Topical treatments

Oral antibiotics

Oral retinoids (isotretinoin)

Adjunctive Therapies

Follow-Up

To address the management of adolescent and adult patients presenting with acne but not the consequences of disease, including the scarring, post-inflammatory erythema, or postinflammatory hyperpigmentation

Evidence-Based Medicine Guidelines collect, summarize, and update the core clinical knowledge essential in general practice. The guidelines also describe the scientific evidence underlying the given recommendations.

• To improve the selection of appropriate treatment for patients with acne based on severity
• To increase the number of patients who report satisfaction with the treatment of their acne
• To increase the number of patients with appropriate follow up for acne treatment

Adolescents and adults with acne vulgaris, i.e., open and/or closed comedones (blackheads and whiteheads) and inflammatory lesions including papules, pustules, or nodules

Patients with acne

All patients with acne vulgaris

Note: This guideline excludes rosacea and folliculitis.

Physicians

Health Care Providers

Physicians

Advanced Practice Nurses

Allied Health Personnel

Health Care Providers

Health Plans

Hospitals

Managed Care Organizations

Nurses

Physician Assistants

Physicians

• Searches of Electronic Databases

The following evidence report is available:

Guidelines of care for acne vulgaris management. Technical report. American Academy of Dermatology Association. 2007. 69 p.

Electronic copies: Not available at this time.

Print copies: Available from the AAD, PO Box 4014, Schaumburg, IL 60168-4014, Phone: (847) 330-0230 ext. 333; Fax: (847) 330-1120; Web site: www.aad.org.

Described Process: A work group of recognized experts was convened to determine the audience for the guidelines, define the scope of the guidelines, and identify nine clinical questions to structure the primary issues in diagnosis and management.

An evidence-based model was used and some evidence was obtained by a vendor using a search of MEDLINE and EMBASE databases spanning the years 1970 through 2006. Only English-language publications were reviewed.

Number of Source Documents: Not stated

Number of References: 180

• Hand-searches of Published Literature (Primary Sources)
• Hand-searches of Published Literature (Secondary Sources)
• Searches of Electronic Databases

Described Process: The evidence reviewed was collected from the Cochrane database of systematic reviews and the Database of Abstracts of Reviews of Effectiveness (DARE). In addition, the Cochrane Library and medical journals were searched specifically for original publications.

Number of Source Documents: Not stated

Number of References: 5

• Searches of Electronic Databases

Described Process: Not stated

Number of Source Documents: Not stated

Number of References: 53

Expert Consensus (Committee)

Weighting According to a Rating Scheme (Scheme Given — refer to Table 6)

Weighting According to a Rating Scheme (Scheme Given — refer to Table 6)

Weighting According to a Rating Scheme (Scheme Given — refer to Table 6)

Described Process:

Key conclusions (as determined by the work group) are supported by a conclusion grading worksheet that summarizes the important studies pertaining to the conclusion. Individual studies are classed according to the system presented below, and are designated as positive, negative, or neutral to reflect the study quality.

Refer to Table 6 for rating schemes.

Systematic Review with Evidence Tables

Described Process: The available evidence was evaluated using a unified system called the Strength of Recommendation Taxonomy (SORT) developed by editors of the US family medicine and primary care journals (i.e., American Family Physician, Family Medicine, Journal of Family Practice, and BMJ-USA). This strategy was supported by a decision of the Clinical Guidelines Task Force in 2005 with some minor modifications for a consistent approach to rating the strength of the evidence of scientific studies.

For each intervention within the Clinical Questions, an effort was made to identify and present the best evidence regarding its use in the treatment of acne. Studies of clinical measurements of outcome were considered for analysis whether or not the clinical outcome was the primary outcome measured.

Systematic Review

Described Process: Not stated

Systematic Review with Evidence Tables

Described Process: Not stated

Expert Consensus

Described Process: Clinical recommendations were developed on the best available evidence tabled in the guidelines and explained further in the companion document Guideline of Care for Acne Vulgaris Management, Technical Report.

Not stated

Not stated

• Usefulness, reliability, and sensitivity of acne severity grading scales
• Usefulness of endocrinologic and microbiologic testing
• Number of lesions
• Severity of lesions
• Psychological and emotional improvement
• Adverse effects of treatment

• Efficacy of treatment
• Adverse effects of treatment

• Patient factors such as contributing medical conditions and medications
• Severity of acne (presence and quantity of papules, pustules, nodules, cysts, and total lesions)
• Quality of life and other psychosocial factors
• Results/outcome of treatments
• Side effects of treatment
• Patient compliance and adherence

Each of the following Work Group Members have served as a consultant, received research support or clinical research grants from the following companies:

Dr. Strauss was a consultant and investigator for Roche Laboratories receiving honoraria and grants, and a consultant for Medicis receiving honoraria.

Dr. Krowchuk has no relevant conflicts of interest to disclose.

Dr. Leyden was a consultant for Stiefel and SkinMedica, receiving honoraria; served on the Advisory Board and was a consultant for Galderma and Obaj, receiving honoraria; was on the Advisory Board and was a consultant and investigator for Connetics, Collagenex, Allergan, and Medicis, receiving honoraria.

Dr. Lucky was an investigator for Connetics, Dow, Galderma, Healthpoint, Johnson & Johnson, QLT, and Stiefel, receiving grants and an investigator and consultant for Berlex receiving grants and honoraria.

Dr. Shalita was a consultant, investigator, stockholder, and speaker for Allergan, receiving grants and honoraria; a consultant for Bradley/Doak receiving honoraria; served on the Advisory Board and was a consultant for Collagenex, receiving honoraria; was a consultant and investigator for Connetics receiving grants and honoraria; an Advisory Board member, consultant, investigator, and speaker for Galderma receiving grants and honoraria; a consultant, speaker, and stockholder for Medicis receiving honoraria; an Advisory Board member for Ranbaxy receiving honoraria; and a consultant, investigator, and speaker for Stiefel, receiving grants and honoraria.

Dr. Siegfried was an investigator for Atrix receiving salary.

Dr. Thiboutot served on the Advisory Board and was an investigator and speaker for Allergan and Galderma, receiving honoraria; was on the Advisory Board and was a consultant and investigator for Collagenex receiving honoraria; was on the Advisory Board and was an investigator for Connetics, Dermik, and QLT, receiving honoraria; and was a consultant, investigator, and speaker for Intendis, receiving honoraria.

Dr. Van Voorhees served on the Advisory Board and was an investigator and speaker for Amgen, receiving grants and honoraria; was an investigator for Astellas, Bristol Myers Squibb, and GlaxoSmithKline, receiving grants; was an Advisory Board Member and investigator for Genentech and Warner Chilcott, receiving grants and honoraria; was on the Advisory Board for Centocor receiving honoraria; was a speaker for Connetics receiving honoraria; and was a stockholder of Merck, owning stock and stock options.

Dr. Beutner was an employee of Anacor receiving salary and stock options and a stockholder of Dow Pharmaceutical Sciences receiving stock.

Ms. Sieck and Dr. Bhushan have no relevant conflicts of interest to disclose.

None stated

No work group members have potential conflicts of interest to disclose.

ICSI's conflict of interest policy and procedures are available for review on ICSI's website at www.icsi.org.

Topical Therapy

• Topical therapy is a standard of care in acne treatment.
• Topical retinoids are important in acne treatment.
• Benzoyl peroxide and combinations with erythromycin or clindamycin are effective acne treatments.
• Topical antibiotics (e.g., erythromycin and clindamycin) are effective acne treatments. However, the use of these agents alone can be associated with the development of bacterial resistance.
• Salicylic acid is moderately effective in the treatment of acne.
• Azelaic acid has been shown to be effective in clinical trials, but its clinical use, compared to other agents, has limited efficacy according to experts.
• Data from peer-reviewed literature regarding the efficacy of sulfur, resorcinol, sodium sulfacetamide, aluminum chloride, and zinc are limited.
• Employing multiple topical agents that affect different aspects of acne pathogenesis can be useful. However, it is the opinion of the work group that such agents not be applied simultaneously unless they are known to be compatible.

Recommendations

Retinoids

Strength of recommendation = A. Level of evidence = I. References: Christiansen et al., 1974, Chalker et al., 1987; Shalita et al., 1999; Lucky et al., 1998

Benzoyl Peroxide

Strength of recommendation = A. Level of evidence = I. References: Belknap, 1979; Schutte, Cunliffe, & Forster, 1982; Smith et al., 1980; Mills et al., 1986

Antibiotics

Strength of recommendation = A. Level of evidence = I. References: Bernstein & Shalita, 1980; Jones & Crumley, 1981; Prince et al., 1981; Lesher et al., 1985; Pochi et al., 1988; Dobson & Belknap, 1980; Mills et al., 2002; Leyden et al., 1987; Becker et al., 1981

Other Agents

Strength of recommendation = A. Level of evidence = I. References: Zouboulis et al., 2000; Chalker et al., 1983; Tschen et al., 2001; Lookingbill et al., 1997; Hjorth & Graupe, 1989

Local Treatment

• Local treatment is usually sufficient for comedonic acne and mild common acne.
• Wash the skin with soap or antibacterial detergents.
• Comedonic acne can be treated with
  • Retinoic acid cream or solution (tretinoin [A], isotretinoin [B])
  • Adapalen gel [C]
  • Benzoyl peroxide (3-10%)] [A] cream or gel
  • All above drugs can be irritating at first. Use a low concentration of the active drug initially, and advise the patient to wash the drug away after a few hours. The tolerance of the skin increases with time.
• Common acne can be treated with
  • Local antibiotics (e.g., clindamycin solution) [A]
  • Combination gel containing benzoyl peroxide and clindamycin
  • Ultraviolet light therapy (as a course of 15 treatments added to other treatment) for widespread disease
• Consider systemic treatment if the effect of local treatment is unsatisfactory 2 to 3 months from the onset of treatment.

Clinical Highlights and Recommendations

• Treatment with both a topical retinoid and a topical antibiotic has been found to be an effective course of treatment. (Annotation #5 in the original guideline document)

Topical Treatment of Acne

An example of treatment for mild acne may include benzoyl peroxide, a topical antibiotic or a combination product one to two times daily; or a topical retinoid once daily in addition to the above. See tables in Annotation 5 of the original guideline document for description of medications.

Over-the-counter Topical Products

A wide variety of over-the-counter (OTC) topical products are available to the patient for self-treatment of acne. A complete listing is beyond the scope of this publication. The most common ingredient in OTC products is benzoyl peroxide in concentrations up to 10%*. Salicylic acid in concentrations of 0.5% to 2% is a keratolytic found in many OTC acne products. Products may also contain glycolic acid (an alpha-hydroxy acid), sulfur, or resorcinol. When evaluating a new patient, it is helpful to know which products they may have tried.

* Many of the expensive acne systems advertised contain benzoyl peroxide and offer no advantages over commercial products.

Benzoyl Peroxide

Benzoyl Peroxide is available without a prescription in products such as Clearasil® and by prescription in the products listed below (refer to the original guideline document). It is also available in combination with antibiotics (see Topical Antibiotics table in the original guideline document.)

• Benzoyl peroxide (Benzac®, Brevoxyl, Desquam-X®, PanOxyl®, generics)

Topical Retinoids for Acne

Topical retinoids (see table in the original guideline document for a description of the topical retinoids listed below) increase the turnover of follicular epithelial cells, promote drainage of comedones and inhibit new comedone (blackhead, whitehead) formation. Topical retinoids are generally applied in the evening.

• Adapalene (Differin®)
• Tazarotene (Tazorac®)
• Tretinoin (Retin-A® generics)
• Tretinoin (Retin - A Micro®)

Azelaic Acid

Azelaic acid is a naturally occurring decarboxylic acid which has been shown to be effective in reducing both inflammatory and non-inflammatory acne lesions.

• Azelaic Acid (Azelex®)

Topical Antibiotics for Acne

Propionibacterium acnes (P.acnes) is an anaerobic bacterium present within the pilosebaceous follicles. It is thought that this microorganism plays a role in acne-associated inflammation. The antibiotics used to treat acne have been shown to reduce colonization of P.acnes and may also possess direct anti-inflammatory effects. In vitro resistance of P.acnes to commonly used antibiotics has been increasing but the clinical significance of this is uncertain. However, it has been recommended that antibiotics be used with either topical retinoids or benzoyl peroxide.

Single Drug Products

• Clindamycin (Cleocin T®, Evoclin generics)
• Erythromycin (A/T/S®, Erygel® Eryderm®, generics)
• Sulfacetamide (Klaron®)

Combination Products

• Benzoyl Peroxide 5% - Clindamycin 1%
• Benzoyl Peroxide 5% - Erythromycin 3%
• Sulfacetamide 10% - Sulfur 5%

Note: Refer to the original guideline document for tables providing a description of the topical treatments discussed here. Medications are listed alphabetically. Brand names are included for reference only and are not meant to be all inclusive.

Systemic Antibiotics

• Systemic antibiotics are a standard of care in the management of moderate and severe acne and treatment-resistant forms of inflammatory acne.
• Doxycycline and minocycline are more effective than tetracycline, and there is evidence that minocycline is superior to doxycycline in reducing P acnes.
• Although erythromycin is effective, use should be limited to those who cannot use the tetracyclines (i.e., pregnant women or children under 8 years of age because of the potential for damage to the skeleton or teeth). The development of bacterial resistance is also common during erythromycin therapy.
• Trimethoprim-sulfamethoxazole and trimethoprim alone are also effective in instances where other antibiotics cannot be used.
• Bacterial resistance to antibiotics is an increasing problem.
• The incidence of significant adverse effects with antibiotic use is low. However, adverse effect profiles may be helpful for each systemic antibiotic used in the treatment of acne.

Recommendations

Tetracyclines

Strength of recommendation = A. Level of evidence = I. References: Smith, Chalker, & Wehr, 1976; Gratton et al., 1982; Blaney & Cook, 1976; Miller et al., 1996

Macrolides

Strength of recommendation = A. Level of evidence = I. References: Skidmore et al., 2003; Gammon et al., 1986; Christian & Krueger, 1975; Stoughton et al., 1980

Trimethoprim-sulfamethoxazole

Strength of recommendation = A. Level of evidence = I. References: Hersle, 1972

Systemic Treatment

• Antibiotics
  • Tetracycline [B] and erythromycin [A] are equally effective. The usual dose is 250-500 mg/day for a few months. Six months' treatment with tetracycline or erythromycin 1 g/day is more effective than a shorter treatment with a smaller dose. Do not use tetracyclines in children below 12 years of age.
  • Local treatment and light therapy can be used simultaneously with systemic treatment.
  • Local treatment is not sufficient in cystic acne and conglobate acne. Use systemic antibiotics or consider referral to a dermatologist. Pus-containing cysts can be drained by incising them with a large-caliber injection needle or narrow-tipped scalpel.

Topical Treatment and Oral Antibiotics for Acne

An example for moderate/severe acne may include examples listed in annotation 5a (of the original guideline document) with the addition of an oral antibiotic while continuing with the topical treatment. (See tables in annotation 5b of the original guideline document for description of products listed below)

First Line Antibiotics

• Erythromycin (Erytabs®, generics)
• Tetracycline
• Doxycycline (monohydrate and hyclate salts available)
• Minocycline (Minocin®, generics)

Second Line Antibiotics

• Clindamycin (Cleocin®, generics)
• Sulfamethoxazole/Trimethoprim (Bactrim®, Septra®, generics)

Other antibiotics such as azithromycin are being used in acne but studies are preliminary and concrete recommendations regarding their use cannot be made at this time.

Supporting evidence is of classes: A, C, D, R

Isotretinoin

• Oral isotretinoin is approved for the treatment of severe recalcitrant nodular acne.
• It is the unanimous opinion of the acne workgroup that oral isotretinoin is also useful for the management of lesser degrees of acne that are treatment-resistant or for the management of acne that is producing either physical or psychological scarring.
• Oral isotretinoin is a potent teratogen. Because of its teratogenicity and the potential for many other adverse effects, this drug should be prescribed only by those physicians knowledgeable in its appropriate administration and monitoring.
• Female patients of child-bearing potential must only be treated with oral isotretinoin if they are participating in the approved pregnancy prevention and management program (iPLEDGE).
• Mood disorders, depression, suicidal ideation, and suicides have been reported in patients taking this drug. However, a causal relationship has not been established.

Recommendations

Isotretinoin

Strength of recommendation = A. Level of evidence = I. References: Peck et al., 1982; Lehucher-Ceyrac & Weber-Buisset, 1993; Goulden et al., 1997; Strauss et al., "A randomized trial," 2001; McElwee et al., 1991; Strauss et al., "Safety," 2001; Dai, LaBraico, & Stern, 1992; Goldsmith et al., 2004; Rubinow et al., 1987

Local Treatment

• Comedonic acne can be treated with
  • Retinoic acid cream or solution (tretinoin [A], isotretinoin [B])

Indications for Specialist Consultation

• If ordinary treatment fails, the dermatologist can consider isotretinoin. However, it has considerable teratogenicity. A program called iPLEDGE has been set up to make sure that pregnant women do not take isotretinoin and that women do not become pregnant while taking isotretinoin.

Clinical Highlights and Recommendations

• Isotretinoin therapy is highly regulated. (Annotation #9 in the original guideline document)

Oral Retinoids

Isotretinoin is the only oral retinoid approved for use in acne and is a well established teratogen. Although causality has not been determined for depression and suicide this is an ongoing concern. In view of these factors its use is highly regulated by the FDA.

Only providers registered with the iPLEDGE program may prescribe Isotretinoin. For information about this program conduct an internet search using: iPLEDGE program. This program is scheduled to start March 1, 2006 and replaces the existing System to Manage Accutane Related Teratogenicity (S.M.A.R.T.) program.

Hormonal Agents

• Estrogen-containing oral contraceptives can be useful in the treatment of acne in some women.
• Oral antiandrogens, such as spironolactone and cyproterone acetate, can be useful in the treatment of acne. While flutamide can be effective, hepatic toxicity limits its use. There is no evidence to support the use of finasteride.
• There are limited data to support the effectiveness of oral corticosteroids in the treatment of acne. There is a consensus of expert opinion that oral corticosteroid therapy is of temporary benefit in patients who have severe inflammatory acne.
• In patients who have well-documented adrenal hyperandrogenism, low-dose oral corticosteroids may be useful in treatment of acne.

Recommendations

Contraceptive Agents

Strength of recommendation = A. Level of evidence = I. References: Lucky et al., 1997; Olson, Lippman, & Robisch, 1998; Thiboutot et al., 2001; Leyden et al., 2002

Spironolactone

Strength of recommendation = B. Level of evidence = II. References: Muhlemann et al., 1986

Antiandrogens

Strength of recommendation = B. Level of evidence = II. References: Greenwood et al., 1985; Miller et al., 1986

Oral Corticosteroids

Strength of recommendation = B. Level of evidence = II. References: Nader et al., 1984

Miscellaneous Therapy

• Intralesional corticosteroid injections are effective in the treatment of individual acne nodules.
• There is limited evidence regarding the benefit of physical modalities including glycolic acid peels and salicylic acid peels.

Recommendations

Intralesional Steroids

Strength of recommendation = C. Level of evidence = III. References: Levine & Rasmussen, 1983; Potter, 1971

Chemical Peels

Strength of recommendation = C. Level of evidence = III. References: Kim et al., 1999; Wang et al., 1997; Grimes, 1999

Comedo Removal

Strength of recommendation = C. Level of evidence = III. References: Pepall, Cosgrove, & Cunliffe, 1991

Complementary Therapy

• Herbal and alternative therapies have been used to treat acne. Although these products appear to be well tolerated, very limited data exist regarding the safety and efficacy of these agents.

Recommendations

Herbal Agents

Strength of recommendation = B. Level of evidence = II. References: Bassett, Pannowitz, & Barnetson, 1990; Paranjpe & Kulkarni, 1995; Laala et al., 2001

Psychological Approaches

Strength of recommendation = C. Level of evidence = III. References: Ellerbroek, 1973

Hypnosis/Biofeedback

Strength of recommendation = B. Level of evidence = II. References: Hughes et al., 1983

Dietary Restriction

• Dietary restriction (either specific foods or food classes) has not been demonstrated to be of benefit in the treatment of acne.

Recommendation

Effect of Diet

Strength of recommendation = B. Level of evidence = II. References: Bett, Morland, & Yudkin, 1967; Fulton, Plewig, & Kligman, 1969

Light Therapy, Cyst Injections, Hormonal Treatment

Local Treatment

• Common acne can be treated with
  • Ultraviolet light therapy (as a course of 15 treatments added to other treatment) for widespread disease

Systemic Treatment

• Antibiotics
  • Local treatment and light therapy can be used simultaneously with systemic treatment.
  • Local treatment is not sufficient in cystic acne and conglobate acne. Use systemic antibiotics or consider referral to a dermatologist. Pus-containing cysts can be drained by incising them with a large-caliber injection needle or narrow-tipped scalpel.
• Hormonal treatment for women
  • Cyproterone acetate (an anti-androgen) + oestrogen for 6 months reduce the excretion of sebaceous glands and alleviate acne.

Consider Adjunctive Therapy

Oral Contraceptives

The addition of combination oral contraceptives has been shown to be effective in the treatment of acne. [Conclusion Grade I: See Conclusion Grading Worksheet C — Annotation #9 (Oral Contraceptives)] in the original guideline document

Treatment with a combined oral contraceptive (estrogen and progestin) is an alternative for women who fail conventional acne therapies. Oral contraceptives are effective for the treatment of acne due to their androgen modulating properties. It is the estrogen component of combined oral contraceptives that reduces androgen production and decreases the amount of free and active testosterone by increasing the production of sex hormone binding globulin. Progestin-only oral contraceptives are not effective and may worsen acne. Responses may not be seen for 3 to 6 months, with some patients showing a flare of symptoms during early cycles. Although some progestins have exhibited androgenic properties during in vitro and animal studies, all combination oral contraceptives have antiandrogenic properties due to the estrogen component. To ensure adherence with therapy, the ideal product is one that has the lowest incidence of adverse effects for a particular patient. Products with FDA indications for acne include Estrostep® and Ortho Tri-cyclen®.

Spironolactone

Spironolactone is a medication primarily used in the treatment of hypertension. Due to its antiandrogenic effect, it has occasionally been used to treat adult onset acne in women when other treatments have been ineffective. It is the effects of testosterone that are felt to be a contributing factor to the development of acne in adult females. The drug acts by blocking the effects of testosterone on the oil glands and hair follicles of the female patient The result is a reduction in oil production that may lead to improvement of their acne. The optimal dosage varies, but ranges from 50 mg to 200 mg daily. Response may take two to three months*. The drug should not be used in pregnancy. Women of child-bearing age should use birth control methods while taking the medication. Side effects are rare, usually related to menstrual irregularity, mild gastrointestinal (GI) upset, or headache. The medication may be taken for one to two years with periodic rest periods.

* Spironolactone can cause decreased sodium and increased potassium. Levels should be initially measured and carefully monitored at appropriate intervals.

Intra-lesional Injections

There are rare circumstances in which you may consider injecting large acne cysts with a corticosteroid for short-term cosmetic improvement. Each injection carries a risk of causing skin atrophy. Repeated injections are not recommended. The concentration of Triamcinolone varies from 2 to 10 mg/cc. The stock 10-, 25- or 40- mg/mL steroid suspension should be diluted with lidocaine and only enough injected through a 1- mL syringe with a 27- or 30- gauge needle to distend the cyst slightly (usually 0.025 mL to 0.1 mL).

Light Therapy

There continue to be numerous studies about light treatment for acne, including blue light and photodynamic therapy with and without pretreatment with topical medications. At this time, the evidence is inadequate to make a recommendation about the efficacy and safety of these treatments.

No recommendations offered.

Indications for Specialist Consultation

• Severe forms of acne (A. cystica, conglobata, fulminans)
• If ordinary treatment fails, the dermatologist can consider isotretinoin. However, it has considerable teratogenicity.

Acne Scars

• Consider treatment of scars by skin abrasion or laser therapy [D] only after the activity of the disease has totally subsided.
• Scars can be treated either by a dermatologist or a plastic surgeon.

Clinical Highlights and Recommendations

• Patient perception of improvement is the best measure of successful treatment (Annotation #4 in the original guideline document)
• The patient needs to understand that acne may get worse before it gets better. It typically takes eight weeks of treatment before a response is noted. (Annotation #7 in the original guideline document)

Follow-Up 6-12 Weeks/Satisfactory Response?

There is no clear evidence to support a specific duration of any treatment for acne. However, clinical experience and clinical trials suggest that a minimum treatment period of 6-12 weeks is needed before an improvement will be noted in most patients.

Assess Outcome and Adherence

Asking non-threatening, open-ended questions during patient interviews can be a useful method of assessing medication adherence. The interview should include probes for factors that contribute to non-adherence including adverse reactions, misunderstandings of asymptomatic or chronic disease treatment, depression, cognitive impairment, complex dosing regimens, and financial constraints.

Supporting evidence is of class: R

Modify Treatment Plan

Consider Different/Additional Medications

It may be necessary to switch to a different class of topical acne medication. For example: if the patient is on a benzoyl peroxide product or a combination product and is not responding, consider switching to a once daily topical retinoid, and a once daily topical anti-infective. For moderate to severe acne, consider adding an oral antibiotic or switching the current oral antibiotic. Selection is based on patient specific factors.

Consider Dermatology Referral

Dermatologists treat all forms of acne, particularly severe cases. For those patients with severe inflammatory acne that has not improved with previously described medications, a retinoid, isotretinoin (Accutane), may be considered. Dermatologists may be helpful to guide you at any point of the algorithm.

Supporting evidence is of classes: A, R

For most current information regarding Isotretinoin: http://www.fda.gov/cdec/drug/infopage/accutane/default.htm

Maintenance

If stable on current topicals, continue treatment indefinitely. If stable on topical and systemic antibiotics, after clearance is achieved for 1 to 3 months, consider tapering oral antibiotics and continue topicals indefinitely.

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Pepall LM, Cosgrove MP, Cunliffe WJ. Ablation of whiteheads by cautery under topical anaesthesia. Br J Dermatol 1991;125: 256-9.

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Prince RA, Busch DA, Hepler CD, Feldick HG. Clinical trial of topical erythromycin in inflammatory acne. Drug Intell Clin Pharm 1981;15:372-6.

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Smith JG Jr, Chalker DK, Wehr RF. The effectiveness of topical and oral tetracycline for acne. South Med J 1976;69: 695-7.

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Stoughton RB, Cornell RC, Gange RW, Walter JF. Doubleblind comparison of topical 1 percent clindamycin phosphate (Cleocin T) and oral tetracycline 500 mg/day in the treatment of acne vulgaris. Cutis 1980;26:424-5, 429.

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Appropriate management of acne vulgaris

Effective treatment of acne

Effective treatment of acne can decrease such negative effects of acne as decreased self-esteem, social withdrawal, anger, conduct disorders, and decreased employability. Patient perception of improvement is the best measure of successful treatment.

Topical Antibiotics

• The use of topical antibiotics alone can be associated with the development of bacterial resistance.

Oral Antibiotics

• A major problem affecting antibiotic therapy of acne has been bacterial resistance, which has been increasing. Resistance has been seen with all antibiotics, but is most common with erythromycin.
• The use of oral antibiotics for the treatment of acne may be associated with adverse effects. Vaginal candidiasis may complicate the use of all oral antibiotics. Doxycycline can be associated with photosensitivity. Minocycline has been associated with pigment deposition in the skin, mucous membranes and teeth particularly among patients receiving long-term therapy and/or higher doses of the medication. Pigmentation occurs most often in acne scars, anterior shins, and mucous membranes. Autoimmune hepatitis, a systemic lupus erythematosus-like syndrome, and serum sickness-like reactions occur rarely with minocycline.

Hormonal Agents

• While flutamide can be effective, hepatic toxicity limits its use.
• Spironolactone may cause hyperkalemia, particularly when higher doses are prescribed or when there is cardiac or renal compromise. It occasionally causes menstrual irregularity.

Isotretinoin

• Oral isotretinoin is a potent teratogen.
• Side effects include those of the mucocutaneous, musculoskeletal, and ophthalmic systems, as well as headaches and central nervous system effects. Most of the adverse effects are temporary and resolve after the drug is discontinued.
• While hyperostosis, premature epiphyseal closure, and bone demineralization have been observed with prolonged use of higher dose retinoids, in the usual course of acne treatment these findings have not been identified. Therefore it is the unanimous opinion of the acne work group that routine screening for these issues is not required. Laboratory monitoring during therapy should include triglycerides, cholesterol, transaminase, and complete blood counts.
• Changes in mood, suicidal ideation, and suicide have been reported sporadically in patients taking isotretinoin. While these events have been seen, a causal relationship has not been established. Nonetheless, patients must be made aware of this possibility and treating physicians should monitor patients for psychiatric adverse effects.

Intralesional Steroids

• Systemic absorption of steroids may occur. Adrenal suppression was observed in one study. The injection of intralesional steroids may be associated with local atrophy.

Adverse Effects of Medication

• Retinoic acid cream or solution, adapalen gel, and benzoyl peroxide (3 to 10%) can be irritating at first. The tolerance of the skin increases with time.
• Isotretinoin has considerable teratogenicity

See the appropriate tables in the original guideline document for information on adverse effects of benzoyl peroxide, topical retinoids, azelaic acid, topical antibiotics, combination products, and first- and second-line oral antibiotics.

Spironolactone

• Side effects are rare, usually related to menstrual irregularity, mild gastrointestinal upset, or headache. Women of childbearing age should use birth control methods while taking the medication.
• Spironolactone can cause decreased sodium and increased potassium. Levels should be initially measured and carefully monitored at appropriate intervals.

Oral Retinoids

• Isotretinoin is a well established teratogen.
• Although causality has not been determined for depression and suicide this is an ongoing concern.
• In view of these factors its use is highly regulated by the U.S. Food and Drug Administration (FDA).

Intra-lesional Injections

• Injections carry the risk of causing skin atrophy.
• Repeated injections are not recommended.

Levels of Evidence

1. Good quality patient-oriented evidence
2. Limited quality patient-oriented evidence
3. Other evidence including consensus guidelines, extrapolations from bench research, opinion, or case studies

Strength of Recommendations

1. Recommendation based on consistent and good quality patient-oriented evidence.
2. Recommendation based on inconsistent or limited quality patient-oriented evidence.
3. Recommendation based on consensus, opinion, or case studies.

Classification of the Quality of Evidence

1. Quality of Evidence: High.

   Further research is very unlikely to change our confidence in the estimate of effect.

   • Several high-quality studies with consistent results
   • In special cases: one large, high-quality multi-centre trial

2. Quality of Evidence: Moderate.

   Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

   • One high-quality study
   • Several studies with some limitations

3. Quality of Evidence: Low.

   Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

   • One or more studies with severe limitations

4. Quality of Evidence: Very Low.

   Any estimate of effect is very uncertain.

   • Expert opinion
   • No direct research evidence
   • One or more studies with very severe limitations

Conclusion Grades:

Grade I: The evidence consists of results from studies of strong design for answering the question addressed. The results are both clinically important and consistent with minor exceptions at most. The results are free of any significant doubts about generalizability, bias, and flaws in research design. Studies with negative results have sufficiently large samples to have adequate statistical power.

Grade II: The evidence consists of results from studies of strong design for answering the question addressed, but there is some uncertainty attached to the conclusion because of inconsistencies among the results from the studies or because of minor doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from weaker designs for the question addressed, but the results have been confirmed in separate studies and are consistent with minor exceptions at most.

Grade III: The evidence consists of results from studies of strong design for answering the question addressed, but there is substantial uncertainty attached to the conclusion because of inconsistencies among the results of different studies or because of serious doubts about generalizability, bias, design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from a limited number of studies of weak design for answering the question addressed.

Grade Not Assignable: There is no evidence available that directly supports or refutes the conclusion.

Study Quality Designations:

The quality of the primary research reports and systematic reviews are designated in the following ways on the conclusion grading worksheets:

Positive: indicates that the report or review has clearly addressed issues of inclusion/exclusion, bias, generalizability, and data collection and analysis.

Negative: indicates that these issues (inclusion/exclusion, bias, generalizability, and data collection and analysis) have not been adequately addressed.

Neutral: indicates that the report or review is neither exceptionally strong nor exceptionally weak.

Not Applicable: indicates that the report is not a primary reference or a systematic review and therefore the quality has not been assessed.

Classes of Research Reports:

1. Primary Reports of New Data Collection:

   Class A:

   • Randomized, controlled trial

   Class B:

   • Cohort study

   Class C:

   • Non-randomized trial with concurrent or historical controls
   • Case-control study
   • Study of sensitivity and specificity of a diagnostic test
   • Population-based descriptive study

   Class D:

   • Cross-sectional study
   • Case series
   • Case report

2. Reports that Synthesize or Reflect upon Collections of Primary Reports

   Class M:

   • Meta-analysis
   • Systematic review
   • Decision analysis
   • Cost-effectiveness analysis

   Class R:

   • Consensus statement
   • Consensus report
   • Narrative review

   Class X:

   • Medical opinion

Recommends benzoyl peroxide, topical retinoids, and topical antibiotics. Notes that data from clinical trials indicate that azelaic acid is effective. Data for other topical therapies is limited.

Recommends benzoyl peroxide, topical retinoids, and topical antibiotics

Recommends benzoyl peroxide, topical retinoids, azelaic acid, and topical antibiotics

Recommends doxycycline and minocycline as first-line therapies, stating that they are more effective than tetracycline. Erythromycin should be reserved for patients who cannot take tetracyclines. Trimethoprim-sulfamethoxazole and trimethoprim alone are also effective in instances where other antibiotics cannot be used.

Cites erythromycin and tetracycline as appropriate oral antibiotics

Cites erythromycin, tetracycline, doxycycline, and minocycline as appropriate first-line antibiotics and clindamycin and sulfamethoxazole/trimethoprim as appropriate second-line antibiotics

Recommends isotretinoin as appropriate for the treatment of severe recalcitrant nodular acne, or for lesser degrees of acne that are treatment-resistant or for the management of acne that is producing either physical or psychological scarring. Warns about its teratogenic properties, addresses iPLEDGE program.

Cites isotretinoin as a possible therapy, but only in the case of ordinary treatment failure and warns about its teratogenetic properties.

Cites isotretinoin as a possible therapy, but only in the case of ordinary treatment failure and warns about its teratogenetic properties. Adds that isotretinoin use is highly-regulated by the FDA and that only providers registered with the iPLEDGE program may prescribe it.

Recommends estrogen-containing oral contraceptives for selected women. Oral antiandrogens can be useful in the treatment of acne. Intralesional corticosteroid injections are effective in the treatment of individual acne nodules, There is limited data regarding herbal and alternative therapies.

Recommends UV light therapy, cystic drainage, and cyproterone acetate with oestrogen as adjunctive treatments.

Recommends combined oral contraceptives, corticosteroid injections, and spironolactone as adjunctive treatments.

No recommendations offered.

Recommends referral to a dermatologist for severe/persistent acne, as well as treatment of acne scars by skin abrasion or laser therapy after the acne has subsided.

Recommends referral to a dermatologist for severe/persistent acne. Also addresses a 6 to 12 week follow-up, medication adherence questionnaires, and maintenance/modification of the treatment plan.