use of antibiotic therapy in acne f075 - keri - 13782 10844.pdfwhat is the evidence? • the...

Use of Antibiotic Therapy in Acne

Jonette Keri, MD, PhDAssociate Professor, University of Miami, Miller School of Medicine

Chief, Dermatology Service, Miami VA Hospital

DisclosuresHoffman-la Roche - consultant

Outline

• Antibiotic stewardship• Evidence for resistance• Guidelines for antibiotic use• Maintenance• Future

Antibiotic Stewardship1,2

•This is to ensure that the patient gets the right dose of the right antibiotic at the right time and for the right duration

1. Centers for Disease Control and Prevention. http://www.cdc.gov/getsmart/healthcare/inpatient-stewardship.html. Accessed June 24, 2013.

2. MacDougall C, Polk RE. Clin Microbiol Rev. 2005;18(4):638-656.

Antibiotic Stewardship in Dermatology

• Limiting antibiotics for acne• Monotherapy (topical or oral) is not recommended due to

better regimens being available• Systemic antibiotics should be used for limited duration (3

months)• Benzoyl peroxide should be used with topical antibiotics to

ward off resistance

Dreno B, Thiboutot D, Gollnick H, Bettoli V, Kang S, Leyden JJ, Shalita A, Torres V.• Eur J Dermatol. 2014 Apr. 11

Antibiotic resistance around the world

• P. acnes resistance has been studied around the world.• USA, UK, Spain, Singapore, Sweden, Italy, Hong Kong• India• Reviewed in reference below

• Sinha M1, Sadhasivam S1, Bhattacharyya A1, Jain S1, Ghosh S1, Arndt KA2, Dover JS2, Sengupta S. Antibiotic-resistant acne: getting under the skin. Semin Cutan Med Surg. 2016 Jun;35(2):62-7.

• Biswal I, Gaind R, Kumar N, Mohanty S, Manchanda V, Khunger N, V R, Deb M. In vitro antimicrobial susceptibility patterns of Propionibacterium acnes isolated from patients with acne vulgaris. Infect Dev Ctries. 2016 Oct 31;10(10):1140-1145

Other Specialties Experiencing Resistance

• P. acnes infections after orthopedic surgery• Shoulder surgery• Men more than Women• Difficult to treat

• Falconer TM, Baba M, Kruse LM, Dorrestijn O, Donaldson MJ, Smith MM, Figtree MC, Hudson BJ, Cass B, Young AA. Contamination of the Surgical Field with Propionibacterium acnes in Primary Shoulder Arthroplasty. J Bone Joint Surg Am. 2016 Oct 19;98(20):1722-1728.

What’s new with respect to resistance?

Hidradenitis Suppuritiva

Antibiotic Resistance in Hidradenitis Suppurativa (HS)

• A cross-sectional analysis• 239 patients with HS seen at the Johns Hopkins Medical Institutions

from 2010 through 2015.

• Fischer AH, Haskin A, Okoye GA. Patterns of antimicrobial resistance in lesions of hidradenitis suppurativa. J Am Acad Dermatol. 2017 Feb;76(2): 309-313.


• Patients using topical clindamycin were more likely to grow clindamycin-resistant Staphylococcus aureus compared with patients using no antibiotics (63% vs 17%; P = .03).

• Patients taking ciprofloxacin were more likely to grow ciprofloxacin-resistant methicillin-resistant S. aureus compared with patients using no antibiotics (100% vs 10%; P = .045).



• Patients taking trimethoprim/sulfamethoxazole were more likely to grow trimethoprim/sulfamethoxazole-resistant Proteus species compared with patients using no antibiotics (88% vs 0%; P < .001).

• No significant antimicrobial resistance was observed with tetracyclines or oral clindamycin resistance.

Antibiotic Resistance in Hidradenitis Suppurativa (HS) - Limitation

Data on disease characteristics and antimicrobial susceptibilities for certain bacteria were limited



• Antibiotic therapy for HS treatment may be inducing antibiotic resistance.

• Support the importance of antibiotic stewardship.


What is the evidence of antibiotic resistance

in acne?

How does the resistance affect treatment?

Adler BL1, Kornmehl H2, Armstrong AW1. Antibiotic Resistance in Acne Treatment. JAMA Dermatol. 2017 Jun 21.

What is the Evidence?

• 5 clinical trials• None were randomized• 120,008 patients


• The clinical efficacy of topical erythromycin has decreased from the 1972 to 2002, and this is attributed to antibiotic resistance1

• Resistant P. acnes is found on the skin of untreated contacts of acne patients prescribed antibiotics2

• Resistant strains of P. acnes are reported to cause severe infections1

• After discontinuation of therapy, resistance may persist1

• 1 Walsh TR, Efthimiou J Dreno B. Systemic review of antibiotic resistance in acne: an increasing topical and oral threat. Lancet Infect Dis. 2016;1693):e23-e33.

• 2 Ross JI, Snelling AM, Carnegie E, et al. Antibiotic-resistance acne: lessons from Europe. Br J Dermatol 2003;148(3):467-478.


• OFF TARGET EFFECTS• Use of topical antibiotics is associated with resistance in S. aureus3

• In a retrospective cohort of those treated with topical or oral antibiotics for at least 6 weeks, were more likely to develop upper respiratory infections during the one year follow up than those who did not receive antibiotics4

• In a prospective cohort of university students who received oral antibiotics for acne, they were more than 3 times likely to report pharyngitis during the year follow up than untreated individuals5

• 3 Fanelli M, Kupperman E, et al. Arch Dermatol 2011;147(8);917-921.

• 4 Margolis DJ, Bowe WP, et al. Arch Dermatol 2005;14(9):1132-1136.

• 5 Margolis DJ, Fanelli M, et al. Arch Dermatol. 2012;148(3);326-332.

How might you experience resistance?

Slow responsesRelapses

Guidelines of care for the management of acne vulgaris

• Zaenglein AL, Pathy AL, Schlosser BJ, Alikhan A, Baldwin HE, Berson DS, Bowe WP, Graber EM, Harper JC, Kang S, Keri JE, Leyden JJ, Reynolds RV, Silverberg NB, Stein Gold LF, Tollefson MM, Weiss JS, Dolan NC, Sagan AA, Stern M, Boyer KM, Bhushan R. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016 May;74(5):945-73.

Topical Antibiotics

Topical Antibiotics

• Topical antibiotics (eg, erythromycin and clindamycin) are effective acne treatments, but are not recommended as monotherapy because of the risk of bacterial resistance.

Topical Antibiotics

• Benzoyl peroxide or combinations with erythromycin or clindamycin are effective acne treatments and are recommended as monotherapy for mild acne, or in conjunction with a topical retinoid, or systemic antibiotic therapy for moderate to severe acne.

Topical Antibiotics

• Benzoyl peroxide is effective in the prevention of bacterial resistance and is recommended for patients on topical or systemic antibiotic therapy.

Benzoyl Peroxide

• NO REPORTED RESISTANCE TO BENZOYL PEROXIDE

• Prevents development of antibiotic- resistant P. acnes strains• Treats non-inflammatory and inflammatory acne• Mild anticomedolytic activity

• Can be a cleanser and leave-on product

Systemic Antibiotics


• Systemic antibiotics are recommended in the management of moderate and severe acne, and forms of inflammatory acne that are resistant to topical treatments.


• Doxycycline and minocycline are more effective than tetracycline, but neither is superior to each other


• Although oral erythromycin and azithromycin can be effective in treating acne, its use should be limited to those who cannot use the tetracyclines (i.e., pregnant women or children under 8 years of age).

• Erythromycin use should be restricted due to its increased risk of bacterial resistance.


• Use of systemic antibiotics, other than the tetracyclines and macrolides, is discouraged as there is limited data for their use in acne.

• Trimethoprim-sulfamethoxazole and trimethoprim use should be restricted to patients unable to tolerate tetracyclines or in treatment resistant patients.


• Systemic antibiotic use should be limited to the shortest possible duration, typically 3 months, to minimize the development of bacterial resistance.

• Monotherapy with systemic antibiotics is not recommended.


• Concomitant topical therapy with benzoyl peroxide and/or a retinoid should be used with systemic antibiotics, as well as for maintenance after completion of systemic antibiotic therapy.


• Tetracyclines• Macrolides• Trimethoprim (with or without sulfamethoxazole)

Evidence supports the use of:• Tetracycline• Doxycycline• Minocycline• Trimethoprim/Sulfamethoxazole• Trimethoprim• Erythromycin• Azithromycin• Amoxicillin• Cephalexin


• Lipophilic antibiotic (tetracyclines [TCNs], macrolides, trimethoprim)• TCN class –generally first line• For Gram negative folliculitis (after treatment with antibiotics for

months) consider gram negative coverage – rarer than we think

Routine Microbiologic Testing is Not Recommended

• Routine microbiologic testing is NOTrecommended in the evaluation and management of patients with acne

• Those who exhibit acne-like lesions suggestive of Gram-negative folliculitis MAY BENEFIT from microbiologic testing

Efficacy and Safety with the

first line medications

Doxycycline Versus Minocycline

Safety of Doxycycline and Minocycline: A Systematic Review

• Medline, EMBASE and Biosis databases 1996-2003

• MedWatch Adverse Events (AE)

• AEs very low for both drugs with fewer for doxycycline despite 3 fold greater number of prescriptions

• Immunological AEs are rare and seen with minocycline

• Smith and Leyden Clinical Therapeutics 2005; 27:1329-1342

Cochrane Review on Minocycline

• 39 Randomized controlled trials• 6013 patients treated for acne

• Minocycline an effective treatment but no evidence of superiority versus other antibiotics

• Minocycline safe but associated with rare more serious side effects such as Drug induced Lupus (8.8 cases per 100,000 patient years)

• Garner et. Al. Cochrane Database of Systematic Reviews 2012

Comparison of the Tetracycline Class for Safety

• French Pharmacovigilance Database, literature• Minocycline Adverse Events more common and more serious than

other tetracyclines

• Gastrointestinal disorders, particularly esophageal, predominated with doxycycline

• Autoimmune disorders, DRESS and other hypersensitivity reactions more frequent with minocycline

• Le-Brun et.al. Brit J. Derm.2012;166:1333-1341

Minocycline controversy

• Roman CJ, Cifu AS, Stein SL. Clinical Guidelines for Management of Acne Vulgaris-Reply. JAMA. 2017 Jan 10;317(2):213.

Anything new with respect to oral antibiotics?

Which is better?

Which is better?

• A systematic search of MEDLINE was conducted to identify randomized controlled clinical trials, systematic reviews, and meta-analyses evaluating the efficacy of oral antibiotics for acne.

• 41 articles examined

• Bienenfeld A, Nagler AR, Orlow SJ. Oral antibacterial therapy for acne vulgaris: an evidence-based review. Am J Clin Dermatol 2017 Aug;18(4):469-490.

Which is better?

• Tetracyclines, macrolides, and trimethoprim/sulfamethoxazole are effective and safe in the treatment of moderate to severe inflammatory acne.

• The combination with a topical therapy is superior to oral antibiotics alone.

• There is insufficient evidence to support one type, dose, or duration of oral antibiotic over another in terms of efficacy.

• Oral Bienenfeld A, Nagler AR, Orlow SJ. Oral antibacterial therapy for acne vulgaris: an evidence-based review. Am J Clin Dermatol 2017 Aug;18(4):469-490.

How can we limit antibiotics in daily practice..

• Maintenance• Maintenance • Maintenance

Maintenance Reminder

• Retinoids• Benzoyl Peroxide• Dapsone

Retinoid MaintenanceAdapalene

Retinoid Maintenance with Adapalene Gel 0.1% as Maintenance Therapy after Use with Doxycycline

Thiboutot et.al. Arch. Derm.2006;142:597-602

Retinoid MaintenanceTazarotene 0.1% gel after Minocycline

Leyden and Thiboutot, Arch Dermatol, 2006; 142(5), 605-612

Retinoid and Benzoyl Peroxide Maintenance

Adapalene and Benzoyl Peroxide after Doxycycline

Tan et.al. J.Drugs Derm. 2012;11: 174-180

Dapsone maintenance

After Doxycycline, Dapsone 5% gel twice daily with Doxycycline 100mg

• .Kircik LH. Use of Dapsone 5% Gel as Maintenance Treatment of Acne Vulgaris Following Completion of Oral Doxycycline and Dapsone 5% Gel Combination Treatment. J Drugs Dermatol. 2016 Feb 1;15(2):191-5.

What else can we use?

What else can we use?

• Niacinamide• Azelaic Acid• Light therapy

Niacinamide

• Topical Niacinamide1

• Oral Niacinamide2

• Oral Niacinamide in combination with Azelaic Acid3

1) Shalita AR, Smith JG, Parish LC, Sofman MS, Chalker DK. Topical nicotinamide compared with clindamycin gel in the treatment of inflammatory acne vulgaris. Int J Dermatol. 1995 Jun;34(6): 434-7.

2) Niren NM1, Torok HM. The Nicomide Improvement in Clinical Outcomes Study (NICOS): results of an 8-week trial. Cutis. 2006. Jan;77(Suppl):17-28.

3) Shalita AR1, Falcon R, Olansky A, Iannotta P, Akhavan A, Day D, Janiga A, Singri P, Kallal JE. Inflammatory acne management with a novel prescription dietary supplement. J Drugs Dermatol. 2012 Dec;11(12):1428-33.

Niacinamide

• Yes it works in moderate inflammatory acne• Efficacy comparable to clindamycin 1% gel

• Reviewed in Barros, BS and Zaenglein, AL. Am J Clin Dermatol, Jan 6, 2017.

What’s the latest on how we are doing with respect to antibiotic usage?

• Systemic agents in the treatment of acne were evaluated in the United States between 2004 and 2013.

• The median duration of therapy with oral antibiotics was• 126 days by dermatologists• 129 days by nondermatologists


• The number of courses of spironolactone increased from: • 2.08 to 8.13 for dermatologists• 1.43 to 4.09 for non-dermatologists

• The median duration of therapy with oral antibiotics was • 126 days by dermatologists• 129 days non-dermatologists

• Barbieri JS1, James WD2, Margolis DJ3. Trends in prescribing behavior of systemic agents used in the treatment of acne among dermatologists and nondermatologists: A retrospective analysis, 2004-2013. J Am Acad Dermatol. 2017 Jul 1. pii: S0190-9622(17)30503-0. doi: 10.1016/j.jaad.2017.04.016. [Epub ahead of print]


• Conclusions• Look for alternative therapies

• Spironolactone• Oral contraceptives• Isotretinoin

• Represents an opportunity to improve the care of patients

Latest study to access resistance,the cheeks, the nose and the toes…

• Comparison to two previous studies accessing resistance in acne patients• This one in Lincoln County, UK• Others in Leeds County, UK and Philadelphia, PA, USA• Areas accessed were the cheeks, nares, and toe webs• Isotretinoin use resulted excellent improvement in acne as well as…• Reductions in the number of P. acnes of the skin, including resistant

isolates possibly acquired from previous treatment with antibiotics, on the cheek, but not the nares or the toe webs.

• Consider isotretinoin for treatment of patients with significant acne• Ryan-Kewley AE, Williams DR, et al. Non-antibiotic Isotretinoin Treatment Differentially Controls Propionibacterium acnes on the Skin of Acne Patients. Frontiers in Microbiology

2017 Jul 25;8 :1381, p. 1-11.

What’s on the horizon?

What’s on the horizon?

• Phage therapy against P. acnes• Bacteriophages are bacterial viruses that naturally control microbial

populations• Known phages that can work against P. acnes• Need more knowledge• May play a role in the future in the treatment of acne

• Jonczyk-Matysiak E, Weber-Dqbrowska B, et al. Prospects of Phage Application in the Treatment of Acne Caused by Propionibacterium acnes. Front Microbiol. 2017; 8: 164.

“Exit plan”

• Envision and discuss with the patient from the beginning an anticipated “exit plan” to discontinue the antibiotics.

• This can always be modified, but it speaks to expectations.

• Del Rosso JQ. Topical and oral antibiotics for acne vulgaris. Semin Cutan Med Surg. 2016 Jun;35(2):57-61.

SUPPORT!!

Thank You!

use of antibiotic therapy in acne f075 - keri - 13782 10844.pdfwhat is the evidence? • the...

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