.

Intralesional steroid injections have been found to be beneficial for large inflammatory lesions. Comedone removal does not affect the course of the disease, but it does improve the patient’s appearance.[33] Additionally, some patients may benefit from superficial peels that use glycolic or salicylic acid, although more research needs to be conducted to establish best practice for these modalities.

Of all forms of laser and light therapy, the most evidence is with photodynamic therapy (PDT) in treating acne.[33] PDT involves a photosensitizer applied to the skin, time allowed for it to be absorbed by the pilosebaceous units, and then application of a light source to activate the photosensitizer, generating reactive oxygen species to damage the glands and reduce Cutibacterium acnes (formerly Propionibacterium acnes). A 2016 Cochrane review was unable to draw firm conclusions regarding the benefit of light therapy in acne, owing to the variation in wavelength, dose, photosensitizer, comparator interventions, and treatment frequency that were studied.[71] However, despite the interstudy variation, many individual trials show PDT to be effective in reducing lesions in mild-to-severe acne, with 5-aminolevulinic acid and methyl aminolevulinate photosensitizers and red light source as promising treatment components.[72, 73]

There is also a growing body of evidence for laser treatment of acne, standalone or in the context of PDT. However, similar to light therapy, the power and quality of research is limited by small patient numbers, lack of a control population, and comparison to standard therapies. Nonetheless, preliminary studies have shown improvement in acne, and even potential long-lasting effects with the 1550-nm erbium-glass laser, 1064-nm Nd:YAG laser, and PDT with laser.[74]

In December 2014, the FDA approved Bellafill, the first dermal filler indicated for acne scarring. Bellafill is a bovine collagen dermal filler.

If the patient is feeling depressed while taking isotretinoin, refer him or her to a specialist for help.

Diet therapy has been suggested. Fulton et al performed a study on chocolate, having teenage patients with acne consume 1 bar of chocolate each day. Some of the patients improved and some worsened, but the vast majority were unchanged.[75] This study helped decrease the emphasis on diet as a causal factor in acne vulgaris. However, investigators always returned to the diet question. Data suggest that the westernization of certain Native American populations and the related consumption of unhealthy "junk" foods (eg, potato chips, soft drinks) has had a negative impact on general and skin health, resulting in acne flares. Skim milk, compared with full-fat milk, has been found to have a positive association with acne, especially in teenagers and young adults.[76, 77] Causation was not able to be drawn from the case control studies, but the mechanism involving hormonal constituents of the skim milk has been postulated.[76] . Whey protein is a commonly used supplement that has been suggested to worsen acne and should be discontinued if flaring of the condition is associated with its use.

Investigators have also focused on a low-glycemic diet to avoid stress from high-carbohydrate diets and to reduce insulin levels. A study found that 12 weeks of a high-protein, low–glycemic load diet decreased the total amount of acne lesions, and this may lead to dermatologists recommending the South Beach Diet to patients with acne.[23] However, guideline groups have not found benefit in acne treatment or control with dietary restrictions.[33]

Hyperkalemia is a potential dangerous adverse effect from spironolactone; however, a 2015 large retrospective study of healthy women aged 18-45 years confirms potassium monitoring is unnecessary for these patients while taking spironolactone.[56] Plovanich et al found the rate of hyperkalemia in patients taking spironolactone is equivalent to the minimal baseline rate of hyperkalemia in this population, and, of the hyperkalemia cases, none was clinically significant.

In 2016, the American Academy of Dermatology (AAD) issued new evidence-based guidelines for treatment of both adolescents and adults. Recommended treatments include topical therapy, antibiotics, isotretinoin, and oral contraceptives.[33] The key recommendations include the following:

• Benzoyl peroxide or combinations with erythromycin or clindamycin as monotherapy for mild acne; benzoyl peroxide with a topical retinoid or systemic antibiotic therapy for moderate-to-severe acne

• Topical antibiotics (eg, erythromycin, clindamycin) are not recommended as monotherapy because of the risk of bacterial resistance

• Topical retinoids as monotherapy in primarily comedonal acne, or in combination with topical or oral antimicrobials for mixed or primarily inflammatory acne

• Topical adapalene, tretinoin, and benzoyl peroxide can be safely used to treat acne in preadolescent children

• Topical dapsone 5% gel for inflammatory acne, particularly in adult females

• Systemic antibiotics are recommended for moderate and severe acne and forms of inflammatory acne that are resistant to topical treatments; doxycycline and minocycline are both more effective than tetracycline

• Topical therapy with benzoyl peroxide or a retinoid should be used with systemic antibiotics and for maintenance after completion of systemic antibiotic therapy

• Monotherapy with systemic antibiotics is not recommended

• Systemic antibiotic use should be limited to the shortest possible duration; to minimize the development of bacterial resistance, reevaluation at 3-4 months

• Use of oral erythromycin and azithromycin should be limited to those who cannot use the tetracyclines (ie, pregnant women or children aged < 8 y); erythromycin use should be restricted because of its increased risk of bacterial resistance

• Isotretinoin is recommended for severe acne or moderate acne that does not respond to other therapy; low-dose isotretinoin can be used to effectively treat acne and reduce the frequency and severity of medication-related adverse effects, but intermittent dosing is not recommended; all patients treated with isotretinoin must adhere to the iPLEDGE risk management program; patients should receive routine monitoring of liver function tests, serum cholesterol, and triglycerides at baseline and again until response to treatment is established, but routine monitoring of complete blood count is not recommended; patients should be educated about the potential risks and monitored for any indication of inflammatory bowel disease and depressive symptoms

• Combined oral contraceptives (COC) containing estrogen are effective for treatment of inflammatory acne in females; physicians should follow the World Health Organization (WHO) recommendations for COC usage eligibility

• Despite the lack of published data, relying on available evidence, experience, and expert opinion, the guidelines support the use of spironolactone in select women

In 2015, as part of the Choosing Wisely® initiative from the American Board of Internal Medicine Foundation (ABIM), the AAD released recommendations regarding low-value care that cautioned against the routine use of microbiologic testing in the evaluation and management of acne. The AAD concluded that determining the type of bacteria present in acne lesions was unnecessary because it did not alter the management of typical acne presentations.[78]

Canadian clinical practice guidelines for acne treatment have been updated; the following is a summary of their recommendations[79, 80] :

• Comedonal acne - Topical retinoids or benzoyl peroxide; fixed-dose combinations adapalene–benzoyl peroxide and clindamycin–benzoyl peroxide; or the combination of clindamycin 1.2% and tretinoin 0.025% (as a gel); and, for women, consider combined oral contraceptives

• Localized mild-to-moderate papulopustular acne - Benzoyl peroxide as monotherapy; topical retinoids as monotherapy; the fixed-dose combination of clindamycin 1% and benzoyl peroxide 5% and the fixed-dose combination of adapalene 0.1% and benzoyl peroxide 2.5% (as gels); or the combination of clindamycin 1.2% and tretinoin 0.025% gel

• More extensive moderate papulopustular acne - Addition of systemic antibiotics to the topical medications above, as recommended for mild-to-moderate papulopustular acne

• More extensive moderate papulopustular acne in women - Addition of combined oral contraceptives to the topical medications above, as recommended for mild-to-moderate papulopustular acne

• Severe acne - Oral isotretinoin or systemic antibiotics in combination with benzoyl peroxide, with or without topical retinoids

• Oral isotretinoin - Should only be prescribed by physicians with experience in prescribing and monitoring the drug; strict pregnancy precautions must be followed

The American Academy of Pediatrics has endorsed the recommendations of the American Acne and Rosacea Society for the diagnosis and treatment of pediatric acne.[25] The evidence-based guidelines used age and pubertal status to delineate classification, diagnosis, evaluation, and management, as well as special concerns such as the psychosocial effects of acne, treatment adherence, and dietary considerations.

The following are among recommendations presented for adolescent, preadolescent, infant, and neonatal acne[25] :

• Benzoyl peroxide is generally safe and effective as monotherapy or when used in topical combination products for mild acne (level A)

• Topical retinoids may be used either as monotherapy or in combination with other products and in therapeutic regimens for all types and severities of acne in children and adolescents of all ages (level A)

• Oral antibiotics may be used for moderate-to-severe inflammatory acne for any age (except for tetracycline in children < 8 years) (level B)

• Hormonal therapy with combination oral contraceptives may be used as second-line therapy in pubertal females with moderate-to-severe acne (level A)

• Isotretinoin is recommended for severe, scarring, and/or refractory acne in adolescents (level A)

In June 2014, FDA announced that "rare but serious and potentially life-threatening" reactions can occur with over-the-counter acne medications.[81] It advised healthcare professionals to instruct consumers to stop using these products and seek emergency medical attention immediately if they experience hypersensitivity reactions such as swelling of the eyes, face, lips, or tongue; difficulty breathing; throat tightness; feelings of faintness; or hives or itching. These reactions may occur within minutes to a day or longer after using the product. The FDA is uncertain whether the reactions are caused by the active ingredient (ie, benzoyl peroxide, salicylic acid), inactive ingredients, or a combination of both. For more information, see Serious Allergic Reactions Possible With Acne Products, FDA Says.

The following information primarily pertains to the treatment of Cutibacterium (formerly Propionibacterium) acne vulgaris.

Antibiotics used to treat anaerobic infections usually suffice for other types of Cutibacterium (formerly Propionibacterium) infections. These include the penicillins, carbapenems, and clindamycin. In addition, vancomycin and teicoplanin (investigational) have been used. Some of these antibiotics are discussed after the treatment of acne vulgaris. Daptomycin has been used for the treatment of Cutibacterium (formerly Propionibacterium) osteomyelitis.[41]

A first-in-class topical selective androgen receptor inhibitor, clascoterone 1% topical cream, was approved by the FDA in August 2020. Clascoterone cream targets androgen receptors in the skin to reduce cutaneous 5-alpha dihydrotestosterone. Favorable results, safety, and tolerability were reported from two phase 3 double-blind, vehicle-controlled, randomized, 12-week, trials that included a total of 1440 subjects.[42]

Class Summary

Acne products are used for the treatment of mild to moderate acne vulgaris. These agents may have antibacterial and comedolytic properties. In severe cases, the agents may be used as an adjunct in therapeutic regimens.

Erythromycin and benzoyl peroxide (Benzamycin)

This combination agent contains erythromycin, which is a macrolide antibiotic, and benzoyl peroxide. Benzoyl peroxide, in addition to being an antibacterial agent, is a keratolytic and desquamative agent. With benzoyl peroxide, free-radical oxygen is released upon administration, oxidizing bacterial proteins in sebaceous follicles and decreasing the number of anaerobic, bacterial, and irritating free fatty acids. This combination has keratolytic and comedolytic effects. Erythromycin is indicated for infections caused by susceptible strains of microorganisms. The combination drug may be applied topically twice daily.

Clindamycin and tretinoin (Ziana, Veltin)

This combination agent contains the topical antibiotic clindamycin 1.2% and tretinoin 0.025%. Clindamycin reduces Cutibacterium acnes (formerly Propionibacterium acnes) levels and is anti-inflammatory. Tretinoin normalizes differentiation of keratinocytes and is anti-inflammatory. Apply daily to affected areas.

Clindamycin and benzoyl peroxide (Acanya, Duac, BenzaClin)

This combination agent contains the topical antibiotic clindamycin and benzoyl peroxide. Clindamycin reduces C acnes (formerly P acnes) levels and is anti-inflammatory. Benzoyl peroxide is an antibacterial, comedolytic, and anti-inflammatory agent. Benzoyl peroxide reduces the risk of development of bacterial resistance to clindamycin. Acanya gel contains 2.5% benzoyl peroxide and Duac CS and BenzaClin contain 5% benzoyl peroxide. Apply Acanya and Duac CS once daily. BenzaClin is applied twice daily.

Azelaic acid (Azelex, Finacea)

Azelaic acid has been shown to help reduce inflammation and may aid in the treatment of postinflammatory hyperpigmentation. Apply azelaic acid twice daily. Improvement may be seen within 4 weeks.

Benzoyl peroxide (BenzEFoam, PanOxyl, Neutrogena Clear Pore, Benzac AC Wash)

Benzoyl peroxide is an oxidizing agent that possesses antibacterial properties and is comedolytic. The antibacterial activity results from the release of active or free-radical oxygen that can oxidize bacterial proteins. Benzoyl peroxide is oxidized into benzoic acid with contact to the skin. It is available over the counter and by prescription.

Class Summary

These agents stimulate cellular retinoid receptors and help normalize keratinocyte differentiation and are comedolytic. In addition, they have anti-inflammatory properties. Oral isotretinoin also reduces sebum production in the skin. Retinoids are classified into 3 generations. The first comprises topical tretinoin and systemic isotretinoin. Acitretin is a second-generation retinoid used to treat psoriasis. The third-generation retinoids include topical adapalene tazarotene.

Topical tretinoin (Retin-A Micro, Atralin, Avita, Tretin-X, Renova)

Topical tretinoin inhibits microcomedo formation. It decreases cohesiveness of keratinocytes in sebaceous follicles, which allows for easy removal. It has anti-inflammatory properties. Topical tretinoin is available as a cream or gel.

Adapalene (Differin)

Adapalene inhibits microcomedo formation. It decreases cohesiveness of keratinocytes in sebaceous follicles, which allows for easy removal. It has anti-inflammatory properties. Adapalene is available as a cream, lotion, or gel.

Tazarotene (Tazorac, Fabior, Avage)

Tazarotene inhibits microcomedo formation. It decreases cohesiveness of keratinocytes in sebaceous follicles, which allows for easy removal. It has anti-inflammatory and immunological properties. Tazarotene is available as a cream or gel.

Trifarotene (Aklief)

Trifarotene is an agonist of retinoic acid receptors (RARs), with particular activity at the gamma subtype of RAR. The stimulation of the RAR results in modulation of target genes that are associated with various processes, including cell differentiation and mediation of inflammation. The exact process by which trifarotene ameliorates acne is unknown. It is indicated for acne vulgaris for patients aged 9 years and older. Trifarotene is available as cream.

Isotretinoin (Claravis, Amnesteem, Absorica, Zenatane)

Isotretinoin is an oral retinoid indicated for recalcitrant, nodulocystic acne. It addresses all four pathogenic factors involved in the development of acne: follicular hyperkeratinization, inflammation, sebum production, and Cutibacterium acnes (formerly Propionibacterium acnes) growth. Treatment is weight-based, usually dosed initially 0.5 mg/kg and increased to 1 mg/kg in 2 divided doses for 15-20 weeks. Once-daily dosing is not recommended. The dose may be adjusted to administer up to 2 mg/kg/day. The patients must be registered into the government-regulated iPledge program in order to receive the medication.

Class Summary

Oral antibiotics are useful in inflammatory acne, and improvement is usually seen after several weeks of use. Antibiotic monotherapy is discouraged due to risk of development of resistant bacteria.

Females should be warned about the development of Candida albicans vaginitis. A rare complication of long-term oral antibiotic use is the development of gram-negative folliculitis. Tetracycline class antibiotics can cause sun sensitivity. Doxycycline is associated with GERD, and should be taken at least 30 minutes prior to sleep. Minocycline is rarely associated with a lupuslike syndrome, minocycline-induced hyperpigmentation, and pseudotumor cerebri.

Topical antibiotics are used in almost all acne patients. Monotherapy should be avoided to reduce risk of antibiotic resistance. Concurrent use of benzoyl peroxide eliminates the risk of development of resistance. Topical antibiotics are available as monotherapy or in fixed-dose combination products along with benzoyl peroxide or retinoids. Topical antibiotics used include clindamycin and erythromycin, though resistance to erythromycin favors the use of clindamycin. Additionally, dapsone and minocycline are approved in topical dosage forms to treat acne vulgaris.

Tetracycline

Tetracycline inhibits bacterial protein synthesis by binding with 30S and, possibly, 50S ribosomal subunit(s). Tetracycline has anti-inflammatory activity. Tetracycline may be administered at 250-500 mg PO bid.

Minocycline (Solodyn, Minocin)

Minocycline treats infections caused by susceptible gram-negative and gram-positive organisms, in addition to infections caused by susceptible Chlamydia, Rickettsia, and Mycoplasma species. The brand name Solodyn is an extended-release formulation indicated for acne and is prescribed as a weight-based 1-mg/kg dose per day. The minocycline dose should be lowered in patients with renal impairment.

Doxycycline (Doryx, Adoxa, Doxy 100, Vibramycin)

Doxycycline treats infections caused by susceptible gram-negative and gram-positive organisms. It inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. Doxycycline may block dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest. The brand name 150-mg Doryx is enteric coated, to reduce adverse gastrointestinal effects.

Sarecycline (Seysara)

Sarecycline is a tetracycline-derived antibiotic specifically created for dermatologic purposes. It possesses a narrow spectrum of activity compared with conventional tetracyclines. It is indicated for treatment of inflammatory lesions of non-nodular moderate-to-severe acne in adults and children aged 9 years or older.

Trimethoprim/sulfamethoxazole (Bactrim, Bactrim DS, Septra DS, Sulfatrim)

Trimethoprim/sulfamethoxazole is an antibiotic with activity against many gram-positive and gram-negative organisms. It inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid. It is available as 80 mg trimethoprim and 400 mg sulfamethoxazole or as 160 mg trimethoprim and 800 mg sulfamethoxazole (double strength).

Clindamycin (Cleocin)

Clindamycin is a lincosamide for the treatment of serious skin and soft tissue staphylococcal infections. It is also effective against aerobic and anaerobic streptococci (except enterococci). It inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Clindamycin is commonly used topically, but it can be given orally. Oral monotherapy administration should be avoided to reduce the risk of antibiotic resistance. It may administered at 75-300 mg/day in divided doses.

Clindamycin topical (ClindaGel, Cleocin-T, ClindaMax)

Topical clindamycin is a lincosamide for treatment of serious skin and soft tissue staphylococcal infections. It is also effective against aerobic and anaerobic streptococci (except enterococci). It inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. It is commonly used topically, but it can be given orally. Apply a thin film twice daily, except for the gel form, which is applied once daily.

Erythromycin topical (Akne-mycin, Erygel, Ery)

Topical erythromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. It is commonly prescribed for acne as a topical gel in combination with benzoyl peroxide. Its use is limited because of resistant Cutibacterium acnes (formerly Propionibacterium acnes) strains. Apply twice daily after washing the skin and drying it.

Daptomycin (Cubicin)

Daptomycin binds to bacterial membranes and causes rapid membrane potential depolarization, thereby inhibiting protein, DNA, and RNA synthesis, ultimately causing cell death. It is indicated for complicated skin and skin-structure infections caused by S aureus (including methicillin-resistant strains), S pyogenes, S agalactiae, S dysgalactiae, and E faecalis (vancomycin-susceptible strains only). Daptomycin has been used for the treatment of Cutibacterium (formerly Propionibacterium) osteomyelitis.

Dapsone topical (Aczone)

Dapsone is a sulfone antibiotic that also has anti-inflammatory properties that are largely thought to contribute to its efficacy for treating mild-to-moderate acne. It is well tolerated, with infrequent and mild adverse events mainly involving local administration site such as dryness, stinging, and erythema. It is available as 5% twice-daily and 7.5% once-daily formulations. The current American Academy of Dermatology guidelines preceded the FDA approval of the 7.5% formulation. Although no research has compared the efficacy of the 5% formulation with the 7.5% formulation, both have been separately shown to be efficacious and safe. The 7.5% formulation has the additional compliance factor of once-daily application.

Minocycline topical (Amzeeq)

The mechanism of action of minocycline foam in treating acne vulgaris is not known. It is indicated for topical treatment of acne vulgaris in adults and children aged 9 years or older.

Class Summary

Hormonal therapies can be used in females with acne, especially those with premenstrual acne flares in whom other therapies have failed. Patients may also have signs of hyperandrogenism (eg, hirsutism, irregular menses, menstrual dysfunction). Serum androgen levels may or may not be elevated.

Available options include combination estrogen-progestin oral contraceptive pills, which suppress ovarian androgen production as well as androgen receptor blockers that block the effect of androgens peripherally at the sebaceous gland.

Ethinyl estradiol, drospirenone, and levomefolate (Beyaz)

Ethinyl estradiol, drospirenone, and levomefolate is a combination of estrogen and progestin that treats acne in adult women. It suppresses ovarian production of androgens.

Ethinyl estradiol and norethindrone (Estrostep Fe, Tilia Fe, Tri-Legest Fe, Femcon FE)

Ethinyl estradiol and norethindrone is a combination of estrogen and progestin that treats acne in adult women. It suppresses ovarian production of androgens.

Ethinyl estradiol and norgestimate (Ortho Tri-Cyclen, Tri-Estarylla, Tri-Previfem, Tri-Sprintec)

Ethinyl estradiol and norgestimate is a combination of estrogen and progestin treats acne in adult women. It suppresses ovarian production of androgens.

Ethinyl estradiol and drospirenone (Yaz, Zarah, Gianvi, Ocella, Yasmin)

Ethinyl estradiol and drospirenone is a combination of estrogen and progestin that treats acne in adult women. It suppresses ovarian production of androgens.

Class Summary

Aldosterone antagonists may reduce free testosterone levels and compete with androgens binding at the sebaceous gland.

Spironolactone (Aldactone)

Spironolactone is an aldosterone antagonist that competes with testosterone and dihydrotestosterone binding at the receptor in the sebaceous gland. It also reduces free testosterone levels as more blood is bound by an increased quantity of SHBG. To treat acne in women, 25-200 mg once daily may be administered.

Class Summary

These agents compete with androgens, specifically dihydrotestosterone, for binding to the androgen receptors within the sebaceous gland and hair follicles.

Clascoterone topical (Winlevi)

Clascoterone 1% topical cream is indicated for treatment of acne vulgaris in patients aged 12 years and older.