Version May 2024
INTRODUCTION — Acne vulgaris is a common cutaneous disorder that can cause discomfort, disfigurement, and negative psychosocial effects. Clinical presentations of acne vulgaris vary widely, ranging from minor skin involvement to extensive presentations. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section on 'Clinical manifestations'.)
Treatment options for acne vulgaris include topical, oral, and procedural therapies (table 1). Although topical therapy is the mainstay of treatment for mild acne vulgaris (algorithm 1), patients with moderate to severe presentations may benefit from systemic therapy (algorithm 2).
The therapeutic approach to moderate to severe acne vulgaris will be reviewed here. General treatment principles and the management of mild acne vulgaris are reviewed separately.
●(See "Acne vulgaris: Overview of management".)
The management of acne vulgaris in infants, young children, and preadolescents is reviewed in detail separately.
●(See "Acne in infants, young children, and preadolescents".)
Other aspects of the manifestations, diagnosis, and management of acne vulgaris and acne scars are reviewed separately.
●(See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris".)
●(See "Oral isotretinoin therapy for acne vulgaris".)
●(See "Postadolescent acne in women".)
●(See "Light-based, adjunctive, and other therapies for acne vulgaris".)
●(See "Management of acne scars".)
DEFINITION OF MODERATE TO SEVERE ACNE — There is no universally accepted grading system for assessing severity. Examples of findings that may be considered supportive of moderate to severe involvement include one or more of the following (picture 1A-D):
●Visually prominent acne consisting of many comedones, inflamed papules, or pustules
●Presence of large, inflamed papules or nodules (lesions >5 mm in diameter)
●Involvement of multiple body areas
●Associated scarring
The clinician should also consider the psychologic burden of acne vulgaris in the assessment of severity. In some patients, acne that appears relatively mild causes significant psychologic distress, warranting a more aggressive therapeutic approach, similar to the approach for moderate to severe acne (algorithm 2).
GENERAL APPROACH — Topical and systemic therapies are the mainstays of treatment for moderate to severe acne vulgaris. Procedural interventions are primarily utilized as adjunctive therapies. (See "Light-based, adjunctive, and other therapies for acne vulgaris".)
When to use systemic therapy — Moderate to severe acne vulgaris is often treated systemically to optimize and simplify treatment. The primary systemic therapies for acne vulgaris include oral antibiotics (typically tetracyclines), hormonal therapies (oral contraceptives or spironolactone), and oral isotretinoin (algorithm 2). With the exception of oral isotretinoin, systemic therapy is typically combined with topical therapy. (See 'Use of topical therapy' below.)
The clinical presentation and patient preference influence the decision to initiate systemic therapy. Clinical findings prompting systemic therapy include nodular lesions, extensive skin involvement, scarring, and psychologic disturbance related to acne. In the absence of such findings, an initial trial of topical therapy alone is a reasonable alternative; however, we typically discuss the option for systemic therapy with all patients with moderate to severe acne vulgaris. (See 'Use of topical therapy' below.)
Selection of a systemic therapy — Selection among the systemic treatments (oral isotretinoin, oral antibiotics, oral hormonal agents) involves consideration of patient-specific characteristics and the values and preferences of individual patients (algorithm 2):
●Clinical manifestations — The types of lesions present and severity of acne vulgaris influence selection of therapy:
•Types of lesions – The classic lesions of acne vulgaris include closed comedones, open comedones, and papulopustular or nodular lesions. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section on 'Classic features'.)
Oral isotretinoin, oral contraceptives, and spironolactone are considered beneficial for all manifestations of acne vulgaris and, therefore, can be used as the primary systemic therapy for patients with exclusively comedonal, papulopustular, nodular, or mixed presentations. In contrast, oral antibiotics are primarily utilized for papulopustular or nodular manifestations. Although oral antibiotics may contribute to improvement in all lesion types, they are considered most effective for papulopustular and nodular lesions. (See 'Oral antibiotics' below.)
•Severity – Although oral isotretinoin, oral antibiotics, oral contraceptives, and spironolactone are all effective treatments, severe, extensive, nodular acne vulgaris warrants early consideration of oral isotretinoin therapy. Oral isotretinoin is considered the only medication that can permanently alter the natural course of acne vulgaris and has the potential to induce long-term remissions off therapy. (See 'Oral isotretinoin' below and 'Acne fulminans' below and 'Acne conglobata' below.)
Use of oral isotretinoin can also be appropriate for less severe presentations. Examples of scenarios in which early use of isotretinoin may be preferred include patients with acne-induced scarring or acne-related, psychosocial distress [1]. Moderate acne that has failed to respond to other treatments is also an appropriate indication for isotretinoin. Risk for multiple adverse effects, including teratogenicity, limit the initial use of oral isotretinoin for mild, uncomplicated acne vulgaris. (See "Oral isotretinoin therapy for acne vulgaris".)
●Sex and age – The option for systemic hormonal therapy (oral contraceptives, spironolactone) for acne vulgaris is limited to postmenarchal female patients.
Special considerations for the treatment of children and adolescents are reviewed separately. (See "Acne vulgaris: Overview of management", section on 'Children' and "Acne in infants, young children, and preadolescents", section on 'Treatment'.)
●Pregnancy and childbearing potential – Certain systemic therapies are not recommended during pregnancy. In particular, pregnant individuals should not receive oral isotretinoin, oral tetracyclines, oral contraceptives, or spironolactone.
Oral isotretinoin is a teratogenic drug that is contraindicated for pregnant individuals and individuals of childbearing potential who are not able or willing to adhere to highly effective measures to prevent pregnancy. In the United States, oral isotretinoin therapy requires participation in a Risk Evaluation and Mitigation Strategy (REMS) program. (See "Oral isotretinoin therapy for acne vulgaris".)
Administration of tetracyclines to pregnant individuals is associated with risk for permanent discoloration of developing teeth. Spironolactone is associated with a theoretical risk for feminization of a male fetus. Oral contraceptives are indicated to prevent pregnancy and are contraindicated in pregnancy. (See 'Tetracyclines' below and 'Oral contraceptives' below and 'Spironolactone' below.)
Alternative antibiotics may be helpful for pregnant individuals who require systemic therapy. (See "Acne vulgaris: Overview of management", section on 'Pregnant individuals'.)
●Risk factors for adverse effects – Systemic acne therapies are generally well tolerated. However, certain characteristics may increase risk for adverse effects, making therapies less favorable for individual patients. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use" and "Oral isotretinoin therapy for acne vulgaris", section on 'Contraindications and precautions' and 'Spironolactone' below.)
●Patient values and preferences – Effective systemic therapies for acne vulgaris vary in respect to regimens, adverse effects profiles, and expected outcomes, contributing to an important role for patient preference in treatment selection. A comprehensive discussion with the patient regarding the treatment options is essential for identifying the ideal approach to therapy. For example, a female patient who prefers to avoid long-term oral therapy may prefer to avoid oral contraceptives or spironolactone.
The discussion with the patient also provides the opportunity to address questions, concerns, and misconceptions regarding specific treatments. Given the high prevalence of acne vulgaris and the common use of acne therapies for other indications, patients often have some familiarity with the treatment options and may have pre-existing impressions of specific therapies.
Use of topical therapy — With the exception of oral isotretinoin, which is typically given as monotherapy, combining topical and systemic therapy is generally advised for patients treated with oral antibiotics or hormonal therapy to optimize the response to therapy.
Patients who prefer to avoid systemic therapy are typically treated with multiple skin-directed therapies. Selection of treatment is focused on combating different aspects of the pathogenesis of acne vulgaris. Our minimum approach resembles the approach to topical therapy for mild acne vulgaris, with the inclusion of a retinoid and benzoyl peroxide for patients with papulopustular manifestations. We have a low threshold for the addition of other topical therapies with different mechanisms of action, such as topical antibiotics, topical dapsone, salicylic acid, and azelaic acid. Combination products can be helpful for simplifying the treatment regimen (table 2). (See 'Other agents' below and "Acne vulgaris: Overview of management", section on 'Mild acne vulgaris' and "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section on 'Pathogenesis'.)
Patients may also benefit from the incorporation of procedural therapies, such as chemical peels or laser therapy. (See 'Procedural therapy' below and "Light-based, adjunctive, and other therapies for acne vulgaris", section on 'Adjunctive therapies' and "Light-based, adjunctive, and other therapies for acne vulgaris", section on 'Light/laser therapies'.)
Topical retinoids — Topical retinoids are effective for both comedonal and papulopustular manifestations of acne vulgaris and are considered a mainstay of acne therapy. We aim to incorporate a topical retinoid for all patients receiving systemic antibiotic or hormonal therapy. Topical retinoids also play a key role in maintaining treatment responses following the discontinuation of oral antibiotics or other therapies [2]. (See "Acne vulgaris: Overview of management", section on 'Topical retinoids' and "Acne vulgaris: Overview of management", section on 'Maintenance of response'.)
Benzoyl peroxide — Antibiotic therapy for acne vulgaris should be given in conjunction with topical benzoyl peroxide whenever feasible. Antibiotics may promote the appearance of antibiotic-resistant strains of Cutibacterium (formerly Propionibacterium) acnes when used alone. Combining antibiotic therapy with the use of benzoyl peroxide decreases the development of antibiotic resistance and improves treatment efficacy [3-8]. The antimicrobial effects of benzoyl peroxide may also be beneficial for patients who are not receiving antibiotic therapy. (See "Acne vulgaris: Overview of management", section on 'Benzoyl peroxide'.)
Other agents — A variety of other topical agents (eg, topical antibiotics, topical dapsone, topical clascoterone, salicylic acid, and azelaic acid) may be beneficial for moderate to severe acne vulgaris. We primarily use these agents when topical retinoids and benzoyl peroxide are unavailable, poorly tolerated, or insufficiently effective. (See "Acne vulgaris: Overview of management", section on 'Resistant disease'.)
Topical antibiotics are generally reserved for patients who are not simultaneously receiving oral antibiotics. Antibiotic resistance to topical antibiotics may limit the efficacy of these agents and has contributed to reduced use of topical erythromycin for acne vulgaris. (See "Acne vulgaris: Overview of management", section on 'Principles' and "Acne vulgaris: Overview of management", section on 'Topical erythromycin' and "Acne vulgaris: Overview of management", section on 'Topical clindamycin'.)
Procedural therapy — Procedural interventions, such as intralesional corticosteroid injections, chemical peels, acne surgery, and light or laser therapies, are primarily utilized as adjunctive treatments. Adjunctive therapies for acne vulgaris are reviewed in detail separately. (See "Light-based, adjunctive, and other therapies for acne vulgaris".)
ORAL ISOTRETINOIN — Oral isotretinoin is a retinoid that counteracts acne vulgaris. It is the only acne medication that combats all four factors in acne pathogenesis (ie, sebum production, follicular hyperkeratinization, inflammation, and C. acnes). This includes inhibition of sebum secretion from sebaceous glands, thereby inhibiting proliferation of C. acnes, inhibition of comedogenesis through promotion of keratinocyte differentiation and normalization of epidermal desquamation, and intrinsic anti-inflammatory properties. (See "Oral isotretinoin therapy for acne vulgaris" and "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section on 'Pathogenesis'.)
Appropriate use — Oral isotretinoin is well accepted as a treatment for severe, recalcitrant, nodular acne [1]. In clinical practice, it is also used for less severe acne that is resistant to other treatments or associated with scarring. The risk for adverse effects, including teratogenicity, inhibits the use of isotretinoin as a routine initial treatment for mild, uncomplicated acne. (See "Oral isotretinoin therapy for acne vulgaris" and 'Selection of a systemic therapy' above.)
Administration and efficacy — Isotretinoin is typically administered over a course of several months and is usually given as monotherapy. Dosing and administration of oral isotretinoin is reviewed in detail separately. (See "Oral isotretinoin therapy for acne vulgaris", section on 'Initiation of therapy'.)
Patients with severe acne vulgaris are at risk for isotretinoin-induced acne flares and may benefit from combination therapy with a systemic glucocorticoid at the start of treatment. (See "Oral isotretinoin therapy for acne vulgaris", section on 'Severe acne' and 'Acne fulminans' below and 'Acne conglobata' below.)
Use of oral isotretinoin is based upon reports of efficacy from randomized trials and observational studies [9-21]. However, high-quality, randomized trials to confirm efficacy and superiority over other therapies are lacking [22]. (See "Oral isotretinoin therapy for acne vulgaris".)
Adverse effects — Isotretinoin is teratogenic and, therefore, contraindicated in pregnancy. Because of this risk, participation in a Risk Evaluation and Mitigation Strategy (REMS) program is required for isotretinoin therapy in the United States. (See "Oral isotretinoin therapy for acne vulgaris", section on 'iPLEDGE program'.)
Examples of other adverse effects of isotretinoin include dry skin and mucous membranes, visual changes, hyperlipidemia, elevation of hepatic transaminase levels, and myalgias. Adverse effects of oral isotretinoin are reviewed in detail separately. (See "Isotretinoin: Drug information".)
ORAL ANTIBIOTICS — Oral antibiotics improve inflammatory lesions of acne vulgaris by inhibiting the growth of C. acnes within the pilosebaceous unit. Benefit of oral antibiotics, particularly tetracyclines, is also thought to result from direct anti-inflammatory properties [23]. (See 'Selection of a systemic therapy' above.)
Appropriate use — A typical course of antibiotic therapy for acne vulgaris consists of continuous treatment for three months [24]. Selection of an appropriate agent and adherence to measures to reduce risk for antibiotic resistance are important considerations for antibiotic therapy. Although lessened use of antibiotics whenever feasible is advised as part of antibiotic stewardship [25], some patients with moderate to severe acne vulgaris are not candidates for other systemic therapies, necessitating the use of oral antibiotics (see "Antimicrobial stewardship in outpatient settings"):
●Antibiotic selection – Tetracyclines are the preferred oral antibiotics for acne vulgaris based upon efficacy and tolerability. Other antibiotics (macrolides, trimethoprim-sulfamethoxazole, cephalosporins, and penicillins) are generally reserved for patients who fail or cannot tolerate tetracyclines [1]. However, we usually proceed to nonantibiotic therapies, such as oral isotretinoin, when patients fail to improve with tetracyclines. (See 'Tetracyclines' below and 'Alternative antibiotics' below.)
●Measures to reduce antibiotic resistance – Appropriate use of oral antibiotics for acne vulgaris involves implementation of measures to reduce risk for the development of antibiotic resistance. (See "Antimicrobial stewardship in outpatient settings".)
Key measures include:
•Limiting duration of treatment – Oral antibiotics should be prescribed for the shortest possible period of time. Ideally, treatment is limited to continuous therapy for three to four months, with simultaneous use of a topical retinoid to facilitate discontinuation of the antibiotic [1]. Select patients who require longer courses should be followed closely to ensure that antibiotic therapy is given for the shortest duration necessary [1].
•Incorporating use of benzoyl peroxide – Benzoyl peroxide should be included in the treatment regimen. Antibiotic therapy can promote the appearance of antibiotic-resistant strains of C. acnes; concomitant use of benzoyl peroxide has an inhibitory effect on the development of antibiotic resistance. (See 'Benzoyl peroxide' above and "Acne vulgaris: Overview of management", section on 'Benzoyl peroxide'.)
Antibiotic resistance is increasing in patients with acne vulgaris [26]. One report suggests that the incidence of C. acnes antibiotic resistance increased from 20 percent in 1978 to 62 percent in 1996 [27]. Factors that contribute to this increasing incidence include the widespread use of oral antibiotics and the practice of rotating antibiotics. Resistance is most commonly reported with erythromycin. Resistance to minocycline is rare but may be emerging in the United States [28].
The rise of C. acnes antibiotic resistance is a concern for acne management; there is some evidence that the presence of resistant organisms can reduce treatment efficacy [29]. There is also concern that long-term antibiotic therapy affects other host bacterial flora, although the clinical impact of this is unclear. In one cross-sectional study (n = 107), patients taking oral tetracyclines (doxycycline, minocycline, or tetracycline) or topical antibiotics for at least three months had a threefold increase in the prevalence of Streptococcus pyogenes in the oropharynx compared with those who were not on antibiotic therapy (33 versus 10 percent) [30]. However, the number of patients reporting upper respiratory tract illness or symptoms was not different in the two groups.
Other studies have found an increased rate of upper respiratory infections in acne patients treated with oral antibiotic therapy. A more than threefold increase in pharyngitis was reported in a prospective, cohort study and a cross-sectional study, and a large, retrospective study (n = 118,496) found a twofold greater risk for upper respiratory infection among acne patients treated with either topical or oral antibiotics [31,32]. In the prospective study, which consisted of 36 university students with acne who received oral antibiotic therapy and 543 students with or without acne who were not treated with oral antibiotics, more students in the antibiotic therapy group reported visits to a health care provider for pharyngitis (11 versus 3 percent; adjusted odds ratio [OR] 4.34, 95% CI 1.51-12.47). In contrast to the cross-sectional study described above, an effect of antibiotic use on group A Streptococcus colonization was not detected. Further prospective studies are necessary to evaluate the effect of antibiotic therapy on upper respiratory tract infections.
There are also data that suggest an association between systemic antibiotic therapy, especially broad spectrum antibiotic therapy, and increased risk for inflammatory bowel disease [33,34]. (See "Definitions, epidemiology, and risk factors for inflammatory bowel disease", section on 'Antibiotics' and "Immune and microbial mechanisms in the pathogenesis of inflammatory bowel disease", section on 'Role of microbes'.)
Tetracyclines — Multiple studies have shown tetracyclines effective for acne vulgaris [35]. Preferred tetracyclines for acne vulgaris therapy in the United States include doxycycline, minocycline, and sarecycline. Doxycycline and minocycline have replaced erythromycin and tetracycline as the most frequently used oral antibiotics for acne therapy by dermatologists in the United States, both due to better tolerability and the presence of higher rates of C. acnes resistance to erythromycin and tetracycline [4,36]. In addition, availability of tetracycline is limited in the United States.
Tetracyclines do not inhibit the efficacy of oral contraceptive pills for contraception (see "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Drug interactions'):
●Doxycycline – Typical dosing for adolescents and adults for doxycycline:
•50 or 100 mg twice daily or 100 mg once daily [1,35,37]
•Delayed release: loading dose of 100 mg every 12 hours for one day, then as 100 mg once daily
•Subantimicrobial dosing: 40 mg once daily (delayed release) or 20 mg twice daily [38-40]
We typically treat with 100 mg twice daily.
Doxycycline and other tetracyclines should not be given to children up to the age of eight years or to pregnant individuals due to the potential for discoloration of developing permanent teeth with long-term treatment. In addition, doxycycline can cause gastrointestinal distress, esophagitis, esophageal ulceration, or idiopathic intracranial hypertension (pseudotumor cerebri). Administration with food can be helpful for reducing symptoms of gastrointestinal distress. Photosensitivity may also occur, and patients should be encouraged to engage in sun-protective behaviors. Additional adverse effects are reviewed separately. (See "Doxycycline: Drug information".)
Several randomized trials have evaluated the efficacy of doxycycline for acne vulgaris. In a cross-over trial in which 62 patients with predominantly inflammatory acne were treated with either doxycycline (50 mg twice daily) or placebo for four weeks, discontinued treatment for four weeks, and then switched treatment for four weeks, statistically significant reductions in inflammatory lesion counts occurred after treatment with doxycycline but not after treatment with placebo [41].
Subantimicrobial dosing of doxycycline (40 mg per day) may also improve acne vulgaris [38-40]. Subantimicrobial doses aim to maintain anti-inflammatory properties but eliminate antibacterial action, reducing the potential for inducing antibacterial resistance. In a 16-week trial in which 662 patients with moderate to severe acne vulgaris were randomly assigned to a modified-release form of doxycycline 40 mg, doxycycline 100 mg, or placebo once daily, modified-release doxycycline 40 mg was associated with greater reductions in the inflammatory lesion count than doxycycline 100 mg and placebo [40]. In addition, adverse effects were less frequent with modified-release doxycycline 40 mg than doxycycline 100 mg.
Subantimicrobial dosing of doxycycline (20 mg twice daily) was also more effective than placebo for moderate to severe acne vulgaris in a randomized trial that included 51 patients with moderate facial acne [38]. In another randomized trial (n = 100), patients with moderate facial acne treated with either 20 mg or 100 mg of doxycycline twice daily exhibited numerically similar reductions in inflammatory lesions [39].
●Minocycline – Minocycline is not typically used as first-line therapy due to greater toxicity concerns compared with other tetracyclines [42,43]. Typical dosing for minocycline for adolescents and adults:
•50 or 100 mg daily or twice daily [1,35,37,44]
•Extended release: 1 mg/kg per day (maximum 135 mg per day) [45-47]
We typically treat with 100 mg twice daily.
In the past, minocycline was widely considered more effective than tetracycline and doxycycline [4,48,49]. This was based on a theory, as minocycline is lipophilic and could thereby better penetrate into the pilosebaceous unit. However, a 2012 systematic review of randomized trials did not find sufficient evidence to support superiority of minocycline [44].
Similar to doxycycline, minocycline should not be given to children up to the age of eight years or pregnant individuals. Minocycline is the only tetracycline member to cross the blood-brain barrier and may impart vestibular side effects, such as headache, dizziness, and vertigo. In addition, minocycline may impart a serum sickness reaction that typically occurs days after initiation, skin discoloration (picture 2A-B), idiopathic intracranial hypertension, a lupus-like syndrome [50-53], and photosensitivity. Minocycline is less photosensitizing than doxycycline and tetracycline. Additional adverse effects are reviewed separately. (See "Minocycline (systemic): Drug information".)
●Sarecycline – Sarecycline is a tetracycline with a narrower spectrum of antibiotic activity [54,55]. Typical dosing:
•Once-daily, weight-based dosing: 60 mg for patients weighing 33 to 54 kg, 100 mg for patients weighing 55 to 84 kg, 150 mg for patients weighing 85 to 136 kg
An advantage of the narrower spectrum of antibiotic activity is a lower propensity to promote the development of C. acnes resistance and the potential for less disruption of the gut microbiome [55]. Other tetracyclines (doxycycline, minocycline, tetracycline) have a broader spectrum of antibiotic activity, including greater activity against gram-negative bacilli in the normal human intestinal microbiome [56]. (See 'Appropriate use' above.)
Sarecycline demonstrated efficacy for moderate to severe acne vulgaris in two placebo-controlled, phase 3, randomized trials (n = 968 and n = 1034) [55]. Rates of treatment success (investigator assessment of clear or almost clear and at least a two-point improvement on a five-point grading scale) for facial acne vulgaris at week 12 were 22 and 23 percent in the sarecycline groups compared with 11 and 15 percent in the placebo groups, respectively. Treatment success rates (at least a two-point improvement in the five-point grading scale) for back and chest acne were also greater for sarecycline than for placebo. The efficacy of sarecycline has not been compared with other tetracyclines.
As with other tetracyclines, sarecycline should not be given to children up to the age of eight years or pregnant individuals. Nausea is a potential adverse effect of sarecycline. (See "Sarecycline: Drug information".)
●Tetracycline – Since 2011, availability of tetracycline has been limited in the United States. Typical dosing for adolescents and adults:
•250 to 500 mg twice daily
Randomized trials support the efficacy of tetracycline for acne vulgaris [57,58]. In an eight-week trial that randomly assigned 305 patients with moderate to severe acne vulgaris to tetracycline (250 mg twice daily), clindamycin 1% solution twice daily, or placebo, both tetracycline and clindamycin were more effective for reducing papule and pustule counts than placebo [57]. In addition, a trial in which 200 patients with moderate to moderately severe acne vulgaris were treated with either tetracycline (1 g per day for four weeks, then 500 mg per day for eight weeks) or erythromycin base (1 g for four weeks, then 333 mg per day for eight weeks) found the treatments similarly effective for reducing acne severity [58].
Absorption of tetracycline is inhibited by food, dairy products, antacids, and iron; it must be taken on an empty stomach. Tetracycline should be taken at least one hour prior to a meal or two hours after eating.
Tetracycline should not be given to children up to the age of eight years or pregnant individuals. Examples of adverse effects include gastrointestinal distress, photosensitivity, and idiopathic intracranial hypertension. (See "Tetracycline: Drug information".)
Alternative antibiotics — Antibiotics other than tetracyclines are generally reserved for patients who cannot tolerate or who fail to respond to tetracyclines and who are not candidates for other systemic therapies, such as isotretinoin, spironolactone, or oral contraceptives. We use alternative antibiotics infrequently.
Macrolides — The macrolides most often used for acne vulgaris are azithromycin and erythromycin:
●Azithromycin – A wide variety of regimens have been utilized in studies that support azithromycin efficacy [58-63]. A 2018 meta-analysis of randomized trials that compared azithromycin pulse therapy (500 mg one to three times per week or four times monthly) with doxycycline (100 mg once or twice daily) found similar efficacy for moderate to severe acne vulgaris [59].
Concern for routine use of azithromycin for acne vulgaris is related to the rising incidence of antibiotic resistance to this drug. Azithromycin is often used as a first-line agent for the treatment of respiratory infections and is also prescribed as an alternative drug for the treatment of other gram-positive cocci infections in patients allergic to beta-lactam antibiotics. The risk of increasing the prevalence of antibiotic resistance makes azithromycin a less favorable choice for routine acne therapy. (See "Azithromycin and clarithromycin", section on 'Resistance' and "Resistance of Streptococcus pneumoniae to the macrolides, azalides, and lincosamides".)
●Erythromycin – Typical dosing for erythromycin for adolescents and adults is 500 mg twice daily. A disadvantage is the common occurrence of the development of C. acnes resistance to erythromycin, resulting in treatment failure [64]. In addition, many patients experience intolerable gastrointestinal side effects.
Data to support efficacy of oral erythromycin are limited. A trial in which 200 patients with moderate to severe acne vulgaris were randomly assigned to oral erythromycin (1 g per day for four weeks, then 333 mg per day for eight weeks) or oral tetracycline (1 g/day for four weeks then 500 mg per day for eight weeks) found similar benefit for reducing acne severity [58].
Other antibiotics — Routine use of antibiotics other than tetracyclines is discouraged [1]. Other antibiotic therapies that may be effective include trimethoprim-sulfamethoxazole (160 mg/800 mg once to twice daily for adults) and cephalexin (500 mg twice daily for adults) [65]. Data to support efficacy of these therapies are limited.
ORAL HORMONAL THERAPIES — Hormonal therapy with oral contraceptives and/or spironolactone is an option for female patients. The goal of hormonal therapy is to inhibit acne through reducing androgen action on cutaneous pilosebaceous units. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section on 'Sebaceous glands and the role of androgens'.)
Androgens contribute to acne vulgaris through the promotion of sebum production by sebaceous glands in the skin [66]. The increase in sebum production contributes to the accumulation of sebum and keratinous material in pilosebaceous follicles. This leads to partial obstruction of the follicle, resulting in the formation of comedones, the primary lesions of acne (picture 3A-B). Sebum also provides a growth medium for C. acnes, a bacterium that resides in pilosebaceous follicles and contributes to the inflammatory response in acne vulgaris (picture 4) [67]. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section on 'Pathogenesis'.)
Appropriate use — Postmenarchal females with moderate to severe acne vulgaris are the primary candidates for hormonal therapy. Both women with acne related to hyperandrogenism and women with acne and normal serum androgen levels can benefit from hormonal treatment [1].
Women with milder acne who choose oral contraceptives for the purpose of pregnancy prevention can also experience the ancillary benefit of improvement in acne vulgaris. However, these patients can often be managed successfully with topical therapy. (See "Acne vulgaris: Overview of management", section on 'Mild acne vulgaris'.)
Selection between oral contraceptives and spironolactone involves consideration of patient preferences and risk factors for adverse effects. Oral contraceptive treatment is often our initial choice for hormonal therapy for patients who also desire continuous contraception or who have other symptoms that may benefit from oral contraceptive therapy [68]. We tend to select spironolactone for patients who have other reliable methods of preventing pregnancy and who prefer to avoid oral contraceptive therapy or have contraindications to oral contraceptive therapy.
Spironolactone and oral contraceptives may also be given simultaneously. In the clinical setting, this is often done in an attempt to augment the response to therapy [69]. Combination therapy also prevents the spironolactone-induced menstrual irregularity that occurs in a subset of patients.
In general, hormonal therapy should be initiated with the intent of continuing treatment long-term to maintain improvement. Initial improvement is often delayed; at least three to six months of therapy is required for evaluation of efficacy.
Patients should be screened for risk factors for adverse effects prior to the start of hormonal therapy. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Candidates' and 'Spironolactone' below.)
Oral contraceptives — Combined oral contraceptives containing both estrogen and progestin are effective therapies for acne vulgaris in female patients. Oral contraceptives containing estrogen and progestin may reduce androgen action via a variety of mechanisms.
The inhibitory effect of estrogens on acne is thought to be related to estrogen-mediated suppression of sebum production. However, the mechanism through which this occurs is not completely understood. Proposed mechanisms include estrogen-mediated opposition of androgens within the sebaceous gland, inhibition of gonadal androgen production through a negative feedback loop on gonadotrophin release, increases in sex hormone-binding globulin (which reduces the bioavailability of androgens), and effects on regulation of genes involved in sebaceous gland growth or lipid production [66]. (See "Management of hirsutism in premenopausal women", section on 'Mechanisms of action in hyperandrogenism/hirsutism'.)
Although most progestins in oral contraceptives have androgenic properties, all low-dose combination oral contraceptives are estrogen dominant and have an overall antiandrogenic effect [68,70,71]. Some progestins (eg, drospirenone, cyproterone acetate, chlormadinone acetate, and dienogest) have antiandrogenic properties [72]. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Hormone components'.)
Progestin-only contraceptives, including low-dose oral pills that contain androgenic progestins (eg, norethindrone or desogestrel), are not effective and may exacerbate acne vulgaris [73]. (See "Contraception: Progestin-only pills (POPs)".)
Administration and efficacy — Treatment regimens for oral contraceptive therapy for acne vulgaris are identical to regimens used for contraception. Only three oral contraceptives have been approved by the US Food and Drug Administration (FDA) for treatment of acne. These include ethinyl estradiol 20/30/35 mcg/norethindrone 1 mg, ethinyl estradiol 35 mcg/norgestimate 180/215/250 mcg, and ethinyl estradiol 20 mcg/drospirenone 3 mg.
A systematic review of randomized trials supported the efficacy of oral contraceptives over placebo [68]. However, efficacy differences between combined oral contraceptives with varying progestins are less clear. While newer, third-generation progestins (eg, norgestimate, desogestrel, and gestodene) are considered to be less androgenic than their earlier-generation precursors (eg, levonorgestrel, norethindrone), data are inadequate to conclude that third-generation agents offer superior efficacy for acne vulgaris [68] (see "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Progestin'):
●Combination oral contraceptives with antiandrogenic progestins – Oral contraceptives with antiandrogenic progestins are a subclass of combination oral contraceptives. These include agents that contain cyproterone acetate, chlormadinone acetate, drospirenone, or dienogest plus an estrogen [74-76]. Oral contraceptives containing cyproterone acetate or chlormadinone acetate are not available in the United States. Ethinyl estradiol 30 mcg/drospirenone 3 mg and ethinyl estradiol 20 mcg/drospirenone 3 mg are the two drospirenone-containing oral contraceptives that are prescribed in the United States.
Examples of studies that support the efficacy of these agents include:
•A pooled analysis of two placebo-controlled, randomized trials with a total of 893 females with moderate facial acne found that patients treated with ethinyl estradiol 20 mcg/drospirenone 3 mg for six cycles were more likely to attain clear or almost clear skin than patients treated with placebo (odds ratio [OR] 3.41, 95% CI 2.15-5.43) and had greater mean reductions in acne lesion counts [77]. In one trial, total lesion counts were reduced 46.3 percent for the combination oral contraceptive group and 30.6 percent for the placebo group [78]. Beneficial effects were observed by the third cycle.
•An oral contraceptive containing ethinyl estradiol 30 mcg/dienogest 2 mg was superior to placebo in a large, randomized trial; total lesion counts were reduced by 55 versus 39 percent [76].
•A randomized trial (n = 40) in which a topical form of cyproterone acetate was compared with oral ethinyl estradiol 35 mcg/cyproterone acetate 2 mg and placebo found that the oral agent was superior to placebo for reduction of the acne severity grade and lesion counts [79].
Although the results of a few randomized trials have suggested slightly greater benefit of ethinyl estradiol 30 mcg/drospirenone 3 mg over ethinyl estradiol 35 mcg/norgestimate 0.18/0.125/0.25 mg [80] and for cyproterone acetate- or chlormadinone acetate-containing oral contraceptives over levonorgestrel-containing agents [81-83], additional high-quality trials are necessary to confirm these results.
●Comparison with oral antibiotic therapy – Few studies have directly compared the efficacy of oral contraceptive and oral antibiotic therapy [84,85], contributing to uncertainty regarding the relative efficacy of the two treatments.
The results of the first meta-analysis to compare the efficacy of oral contraceptive therapy and oral antibiotic therapy suggest similar efficacy for the treatment of acne [86]. The meta-analysis included randomized trials that contained at least one investigational arm that consisted of oral antibiotic or oral contraceptive therapy and assessed efficacy for acne after three and/or six months of treatment. Analysis of the data after six months of treatment revealed that mean percent reductions in acne lesions after oral antibiotic treatment and oral contraceptive therapy were similar and superior to placebo (53, 55, and 25 percent, respectively). However, antibiotic therapy appeared to induce a more rapid response than oral contraceptive treatment. The mean percent reduction in acne lesions was significantly greater for oral antibiotics than oral contraceptives at the three-month time point (48 versus 37 percent, respectively).
The findings of this study suggest similar efficacy of oral contraceptives and oral antibiotics and support the status of oral contraceptives as effective therapies for acne. Limitations of the meta-analysis included wide variation in treatment protocols and patient population (eg, trials of antibiotic therapy included both men and women, while oral contraceptive trials were limited to women). The performance of head-to-head trials would help to clarify the comparative efficacy of these treatments.
Adverse effects — The risks and benefits of oral contraceptives should be discussed with all patients prior to the initiation of therapy. Thromboembolism is a potential serious adverse effect of oral contraceptive use, and treatment should be avoided in patients with underlying thrombophilic disorders or a history of a venous thromboembolic event [87,88]. Characteristics that inhibit the use of oral contraceptives are reviewed in detail separately. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Candidates'.)
Drospirenone has a potassium-sparing, diuretic effect similar to spironolactone. Considerations for monitoring for hyperkalemia in patients treated with drospirenone-containing oral contraceptives are reviewed in detail separately. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Progestin'.)
Package labeling for drospirenone-containing oral contraceptives advises against use in patients with renal impairment or adrenal insufficiency [89].
In some cases, patients may be treated with oral contraceptives and oral antibiotics simultaneously. There is no definitive evidence that oral antibiotics, with the exception of rifampin, reduce oral contraceptive effectiveness for pregnancy prevention [90]. The use of antibiotics other than rifampin does not warrant an additional form of pregnancy protection. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Drug interactions'.)
Additional guidelines for the use of oral contraceptives are reviewed in detail separately. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use" and "Combined estrogen-progestin contraception: Side effects and health concerns".)
Spironolactone — Spironolactone is an oral antiandrogen that blocks androgen receptors and inhibits androgen biosynthesis [66]. The drug decreases 17-beta-hydroxysteroid dehydrogenase, therefore halting the conversion of androstenedione to testosterone [91]. Spironolactone may also inhibit 5-alpha-reductase, thereby preventing the conversion of testosterone to dihydrotestosterone (DHT). Additionally, spironolactone may increase steroid-hormone binding globulin [92]. Together, these mechanisms of action result in a 30 to 50 percent reduction in sebum excretion [93].
Administration and efficacy — Although the authors of a 2009 systematic review of randomized trials found insufficient evidence to confirm the efficacy of spironolactone for women with acne [94], multiple studies have reported treatment benefit [69,95-104].
We typically utilize doses of 50 to 100 mg per day (given in a single dose or in two divided doses) [105]. Initiating treatment with total doses of 25 or 50 mg per day, with subsequent dose escalation according to patient tolerance and response, may help to minimize side effects [73].
The largest studies assessing spironolactone therapy for acne vulgaris are retrospective analyses [100,101]. In a retrospective study of 395 patients with acne vulgaris (aged ≥21 years) treated with spironolactone (25 to 200 mg per day, median dose 100 mg per day, median treatment duration 13 months), 261 (66 percent) had an estimate of ≥90 percent improvement, 75 (19 percent) had 51 to 89 percent improvement, 25 (6 percent) had ≤50 percent improvement, and 34 (9 percent) had no evidence of response [101]. The median times to initial and maximal response were three and five months, respectively. Most patients (83 percent) received no other systemic acne therapies simultaneously other than oral contraceptive pills started more than six months prior to spironolactone. Adverse effects occurred in 10 percent of patients, with dizziness, irregular menstrual bleeding, and fatigue most common.
A similar retrospective study of 80 younger patients (ages 14 to 20 years) treated with spironolactone (25 to 200 mg per day, median dose 100 mg per day, median treatment duration seven months) for acne vulgaris at the same institution also supported benefit of spironolactone [69]. The study found ≥90 percent improvement in 18 patients (23 percent), 51 to 89 percent improvement in 29 patients (36 percent), ≤50 percent improvement in 17 patients (21 percent), and no response in 16 patients (20 percent).
Although spironolactone has been prescribed in doses of up to 200 mg per day for acne vulgaris and has demonstrated efficacy at this dose in a small, randomized trial [69,95-97,101,106], lower doses may still be effective and may reduce the risk for adverse effects [98,107,108]. In a randomized trial in which patients with moderate acne vulgaris received daily benzoyl peroxide plus spironolactone 50 mg, spironolactone 25 mg, or placebo, benzoyl peroxide plus spironolactone 50 mg was more effective than benzoyl peroxide plus placebo [104]. Moreover, a retrospective analysis found that responses to 50 to 100 mg per day of spironolactone were similar to previously reported responses to doses of 150 to 200 mg per day [107].
Adverse effects — Side effects of spironolactone include menstrual irregularities, breast tenderness, minor gastrointestinal symptoms (anorexia, nausea, vomiting, and diarrhea), hyperkalemia, orthostatic hypotension, and central nervous system symptoms (headaches, dizziness, and fatigue). Side effects (excluding central nervous system symptoms) are less frequent at lower doses (≤100 mg per day) [107]. Side effects such as menstrual irregularities and breast tenderness can be counteracted by concomitant use of an oral contraceptive:
●Hyperkalemia – Spironolactone is a potassium-sparing diuretic, and hyperkalemia is a potentially serious adverse effect when given at high doses or to patients with renal insufficiency or severe heart failure [109,110]. However, there does not appear to be a significant risk for hyperkalemia in young, healthy women given spironolactone in doses typically used for acne [106,107,111,112]. Given that the risk of hyperkalemia is low, we do not monitor serum potassium levels in healthy, young women under the age of 45 years receiving spironolactone therapy for acne.
However, the patient's comorbidities and medication history must be considered. Periodic laboratory monitoring of serum potassium is appropriate in women with multiple medical problems, cardiac disease, or renal disease and women who are taking medications that may increase risk for hyperkalemia [66]. In these patients, potassium levels can be checked at baseline, during therapy, and after dose increases [1]. Monitoring of serum potassium may also be beneficial for healthy women over the age of 45; we suggest periodic monitoring in this population:
•The largest study of the risk for spironolactone-induced hyperkalemia in acne patients is a retrospective analysis of women (ages 18 to 45 years) prescribed spironolactone for acne or an endocrine disorder with acne as a secondary feature [112]. The rate of hyperkalemia in 1802 measurements from 974 women during treatment with spironolactone was 0.72 percent, and the baseline rate of hyperkalemia in 4209 measurements from 1165 women taking or not taking spironolactone was 0.76 percent. There were no serious elevations of potassium in the group taking spironolactone; all the elevations were mild or moderate. Of note, patients with heart failure or renal disease and patients receiving medications that affect the renin-angiotensin-aldosterone system were excluded.
•A study that compared the rate of incident hyperkalemia during spironolactone therapy among 112 women aged 18 to 45 years and 12 women aged 46 to 65 years through the analysis of data in a medical record data repository supports a higher likelihood of hyperkalemia in older women (incident hyperkalemia in 0.01 and 17 percent of women, respectively) [113]. Included women had assessments of serum potassium at baseline (or within one year prior to the start of spironolactone) and within one year after the start of spironolactone. Women with hypertension, renal failure, or diabetes mellitus were excluded.
The oral contraceptive progestin drospirenone also possesses potassium-sparing, diuretic properties; 3 mg of drospirenone is equivalent to approximately 25 mg of spironolactone [111]. Although hyperkalemia was not demonstrated in one small, prospective study of patients concurrently taking oral contraceptives with drospirenone and 100 mg per day of spironolactone [114], further larger studies are needed to fully elucidate the risk of hyperkalemia.
●Malignancy – There is a theoretical concern for increased risk for breast cancer based upon spironolactone's estrogenic effects. However, no definitive evidence linking human breast, or other estrogen-dependent tumors, to the use of spironolactone exists, and data to support safety of spironolactone in this regard are increasing [115-117]. For example, a retrospective analysis of 29,146 patients with a history of breast cancer (including 746 who were prescribed spironolactone) did not find an association between spironolactone treatment and increased breast cancer recurrence [115].
●Fetal effects – Feminization of the male fetus is a potential risk for patients who become pregnant while taking spironolactone. Animal studies have demonstrated feminization of male offspring of rodents treated with high doses of spironolactone [118]. While there are case reports of feminization of the human male fetus, there are also reports of women taking oral spironolactone and delivering male fetuses without this adverse effect [119,120].
We advise patients to avoid pregnancy during spironolactone therapy and to discontinue treatment immediately if pregnancy occurs. Coadministration of spironolactone with an oral contraceptive is often a favorable option for contraception because of the beneficial effects on acne and prevention of menstrual irregularity secondary to spironolactone. (See 'Oral contraceptives' above.)
Other agents — Additional therapies with antiandrogenic properties may improve acne but are not typically used for this indication due to specific indications or concern for adverse effects:
●Systemic glucocorticoids – Systemic glucocorticoid therapy is used to suppress adrenal androgen production in patients with hyperandrogenism secondary to congenital adrenal hyperplasia [121]. Treatment with systemic glucocorticoids provides cortisol replacement, thereby reducing the excessive secretion of corticotropin-releasing hormone (CRH) and corticotropin (ACTH) that contributes to excessive adrenal androgen production, acne, and other associated clinical manifestations (figure 1). (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults".)
●Flutamide – Flutamide is an androgen receptor blocker that is not typically used for the treatment of acne because of the potential for flutamide-induced fatal hepatitis [122,123].
APPROACH TO SEVERE VARIANTS — Patients with acne fulminans or acne conglobata may benefit from distinct approaches to therapy.
Acne fulminans — Acne fulminans is a rare, severe form of acne vulgaris characterized by the abrupt development of large, inflammatory nodules and friable plaques with erosions, ulcers, and hemorrhagic crusts, with or without associated systemic findings. Acne fulminans may occur following the initiation of isotretinoin or spontaneously. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section on 'Acne fulminans'.)
Oral glucocorticoids (typically, prednisone 0.5 to 1 mg/kg per day) and oral isotretinoin are the mainstays of treatment for acne fulminans. There is a paucity of high-quality data to guide the approach to treatment. Recommendations from a panel of clinicians with expertise in severe acne vulgaris include the following (algorithm 3) [124]:
●For patients with isotretinoin-induced acne fulminans (with or without systemic symptoms), discontinue isotretinoin immediately and treat similarly to patients without isotretinoin-induced disease.
●For patients with acne fulminans with systemic symptoms, initiate oral glucocorticoid monotherapy at least four weeks prior to starting oral isotretinoin to prevent a flare of the condition.
●For patients with acne fulminans without systemic symptoms, initiate oral glucocorticoid monotherapy at least two weeks prior to starting oral isotretinoin.
●Start low-dose isotretinoin (0.1 mg/kg per day) and continue with prednisone for at least four weeks. After this period, the dose of isotretinoin can be gradually increased, as tolerated, and the oral glucocorticoid can be slowly tapered over four to eight weeks, as tolerated.
●If flares occur during treatment, extending the course of oral glucocorticoid therapy or temporary discontinuation of oral isotretinoin may be required (algorithm 3).
The typical goal cumulative dose of isotretinoin for acne vulgaris is 120 to 150 mg/kg. Greater cumulative doses may be required for patients with refractory acne fulminans [124]. (See "Oral isotretinoin therapy for acne vulgaris".)
Combination therapy with oral glucocorticoids and oral tetracyclines (eg, doxycycline or minocycline [100 mg twice daily] or tetracycline [500 to 1000 mg twice daily]) has also been used for treatment but may not be as effective as oral glucocorticoids and isotretinoin and is not recommended as first-line treatment [124]. Other alternative treatments that have seemed beneficial in case reports include high-potency topical corticosteroids [125], cyclosporine [126], dapsone [127,128], levamisole [124], and pulsed dye laser [129].
There is a lack of data on the effects of biologic therapies for recalcitrant acne fulminans. Based upon reports of benefit of anti-tumor necrosis factor (TNF) biologic therapy in patients with acne conglobata and SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome, it is conceivable that such treatment may be beneficial. (See 'Acne conglobata' below and "SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome", section on 'Treatment'.)
Acne conglobata — Acne conglobata is a severe form of nodular acne vulgaris that may result in drainage, sinus tracts, and severe scarring. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section on 'Acne conglobata'.)
Oral isotretinoin is the treatment of choice for acne conglobata. However, patients may experience severe flares at the start of isotretinoin therapy. Similar to acne fulminans, low initial doses of isotretinoin (0.5 mg/kg per day or less) plus systemic glucocorticoids before or during isotretinoin therapy are often required for patients with acne conglobata [130]. (See "Oral isotretinoin therapy for acne vulgaris", section on 'Initiation of therapy'.)
Other treatments that have been used for acne conglobata include systemic antibiotics, intralesional glucocorticoids, systemic glucocorticoids, and surgical intervention [130]. Case reports have documented improvement in acne conglobata during treatment with biologic TNF-alpha inhibitors (etanercept [131], adalimumab [132], and combination therapy with infliximab and isotretinoin [133]). However, further study is necessary before treatment with these agents can be recommended.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acne vulgaris".)
SUMMARY AND RECOMMENDATIONS
●Moderate to severe acne vulgaris – Acne vulgaris is a common disorder that may cause discomfort, disfigurement, and psychosocial distress. There is no universally accepted method of assessing acne severity. Moderate to severe acne may be considered acne that is (picture 1A-D) (see 'Definition of moderate to severe acne' above):
•Visually prominent, consisting of many comedones, inflamed papules, or pustules
•Associated with large papules or nodules (>5 mm diameter)
•Involving multiple body areas
•Associated with scarring
●Role of systemic therapy – Systemic therapy is commonly utilized for moderate to severe acne vulgaris in an attempt to optimize and simplify treatment. The major systemic therapies for acne vulgaris include oral isotretinoin, oral antibiotics, and oral hormonal therapies (oral contraceptives and spironolactone) (algorithm 2). (See 'General approach' above.)
Certain features of moderate to severe acne vulgaris prompt strong consideration of systemic therapy. For patients with nodular lesions, extensive skin involvement, or acne scarring, we suggest early initiation of systemic therapy, rather than delaying systemic treatment until failure of topical therapy (Grade 2C). (See 'When to use systemic therapy' above.)
Patients with a high psychologic burden from acne vulgaris are also candidates for early initiation of systemic therapy. (See 'When to use systemic therapy' above.)
●Role of other therapies – Topical therapy often plays an important role in the treatment of moderate to severe acne vulgaris in patients who are receiving systemic therapy, with the exception of oral isotretinoin, which is typically given as monotherapy. In addition, patients who decline or cannot receive systemic therapy are managed with topical and/or procedural therapies. (See 'Use of topical therapy' above.)
●Selection and use of systemic therapy – Selection of an appropriate systemic therapy for acne vulgaris involves consideration of the clinical manifestations (lesion type and severity), patient characteristics (eg, sex, age, pregnancy status, risk factors for adverse effects), and patient preference (algorithm 2) (see 'Selection of a systemic therapy' above):
•Oral isotretinoin – For patients who present with severe, extensive, nodular acne vulgaris, we suggest oral isotretinoin, rather than other treatments, as initial therapy (Grade 2C). Oral isotretinoin is considered the only medication that can permanently alter the natural course of acne vulgaris and has the potential to induce long-term remissions off therapy. Patients with acne fulminans or acne conglobata often require coadministration of a systemic glucocorticoid to reduce risk for isotretinoin-induced acne flares (algorithm 3). (See 'Oral isotretinoin' above and 'Approach to severe variants' above and "Oral isotretinoin therapy for acne vulgaris".)
Oral isotretinoin is also appropriate for less severe acne vulgaris that has failed to respond to other therapies or is associated with scarring or acne-induced psychologic distress. (See 'Oral isotretinoin' above.)
•Antibiotics – Conscientious use of oral antibiotics is advised as part of antimicrobial stewardship. For patients who are treated with oral antibiotics for acne vulgaris, we suggest use of tetracycline antibiotics, rather than other antibiotic therapies (Grade 2C). Examples include doxycycline, minocycline, and sarecycline. Other antibiotics are reserved for patients who cannot tolerate or fail to respond to tetracyclines. (See 'Oral antibiotics' above.)
Treatment course for oral antibiotics should be limited to three to four months whenever feasible. In addition, antibiotics should be used in conjunction with topical benzoyl peroxide. Combining oral antibiotic therapy with the use of benzoyl peroxide decreases the development of antibiotic resistance. (See 'Appropriate use' above.)
•Hormonal therapies – Postmenarchal females are candidates for hormonal therapies, including oral contraceptives and spironolactone. Selection between these therapies is based upon consideration of patient preference and risk for treatment-related adverse effects. For patients of childbearing potential who also desire a contraception method and lack contraindications to oral contraceptive treatment, we suggest an oral contraceptive, rather than spironolactone, as the initial hormonal therapy (Grade 2C). (See 'Oral hormonal therapies' above.)
Hyperkalemia is a potential adverse effect of spironolactone therapy; however, the risk for hyperkalemia is low in young, healthy women given spironolactone for acne. We suggest not performing routine monitoring of serum potassium levels in healthy women under the age of 45 years receiving spironolactone for acne vulgaris (Grade 2C). We typically monitor serum potassium levels in women over the age of 45, women taking medications that may increase risk for hyperkalemia, and women with multiple medical problems, cardiac disease, or renal disease. (See 'Spironolactone' above.)
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