Disclosures. Systemic Therapies for Acne. Antibiotics: MOA in Acne. Oral Antibiotics. Systemic Acne Medication Options

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1 Disclosures Systemic Therapies for Acne Joshua Zeichner, MD Assistant Professor Icahn School of Medicine at Mt Sinai New York, NY Advisory Board Member, Consultant, or Speaker: Aclaris Johnson & Johnson Allergan La Roche Posay Anacor L Oreal Bayer Medimetriks Cipher Novan Exeltis Promius Foamix SkinFix Glossier Taro Galderma Unilever Isdin Valeant Janssen Systemic Acne Medication Options Oral Antibiotics Hormonal Therapies Isotretinoin Indication: moderate - severe acne inflammatory acne resistant to topicals Large surface areas involved Oral Antibiotics Antibiotics: MOA in Acne Antibacterial properties: bactericidal and bacteriostatic reduce P. acnes in sebaceous follicles Anti-inflammatory properties (eg. Tetracyclines): inflammatory cell chemotaxis metalloproteinase activity P. acne produced lipases Patel M, et al. J Drugs Dermatol 2010 Jun;9(6): Sapadin AN, Fleischmajer R. J Am Acad Dermatol 2006 Feb;54(2): Webster GF, et al. Br J Dermatol 1981 Apr; 104(4): Jeremy A et al J Inv Derm. 121:20-27; 2003 Webster G, et al. Dermatol Clin. 2007;25: ; 2. Del Rosso JQ. Cutis. 2007;80: ; 3. Korting HC, Schollmann C. Skin Pharmacol Physiol. 2009;22: ; 4. Golub LM, Lee HM, Ryan ME, et al. Adv Derm Res. 1998;12: Freinkel RK, et al. N Eng J Med 1965;273: Marples RR, et al. J Invest Dermatol Feb;56(2): Leyden J et al. J Invest. Derm ;

2 Antibiotics for Acne Tetracyclines Lipophilic antibiotics are best Penetrate the lipid-filled, sebaceous environment tetracyclines (tetracycline, doxycycline, minocycline) macrolides (erythromycin, azithromycin) clindamycin trimethoprim First-line therapy Contraindications: pregnancy <8 yo allergy Minocycline previously reported superior to doxycycline, but not shown in a recent Cochrane review Leyden JJ, Del Rosso JQ. J Clin Aesthet Dermatol Feb;4(2):40-7. Patel M et al. J Drugs Dermatol 2010 Jun;9(6): Garner SE, Eady A, Bennett C, Newton JN, Thomas K, Popescu CM. Minocycline for acne vulgaris: efficacy and safety. Cochrane Database Syst Rev. 2012;(8):CD Limited data on use Non-Tetracycline Abx Azithromycin to be used only if TCNs contraindicated Erythromycin - avoided bc of high rate of bacterial resistance Trimethoprim for patients cannot tolerate tetracyclines or are treatment-resistant Antibiotic Resistance: A Global Priority Development of antibiotic resistance has been recognized as a global healthy threat science ministers of G8 countries 1 WHO s 66th World Health Assembly 2 CDC: Antibiotic stewardship 3,4 right antibiotic, right dose, at the right time, for the right duration 1 Cookson C. Financial Times. Accessed June 24, World Health Organization. wha66_side_event/en/index.html. Accessed June 24, Centers for Disease Control and Prevention. Accessed June 24, MacDougall C, Polk RE. Clin Microbiol Rev. 2005;18(4): Acne Prescription Profiles in Dermatology 1 Acne Prescription Profiles in Dermatology 1 5,116,599 Dermatologists represent 1% of healthcare providers But prescribe approximately 5% of all antibiotics 1 Oral and Topical Antibiotics = 54% of all prescriptions written for acne in Dermatology 289,220 1,669,213 1,230,883 1 Symphony Health PHAST Monthly Prescription. 1 Symphony Health PHAST Monthly Prescription

3 Best Practices in Prescribing Limit use to shortest duration possible Re-evaluate at 3-4 months Do NOT use as monotherapy Combine use with topical BPO or retinoid Do NOT use as maintenance Antibiotics promote bacterial resistance Both correct and incorrect use of antibiotics in dermatology can promote resistance.1 skin does not know the difference! Influences normal skin flora 1. Patel M et al. J Drugs Dermatol. 2010;9(6): Rosen T. J Drugs Dermatol. 2011;10(7): Levy RM et al. Arch Dermatol. 2003;139(4): Margolis DJ et al. Arch Dermatol. 2012;148(3): Adams SJ et al. J Invest Dermatol. 1985;85(1): Valtonen MV et al. Br J Dermatol. 1976;95(3): image accessed 9/23/13 Resistance P. acnes 1970 s: first reports of bacterial resistance Mutations in 23S ribosomal RNA: cross resistance to erythro/clinda Clindamycin monotherapy BID for 16 weeks P. acnes counts >1600% from baseline P. acnes Resistance: Global Phenomenon European Data on P. acnes Abx resistance: 1991: 34.5% 1997: 55.5% 2000: 64% Worldwide prevalence 1978: 20% 1996: 62% Percentages of antibiotic-resistant P acnes isolated from acne patients Country Clindamycin Erythromycin Oxytetracycline Doxycycline Spain United States Greece Egypt Italy United Kingdom Hong Kong Singapore >50 >50 >11.5 >11.5 Iran Sweden Hungary Patel M, et al. J Drugs Dermatol 2010 Jun;9(6): Coates P, Cunliffe W et al. Br J Derm. 146 (5): 840 (2002) Eady EA, Cove JH. Drugs Exp Clin Res 1990;16: Cunliffe WJ et al. Clinical Therapeutics (7): Del Rosso JQ, Kim G Jan;27(1): Fleischer AB, et al. Cutis. 2006; 78(4 Suppl): Rosen T. J Drugs Dermatol. 2011;10(7): Abdel Fattah NSA, Darwish YW. J Eur Acad Dermatol Venereol Dec 20 [epub]. Leyden JJ et al. J Clin Aesthet Dermatol. 2011;4(5): Northern Mexico Japan France Baseline Antibiotic Resistance Oral Antibiotics Commonly Used For Acne Therapy Characteristics of Tested P acnes Strains (Forehead) ANTIBIOTIC (N) Tetracycline (28) Doxycycline (25) Minocycline (19) Erythromycin (30) High-level Resistance* (n) Low-level Resistance** (n) The real question Is P. acnes bacterial resistance clinically meaningful? We don t know P. acnes is a low risk bug antisocial *High-level resistance; >512 μg/ml erythromycin; >8 μg/ml tetracycline family **Low-level resistance; >2 <8 μg/ml tetracycline family; >1 <8 μg/ml erythromycin Leyden JJ, Wortzman. Cutis. 2008;82(6):

4 Collateral Damage Topical antibiotics -> resistance in treated sites Oral antibiotics -> resistance in commensal flora in all body sites Staph 1 -> MRSA Strep pyogenes in oropharynx 3 -> pharyngitis Resistant bacteria on skin and & GI tract of acne patients and their close contacts 2,5 Reservoir for resistance factors -> transferred to other people 6 Development of virulent strains of resistant bacteria CDC Antibiotic Resistance Report 2013: Estimated minimum number of illnesses and deaths caused by antibiotic resistance -2,049,442 illnesses -23,000 deaths Thiboutot D, et al. J Am Acad Dermatol May;60(5 Suppl):S1-50. Eady EA, Cove JH. Drugs Exp Clin Res 1990;16: Patel M, et al. J Drugs Dermatol 2010 Jun;9(6): Coates P, Cunliffe W et al. Br J Derm. 146 (5): 840 (2002) Patel M et al. J Drugs Dermatol. 2010;9(6): Rosen T. J Drugs Dermatol. 2011;10(7): Levy RM et al. Arch Dermatol. 2003;139(4): Margolis DJ et al. Arch Dermatol. 2012;148(3): Adams SJ et al. J Invest Dermatol. 1985;85(1): Valtonen MV et al. Br J Dermatol. 1976;95(3): image accessed 9/23/13 Antibiotic Resistance Threats in the United States CDC Report 2013 CDC Antibiotic Resistance Report Take home messages It is ok to continue using antibiotics, just use them appropriately and cautiously Antibiotic stewardship Global Responsibility Prevent disease Reduce Health Costs Antibiotic Resistance Threats in the United States CDC Report 2013 Hormonal Therapies Oral Contraceptive Pills Spironolactone When to use hormonal therapies? States of hyperandrogenemia Late-onset or persistent acne Acne on lower 1/3 of face & neck History of perimenstrual flare Resistance to conventional therapies Alternative to isotretinoin 4

5 Oral Contraceptive Pills Estrogen-containing combination OCPS are effective and recommended for inflammatory acne in women MOA: SHBG and testosterone levels 5α-reductase and conversion of testosterone to DHT sebum production 4 FDA Approved Pills Ortho Tri-cyclen (ethinyl estradiol / norgestimate) Estrostep (ethinyl estradiol / norethindrone) Yaz (ethinyl estradiol / drosperinone) Beyaz (ethinyl estradiol / drosperinone / folic acid) Drosperinone is a progestin with antiandrogenic properties OCPs for Acne Ebede TL, et al. Hormonal Treatment of Acne in Women. J Clin Aesth Dermatol. 2009; 2 (12): OCP Acne Indication At least moderate inflammatory acne At least 15 years old Has reached menarche Desires contraception Plans to take OCP for at least 6 months Has not responded to topical anti-acne medications Stroke Risk and OCPs OCPs increase stroke risk by 2.5x in women yo Risk proportional with estrogen dose Risk with age, hx of HTN, cigarettes, and migraine Spironolactone Synthetic steroid and aldosterone antagonist Androgen Receptor Blocker: competes with testosterone for receptor binding Dosage: mg /day Efficacy after 3 months Lancet 1996;348: Ebede TL, et al. Hormonal Treatment of Acne in Women. J Clin Aesth Dermatol. 2009; 2 (12):

6 Spironolactone Side Effects Breast tenderness and menstrual irregularities Dose related Risk of hyperkalemia has not been found to be significant Avoid NSAIDs, salt substitutes, coconut water, ACE inhibitors, ARBs Black box warning: tumors in mice Lightheadedness and diuretic effect Pregnancy Category C/D Spironolactone Lab Monitoring JAMA Dermatology Study 1,000 adult women with acne 1,200 women on spironolactone Of 1,800 lab tests, only 13 K+ abnormalities Half normalized when test repeated Incidence of hyperkalemia in young, healthy women on spironolactone equivalent to general population. Regular potassium monitoring not necessary Ebede TL, et al. Hormonal Treatment of Acne in Women. J Clin Aesth Dermatol. 2009; 2 (12): Plovanich M, et al. Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne. JAMA Dermatol. 2015;151(9): What should you do? One study is NOT an absolute guideline. Population-based studies do not account for potential outliers in clinical practice. Use your own clinical judgment for each individual patient. Indication: severe nodular acne moderate acne that is treatment-resistant acne that is producing physical scarring or psychosocial distress Isotretinoin Lipophilic Drug Isotretinoin Should be taken with high-fat, high-calorie meal for optimal absorption FDA food requirements High fat (50% of total caloric intake) High calories (800 to 1000 calories) 150 calories from proteins 250 calories from carbohydrates calories from fat Effect of food on isotretinoin In the absence of food, less than half the concentration of isotretinoin is absorbed 1. Colburn WA, Gibson DM, Wiens RE, Hanigan JJ. Food increases the bioavailability of isotretinoin. J Clin Pharmacol Nov-Dec;23(11-12): US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies. Washington DC: Office of Training and Communications; December Study Data on file. Jacksonville, FL: Ranbaxy Laboratories, Inc. 6

7 Evaluate Patients When they Come to the Office Skin dryness = adequate absorption If skin and lips are not dry Are patients taking their meds? Are they absorbing their meds? Studies on IBD/Isotretinoin 2009: Canadian Study No causal relationship found 2010: US Study Association between isotretinoin and UC but not Crohn s Absolute risk is low 2013: Canadian Study yr olds: small increase risk of isotetinoin and IBD 2013: US Study in Women of Reproductive Age No association found 2014: Minnesota Study No association with IBD? Decreased risk Bernstein CN, et al Am J Gastroenterol Nov; 104(11): Crockett et al Am J Gastroenterol Mar 30. Rashtak S, et al. JAMA Dermatol 2014 Dec;150(12): Alhusayen RO J Invest Dermatol Apr;133(4): Etminan M JAMA Dermatol Feb;149(2): French Nationwide Study Case-control study 7600 cases of IBD 0.3% (26) of these cases exposed to isotretinoin 30,000 matched controls 0.4% (140) exposed to isotretinoin Isotretinoin exposure NOT associated with UC Isotretinoin exposure associated with a DECREASED risk of Crohn s disease Am J Gastroenterology Editorial In the absence of prospective randomized controlled clinical trials, the author's use of a large administrative database to evaluate isotretinoin and IBD provides the best evidence to date that there is no causal association. Racine A, et al. Am J Gastroenterol 2014; 109: Tenner S. Am J Gastroenterol 2014; 109: Guidelines Recommendations Routine monitoring: liver function tests serum cholesterol triglycerides baseline and again until response to treatment is established Routine monitoring of complete blood count is not recommended Lab Monitoring Study Meta analysis in JAMA Dermatology After 2 months, uncommon to see laboratory abnormalities Monthly testing may not be necessary Use clinical judgment Lee YH. JAMA Dermatol Jan;152(1):

8 Conclusion Oral Antibiotics Hormonal Therapies Isotretinoin Find the balance between efficacy and safety! 8