General considerations

• antibiotics appear to work by anti-inflammatory as well antibacterial mechanisms that inhibit Propionibacterium acnes⁽⁴⁾
• American Academy of Dermatology (AAD) 2016 recommendations for topical antibiotics⁽⁴⁾
  • topical antibiotics such as erythromycin and clindamycin are effective (AAD Strength of Recommendation A, Level I-II)
  • do not use as monotherapy due to risk of bacterial resistance
  • clindamycin preferred over erythromycin due to erythromycin-resistance of staphylococci and Propionibacterium acnes
• European (S3) 2016 guidelines for treatment of acne
  • for mild-to-moderate papulopustular acne, topical clindamycin plus benzoyl peroxide is strongly recommended as a first-line option (EUS3 High strength)
  • for mild-to-moderate papulopustular acne, topical fixed combination with clindamycin plus tretinoin can be recommended as an option (EUS3 Medium strength)
  • for mild-to-moderate papulopustular acne, topical fixed combination with erythromycin plus isotretinoin or topical erythromycin plus tretinoin can be considered as alternative options (EUS3 Low strength)
  • Reference - J Eur Acad Dermatol Venereol 2016 Aug;30(8):1261
• American Acne and Rosacea Society 2013 recommendations for pediatric acne⁽⁵⁾
  • topical antibiotics not recommended as monotherapy because of slow onset of action and predictable emergence of antibiotic-resistant bacteria (AARS Level C)
  • if treatment prolonged for more than a few weeks, topical benzoyl peroxide should be added or used in combination products (AARS Level C)
• treatment strategies to limit antibiotic resistance (GA Grade V)⁽³⁾
  • co-prescribe benzoyl peroxide-containing product
  • avoid concurrent use of oral and topical antibiotics, especially if chemically different
  • do not switch antibiotics without adequate justification; use same antibiotic for relapses
  • avoid antibiotics for maintenance therapy; use topical retinoids for maintenance therapy, adding benzoyl peroxide if antimicrobial effect needed
  • these recommendations persisted in literature review reported in 2014 (Eur J Dermatol 2014 May-Jun;24(3):330)
• Canadian 2014 consensus opinion on antibiotic resistance and topical acne treatment
  • combination of antibiotics with topical retinoids, benzoyl peroxide, or benzoyl peroxide are effective in reducing antibiotic resistance
  • antibiotic therapy should be re-evaluated in 6-8 weeks (not 12 weeks)
  • Reference - J Drugs Dermatol 2014 Nov;13(11):1358
• topical antibiotics appear to reduce inflammatory lesion counts by about 46%-70% in patients with acne (level 2 [mid-level] evidence)
  • based on systematic review with assessment of trial quality not reported
  • systematic review of 29 randomized double-blinded trials and 1 meta-analysis of investigator-blinded trials evaluating efficacy of different acne medication regimens
  • primary outcomes were percent reduction in inflammatory, noninflammatory, and total lesions
  • 7 trials reported on topical antibiotics
    • 46%-70% reduction of inflammatory lesions with single-agent antimicrobials (erythromycin or clindamycin) in 4 trials with 992 patients
    • greater reduction in lesion count associated with combination antimicrobial therapy in 3 trials with 535 patients, including
      • erythromycin plus zinc compared to erythromycin alone (inflammatory lesions [p < 0.001]) in 1 trial with 122 patients
      • clindamycin with benzoyl peroxide compared with clindamycin alone (total lesions [p = 0.013]) in 1 trial with 79 patients
  • topical azelaic acid and oral tetracycline had similar inflammatory lesion reduction in 2 studies with 594 patients
  • Reference - JAMA 2004 Aug 11;292(6):726
• antibiotic treatment for acne (topical or oral) may be associated with increased risk for upper respiratory infections (level 2 [mid-level] evidence)
  • based on retrospective cohort study
  • 118,496 patients aged 15-35 years with acne from United Kingdom General Practice Research Database, 1987-2002
  • 84,977 (71%) received topical or oral antibiotic (tetracyclines, erythromycin, or clindamycin), most used combination of oral and topical agents
  • 18,281 (15.4%) had at least 1 upper respiratory infection within 1 year
  • antibiotic use associated with increased risk of upper respiratory infection
    • odds ratio (OR) 2.15 (95% CI 2.05-2.23) for any antibiotic use
    • OR 2.37 (95% CI 2.12-2.64) for topical antibiotics only
    • OR 2.75 (95% CI 2.37-3.18) for oral antibiotics only
    • OR 1.88 (95% CI 1.8-1.96) for topical and oral antibiotics
  • Reference - Arch Dermatol 2005 Sep;141(9):1132 full-text

Clindamycin

• topical clindamycin
  • available as 1% lotion, gel, solution, or pledget
  • apply thin film once daily to skin where lesions appear⁽⁴⁾
  • Pregnancy category B
  • adverse effects may include dermatitis, folliculitis, photosensitivity reaction, pruritus, erythema, dry skin, peeling, and severe colitis⁽⁴⁾
• topical clindamycin preferred over erythromycin due to erythromycin-resistance of staphylococci and Propionibacterium acnes⁽⁴⁾
• addition of topical benzoyl peroxide recommended for patients on topical antibiotics (combination products available)⁽⁴⁾
• topical clindamycin 1% applied nightly or twice daily reduces inflammatory lesions and/or comedones (level 1 [likely reliable] evidence)
  • based on 7 placebo-controlled trials (4 were randomized) in patients with mild-to-severe inflammatory acne
  • References - Arch Dermatol 1981 Aug;117(8):482, Scand J Infect Dis Suppl 1984;43:71, J Am Acad Dermatol 1997 Oct;37(4):590, Cutis 1986 Sep;38(3):203, J Am Acad Dermatol 1996 Jul;35(1):58, Arch Dermatol 1980 Sep;116(9):1031, Int J Dermatol 1981 May;20(4):286
  • DynaMed commentary -- some of these trials were small and had limited assessment of clinically relevant outcomes, but clindamycin 1% consistently better than placebo across these trials

Erythromycin

• erythromycin
  • available as 2% solution, pledget, or gel
  • apply as thin film once or twice daily⁽⁴⁾
  • Pregnancy category B
  • adverse effects may include superinfection/Clostridium difficile associated colitis⁽⁴⁾
• topical erythromycin may be less effective than topical clindamycin, due to erythromycin-resistance of staphylococci and Propionibacterium acnes⁽⁴⁾
• addition of topical benzoyl peroxide recommended for patients on topical antibiotics (combination products available)⁽⁴⁾
• topical erythromycin efficacy (but not clindamycin efficacy) appears to be decreasing (level 2 [mid-level] evidence)
  • based on systematic review without assessment of trial quality
  • systematic review of 50 trials evaluating efficacy of topical erythromycin and clindamycin for mild-to-moderate inflammatory acne from mid-1970s to 2003
  • in analysis of 45 trials with > 2,500 patients using lesion counts as outcome measure
    • erythromycin efficacy decreased
      • 1.352% per year for inflammatory lesions (p = 0.003) and 1.114% per year for noninflammatory lesions (significant) in all trials
      • 2.14% per year for inflammatory lesions (p = 0.001) and 2.032% per year for noninflammatory lesions (p = 0.001) in trials > 12 weeks
    • no significant change in efficacy with clindamycin
  • authors suggest decrease in erythromycin efficacy due to increased antibiotic resistance of propionibacteria
  • Reference - Br J Dermatol 2005 Aug;153(2):395

Azelaic acid

• azelaic acid ^{(1, 4)}
  • available as 20% cream (Azelex) or 15% gel or foam (Finacea)
  • Azelex 20% cream used for acne
  • apply twice daily (morning and evening)
  • works as comedolytic and antibacterial agent
  • Pregnancy Category B
  • adverse reactions include contact dermatitis, pruritus, burning, stinging, tingling, erythema, dryness, rash, peeling, and irritation⁽⁴⁾
  • see Azelaic Acid for additional prescribing information
• American Academy of Dermatology (AAD) 2016 recommendations for azelaic acid (AAD Strength of Recommendation A, Level I)⁽⁴⁾
  • recommended as useful adjunct in acne treatment
  • especially in the treatment of postinflammatory dyspigmentation
• European (S3) 2016 guidelines for treatment of acne
  • for mild-to-moderate papulopustular acne,topical azelaic acid can be recommended as an option (EUS3 Medium strength)
  • for comedonal acne, topical azelaic acid can be considered as an alternative option (EUS3 Low strength)
  • Reference - J Eur Acad Dermatol Venereol 2016 Aug;30(8):1261
• azelaic acid may improve mild-to-moderate acne (level 2 [mid-level] evidence)
  • based on small randomized trial with allocation concealment not stated
  • 60 patients aged 15-35 years with mild-to-moderate acne randomized to 20% azelaic acid topically vs. placebo twice daily for 45 days
  • acne reduction from baseline comparing azelaic acid vs. placebo
    • comedones by 87.3% vs. 23.2% (p = 0.001)
    • total lesions by 60.6% vs. 19.9% (p = 0.002)
    • papules by 51.2% vs. 19.3% (p = 0.003)
    • pustules by 42.1% vs. 17.8% (p = 0.08)
  • Reference - Indian J Dermatol Venereol Leprol 2007 Mar-Apr;73(2):94 full-text

Sodium sulfacetamide

• sodium sulfacetamide
  • available as sulfacetamide sodium 10% plus sulfur 5% lotion or sulfacetamide sodium 9% plus sulfur 4.5% wash FDA approved for topical control of acne vulgaris
  • apply once or twice daily to affected areas
  • may have mild antibacterial and keratolytic properties⁽⁵⁾
• American Academy of Dermatology (AAD) 2016 guidelines state limited evidence to support recommendation for sodium sulfacetamide⁽⁴⁾
• sodium sulfacetamide 10%/sulfur 5% lotion reported to reduce inflammatory lesions (level 3 [lacking direct] evidence)
  • based on case series
  • 60 women aged 22-45 years with acne were treated with sodium sulfacetamide 10%/sulfur 5% lotion twice daily for 12 weeks
  • reduction in lesion count from baseline was 78% for total lesions and 83% for inflammatory lesions (both p < 0.001)
  • mild-to-moderate dryness and transient itching in 65% were most common adverse events
  • Reference - Int J Dermatol 1993 May;32(5):365
• satisfactory patient-rated results reported with sodium sulfacetamide 10%/sulfur 5% emollient foam used as monotherapy or combined with other topical products in 8 patients with acne in case series (J Clin Aesthet Dermatol 2009 Aug;2(8):26 full-text)

Dapsone gel

• dapsone (Topical), available as
  • 7.5% gel (applied daily)
  • 5% gel (applied twice daily)
  • Reference - DailyMed 2016 Aug
• American Academy of Dermatology (AAD) 2016 recommendations for dapsone (AAD Strength of Recommendation A, Level I-II)⁽⁴⁾
  • use topical dapsone 5% for inflammatory acne, mainly in adult females with acne
  • apply a pea-sized amount as a thin layer twice daily
  • adverse reactions include oiliness, dryness, erythema, burning, pruritus, and peeling
• dapsone 5% gel reduces inflammatory and noninflammatory acne lesions (level 1 [likely reliable] evidence)
  • based on 2 randomized trials with same study design
  • 3,010 patients > 12 years old with facial acne (20-50 inflammatory and 20-100 noninflammatory lesions) were randomized to dapsone 5% vs. vehicle gel twice daily to acne-involved areas of face for 12 weeks
  • intention-to-treat analysis included all patients to whom study drug was dispensed using last observation carried forward
  • 2,507 patients (83%) completed the trial
  • comparing dapsone vs. placebo
    • no or few lesions in 40.5% vs. 32.8% at 12 weeks (p < 0.001, NNT 13)
    • mean reduction in lesion counts
      • noninflammatory
        • 25% vs. 20% at 8 weeks (p = 0.003)
        • 32% vs. 24% at 12 weeks (p < 0.001)
      • inflammatory
        • 35% vs. 31% at 4 weeks (p = 0.008) (4 weeks is earliest time point that showed statistically significant difference)
        • 48% vs. 42% at 12 weeks (p < 0.001)
      • total
        • 28% vs. 25% at 6 weeks (p = 0.007) (6 weeks is earliest time point that showed statistically significant difference)
        • 39% vs. 32% at 12 weeks (p < 0.001)
    • adverse effects in 58.2% vs. 58.6% (not significant)
  • Reference - J Am Acad Dermatol 2007 Mar;56(3):439e1
• dapsone 7.5% gel topically once daily may decrease total acne lesions in patients with moderate acne (level 2 [mid-level] evidence)
  • based on 2 randomized trials with allocation concealment not stated
  • 2,102 patients (mean age 20 years) with moderate acne (Global Acne Assessment Score [GASS] of 3) randomized to dapsone gel 7.5% vs. vehicle applied once daily to entire face as well as acne-affected areas of the neck, upper chest, upper back, and shoulders (within their reach) for 12 weeks
  • treatment success defined as reduction GAAS to 0 or 1
  • comparing dapsone 7.5% gel vs. vehicle at week 12
    • GAAS success in 29.9% vs. 21.2% (p < 0.001, NNT 12)
    • decrease in total lesions 48.7% vs. 42.4% (p < 0.001)
    • adverse events in 19.1% vs. 20.6% (not significant)
  • Reference - J Drugs Dermatol 2016 May 1;15(5):553
• dapsone 5% gel reported to reduce acne in women with skin of color (Fitzpatrick skin type IV-VI (level 3 [lacking direct] evidence)
  • based on case series
  • 67 women ≥ 18 years old with Fitzpatrick skin type IV, V, or VI and facial acne (15-40 inflammatory and 15-40 noninflammatory lesions) treated with dapsone 5% gel twice daily to acne-involved areas of face for 12 weeks
  • mean decrease in acne severity from baseline 39%
  • adverse effects in 20.6%, including nasopharyngitis in 4.4%), bronchitis in 2.9%, nasal congestion in 2.9%, and urticaria in 2.9%
  • J Drugs Dermatol 2016 Feb;15(2):197
• dapsone 5% gel reported to be safe and effective for long-term use (level 3 [lacking direct] evidence)
  • based on large case series
  • 486 patients ≥ 12 years old with acne treated with twice daily dapsone gel for up to 12 months (mean 253 days)
  • 49% total lesion count reduction from baseline (58.2% for inflammatory lesions, 19.5% for noninflammatory lesions)
  • adverse events
    • application site reaction in 8.2% (most mild-moderate)
    • headache in 20%
    • nasopharyngitis in 15%
    • no significant changes in hematology or blood chemistry profiles
  • Reference - J Drugs Dermatol 2007 Oct;6(10):981 and Am J Clin Dermatol 2009;10(4):221
• dapsone-induced hemolytic anemia not reported in topical treatment of acne in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency (level 3 [lacking direct] evidence)
  • based on randomized crossover trial without clinical outcomes
  • 64 patients ≥ 12 years old with G6PD deficiency and acne vulgaris were randomized to dapsone 5% gel vs. placebo twice daily for 12 weeks, then crossed over to alternate treatment after 2-week washout
  • no significant differences in proportion of patients with 1-g/dL decrease in hemoglobin at week 2 or week 12, no clinical signs of symptoms of hemolytic anemia noted
  • Reference - Arch Dermatol 2008 Dec;144(12):1564

General considerations

• antibiotics primarily inhibit Propionibacterium acnes⁽³⁾
• American Academy of Dermatology (AAD) 2016 guidelines for treatment of acne⁽⁴⁾
  • for moderate-to-severe acne and inflammatory acne resistant to topical therapies, add oral antibiotics to topical benzoyl peroxide or topical retinoid
  • use tetracyclines (doxycycline, minocycline, or tetracycline) as first-line for nonpregnant patients > 8 years old (AAD Strength of Recommendation A, Level I, II)
    • minocycline and doxycycline are equally effective
    • both minocycline and doxycycline appear more effective than tetracycline
    • minocycline associated with more serious adverse effects than doxycycline
  • a macrolide (azithromycin or erythromycin) is an alternative option (AAD Strength of Recommendation A, Level I)
    • azithromycin and erythromycin are effective but should be limited to patients who cannot use tetracyclines, such as in pregnancy or children < 8 years old
    • limit erythromycin use due to increased risk of bacterial resistance
  • limit antibiotic use to shortest possible duration, usually 3 months to reduce antibiotic resistance (AAD Strength of Recommendation A, Level I-II)
  • use of trimethoprim with or without sulfamethoxazole has limited evidence, and should be limited only to treatment-resistant patients or those who cannot use a tetracycline
• European (S3) 2016 guidelines for treatment of acne
  • for mild-to-moderate papulopustular acne, oral antibiotic plus adapalene can be recommended as an option (EUS3 Medium strength)
  • for severe papulopustular or moderate nodular disease, alternative options that can be recommended include (EUS3 Medium strength)
    • oral antibiotic plus adapalene
    • oral antibiotic plus azelaic acid
    • oral antibiotic plus adapalene plus benzoyl peroxide (topical fixed combination)
  • for severe nodular/conglobate acne
    • oral antibiotic plus azelaic acid can be recommended as an alternative option (EUS3 Medium strength)
    • oral antibiotic plus adapalene plus benzoyl peroxide can be recommended as an alternative option (EUS3 Medium strength)
  • doxycycline or lymecycline preferred to minocycline and tetracycline for choice of antibiotic
  • limit oral antibiotics to 3-month duration
  • Reference - J Eur Acad Dermatol Venereol 2016 Aug;30(8):1261
• American Acne and Rosacea Society 2013 recommendations for pediatric acne⁽⁵⁾
  • oral antibiotics are appropriate for moderate-to-severe inflammatory acne vulgaris at any age, but tetracycline and tetracycline derivatives should not be used in children < 8 years old (AARS Level B)
  • second-generation tetracyclines are sometimes preferred to tetracycline because of ease of use, fewer problems with absorption with food and minerals in vitamins and other supplements, and less-frequent dosing (AARS Level C)
  • patients should be educated and monitored for potential adverse events when using oral antibiotics (AARS Level B)
• consider treatment strategies to limit antibiotic resistance (GA Grade V)⁽³⁾
  • do not use antibiotics (oral or topical) as monotherapy
  • limit use of antibiotics to short periods and discontinue when there is no further improvement or only slight improvement
    • ideal duration of oral antibiotics 3 months
    • assess response to oral antibiotics 6-8 weeks into treatment
  • coprescribe benzoyl peroxide-containing product or use as washout
  • avoid concurrent use of oral and topical antibiotics, especially if chemically different
  • do not switch antibiotics without adequate justification; use same antibiotic for relapses
  • avoid antibiotics for maintenance therapy; use topical retinoids for maintenance therapy, adding benzoyl peroxide if antimicrobial effect needed
  • these recommendations persisted in reviews reported in 2014 (Eur J Dermatol 2014 May-Jun;24(3):330) and 2016 (Lancet Infect Dis 2016 Mar;16(3):e23)
  • antibiotic duration prior to isotretinoin often prolonged in patients with inflammatory and nodulocystic acne despite guideline recommendations to limit use
    • based on retrospective cohort study
    • 137 patients ≥ 12 years old with inflammatory or nodulocystic acne treated with oral antibiotics followed by oral isotretinoin were reviewed
    • antibiotic use
      • mean duration 331.3 days (range 37-1,501 days)
      • 21 (15.3%) given antibiotic for < 90 days, 88 (64.2%) patients given antibiotic for > 6 months and 46 (33.6%) given antibiotics for > 1 year
    • mean time between first notation of isotretinoin in medical record and initiation of isotretinoin use was 155.8 days (range 0-2,585 days)
    • Reference - J Am Acad Dermatol 2016 Feb;74(2):273
• oral antibiotics (including erythromycin, tetracycline, clindamycin, doxycycline and minocycline) may reduce inflammatory lesions by 50%-72% in patients with acne, based on 4 randomized trials with 670 patients (JAMA 2004 Aug 11;292(6):726)
• antibiotic use (topical or oral) may reduce Staphylococcus aureus carriage rates in patients with acne vulgaris, but might not affect antibiotic resistance of S. aureus (level 3 [lacking direct] evidence)
  • based on cohort study without outcome
  • 263 patients (mean age 22.5 years) with acne vulgaris had anterior nasal swabs collected and examined for S. aureus
  • 142 patients on antibiotics including 79 on orals, 23 on topicals, and 40 on both oral and topical treatment
  • S. aureus colonization in 6.3% on antibiotics vs. 15.7% not on antibiotics (p = 0.016)
  • no significant difference in antibiotic resistance between S. aureus from patients on antibiotics vs. S. aureus from patients not on antibiotics
  • Reference - J Am Acad Dermatol 2016 Apr;74(4):673
• antibiotic treatment for acne (topical or oral) may be associated with increased risk for upper respiratory infections (level 2 [mid-level] evidence)
  • based on retrospective cohort study
  • 118,496 patients aged 15-35 years with acne from United Kingdom General Practice Research Database, 1987-2002
  • 84,977 (71%) received topical or oral antibiotic (tetracyclines, erythromycin, or clindamycin), most used combination of oral and topical agents
  • 18,281 (15.4%) had at least 1 upper respiratory infection within 1 year
  • antibiotic use associated with increased risk of upper respiratory infection
    • odds ratio (OR) 2.15 (95% CI 2.05-2.23) for any antibiotic use
    • OR 2.37 (95% CI 2.12-2.64) for topical antibiotics only
    • OR 2.75 (95% CI 2.37-3.18) for oral antibiotics only
    • OR 1.88 (95% CI 1.8-1.96) for topical and oral antibiotics
  • Reference - Arch Dermatol 2005 Sep;141(9):1132 full-text

Tetracyclines

• American Academy of Dermatology (AAD) 2016 guidelines⁽⁴⁾
  • use tetracyclines (minocycline, doxycycline, or tetracycline) as first-line option
  • minocycline and doxycycline are equally effective and both minocycline and doxycycline appear more effective than tetracycline
  • minocycline associated with more severe adverse effects than other tetracyclines
• European (S3) 2016 guidelines for treatment of acne
  • doxycycline or lymecycline preferred to minocycline and tetracycline for choice of antibiotic
  • limit antibiotic duration to 3 months
  • Reference - J Eur Acad Dermatol Venereol 2016 Aug;30(8):1261
• not advised for children < 8 years old⁽²⁾
• avoid oral tetracyclines (minocycline, doxycycline, or tetracycline) in conjunction with oral isotretinoin due to potential increased risk for idiopathic intracranial hypertension (pseudotumor cerebri) (Dermatoendocrinol 2009 May;1(3):162  full-text)
• different tetracyclines and different doses appear to have equivalent efficacy in reducing acne lesion counts (level 2 [mid-level] evidence)
  • based on systematic review with heterogeneity
  • systematic review of 57 trials evaluating oral tetracyclines for inflammatory acne
  • studies varied widely in outcome measures, treatment duration, and study design
  • drugs evaluated included tetracycline (48 trials), minocycline (29 trials), doxycycline (10 trials), and lymecycline (7 trials)
  • different tetracyclines showed no significant differences in reducing
    • total lesion count in 7 randomized trials
    • inflammatory lesions in 32 trials
    • noninflammatory lesions in 23 trials
  • no significant differences between tested doses in reducing inflammatory or noninflammatory lesions
  • Reference - Br J Dermatol 2008 Feb;158(2):208
• doxycycline
  • dosing for acne includes⁽⁴⁾
    • for adults and children > 100 lbs (45.4 kg), give 100 mg every 12 hours on day 1, then 50-100 mg orally once-twice daily
    • for children > 8 years old and < 100 pounds, give 2 mg/pound divided into 2 doses on day 1, then 1 mg/pound once daily or divided into 2 doses
    • 20 mg twice daily or 40 mg once daily may also be effective for moderate inflammatory acne
  • Pregnancy Category D
  • adverse events may include photosensitivity (dose-dependent) and esophageal irritation, pseudotumor cerebri⁽²⁾
  • doxycycline 40 mg may be as effective in reducing lesions as doxycycline 100 mg in patients over 12 years old with moderate to severe acne (level 2 [mid-level] evidence)
    • based on randomized trial with high dropout rate
    • 662 patients (mean aged 19 years) with moderate-to-severe acne received 1 of 3 treatments for 16 weeks
      • doxycycline modified-release (MR) 40 mg orally daily
      • doxycycline 100 mg orally daily
      • placebo orally once daily
    • 487 (73.6%) completed the study (68 requested to discontinue and 65 lost to follow-up)
    • success (defined as at least 2-grade improvement from baseline on Investigator's Global Assessment [IGA] score) in
      • 14.4% with doxycycline MR 40 mg (p = 0.025 vs. placebo, not significant vs. doxycycline 100 mg)
      • 13,8% with doxycycline 100 mg (p = 0.035 vs. placebo)
      • 8% with placebo
    • adverse effects (most commonly headache or nausea/vomiting with doxycycline) in
      • 3.7% with doxycycline MR 40 mg
      • 17% with doxycycline 100 mg
      • 4,1% with placebo
    • Reference - J Drugs Dermatol 2015 Jun;14(6):581
  • low-dose doxycycline may improve acne without resulting in antimicrobial resistance (level 2 [mid-level] evidence)
    • based on small randomized trial
    • 51 adults aged 18-37 years with moderate facial acne were randomized to doxycycline hyclate 20 mg (Periostat) orally twice daily vs. placebo for 6 months
    • 40 patients (78%) completed the trial
    • doxycycline associated with reduced inflammatory lesions (p = 0.04), comedones (p < 0.01), and total lesions (p < 0.01)
    • no significant differences in skin flora microbial counts or antibiotic susceptibility
    • Reference - Arch Dermatol 2003 Apr;139(4):459 full-text, commentary can be found in J Fam Pract 2003 Aug;52(8):594
• lymecycline
  • not available in United States
  • dosing for acne, lymecycline 408 mg orally daily for at least 8 weeks for patients ≥ 12 years old
  • contraindicated in renal insufficiency or pregnancy
  • adverse effects may include photosensitivity, hepatic toxicity, exacerbation of systemic lupus erythematosus, weak neuromuscular blockade
  • Reference - electronic Medicines Compendium (eMC) 2016 July
• minocycline
  • dosing immediate-release formulation 50-100 mg orally once or twice daily⁽⁵⁾
  • extended-release formulation, 1 mg/kg (45-135 mg) orally once daily⁽⁵⁾
  • Pregnancy Category D
  • adverse events may include^{(1, 2)}
    • vestibular disturbances, dizziness, vertigo
    • urticaria
    • pigmentation deposition in skin, mucous membranes, gingiva, nails, conjunctiva, sclera, teeth (especially with prolonged use or higher doses)
    • photosensitivity
    • idiopathic intracranial hypertension (pseudotumor cerebri)
    • autoimmune conditions including autoimmune hepatitis, serum sickness-like reaction, drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, systemic lupus erythematosus-like reaction (rare)
    • polyarthritis nodosa, lupus-like syndrome, vasculitis (rare)
  • minocycline may improve symptoms of acne vulgaris but may not be more effective than other antibiotics (level 2 [mid-level] evidence)
    • based on Cochrane review of trials with inadequate or unclear allocation concealment
    • systematic review of 39 randomized trials evaluating minocycline in 6,013 patients with acne vulgaris
    • minocycline significantly improved symptoms compared to placebo in 4 trials with 1,109 patients
    • no significant differences comparing different minocycline dosing schedules in 1 trial with 307 patients
    • minocycline had similar efficacy for lesion improvement compared to
      • topical erythromycin plus benzoyl peroxide in 1 trial with 388 patients
      • lymecycline in analysis of 2 trials with 270 patients
      • tetracycline in 1 trial with 261 patients
      • benzoyl peroxide in 1 trial with 260 patients
      • doxycycline in analysis of 3 trials with 150 patients
      • topical clindamycin in 1 trial with 80 patients
    • minocycline less effective than
      • josamycin in 1 trial with 122 patients
      • topical erythromycin plus zinc in 1 trial with 105 patients
    • Reference - Cochrane Database Syst Rev 2012 Aug 15;(8):CD002086, commentary on earlier version can be found in BMJ 2007 Jan 20;334(7585):154
  • serious adverse events may be more common with minocycline than with other tetracyclines (level 2 [mid-level] evidence)
    • based on literature and record review
    • 3 databases assessed for reports of adverse events attributable to tetracyclines
      • Glaxo Wellcome-Sunnybrook Drug Safety Clinic, Toronto, Ontario - records from 1985 to 1996
      • Adverse Drug Reaction Monitoring Division database of Health Protection Branch, Ottawa, Ontario - records from 1966 to 1996
      • Medline search from 1966 to 1996
    • rare but serious adverse effects of severe cutaneous reaction, hypersensitivity syndrome, serum sickness-like reaction, and isolated single-organ dysfunction
    • adverse events comparing minocycline vs. tetracycline vs. doxycycline
      • hypersensitivity syndrome reaction in 19 vs. 2 vs. 1 patient
      • serum sickness-like reaction in 11 vs. 3 vs. 2 patients
      • drug-induced lupus in 33 vs. 0 vs. 0 patients
      • single-organ dysfunction in 40 vs. 37 vs. 6 patients
    • average time of onset from start of therapy
      • 4 weeks for hypersensitivity syndrome reaction, serum sickness-like reaction and single-organ dysfunction
      • 2 years for minocycline-induced lupus
    • Reference - Arch Dermatol 1997 Oct;133(10):1224
  • minocycline but not other tetracyclines associated with increased risk for lupus-like syndrome (level 2 [mid-level] evidence)
    • based on case-control study
    • 29 patients aged 15-29 years with acne and lupus-like syndrome were compared with 152 controls with acne for exposure to minocycline and other tetracyclines (doxycycline, oxytetracycline, or tetracycline)
    • lupus-like syndrome defined as first-time diagnosis of polyarthritis or polyarthralgia of unknown origin, with negative rheumatoid factor or latex agglutination test, positive or unmeasured antinuclear factor, elevated or unmeasured erythrocyte sedimentation rate, and absent or unmeasured antinative DNA antibody levels
    • tetracycline exposure comparing cases vs. controls
      • in 34% vs. 13% with current use (odds ratio [OR] 3.5, 95 CI 1.3-10)
      • in 21% vs. 4% with minocycline (OR 8.5, 95% CI 2.1-35)
      • in 10% vs. 6% with other tetracyclines (not significant)
      • in 3% vs. 3% with multiple tetracyclines (not significant)
    • Reference - Arch Intern Med 1999 Mar 8;159(5):493 full-text
• tetracycline
  • 500 mg orally twice daily for adults⁽²⁾
  • 25-50 mg/kg/day in 4 divided doses for children > 8 years old⁽⁴⁾
  • may lower to maintenance dose of 125-500 mg/day to be continued until clinical improvement allows discontinuation⁽⁴⁾
  • Pregnancy Category d
  • adverse effects may include^{(2, 4)}
    • idiopathic intracranial hypertension (pseudotumor cerebri), photosensitivity, onycholysis
    • usually contraindicated in children ≤ 8 years old due to drug deposition in bones and tooth discoloration
    • hepatic and renal toxicity (rare)
    • gastrointestinal distress
  • tetracycline 500 mg/day appears to improve moderate-to-severe acne (level 2 [mid-level] evidence)
    • based on randomized trial with allocation concealment not stated
    • 305 patients aged 18-35 years with moderate-to-severe acne were randomized to twice-daily tetracycline 250 mg orally plus placebo solution topically vs. 1% clindamycin topically plus placebo orally vs. oral and topical placebo for 8 weeks
      • tetracycline and clindamycin associated with lower pustule counts at 8 weeks (p < 0.05)
      • Reference - J Am Acad Dermatol 1982 Jul;7(1):50
      • similar findings can be found in J Am Acad Dermatol 1984 Dec;11(6):1076, South Med J 1976 Jun;69(6):695, J Invest Dermatol 1976 Mar;66(3):172, Arch Dermatol 1976 Jul;112(7):971, BMJ 1969 Apr 12;2(649):76 PDF, JAMA 1965 Sep 13;193:906

Macrolides

• macrolides used in acne include azithromycin and erythromycin (AAD Strength of Recommendation A, Level I)⁽⁴⁾
  • limit use of macrolides to patients unable to take tetracyclines, such as pregnant women or children < 8 years old
  • erythromycin associated with increased risk of bacterial resistance
• not FDA approved for treatment of acne⁽⁴⁾
• erythromycin dosing
  • 250-500 mg twice daily (Am Fam Physician 2004 May 1;69(9):2123)
  • Pregnancy Category B
  • adverse effects may include gastrointestinal distress, hepatic dysfunction, acute renal failure, skin rash, thrombocytopenia⁽⁴⁾
• azithromycin dosing
  • 500 mg orally 3 times weekly used in trials
  • Pregnancy Category B
  • adverse effects may include gastrointestinal distress, palpitations, arrhythmias, QT prolongation, hepatic dysfunction, acute renal failure, skin rash, thrombocytopenia⁽⁴⁾
• azithromycin appears as effective as doxycycline (level 2 [mid-level] evidence)
  • based on small randomized trial
  • 51 adults aged 18-30 years with acne randomized to azithromycin vs. doxycycline for 3 months and evaluated for reduction in lesion count at 3 months and during 2-month posttreatment follow-up
    • azithromycin 500 mg/day for 3 consecutive days per week in first month, for 2 consecutive days per week in second, and 1 day per week in third month
    • doxycycline twice daily for first month and once daily for second and third months
  • no significant differences for mean reduction in inflammatory or noninflammatory lesions at 3 months or at 2 months post treatment
  • side effects included diarrhea in 3 patients with azithromycin and photosensitivity in 2 patients with doxycycline
  • Reference - Clin Exp Dermatol 2005 May;30(3):215
• azithromycin reported to improve acne in adolescents (level 3 [lacking direct] evidence)
  • based on case series
  • 52 adolescents aged 13-17 years with moderate-to-severe papulopustular acne were treated with azithromycin 500 mg orally 3 times weekly for 8 weeks
  • lesion count significantly reduced at 6 weeks, 8 weeks, and at 2-month follow-up
  • Reference - Dermatol Online J 2007 Oct 13;13(4):4 full-text
• monthly 3-day pulses with azithromycin reported to be safe and effective for acne (level 3 [lacking direct] evidence)
  • based on case series
  • 57 patients with inflammatory and pustular acne were treated for 3 months with azithromycin 500 mg orally for 3 consecutive days per month
  • mean lesion reduction 55.5% (p < 0.001)
  • adverse events included mild-to-moderate gastrointestinal symptoms, headache, drowsiness, and vaginitis; withdrawal due to adverse events in 2 patients
  • Reference - J Dermatolog Treat 2008;19(4):210

Trimethoprim

• AAD 2016 guidelines for treatment of acne⁽⁴⁾
  • use of trimethoprim with or without sulfamethoxazole has limited evidence, and should be limited only to treatment-resistant patients or those who cannot use a tetracycline (AAD Strength of Recommendation B, Level II)
  • trimethoprim with or without sulfamethoxazole not FDA approved for treatment of acne
• trimethoprim reported to be effective for acne in about 66% of patients unresponsive to other oral antibiotics (level 3 [lacking direct] evidence)
  • based on large case series
  • 611 patients with acne unresponsive to 2 courses of oral antibiotics were treated with trimethoprim 300 mg orally twice daily for mean 8 months
  • discontinuation in 34% (lack of efficacy in 177 patients, widespread rash in 29 patients, possible intracranial hypertension in 3 patients)
  • remaining 402 patients (66%) showed significantly decrease acne severity from baseline at 4 and 8 months (p < 0.001)
  • Reference - Br J Dermatol 1999 Oct;141(4):757
• review of oral trimethoprim/sulfamethoxazole for acne can be found in Cutis 2007 Jun;79(6):430

Potential indications for hormonal treatment

• American Academy of Dermatology (AAD) 2016 recommendations for hormonal agents⁽⁴⁾
  • in females with inflammatory acne, estrogen-containing combined oral contraceptives are effective (AAD Strength of Recommendation A, Level I)
  • in select females with acne, oral spironolactone may be used (AAD Strength of Recommendation B, Level II, III)
  • in patients with severe inflammatory acne (while starting standard therapy), oral corticosteroids may be of temporary benefit (AAD Strength of Recommendation B, Level II)
  • for patients with well-documented adrenal hyperandrogenism, low-dose oral corticosteroids are recommended for acne treatment
• European (S3) 2016 guidelines for treatment of acne
  • for severe papulopustular or moderate nodular acne in female patients, hormonal antiandrogens plus topical treatment (except antibiotics) with or without oral antibiotics can be considered as an option for treatment (EUS3 Low strength)
  • for severe nodular/conglobate acne in female patients, hormonal antiandrogens plus topical treatment (except antibiotics) with or without oral antibiotics can be considered as an option for treatment (EUS3 Low strength)
  • Reference - J Eur Acad Dermatol Venereol 2016 Aug;30(8):1261

Oral contraceptives

• in females with inflammatory acne, estrogen-containing combined oral contraceptives are effective (AAD Strength of Recommendation A, Level I)
• American Acne and Rosacea Society 2013 recommendations for pediatric acne⁽⁵⁾
  • hormonal therapy with combined oral contraceptive (estrogen plus progestin) may be useful as second-line therapy in regimens of care in pubertal females with moderate-to-severe acne, but tobacco use and family history of thrombotic events should be assessed before use for adolescents (AARS Level A)
  • many experts recommend withholding oral contraceptives for treatment of acne not associated with endocrine pathology until 1 year after onset of menstruation because of concerns about growth and bone density (AARS Level C)
• potential adverse effects of combination oral contraceptives (COCs) (though rare in younger patients treated for acne) may include myocardial infarction, ischemic stroke, or venous thromboembolism⁽²⁾
• oral contraceptives may be contraindicated in patients with hypertension, migraine headaches with neurologic signs, smoking, clotting disorders, or systemic lupus erythematosus⁽²⁾

• FDA-approved COCs for moderate acne vulgaris include
  • ethinyl estradiol (EE) 35 mcg plus norgestimate 180 mcg, 215 mcg, or 250 mcg
  • EE 20 mcg, 30 mcg, and 35 mcg plus norethindrone acetate 1 mg plus ferrous fumarate
  • EE 20 mcg plus drospirenone (DRSP) 3 mg
  • EE 20 mcg plus drospirenone 3 mg plus levomefolate 0.451 mg
  • Reference - Dermatol Clin 2016 Apr;34(2):159
• co-cyprindiol (Dianette) (cyproterone acetate plus ethinyl estradiol) licensed in United Kingdom for treatment of severe acne refractory to oral antibiotics
  • should not be used solely for contraceptive purposes due to increased risk for venous thromboembolism (VTE) compared to other COCs
  • ideally, discontinue co-cyprindiol 3-4 months after acne has resolved
  • may be restarted any time if acne or hirsutism recurs after stopping treatment
  • Reference - Faculty of Sexual and Reproductive Healthcare (FSRH) guideline on combined hormonal contraception (FSRH 2011 Oct PDF)
• combined oral contraceptives may reduce inflammatory and noninflammatory facial acne (level 2 [mid-level] evidence)
  • based on Cochrane review of trials with methodologic limitations
  • systematic review of 31 randomized trials evaluating COCs in 12,579 women with inflammatory or noninflammatory facial acne
  • all trials had ≥ 1 limitation, including
    • unclear allocation concealment (25 trials)
    • inadequate allocation concealment
    • lack of blinding
    • high dropout rate
    • no intention-to-treat analysis performed
  • compared to placebo, significantly reduced acne symptoms (such as lesion count, acne severity, and clinician and/or self-assessed acne) associated with
    • levonorgestrel 100 mcg/ethinyl estradiol 20 mcg in analysis of 2 trials
    • norgestimate 180 mcg, 215 mcg, or 250 mcg plus ethinyl estradiol 35 mcg in analysis of 2 trials
    • drospirenone 3,000 mcg/ethinyl estradiol 20 mcg in analysis of 2 trials
    • norethindrone acetate 1,000 mcg/ethinyl estradiol 20 mcg, 30 mcg, 35 mcg in 1 trial
    • dienogest 2,000 mcg/ethinyl estradiol 30 mcg in 1 trial
    • chlormadinone acetate 2,000 mcg/ethinyl estradiol 30 mcg in 1 trial
  • in head-to-head comparison of COCs
    • improvement in some (but not all) acne outcomes associated with
      • desogestrel/ethinyl estradiol compared to levonorgestrel/ethinyl estradiol in 2 trials with 558 women
      • chlormadinone acetate 2,000 mcg/ethinyl estradiol 30 mcg compared to levonorgestrel 150 mcg/ethinyl estradiol 30 mcg in 1 trial with 149 women
      • cyproterone acetate/ethinyl estradiol compared to levonorgestrel/ethinyl estradiol in 2 trials with 236 women
      • drospirenone 3,000 mcg/ethinyl estradiol 30 mcg compared to
        • levonorgestrel 150 mcg/ethinyl estradiol 30 mcg in 1 trial with 424 women
        • nomegestrol acetate 2,000 mcg/17 beta-estradiol 1,500 mcg in 1 trial with 2,083 women
        • norgestimate 180 mcg, 215 mcg, or 250 mcg/ethinyl estradiol 35 mcg in 1 trial with 1,108 women
    • no significant differences in acne outcomes comparing
      • drospirenone 3,000 mcg/ethinyl estradiol 30 mcg vs. cyproterone acetate 2,000 mcg/ethinyl estradiol 35 mcg in 1 trial with 118 women
      • desogestrel 150 mcg/ethinyl estradiol 30 mcg vs. gestodene 75 mcg/ethinyl estradiol 30 mcg in analysis of 2 trials with 1,180 women
      • dienogest 2,000 mcg/ethinyl estradiol 30 mcg vs. cyproterone acetate 2,000 mcg/ethinyl estradiol 35 mcg in 1 trial with 1,037 women
      • norgestimate 180 mcg, 215 mcg, or 250 mcg/ethinyl estradiol 35 mcg vs. cyproterone acetate 2,000 mcg/ethinyl estradiol 35 mcg in 1 trial with 45 women
  • no significant differences in acne outcomes comparing cyproterone acetate 2 mcg/ethinyl estradiol 50 mcg vs. minocycline hydrochloride 50 mg in 1 trial with 78 women
  • Reference - Cochrane Database Syst Rev 2012 Jul 11;(7):CD004425

• oral contraceptives may reduce inflammatory lesions by 32%-75% in patients with acne, based on 5 randomized trials with 1,356 women (JAMA 2004 Aug 11;292(6):726)
• insufficient evidence to compare oral contraceptives to antibiotics in patients with acne
  • based on systematic review
  • systematic review of 32 randomized trials evaluating oral contraceptives and antibiotics for acne management in 8,991 patients
  • review only reported mean reduction and 95% CIs for each group and did not present any direct comparisons of oral contraceptives and antibiotics or perform any indirect analyses
  • Reference - J Am Acad Dermatol 2014 Sep;71(3):450
• American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin 110 on noncontraceptive uses of hormonal contraceptives can be found in Obstet Gynecol 2010 Jan;115(1):206, reaffirmed 2014 Aug, commentary can be found in ACOG News Release 2009 Dec 21

Antiandrogens

• antiandrogens also called androgen receptor blockers
  • include spironolactone, cyproterone, drospirenone, flutamide
  • contraindicated in men due to feminizing effects, and in pregnant women due to possible feminization of male fetus (Clin Dermatol 2010 Jan-Feb;28(1):17)
• Global Alliance to Improve Outcomes in Acne considers oral antiandrogen an alternative choice for therapy in females with⁽³⁾
  • moderate inflammatory acne (papules, pustules, mixed)
  • moderate nodular acne (nodules < 0.5 cm)
  • severe nodular or conglobate acne
• spironolactone
  • AAD 2016 guidelines recommend oral spironolactone may be used as alternative in females with moderate-to-severe acne (AAD Strength of Recommendation B, Level II, III)⁽⁴⁾
    • spironolactone not approved for use in acne
    • 50-200 mg orally/day for average 10 months (commonly 6-12 months)
    • adverse effects may include renal dysfunction, hyperkalemia, gynecomastia, amenorrhea, breast tenderness, fatigue, headache, dizziness, skin rash or hypersensitivity
    • contraindicated in acute renal failure, Addison disease, hyperkalemia, anuria, concomitant eplerenone or triamterene use, or significant renal impairment
    • Pregnancy Category C
  • reported to reduce sebum excretion rate and improve acne
    • lower doses (25 mg once or twice daily) may be sufficient for some women with sporadic outbreaks or isolated cysts (Clin Dermatol 2010 Jan-Feb;28(1):17)
  • no randomized trial evidence to evaluate oral spironolactone for treatment of acne vulgaris
    • based on Cochrane review
    • systematic review of randomized trials evaluating spironolactone to reduce hair growth and acne in women
    • 1 small crossover study of spironolactone 200 mg orally daily vs. placebo had incomplete data for analysis, but showed no significant difference in mean inflamed lesions at follow-up
    • 1 small placebo-controlled trial (< 32 patients) of topical spironolactone identified, which found significant decrease in sebum excretion rate using spironolactone but no significant difference in acne severity
    • Reference - Cochrane Database Syst Rev 2009 Jan 21;(1):CD000194, commentary on earlier version can be found in ACP J Club 2004 May-Jun;140(3):74
• flutamide
  • AAD 2016 guidelines for flutamide in treatment of acne (AAD Strength of Recommendation C, Level III)⁽⁴⁾
    • discourage flutamide except where benefit outweighs risk
    • flutamide not approved for use in acne
    • dosing in trials ranged from 62.5 mg once daily to 250 mg orally twice daily
    • adverse effects may include gastrointestinal distress, breast tenderness, hot flushes, headache, xerosis, decreased libido
    • fatal hepatotoxicity reported
    • Pregnancy Category D
• cyproterone acetate
  • cyproterone acetate not approved for use in United States
    • 2-100 mg/day orally starting on first day of menstrual period, usually combined with ethinyl estradiol as oral contraceptive
    • most common side effect is amenorrhea or oligomenorrhea; other side effects include nausea, vomiting, fluid retention, leg edema, headache, and melasma
    • Reference - Clin Dermatol 2010 Jan-Feb;28(1):17
  • cyproterone acetate orally (with estrogen) and as lotion may be equally effective in reducing acne lesion counts (level 2 [mid-level] evidence)
    • based on small randomized trial
    • 40 women with mild-to-moderate inflammatory acne were randomized to placebo lotion vs. topical cyproterone acetate lotion 20 mg vs. oral cyproterone acetate 2 mg/ethinyl estradiol 0.035 mg for 3 months
    • both active treatments decreased lesion counts significantly more than placebo, serum cyproterone acetate levels 10 times lower with topical treatment than oral treatment
    • Reference - Arch Dermatol 1998 Apr;134(4):459 full-text

Isotretinoin recommendations and general considerations

• isotretinoin is 13-cis-retinoic acid
• American Academy of Dermatology 2016 guidelines for use of isotretinoin⁽⁴⁾
  • consider for moderate acne that is treatment-resistant or associated with psychosocial distress
  • recommended for treatment of severe nodular acne
  • use as conventional dosing or low-dose for moderate acne (AAD Strength of Recommendation A, Level I-II)
  • low-dose isotretinoin may be used effectively (to minimize frequency and severity of isotretinoin side effects), but intermittent therapy is not recommended
  • routinely monitor liver function tests, serum cholesterol, and triglycerides at baseline and again until response to treatment is established (AAD Strength of Recommendation B, Level II)
  • adherence to iPLEDGE risk management program is required (AAD Strength of Recommendation A, Level II)
  • monthly pregnancy testing with urine or serum human chorionic gonadotropin (hCG) monitoring required
  • females of childbearing potential should be counseled on contraception methods (AAD Strength of Recommendation A, Level II)
  • due to potential risks, counsel and monitor for inflammatory bowel disease and depression, mood changes, anxiety, and suicidal ideation
• European (S3) 2016 guidelines for treatment of acne
  • for severe papulopustular or moderate nodular disease, isotretinoin orally is strongly recommended as monotherapy (EUS3 High strength), with dosing of 0.3-0.5 mg/kg
  • for severe nodular/conglobate acne, isotretinoin orally is strongly recommended as monotherapy (EUS3 High strength) with dosing of ≥ 0.5 mg/kg
  • continue treatment for at least 6 months
  • monitor liver enzymes and lipids prior to starting treatment, 1 month after starting, then every 3 months
  • Reference - J Eur Acad Dermatol Venereol 2016 Aug;30(8):1261
• American Acne and Rosacea Society 2013 recommendations for pediatric acne⁽⁵⁾
  • isotretinoin is recommended for severe, scarring, and/or refractory acne in adolescents (AARS Level A) and may be used in younger patients (AARS Level C)
  • extensive counseling, particularly on need to avoid pregnancy, as well as careful monitoring of potential side effects and toxicities, is recommended
• avoid isotretinoin in conjunction with oral tetracyclines (minocycline, doxycycline, or tetracycline) due to potential increased risk for idiopathic intracranial hypertension (pseudotumor cerebri) (Dermatoendocrinol 2009 May;1(3):162 full-text)
• reduces all 4 major pathogenetic factors in acne
  • sebum production
  • comedone formation by decreasing hyperkeratinization
  • Propionibacterium acnes colonization of skin surface and pilosebaceous duct
  • inflammation
  • Reference - Dermatoendocrinol 2009 May;1(3):162 full-text

Brands

Isotretinoin dosing

• recommended dosing (patients ≥ 12 years old)^{(1, 2, 4)}
  • for moderate acne in adolescents and for adults, isotretinoin 0.5-1 mg/kg/day orally in divided doses
  • for moderate acne in adolescents, isotretinoin 0.3-0.5 mg/kg/day
  • continue for 15-20 weeks (may be dosed until goal dose of 125-150 mg/kg total)
  • contraindicated in pregnancy
• lower starting dose and slower increase may reduce initial acne flare without need for greater cumulative isotretinoin dose (level 2 [mid-level] evidence)
  • based on before-and-after study
  • 132 patients (mean age 20.3 years) with acne were treated with isotretinoin at starting dose ≤ 0.2 mg/kg/day from 2002 to 2007 and were compared with 142 patients treated with isotretinoin at starting dose 0.5 mg/kg/day from 1998 to 2002
  • isotretinoin increased to maximum tolerated dose by 5 mg/week in higher dose group vs. every 2 weeks in lower dose group
  • total cumulative dose ≤ 150 mg in both groups; all patients were treated until remission
  • flare during first 4 weeks in 7.5% with lower dose vs. 15.5% with higher dose (p = 0.0415, NNT 13 for lower dose)
  • Reference - Dermatology 2009;218(2):178
• low-dose oral isotretinoin associated with similar reduction in acne lesions compared to conventional dose but with increased patient satisfaction and fewer side effects (level 2 [mid-level] evidence)
  • based on small randomized trial without placebo control
  • 60 patients with moderate acne randomized to 1 of 3 groups for 24 weeks and followed for 1 year
    • isotretinoin 0.5-0.7 mg/kg/day orally (conventional)
    • isotretinoin 0.25-0.4 mg/kg/day orally (low)
    • isotretinoin conventional dose for 1 week every 4 weeks (intermittent)
  • comparing mean inflammatory lesion count at 24 weeks
    • 2.44 with conventional
    • 2.59 with low (not significant vs. conventional)
    • 6.31 with intermittent (p < 0.005 vs. conventional, p = 0.048 vs. low)
  • similar results for noninflammatory lesions
  • relapse at 1 year in
    • 13% with conventional
    • 18% with low
    • 56% with intermittent
  • low dose associated with greater patient satisfaction and lower risk of side effects
  • Reference - Br J Dermatol 2011 Jun;164(6):1369

Isotretinoin efficacy

• oral isotretinoin may reduce inflammatory lesions in patients with acne (level 2 [mid-level] evidence)
  • based on systematic review with assessment of trial quality not reported
  • systematic review of 29 randomized double-blinded trials and 1 meta-analysis of investigator-blinded trials evaluating efficacy of different acne medication regimens
  • 79%-90% reduction of inflammatory lesions in 3 randomized trials with 826 patients
  • adverse effects included mucocutaneous (cheilitis) in 95%, hypertriglyceridemia in 25%, elevated liver transaminases in 15%, hypercholesterolemia in 7%, and teratogenicity in 25%-40% of exposed fetuses
  • Reference - JAMA 2004 Aug 11;292(6):726
• oral isotretinoin may reduce cyst counts and size in treatment-resistant cystic and conglobate acne (level 2 [mid-level] evidence)
  • based on 2 small randomized trials
  • 33 patients with treatment-resistant and conglobate acne were randomized to isotretinoin 0.5-2 mg/kg/day (mean dose 1.2 mg/kg/day) vs. placebo
    • isotretinoin associated with 95% improvement
    • placebo associated with 57% increase in cystic lesions; subsequent treatment with isotretinoin associated with 98% improvement
    • complete clearing of acne in 82% (27 of 32 patients ultimately treated with isotretinoin)
    • Reference - J Am Acad Dermatol 1982 Apr;6(4 Pt 2 Suppl):735
  • 30 patients ≥ 18 years old with treatment-resistant cystic and conglobate acne were randomized to isotretinoin vs. tetracycline for 16 weeks and were evaluated at 24 weeks
    • outcomes comparing isotretinoin vs. tetracycline at 24 weeks
      • mean cyst count decreased by 82% vs. 54% (p < 0.02)
      • mean sum of longest cyst diameters decreased 88% vs. 60% (p < 0.01)
    • no significant differences in outcomes at 16 weeks
    • Reference - Int J Dermatol 1985 May;24(4):252
• isotretinoin associated with about 40% acne relapse rate after stopping treatment (level 2 [mid-level] evidence)
  • based on cohort study
  • 17,351 patients aged 13-45 years with acne and first-time treatment with isotretinoin between 1984 and 2003 were assessed for relapse
  • 7,100 patients (40.9%) had relapse defined as use of further antiacne medication after first treatment period
  • compared to 35,000 matched controls (controls could be matched to > 1 case, cases may have served as controls prior to relapse), relapse associated with
    • age < 16 years (adjusted rate ratio [RR] 1.4, 95% CI 1.26-1.54)
    • male gender (adjusted RR 1.14, 95% CI 1.07-1.2)
    • living in urban area (adjusted RR 1.09, 95% CI 1.01-1.16)
    • ≥ 1 physician visit after first treatment (adjusted RR 3.83, 95% CI 3.53-4.15)
    • ≥ 1 other antiacne medication during first isotretinoin treatment (adjusted RR 1.71, 95% CI 1.55-1.89)
    • ≥ 1 antiacne medication in 12 months prior to first isotretinoin treatment (adjusted RR 1.36, 95% CI 1.29-1.44)
  • 4,443 patients (26%) had relapse requiring second course of isotretinoin
  • compared to 22,215 controls, second course of isotretinoin associated with
    • age < 16 years (adjusted RR 1.26, 95% CI 1.12-1.43)
    • male gender (adjusted RR 1.32, 95% CI 1.22-1.41)
    • ≥ 1 other acne medication after first isotretinoin treatment (adjusted RR 1.51, 95% CI 1.36-1.68)
    • ≥ 1 physician visit after first treatment (adjusted RR 2.71, 95% CI 2.46-2.98)
  • Reference - Br J Dermatol 2007 Dec;157(6):1240, commentary can be found in Br J Dermatol 2009 Jan;160(1):217
• cumulative isotretinoin dose ≥ 220 mg/kg over 1 year associated with decreased risk of relapse compared to lower cumulative dose in patients with treatment-resistant acne vulgaris (level 2 [mid-level] evidence)
  • based on prospective cohort study
  • 180 patients (mean age 19 years) with treatment-resistant acne vulgaris received isotretinoin with dosing determined by healthcare provider and were followed for 1 year
  • 64.4% completed follow-up survey and were included in analyses
  • acne improvement in 97.4%
  • comparing isotretinoin cumulative dose ≥ 220 mg/kg vs. lower cumulative dose
    • relapse (need for topical or oral acne medication following isotretinoin) in 26.9% vs. 47.4% (p = 0.03, NNT 5)
    • retinoid dermatitis in 53.8% vs. 31.6% (p = 0.02, NNH 4)
  • no significant differences in other adverse events, nearly all patients developed cheilitis and xerosis
  • Reference - JAMA Dermatol 2013 Dec;149(12):1392, editorial can be found in JAMA Dermatol 2013 Dec;149(12):1398, commentary can be found in JAMA 2014 May 28;311(20):2121

Adverse effects

• may be associated with significant adverse effects; monthly laboratory monitoring required^{(1, 2)}
  • teratogenic
  • mucocutaneous, musculoskeletal, ophthalmic, neurologic, gastrointestinal, and dyslipidemic effects
  • inflammatory acne flare may occur during first 3-5 weeks of therapy (Dermatology 2009;218(2):178)
  • idiopathic intracranial hypertension (pseudotumor cerebri)
• a review of the management of nonteratogenic adverse effects of isotretinoin treatment of acne can be found in JAAPA 2015 Jul;28(7):34
• see Isotretinoin for information on contraindications, warnings, precautions, and common adverse effects

Fetal risk and iPLEDGE program

• regulatory steps to prevent birth defects with isotretinoin include FDA-approved iPLEDGE program
  • requires program registration for all patients before isotretinoin can be prescribed
  • prescription limited to 30-day supply
  • negative pregnancy test required for prescription refill in females with childbearing potential
  • Reference - iPLEDGE
  • FDA approved strengthened risk management program (iPLEDGE) for Accutane and generic isotretinoin (FDA MedWatch 2005 Aug 12, FDA Press Release 2005 Aug 12), iPLEDGE program to be implemented March 1, 2006 (FDA Press Release 2006 Feb 23)
  • iPLEDGE program modified to eliminate lockout period for males and for females of nonchildbearing potential (FDA MedWatch 2006 Oct 6)

Possible adverse effects not well established

• psychiatric side effects
  • suicide and suicide attempts
    • suicide reported with isotretinoin, but not clearly related to drug instead of associated with severe acne
      • isotretinoin has been reported to be associated with increased risk of suicide attempts
      • cohort studies have found increased risk of suicide attempts associated with severe acne, but risk of suicide attempts with isotretinoin was not found to be significantly higher than other acne treatments or period of time preceding isotretinoin use
      • monitoring may be warranted due to increased risk of suicide attempts in patients with severe acne
      • Reference - Am J Clin Dermatol 2013 Apr;14(2):71
    • severe acne associated with increased risk of attempted suicide, and slight increase in risk of attempted suicide may be present within 6 months after starting isotretinoin (level 2 [mid-level] evidence)
      • based on retrospective cohort study in Sweden
      • 5,756 patients aged 15-49 years taking isotretinoin for severe acne were followed for 17,197 person-years before, 2,905 person-years during, and 87,120 person-years after treatment
      • 128 patients hospitalized for 210 suicide attempts
      • standardized incidence ratio (compared to general population)
        • 1.57 (95% CI 0.86-2.63) for all suicide attempts during year before treatment
        • 1.36 (95% CI 0.65-2.5) for first suicide attempt during year before treatment
        • 1.78 (95% CI 1.04-2.85) for all suicide attempts within 6 months after treatment
        • 1.93 (95% CI 1.08-3.18) for first suicide attempt within 6 months after treatment
        • 1.04 (95% CI 0.74-1.43) for all suicide attempts during 3 years after treatment ended
        • 0.97 (95% CI 0.64-1.4) for first suicide attempt during 3 years after treatment ended
      • if isotretinoin is potentially causative of exacerbating risk of suicide attempts in patients with severe acne, then estimated NNH for additional risk in first 6 months of isotretinoin treatment
        • 2,300 for 1 additional first suicide attempt
        • 5,000 for 1 additional repeat attempt
      • Reference - BMJ 2010 Nov 11;341:c5812 full-text
  • isotretinoin may not be associated with increased risk of depression or anxiety in patients with acne (level 2 [mid-level] evidence)
    • based on prospective cohort study
    • 60 patients (mean age 22 years) with acne were treated with isotretinoin 30 mg orally/day or other treatment for 12 weeks
    • other treatment consisted of combination of antibiotics (oral or topical) and benzoyl peroxide
    • 25% in isotretinoin group and 0% in other treatment group had severe acne at baseline (p = 0.008)
    • comparing isotretinoin vs. other treatment at 12 weeks
      • any depression in 8.3% vs. 8.3% (not significant)
      • any anxiety in 11.1% vs. 4.2% (not significant)
    • Reference - World J Psychiatry 2016 Mar 22;6(1):136 full-text
  • depression and anxiety are common in patients with severe acne requiring isotretinoin therapy, but not clearly associated with isotretinoin
    • isotretinoin has been reported to be associated with increased risk of depression in very small subset of patients with severe acne
    • however, ≥ 9 controlled studies found isotretinoin use to be associated with improved depression and anxiety
    • monitoring may be warranted due to increased risk of depression in patients with severe acne
    • Reference - Am J Clin Dermatol 2013 Apr;14(2):71
  • no association of isotretinoin with depression, psychosis, suicide, or suicide attempts (level 2 [mid-level] evidence)
    • based on comparison of 7,535 isotretinoin users and 14,376 oral antibiotic users with acne in Canada and United Kingdom
    • Reference - Arch Dermatol 2000 Oct;136(10):1231 full-text
  • isotretinoin use not associated with depressive symptoms (level 2 [mid-level] evidence) based on cohort study in 101 teenagers with moderate-to-severe acne (Arch Dermatol 2005 May;141(5):557 full-text)
  • review of isotretinoin and psychiatric side effects can be found in Ann Gen Psychiatry 2009 Jan 20;8(1):2
• inflammatory bowel disease (IBD) reported to be associated with isotretinoin but not confirmed (level 3 [lacking direct] evidence)
  • isotretinoin use associated with increased risk of ulcerative colitis in 1 study, but no association found in multiple other studies
  • despite such findings, cautions suggested
    • use of isotretinoin in patients with IBD and/or with strong family history of IBD should be minimized
    • comanagement with gastroenterologist suggested if isotretinoin therapy determined to be appropriate in specific patients
  • Reference - Am J Clin Dermatol 2013 Apr;14(2):71
• liver function abnormalities and dyslipidemia
  • isotretinoin reported to increase lipid and liver enzyme levels in patients with acne vulgaris (level 3 [lacking direct] evidence)
    • based on systematic review without clinical outcomes
    • systematic review of 61 observational studies evaluating laboratory changes with oral isotretinoin in 19,489 patients with acne vulgaris
    • meta-analyses included 26 studies with 1,574 patients
    • compared to baseline, isotretinoin associated with increased
      • triglyceride levels at mean follow-up 11.3 weeks (mean difference 36.96 mg/dL, 99% CI 22.12-51.79 mg/dL) in analysis of 24 studies
      • total cholesterol levels at mean follow-up 11.1 weeks (mean difference 19.73 mg/dL, 99% CI 16-23.47 mg/dL) in analysis of 22 studies
      • aspartate aminotransferase levels at mean follow-up 6.6 weeks (mean difference 3.72 units/L, 99% CI 2.44-5.01 units/L) in analysis of 11 studies
      • alanine aminotransferase levels at mean follow-up 6.5 weeks (mean difference 3.22 units/L, 99%CI 0.99-5.45 units/L) in analysis of 10 studies
    • mean increase in lipid and liver enzyme levels were below prespecified high-risk cutoffs for all measurements
    • Reference - JAMA Dermatol 2016 Jan 1;152(1):35
  • laboratory abnormalities reported to be common in patients using isotretinoin (level 3 [lacking direct] evidence)
    • based on retrospective cohort study
    • medical records of 13,772 patients aged 13-50 years taking oral isotretinoin for acne were assessed for abnormal laboratory values
    • laboratory values included serum triglyceride, total cholesterol, liver transaminase, white blood cell count, hemoglobin level, platelet count
    • cumulative incidence of new abnormalities in patients with normal values at baseline
      • 44% for triglyceride level
      • 31% for total cholesterol level
      • 11% for transaminase level
    • Reference - Arch Dermatol 2006 Aug;142(8):1016 full-text
  • laboratory abnormalities reported to be uncommon in patients using isotretinoin (level 3 [lacking direct] evidence)
    • based on retrospective cohort study
    • 876 patients aged 12-55 years who used isotretinoin 1 mg/kg/day for 4-5 months had blood tests every 4 weeks during first 2 years of practice then only after first 4 weeks for subsequent 7 years
    • liver function tests moderately elevated in minority of patients, but all returned to normal without drug discontinuation
    • cholesterol levels > 200 mg/dL (2.18 mmol/L) in 54 patients (6%) and > 300 mg/dL (7.8 mmol/L) in 5 patients (0.6%)
    • triglyceride levels > 200 mg/dL (2.26 mmol/L) in 45 patients (5%)
    • Reference - J Dermatolog Treat 2001 Mar;12(1):9
• reported ocular effects with isotretinoin (level 3 [lacking direct] evidence)
  • based on 1,741 case reports, drug manufacturer database, and literature review
  • reported ocular effects include abnormal meibomian gland secretion, blepharoconjunctivitis, corneal opacities, decreased dark adaptation, decreased tolerance to contact lens, decreased vision, increased tear osmolarity, keratitis, meibomian gland atrophy, myopia, ocular discomfort, ocular sicca, photophobia, and teratogenic ocular abnormalities
  • probable or possible effects include decreased color vision (reversible), permanent loss of dark adaptation, permanent keratoconjunctivitis sicca
  • Reference - Am J Ophthalmol 2001 Sep;132(3):299
• other adverse effects reported with isotretinoin in case reports (level 3 [lacking direct] evidence)
  • Guillain-Barre syndrome in 3 patients taking isotretinoin, causal link not established (BMJ 2004 Jun 26;328(7455):1537)
  • acute pancreatitis related to isotretinoin-induced hyperlipidemia in case report (J Okla State Med Assoc 2002 Feb;95(2):79)

Montelukast

• montelukast may reduce acne severity as much as doxycycline in patients with moderate acne (level 2 [mid-level] evidence)
  • based on small randomized trial
  • 52 patients with moderate acne were randomized to montelukast 5 mg orally daily vs. doxycycline 100 mg orally daily for 3 months
  • montelukast 5 mg orally daily plus clindamycin 1% topically daily for 3 months (mean age 27 years) all patients received clindamycin 1% topically daily
  • comparing montelukast vs. doxycycline for outcome of acne severity score in
    • mean acne severity score at 1 month, 10.5 vs. 12.9 (p = 0.001)
    • mean acne severity score at 3 months, 8.6 vs. 8.2 (no p value reported)
  • both groups had significant reductions in acne severity score from baseline
  • no adverse events in montelukast group and 2 cases of dyspepsia in doxycycline group
  • Reference - J Res Med Sci 2015 Apr;20(4):379 full-text

Zinc

• oral zinc might be effective for improving acne but may not be as effective as minocycline (level 2 [mid-level] evidence)
  • based on systematic review with limited evidence and clinical heterogeneity
  • systematic review of 9 studies (with patients-oriented outcomes) evaluating oral or topical zinc for treatment of acne vulgaris
  • studies differed in
    • zinc concentration used
    • evaluation of zinc alone or mixed zinc-antibiotic formulations
    • comparator
  • in 2 randomized trials evaluating oral zinc
    • oral zinc gluconate associated with improved inflammatory scores (based on number and type of lesions) vs. placebo in 1 trial with 66 patients (p < 0.02)
    • oral zinc gluconate associated with lower treatment response at 3 months vs. minocycline (50% vs. 67% reduction in number of papules and pustules compared to baseline) in 1 trial with 318 patients (p < 0.001)
  • Reference - J Drugs Dermatol 2013 May;12(5):542

Lactoferrin

• lactoferrin may reduce lesion counts in patients with acne (level 2 [mid-level] evidence)
  • based on small randomized trial
  • 56 patients (mean age 21.8 years) with acne randomized to addition of lactoferrin to fermented milk with Lactobacillus bulgaricus and Streptococcus thermophilus vs. fermented milk with L. bulgaricus and S. thermophilus 200 mg/day orally for 12 weeks
  • 13 patients dropped out and 7 patients with nonadherence were not included in analyses
  • comparing lactoferrin with fermented milk and probiotics vs. fermented milk and probiotics alone
    • reduction in inflammatory lesion count 69.8% vs. 36.3% (p = 0.019)
    • reduction in total lesion count 56.3% vs. 33.2% (p = 0.033)
  • Reference - Nutrition 2010 Sep;26(9):902

Gugulipid

• oral gugulipid and tetracycline associated with similar reduction in inflammatory lesions in patients with nodulocystic acne (level 2 [mid-level] evidence)
  • based on small randomized trial
  • 20 patients with nodulocystic acne randomized to oral gugulipid (equivalent to guggulsterone 25 mg) vs. tetracycline 500 mg twice daily for 3 months
  • compared to baseline, both treatments associated with progressive reduction in lesions in majority of patients
  • comparing gugulipid vs. tetracycline
    • percentage reduction in inflammatory lesions was 68% vs. 65% (not significant)
    • relapse at 3 months in 2 patients vs. 4 patients
  • patients with oily faces reported to respond better to gugulipid
  • Reference - J Dermatol 1994 Oct;21(10):729

Herbal medicines

• insufficient evidence to determine efficacy or comparative efficacy for herbal medicines in patients with acne vulgaris
  • based on Cochrane review of trials with methodologic limitations
  • systematic review of 35 randomized trials evaluating complementary therapies in 3,227 patients with acne vulgaris
  • all trials had ≥ 1 limitation including unclear or lack of blinding of outcome assessor, unclear allocation concealment, or small sample size
  • variations in herbal medicines included type, dosage, and route of administration
  • herbal medicine evaluated in 20 trials identified in review
    • comparing herbal medicine to wait-list control, no significant difference in acne outcomes in 1 trial
    • comparing herbal medicine to antibiotics, mixed results for acne outcomes among 6 trials
    • comparing herbal medicine to vitamin A, mixed results for acne outcomes among 7 trials
    • comparing herbal medicine to vitamin A plus antibiotics, herbal medicine associated with improved acne outcomes in 1 trial
    • comparing herbal medicine to Staphylococcus injection, inconsistent outcomes in 1 trial
    • comparing herbal medicine plus pharmacologic therapy to pharmacologic therapy alone, herbal medicine plus pharmacologic therapy associated with improved acne outcomes in 2 trials
    • comparing herbal medicine plus phototherapy to phototherapy alone, no significant difference in acne outcomes in 1 trial
    • comparing herbal medicine plus wet-cupping to wet-cupping alone, no significant difference in acne outcomes in 1 trial
  • adverse effects reported with herbal medicines included dizziness, mild nausea, abdominal pain, and diarrhea
  • authors conclude lack of evidence to support use of herbal medicines for acne
  • Reference - Cochrane Database Syst Rev 2015 Jan 19;(1):CD009436

International guidelines

• expert working group consensus on evidence-based practice in acne can be found in J Dermatol 2011 Nov;38(11):1041
• Global Alliance to Improve Outcomes in Acne Group guideline on management of acne can be found in J Am Acad Dermatol 2009 May;60(5 Suppl):S1

United States guidelines

• American Academy of Dermatology (AAD) guideline on acne vulgaris management can be found in J Am Acad Dermatol 2016 May;74(5):945 full-text
• American Academy of Dermatology (AAD) position statement on isotretinoin can be found at AAD 2010 Nov 13 PDF
• American Acne and Rosacea Society evidence-based recommendations for the diagnosis and treatment of pediatric acne can be found in Pediatrics 2013 May;131 Suppl 3:S163
• American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin 110 on noncontraceptive uses of hormonal contraceptives can be found in Obstet Gynecol 2010 Jan;115(1):206, reaffirmed 2014 Aug, commentary can be found in ACOG News Release 2009 Dec 21
• expert consensus recommendations for use of erbium-doped 1,550 nm fractionated laser for acne scars can be found in Dermatol Surg 2010 Apr;36(4):461

United Kingdom guidelines

• British Association of Dermatologists (BAD) advice on safe introduction and continued use of isotretinoin in acne in United Kingdom 2010 can be found in Br J Dermatol 2010 Jun;162(6):1172

Canadian guidelines

• Canadian Acne Working Group clinical practice guideline on management of acne can be found in CMAJ 2016 Feb 2;188(2):118 PDF

European guidelines

• European evidence-based (S3) guideline for the treatment of acne - update 2016 - short version. J Eur Acad Dermatol Venereol. 2016 Aug;30(8):1261-8
• Polish Gynecologic Society expert panel recommendations on complex hormonal therapy in women with acne can be found in Ginekol Pol 2012 Mar;83(3):229 [Polish]
• German Society of Dermatology/Association of German Dermatologists (DDG/BVDD) guideline on therapy of acne can be found in J Dtsch Dermatol Ges 2010 Jul;8 Suppl 2:s1 [German]

Asian guidelines

• Indian Acne Alliance (IAA) guidelines on acne management can be found in Indian J Dermatol Venereol Leprol 2009 Jan;75 Suppl 1:1 TOC
  • IAA acne management algorithms can be found in Indian J Dermatol Venereol Leprol 2009 Jan;75 Suppl 1:62 full-text
    • treatment of mild acne
    • treatment of moderate acne
    • treatment of severe acne
    • endocrine evaluation

Mexican guidelines

• Mexican expert position paper on isotretinoin on acne vulgaris can be found in Rev Med Inst Mex Seguro Soc 2011 May-Jun;49(3):281

Central and South American guidelines

• Ministério da Saúde (Brasil) protocolos clínicos e diretrizes terapêuticas pode ser encontrada em Ministerio da Saude [Brasil] [Portuguese]