Antibiotic resistance has quickly developed into one of the most important global problems in the practice of medicine. According to a report from the Centers for Disease Control and Prevention in 2013, an estimated two million illnesses and 23,000 deaths developed from infections with resistant bacteria.¹ Antibiotic resistance has been prioritized by the science ministers of the G8 countries and deemed by the World Health Organization (WHO) as a rapidly evolving health issue extending far beyond the human health sector” that requires “urgent action... at the highest political level.”^2,3 This article will explore the global implications for antibiotic resistance, assess the next steps, and examine the relevance for our own specialty.

Running the Numbers on Antibiotics

Since the first observations in 1979, data collected from acne patients in several countries has revealed a growing emergence of antibiotic-resistant isolates of P. acnes. The worldwide prevalence rate has been reported to increase from 20 percent 1978 to 62 percent in 1996.^4-6 Erythromycin is particularly problematic in treating acne, as most P. acnes bacteria demonstrate high levels of resistance.¹¹ While resistance to various topical antibiotics is a global phenomenon, it is perhaps most noteworthy in the United States.⁵

In 2012, healthcare providers prescribed more than 260 million courses of antibiotics in 2012.⁷ Of these prescriptions, dermatologists prescribed 9.6 million of these courses. While dermatologists represent only one percent of all health care professionals in the United States, they prescribe almost five percent of antibiotics. Oral and topical antibiotics account for 54 percent of acne prescriptions in dermatology. If you include fixed dose combination topics drugs, 66 percent of all dermatology prescriptions written for acne contain an antibiotic. In 2012, tetracyclines (including doxycycline and minocycline) account for 70 percent of oral antibiotics prescriptions, followed by cephalosporins, which accounted for 11 percent.

Antibiotics in Dermatology

Antibiotic monotherapy is not recommended to treat acne because of the risk of developing resistant bacteria. Application of topical antibiotics has been shown to promote resistant flora in skin of treated site^12,13 and oral antibiotics affects flora on all body sites.^14,15 Moreover, antibiotic monotherapy is not as effective as combination therapy with other agents, such as benzoyl peroxide. One meta-analysis found only an incremental benefit in adding clindamycin to benzoyl peroxide (BPO), with no benefit in within the first two to four weeks and marginal benefit after 10-12 weeks.⁸ Moreover, one study looking at mild to moderate acne demonstrated similar efficacy between oral doxycycline 100 mg daily and BPO 5%.⁹ In another study evaluating five different acne regimens, topical BPO and a combination BPO and erythromycin were found to have similar efficacy to oral antibiotics.¹⁰

While antibiotic resistant P. acnes is a known phenomenon, the question that arises is whether this is clinically meaningful. At this point, we do not know. P. acnes is a low risk bug that can be considered “antisocial.” As such, the risk of spreading resistance from P. acnes to other organisms is low.

Collateral damage to commensal skin flora is the major issue with antibiotic monotherapy. Both correct and incorrect use of antibiotics for the treatment of acne can promote antibacterial resistance.18 In other words, whether the antibiotic is being prescribed for an anti-microbial or anti-inflammatory reason, their use promotes resistance among even normal skin flora. Examples include coagulase-negative staphylococci on the skin and mucous membranes; Streptococcus pyogenes in the oropharynx (with an increased risk of pharyngitis); and flora of the gastrointestinal tract of both patients and their close contacts. The development of resistance factors in patients on antibiotics creates a resistance reservoir that can be transmitted pathogenic bacteria which in turn lead to diseasea. ^{14, 16-20}

Oral antibiotics are an effective therapy for acne. However, they should be used along with topicals and discontinued after patients improve. Topicals are effective maintenance therapies, and not necessarily better than using an antibiotic. In one study, maintenance regimens using topical tazarotene 0.1% gel, oral minocycline 100 mg BID, or the combination of both were evaluated.²¹ There were no statistical differences in the efficacy results, demonstrating that the oral antibiotics (either alone or along with tazarotene) were no better than the topical retinoid alone. Given this data, along with what is known about the risks of unnecessary antibiotic exposure, topical retinoids should play a major role in acne maintenance regimens and play an important role in minimizing unnecessary antibiotic exposure.²¹

Strategies to Limit Antibiotic Resistance

Randomized, controlled trials evaluating antibiotic resistance and optimal antibiotic regimens are lacking. Most of the data we have regarding proper antibiotic use come from guidelines set forth by expert panels of key opinion leaders, case reports, and small studies. Several strategies have been suggested to minimize the risk of developing antibiotic resistance.

First, topical BPO should be used along with topical antibiotics, either as a fixed dose combination or a second product. BPO is directly toxic to P. acnes, and has been shown to improve acne in patients with previously demonstrated antibiotic resistance. To date there have been no reports of BPO resistant P. acnes.

Second, use of oral antibiotics should be limited and clinical improvement should be assessed. Antibiotics should not be changed without adequate justification. If patients demonstrate no improvement after six to eight weeks of use, then a switch can be considered. In addition, European guidelines suggest that oral antibiotic use should be limited to three months, after which they should be discontinued.^12,22-28

Appropriately and Cautiously

Despite the rising concern regarding resistance, antibiotics are effective treatments for our acne patients, and we should continue to use them when appropriate. However, we each need to consider ourselves stewards of proper antibiotic use. We each must consider our global responsibility to minimize the collateral damage antibiotics cause so that we can reduce the number of illnesses and deaths from multi-drug resistant bacterial infections.

Tips for Avoiding Resistance When Prescribing Antibiotics

• Use topical retinoids from the beginning
• Do not use antibiotics for maintenance long term or as monotherapy
• Maintain acne clearance with topical agents
• Retreat with the same oral antibiotic
• Only use antibiotics if antibiotic therapy was effective previously

Antibiotic Resistance: A Short History of Recognition and Response

Antibiotic resistance was first recognized on a national level in 1999 by the Interagency Task Force on Antimicrobial Resistance (ITFAR), which was initiated following a congressional hearing on the topic Antimicrobial Resistance: Solutions to a Growing Public Health Problem.¹ ITFAR originally published its Public Health Action Plan to Combat Antimicrobial Resistance in 2001, revising it in 2011, and updating it again in 2012. The Action Plan is a blueprint for specific, coordinated federal actions to address the growing threat of antimicrobial resistance in the United States. The Action Plan addresses the four areas of federal action: surveillance, prevention and control, research, and product development.

The CDC promotes antibiotic stewardship, a multidisciplinary initiative to optimize antimicrobial therapy, lessen the risk of adverse events, promote therapeutic cost-effectiveness, improve patient outcomes, and reduce or stabilize antimicrobial resistance. Antibiotic stewardship interventions have been shown to improve individual patient outcomes, reduce the overall burden of antimicrobial resistance, and save healthcare dollars. Implementation of an antibiotic stewardship program in any healthcare facility helps to ensure that hospitalized patients receive the right dose of the right antibiotic at the right time and for the right duration. This promotes reduced mortality, reduced risks of Clostridium difficile-associated diarrhea, shorter hospital stays, reduced overall antimicrobial resistance within the facility, and cost savings.

However, despite these benefits, antibiotic stewardship programs and interventions are far from the norm in US hospitals at the present time.

—Joshua A. Zeichner, MD

Joshua A. Zeichner, MD is Director of Clinical and Cosmetic Research at Mount Sinai School of Medicine in New York City.

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