Galderma Media Center, November 2014 For medical journalists outside the U.S. only

Antibiotic resistance and acne treatment Tackling the challenge

Key points  At the G8 Summit in June 2013, science ministers focused on antimicrobial drug resistance (i.e. anti-viral, anti-bacterial, anti-fungal and anti-parasite) strategies to stem the misuse of antibiotics by optimizing doctor prescribing patterns to preserve the efficacy of existing antibiotics against infections1  Antibacterial resistance has been a major health issue for over 10 years. The over prescription of antibiotics for the common cold in children has significantly contributed to bacterial resistance to antibiotics2  If the global spread of resistance is not slowed, this could have serious health implications – many common infections would become difficult or impossible to treat and routine surgical procedures could become life-threatening3,4  In acne therapy, the widespread use of antibiotics has led to the increased prevalence of Propionibacterium acnes (P. acnes) resistant strains worldwide and is a contributing factor to the global antimicrobial resistance issue5,6  The emergence of antibacterial resistance via several mechanisms7 has resulted in treatment failures, decreased response in acne patients8,9  Oral antibiotics are an important treatment option for more severe acne patients and at this time, other alternatives such as oral isotretinoin are associated with severe side effects. However, there are highly effective alternatives to topical antibiotics  Responding to the urgent need to tackle this growing threat, guidelines have been issued calling for responsible and appropriate use of antibiotics, including those used in acne therapy1,4,9

Antibiotic resistance: a major security threat High on the agenda of the Group of Eight (G8) Summit 2013 and headlining a landmark report from the Center for Disease Control (CDC) in the U.S was antibiotic resistance, an issue that is escalating at an alarming rate. Science ministers at the meeting identified it as a ‘major health security challenge of the 21st century’.1,9,10 More recently, the U.S. government released its National Strategy to Combat AntibioticResistant Bacteria (September 2014), promising to prevent, detect, and control illness and death related to antibiotic-resistant bacteria, by implementing measures to mitigate its emergence and spread11, signalling the seriousness of the situation worldwide. In dermatology, the issue of antibiotic resistance is of rising importance due to the growing number of bacterial strains exhibiting resistance in acne therapy. Guidelines published by the Global Alliance to Improve Outcomes in Acne, and endorsed by the American Academy of Dermatology (AAD) in 2014, outline recommended treatment and management steps dermatologists can take to limit the growing threat of antibiotic resistance9. Specifically mentioned is that oral and topical antibiotics should not be used as monotherapy, yet 35% of oral antibiotics and 46% of topical antibiotics are currently prescribed alone.12 Drug resistance has resulted largely from the extensive use of antibiotics in human and animal health as well as in food production.3,4 Antibiotic overuse for the treatment of the common cold in children is thought to be a significant factor contributing to the rapid rise in antibiotic resistant bacteria2 and traditionally this has been the focus of governments for tackling the misuse of antibiotics. In 2004, further authority attention was aimed at hospital-acquired bacterial infections as the spread of Methicillinresistant Staphylococcus aureus (MRSA) and Clostridium difficile became headline news in the UK.

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Measures put in place successfully reduced the number of MRSA and C. difficile cases by 84.7% and 53% respectively.4 The prevalence of antibiotic resistance is rising rapidly around the world, with virtually every area of the globe affected.12 The problem is also expanding in scope, with increasing numbers of microbial strains exhibiting resistance against a growing list of antibiotics.6 Left unaddressed, antibiotic resistance could escalate into a global outbreak of previously treatable diseases and could increase the risk of routine surgical procedures.10 The impact of antibiotic resistant bacteria (ARB) is a global issue13

Antibiotic resistance poses a major public health risk as it is associated with prolonged illness and hospital stays, more complicated treatments and higher mortality rates.3,13 In Europe, the estimated annual impact of antibiotic resistance is signficant:14  25,000 excess deaths (due to resistant bacterial hospital infections)  2.5 million avoidable days in hospital  €1.5 billion in healthcare costs and productivity losses

The emergence of antibiotic resistance Antibiotic resistance occurs when strains of bacteria no longer respond to the antibiotics used to treat infections caused by these microbes. Resistance can arise via several mechanisms:6,8  Random genetic mutations in bacterial DNA  Transfer of antibiotic-resistant genes among bacteria  Intrinsic properties that neutralize the effect of antibiotics The use of antibiotics results in resistant bacteria surviving and reproducing, while susceptible strains get eliminated.4,15 Over time, this has led to a gradually increasing spread of antibiotic-resistant bacterial strains.4

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Rise in prevalence of P. acnes resistant strains Until recently the focus of antibiotic misuse has been limited, but it is now shifting to include other diseases where antibiotics have been the main treatment option, such as acne. Reflecting the global rise in antibiotic resistance is the growing number of bacterial strains exhibiting resistance in acne therapy. This emergence of resistant P. acnes, one of the factors involved in acne pathogenesis, has been attributed to the widespread prescribing of both oral and topical antibiotics when treating acne.5,6 Reports estimate that the global prevalence of P. acnes resistant strains has steadily increased over the last 30 years16,17 rising from 20% in 1978 to 62% in 1996.6 According to current guidelines, oral and topical antibiotics should not be used together to treat acne, yet prescribing data indicates that 23% of oral antibiotic prescriptions continue to be combined with a topical antibiotic. Oral antibiotics continue to be an important treatment option for patients with moderate to severe acne. Oral isotretinoin can be used in patients with severe acne but it may induce numerous serious side effects such as teratogenicity (fetal malformation). However, there are alternatives to topical antibiotics including topical retinoids and benzoyl peroxide (BPO). An important tactic to preserve the efficacy of antibiotics is to ensure that oral antibiotics are only used for a limited time and not used in combination with a topical antibiotic.16 Antibiotic resistance can have serious implications for patients and the wider community. For acne patients, resistant P. acnes can result in failed treatments, with acne patients displaying decreased, poor or no response to therapy, or possibly suffering relapses that may otherwise have been prevented.8,9 P. acnes has also been rarely associated with more severe infections in conditions such as arthritis,18,19 endocarditis 20 and generally associated with surgeries, implants and immunocompromized patients.21 In addition, bacteria present in other areas of the body, such as normal, protective flora present in the gut or those carried as human commensals, may be submitted to changes due to antibiotic selection pressure.9

Contributing factors The rapid rise of antibiotic resistance in acne therapy has been attributed to a number of factors:

Prescribing practices16  Inappropriate and/or indiscriminate use of antibiotics  Long-term antibiotic treatment (>12 weeks)  Dosing below recommended levels  Antibiotics in monotherapy  Concurrent use of oral and topical antibiotics  Simultaneous use of chemically different antibiotics

Antibiotic use3,16  Poor adherence  Failing to complete the full course of antibiotics  Multiple antibiotic courses  Easy access to antibiotics

Limited monitoring3  Lack of surveillance systems tracking antibiotic use and emergence and spread of resistant strains  Insufficient crossinfection control

Community transmission6  Close contact between individuals results in the spread of resistant strains  International travel and commerce facilitates easy and quick dissemination of bacteria across the world

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Addressing the overall antibiotic resistance problem There is an urgent need for governments, the medical profession, the pharmaceutical industry and individuals to work together and combat the threat of antibiotic resistance. Recommendations to address the challenge include:1,3,4     

Preserving the efficacy of existing antibiotic agents Fostering the appropriate use of antibiotic drugs Developing rapid diagnostics to inform use Supporting international cooperation and sharing of surveillance data Encouraging the development of new antibiotics

What can we do in dermatology to help combat antibiotic resistance? Oral antibiotics are an important treatment option for acne and have helped many patients, but clinicians now have a responsibility to ensure that they optimize their prescribing patterns to reduce the spread of antibiotic-resistant acne; responsibly prescribing oral antibiotics and avoiding the use of any topical antibiotics. Oral antibiotics should be prescribed for moderate to moderately severe acne for only short treatment durations and be combined with BPO and topical retinoids to target as many physiopathological factors as possible and reduce the risk of new acne lesions forming.9 Combination therapy should be started as early as possible, preferably at the initiation of treatment, to simultaneously attack as many different pathogenic factors as possible.22 The key recommendations by the Global Alliance to Improve Outcomes in Acne, endorsed by the AAD in 2014, provides clear guidance on appropriate acne treatments which takes into account both the physiopathology of acne, and the issue of antibiotic resistance.9

Guidelines from the Global Alliance to Improve Outcomes in Acne recommend:9  Oral antibiotics are recommended for moderate to moderately severe acne  Using a combination of topical retinoid and antimicrobial as first-line therapy as it achieves significantly faster and greater clearing versus monotherapy  Avoiding oral and topical antibiotics as monotherapy or using them concurrently  Limiting to use of antibiotics to short periods  Discontinuing antibiotic use when there is no further improvement or only a slight improvement is seen  Using topical retinoids rather than antibiotics for maintenance therapy, adding benzoyl peroxide

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References 1. Group of Eight (2013). G8 science ministers statement London UK, 12 June 2013. Available at: https://www.gov.uk/government/publications/g8-science-ministers-statement-london-12-june-2013 (date accessed: November 2014). 2. Nyquist A-C, Gonzales R, Steiner JF. Antibiotic prescribing for children with colds, upper respiratory tract infections, and bronchitis. JAMA 1998;279(11):875–877. 3. World Health Organization (2012). The evolving threat of Antibiotic resistance: options for action. Available at: http://www.who.int/patientsafety/implementation/amr/publication/en/ (date accessed: November 2014). 4. Department of Health (2013). Annual report of the Chief Medical Officer, volume two, 2011:infections and the rise of antimicrobial resistance. Available at: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/138331/CMO_Annual_Report_Volume_2_2011.p df (date accessed: November 2014). 5. Dreno B. Topical antibacterial therapy for acne vulgaris. Drugs 2004;64(21):2389–2397. 6. Rosen T. Antibiotic resistance: an editorial review with recommendations. J Drugs Dermatol 2011;10(7):724–733. 7. Todar K. Todar’s Online Textbook of Bacteriology. Available at: http://textbookofbacteriology.net/resantimicrobial_3.html (date accessed: November 2014). 8. Leyden JJ, McGinley KJ, Cavalieri S, et al. Propionibacterium acnes resistance to antibiotics in acne patients. J Am Acad Dermatol 1983;8:41–45. 9. Thiboutot D, Gollnick H, Bettoli V, et al. New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne Group. J Am Acad Dermatol 2009;60(Suppl 5):S1–50. 10. BBC news (2013). Antibiotics resistance ‘as big a risk as terrorism’ – medical chief. Available at: http://www.bbc.co.uk/news/health-21737844 (date accessed: November 2014). 11. United States government. National Strategy For Combating Antibiotic-Resistant Bacteria, September 2014. Available at: http://www.whitehouse.gov/sites/default/files/docs/carb_national_strategy.pdf (date accessed November 2014) 12. Market Insights IMS D+J Market - MAT Q4 2012 - WW (39 Countries) 13. World Economic Forum (2013). The dangers of hubris on human health. Available at: http://reports.weforum.org/global-risks2013/view/risk-case-1/the-dangers-of-hubris-on-human-health/ (date accessed: November 2014). 14. European Centre for Disease Prevention and Control and European Medicines Agency (2009). ECDC/EMEA Joint Technical Report - The bacterial challenge: time to react. Available at: http://www.emea.europa.eu/docs/en_GB/document_library/Report/2009/11/WC500008770.pdf (date accessed: November 2014). 15. Tanghetti E. The impact and importance of resistance. Cutis 2007;80(Suppl1):5–9. 16. Eady EA, Gloor M, Leyden JJ. Propionibacterium acnes resistance: a worldwide problem. Dermatology 2003;206:54–56. 17. Tzellos T, Zampeli V, Makrantonaki E, et al. Treating acne with antibiotic-resistant bacterial colonization. Expert Opin Pharmaco 2011;12:1233–1247. 18. Levy PY, Fenollar F, Stein A, et al. Propionibacterium acnes postoperative shoulder arthritis: an emerging clinical entity. Clin Infect Dis 2008;46:1884–1886. 19. Berthelot P, Carricajo A, Aubert G, et al. Outbreak of postoperative shoulder arthritis due to Propionibacterium acnes infection in nondebilitated patients. Infect Control Hosp Epidemiol 2006;27:987–990. 20. Delahaye F, Fol S, Celard M, et al. Propionibacterium acnes infective endocarditis. Study of 11 cases and review of literature. Arch Mal Coeur Vaiss 2005;98:1212–1218. 21. Chanet V, Romaszko JP, Rolain JM, et al. Propionibacterium acnes adenitis. Presse Med 2005;34:1005–1006. 22. Gollnick H, Cunliffe W. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol 2003;49(Suppl 1):S1–37.