What Is Antibiotic Resistance?
Antibiotic resistance is defined as reduced susceptibility of specific bacterial strains to antibiotics with previous efficacy against the species. In clinical practice, antibiotic resistance is manifested through the reduced response, lack of response, or relapse of resistant bacterial strains during or after antibiotic treatment. Multiple drug resistance (MDR) has resulted in the loss of multiple classes of antibiotics targeting specific bacteria, which has led to a pervasive expansion of bacterial strains that are harder or impossible to treat. The problem of antibiotic resistance is compounded by a rapid decline in the development of new antimicrobial agents; compared to almost 20 new drug applications (NDA) approvals in the United States in 1980-1984, only 2 new antibacterial agents were granted NDA approval in 2010-2012, resulting in fewer medications to combat the problem.
Antibiotic resistance is a worldwide problem, with significant impact on health and health-related costs. In the United States (US), the scope of this problem has been estimated with staggering statistics: that 2 million individuals will be infected with antibiotic-resistant bacteria annually, with 23,000 fatal cases per year. The impact on health-related costs is equally disturbing; in the US alone, the annual cost to the health care system has been estimated between $21-34 billion dollars to address complications stemming from this problem, with similar statistics in other countries. There is sufficient evidence demonstrating that antibiotic resistance impacts not only patients treated with antibiotics but also their close contacts.
Eighteen bacteria have been identified on the Centers for Disease Control list which pose the biggest current threat, stratified into tiers of severity (urgent, serious, concern). At the top of this list (urgent) are Clostridium difficile, Neisseria gonorrhoeae, and carbapenem-resistant enterococcus. The mechanisms by which these bacteria become resistant have been characterized. Transfer of antibiotic-resistance elements between bacteria, accelerated under the selection pressure of antibiotic monotherapy, is facilitated by several mechanisms, including vertical transmission (through chromosomal mutations) as well as horizontal transmission (through conjugation, transduction, and transformation). Organisms that gain resistance to one medication are more likely to gain resistance to additional medications.
Antibiotic resistance has evolved progressively since the introduction of antibiotics, and importantly may stem from both correct and incorrect antibiotic prescribing by health care providers. Contributing factors to the development of antibiotic resistance include prescribing patterns, most significant of which are indiscriminate or empiric prescription of antibiotics and prescription of long-duration antibiotic therapy (defined as >12 weeks). Additional factors include suboptimal dosing, simultaneous use of antibiotics from similar classes, multiple antibiotic courses, poor patient adherence to antibiotic regimens, failure to utilize strategies known to mitigate resistance (such as co-administration of benzoyl peroxide or topical retinoids with topical antibiotics) and insufficient cross-infection control measures by individual prescribers. Multiple studies have shown that over 50% of antibiotic prescriptions are issued without proper indication. There are notable trends relevant to dermatologists and the treatment of cutaneous disease. First, though dermatologists represent 1% of all physicians, they are responsible for 4.9% of all antibiotic prescriptions by doctors. Antibiotics make up over 55% of all acne treatment prescriptions, and two-thirds of dermatologists’ antibiotic prescriptions are intended to treat acne.
Methicillin-resistant staphylococcus aureus, once known as a cause of nosocomial or hospital-acquired complications, has been recognized as a major cause of community-acquired skin and soft tissue infections, with long-term carriers identified within the community. Colonization by antibiotic resistant streptococcus pyogenes and staphylococcus aureus has been reported in individuals treated with antibiotics for their acne. Resistance to antibiotics that are the mainstay of acne treatment have resulted in the development of resistant strains on the top 18 list designated by the CDC, including clindamycin-resistant group B streptococcus (cause of necrotizing fasciitis) and erythromycin-resistant streptococcus; both are on the concerning list. It is important to recognize that antimicrobial resistance extends beyond just antibiotics, with fluconazole-resistant strains of candida albicans also identified on the CDC list of threats (designated as serious threat). Striking data has demonstrated the development of pseudomembranous colitis attributed to Clostridium difficile even in patients treated with topical clindamycin, suggesting systemic absorption and important health impacts stemming from acne treatment. Increased risk of upper respiratory infections has been documented in individuals undergoing treatment for acne, a large majority of which were treated with topical and systemic antibiotics.
Antibiotic resistance has impacted the efficacy of acne treatment, with data demonstrating declining efficacy of antibiotics in controlling Propionibacterium acnes (P. acnes) growth over the past three decades. Antibiotic resistant strains of P. acnes have been identified widely, including clindamycin-, erythromycin-, tetracycline-, and doxycycline-resistant forms, including strains with resistance to all four antibiotics. The prevalence of these strains has been steadily increasing, with 20% prevalence in 1978 to 94% prevalence in 2002. Despite this, many studies have shown that antibiotics, including long-term systemic antibiotic therapy and topical antibiotic monotherapy, remain widely prescribed among both dermatologists and non-dermatologists for the treatment of acne; there is notable room for improvement.
Addressing Antibiotic Resistance
The problem of antibiotic resistance has been addressed by a number of key organizations. The CDC has identified a four part plan, including infection prevention, antibiotic stewardship, tracking, and development of new medications and diagnostic tests. International collaborations, including the Interagency Task Force on Antimicrobial Resistance (ITFAR) and the Transatlantic Taskforce on Antimicrobial Resistance (TATFAR), have provided additional recommendations. Dermatology-specific initiatives have been led by the American Academy of Dermatology (AAD) and the Specific Panel on Antibiotic Use in Dermatology (SPAUD).
Action Plan: Focus on Implementing Antibiotic Stewardship
What does antibiotic stewardship look like for practicing dermatologists? Key areas in which to consider antibiotic stewardship are acne, rosacea, and cutaneous infections/ superinfections of inflammatory skin disease. Concomitant use of systemic and topical antibiotics should also be avoided. For acne, recognizing that most of the beneficial effect of antibiotics is through the anti-inflammatory actions of antibiotics should change practice; specific recommendations include reduced duration of antibiotic use and cessation of prescription of antibiotic monotherapy through concomitant prescription of benzoyl peroxide and use of topical retinoids, including in combination with benzoyl peroxide. Additional actions of antibiotic stewardship include the judicious use of antibiotics and also improved rational antibiotic selection guided by diagnostic testing.
On an individual provider level, antibiotic prescription habits may only be changed with specific action plans in place. An important message is that the use of systemic antibiotics will continue to be a common and recommended intervention for acne; however, numerous groups, including the AAD and international guidelines have recommended short course systemic antibiotic durations, defined as 3-6 months. Dermatologist prescribing habits have recently been documented: approximately 84 percent of systemic antibiotic treatment courses for patients with acne align with international guidelines. Specific guidelines for duration of topical antibiotics for treatment of acne have not been specified. For both topical and systemic antibiotics, the concomitant use of benzoyl peroxide is strongly recommended, as there is excellent evidence to suggest that this practice significantly delays, if not eliminates, the development of antibiotic resistance. Additionally, there is clear evidence that combined formulations of topical antibiotic/ benzoyl peroxide have superior clinical efficacy over use of either agent used as monotherapy. Benzoyl peroxide has purported mechanisms of action including antimicrobial (through potent oxidative activity), anti-inflammatory (through modulation of free fatty acid signaling pathways), keratolytic and comedolytic (but not anti-comedogenic) properties; importantly, benzoyl peroxide has not been associated with antibiotic resistance.
Several consensus statements have also identified topical retinoids as first line treatment for acne, with evidence supporting enhanced clinical efficacy of antimicrobials and retinoids used in combination. Specifically, combination retinoid/benzoyl peroxide formulations have been shown to reduce colonization by antibiotic resistant P. acnes, and these combination formulations have been shown to enhance the clinical efficacy of systemic antibiotics for acne treatment in comparison to systemic antibiotics and vehicle. Systemic isotretinoin remains an important non-antimicrobial therapy option for patients, especially those with severe acne.
An additional important alternative for females with acne includes hormonal therapies such as oral contraceptives used as monotherapy or in combination with spironolactone. Hormonal therapy has long been recognized as an effective treatment for acne in women, and new data support its efficacy in comparison to systemic antibiotics. A 2014 meta-analysis demonstrated that oral contraceptives had equivalent efficacy for treating acne to systemic antibiotics after 6 months of treatment, though a notable additional finding was that systemic antibiotics were superior to oral contraceptives at the 3 month treatment mark.
Additional options that do not induce bacterial resistance include azelaic acid and zinc, in addition to emerging acne treatments such as sebum inhibitors, nitric oxide-releasing medications, and laser/ light treatments. In cases of rosacea, a condition for which topical antibiotics are the mainstay of treatment, important non-antibiotic options include topical retinoids, brimonidine, and ivermectin.
Changing prescribing patterns by dermatologists for the treatment of acne is an important challenge and should be a priority. Though antibiotic prescribing patterns has been recognized as the most important driver for antibiotic resistance highlighting the importance of antibiotic stewardship, it is only one of the four aims laid out by CDC in addition to infection prevention, tracking, and development of new medications and diagnostic tests. Research will be a very important aspect of this action plan. Validating important alternatives to antibiotics and setting standards of care will only be one aspect of this effort. Understanding current trends in prescribing practices is critical to setting clear goals for change in prescribing habits. Evidence supporting alternative practices will be instrumental to shifting prescribing habits in the future. Research has already demonstrated that reducing antibiotic duration to 6 months maximum results in cost savings, an additional benefit of limited duration prescription patterns. It is also important to note that antibiotic prescriptions for human use comprise only 19% of all antibiotic prescriptions on an annual basis (with a majority prescribed for veterinary use), signifying that physician prescribing practices are only part of the problem. How will we know when we have met our goal? Tracking prescribing practices in the era of antibiotic-stewardship will be important. Setting up specialty-specific, regional, institutional, and individual prescribing habits will inform our progress. Use of electronic medical records may enable dermatologists to track their practices as part of individual and group quality safety initiatives. There is clear evidence for the efficacy of antibiotic stewardship. Policy may play an important role, with mandates set to limit inappropriate antibiotic prescriptions and/or incentives for appropriate prescription practices, and policies to establish standards of care. The important problem of antibiotic resistance is one that all physicians should know about and understand in the context of their own specialty, and all physicians should commit to improving in the name of individual patient and global health.
- Arnold SR et al (2005) Interventions to improve antibiotic prescribing practices in ambulatory care, Cochrane Data Syst Rev, 4:CD003539.
- Blair JMA et al (2015) Molecular mechanisms of antibiotic resistance, Nature Rev Microbiol, 13:42-51.
- Bowe WP (2014) Antibiotic resistance and acne: where we stand and what the future holds, J Drugs Derm, 13(supp6):s66-70.
- Davis SA et al (2013) Treatment of preadolescent acne in the United States: an analysis of nationally-representative data, Ped Derm, 30:689-694.
- Hampton T (2013) Report reveals scope of US antibiotic resistance threat, JAMA, 310:1661-1663.
- Hoover WD et al (2014) Topical antibiotic monotherapy prescribing practices for acne vulgaris, J Derm Treatment, 25:97-99.
- Koo EB et al (2014) Meta-analysis comparing efficacy of antibiotics versus oral contraceptives in acne vulgaris, JAAD, 71:450-459.
- Lapolla WJ et al (2011) Topical antibiotic trends from 1993 to 2007: use of topical antibiotics for non-evidenced indications, Derm Surgery, 37:1427-1433.
- Leccia MT et al (2015) Topical acne treatments in Europe and the issue of antimicrobial resistance, JEADV, 29:1485-1492.
- Lee YH et al (2014) A retrospective analysis of the duration of oral antibiotic therapy for the treatment of acne in adolescents: investigating practice gaps and potential cost-savings, JAAD, 71:70-76.
- Patel M et al (2010) The development of antimicrobial resistance due to the antibiotic treatment of acne vulgaris: a review, J Drugs Derm, 6:655-664.
- Ranji SR et al (2008) Interventions to reduce unnecessary antibiotic prescribing: a systematic review and quantitative analysis, Med Care, 46:847-862.
- Ross JI et al (2003) Antibiotic-resistance acne: lessons from Europe, BJD, 148:467-478.
- Sardana K et al (2015) Antibiotic resistant P acnes: worldwide scenario, diagnosis, and management, Exp Rev Anti Infect Ther, 13:883-896.
- Straight CE et al (2015) Duration of oral antibiotic therapy for the treatment of adult acne: a retrospective analysis investigating adherence to guideline recommendations and opportunities for cost-savings, JAAD, 72:822-827.
- Thiboutot D et al. (2009) New insights into the management of acne: a report from a global alliance to improve outcomes in acne, JAAD, 60(5 Suppl)S1-50.
- World Economic Forum, Global Risks (2013) http://reports.weforum.org/global-risks-2013/view/risk-case-1/the-dangers-of-hubris-on-human-health/#read
- CDC 2013 Guidelines (http://www.cdc.gov/drugresistance/resources.html)
- Information on Transatlantic Task Force on Antibiotic Resistance, TATFAR (http://www.cdc.gov/drugresistance/tatfar/)
- Barack Obama -> Presidential Executive order re: antibiotic stewardship (https://www.whitehouse.gov/the-press-office/2014/09/18/executive-order-combating-antibiotic-resistant-bacteria)
- Infectious Diseases Society of America (IDSA) (2011): Combating Antimicrobial Resistance: Policy Recommendations to Save Lives, Clin Infect Dis, 52 (suppl 5): S397-3428.
- World Health Organization (WHO) Global Report on Surveillance of Antimicrobial Resistance (http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf)