Department of Dermatology, Baylor College of Medicine, Houston, TX, USA
Administration of antibiotics, often for prolonged periods, has become the de facto standard of care for acne (and rosacea). However, the world is now facing a health crisis relating to widespread antibiotic resistance. The authors provide current evidence to suggest that dermatologists should consider a radical departure from standard operating procedure by severely curtailing, if not outright discontinuing, the routine and regular use of antibiotics for acne.
acne vulgaris, antibacterial agents, antibiotic resistance, benzoyl peroxide, topical combination therapy
At the outset of the 20th century, infection was the primary cause of worldwide mortality and the concept of antibiotic therapy was essentially wishful thinking. Needless to say, modern medicine has made major advancements since Alexander Fleming’s discovery of penicillin in 1928. Increased public health awareness, widespread availability and utilization of immunizations, better sanitation practices, and greater usage of a myriad of antibiotics have all led to infection becoming only the fourth leading cause of mortality in the 21st century. Antibiotics are powerful medicines that can limit bacterial growth and kill bacteria. However, accompanying the growing use of antibiotics, a new and serious problem has emerged: namely, the expanding development of antibiotic resistance. In fact, antibiotic resistance has become the preeminent public health concern in modern medicine. Drugresistant organisms often necessitate the use of second or even third-line antibiotics, which are costlier, possess less favorable side effect profiles, and may be unavailable in many parts of the world. With a decreased number of new antibiotics entering the medical marketplace, the problem of antibiotic resistance is further compounded. In dermatology, prolonged antibiotic use in the management of acne has become a common standard of care. In the milieu of antibiotic resistance as a public health menace, is it possible that dermatologists should temper their reliance on such agents and consciously step away from antibiotic use in favor of other acne treatment modalities?
The Reality of Antibiotic Resistance and Rise of Superbugs
Numerous recent reports document an ever increasing number of infections which have become difficult or impossible to treat due to antibiotic resistance. The notorious and well-known story of methicillin-resistant Staphylococcus aureus (MRSA) is one example. Although MRSA primarily causes skin and soft tissue infections, particularly furuncles, it is also capable of causing life-threatening illnesses such as pneumonia, meningitis, osteomyelitis, endocarditis, and toxic shock syndrome.1 Many of the first-line oral treatments for community-acquired MRSA (clindamycin, trimethoprim-sulfamethoxazole, and doxycycline) are commonly prescribed as long-term therapy for acne vulgaris.1 Thus, treating acne with such antibiotics can theoretically induce staphylococcal resistance against these first-line drugs1— jeopardizing the health of both patients and the community at large.
Despite its prevalence and clear applicability to dermatology, MRSA is not the only pathogen of concern. The cleverly coined “ESKAPE” pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) currently cause the majority of hospital infections in the US and often “escape” antibiotic treatment.2 Vancomycin-resistant Enterococcus, MRSA, carbapenem-resistant Klebsiella, multi-drug resistant (MDR) Acinetobacter, MDR Pseudomonas, and extended spectrum β-lactamase-producing Enterobacter are emerging as significant pathogens around the world.2 With limited therapeutic options, mortality from these organisms is rising. Cases of sepsis and death secondary to Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella or that of Mariana Bridi da Costa, the Brazilian model who made headlines after suffering multiple amputations and eventually dying from urosepsis secondary to MDR Pseudomonas, exemplify the truly virulent nature of these organisms.3-5 Aside from the ESKAPE microbes, resistant strains of tuberculosis (TB), gonorrhea, and the plague have emerged. Reports of total drug-resistant TB in India are distressing. Patients often seek treatment from private doctors who inappropriately prescribe antibiotics that serve to only amplify resistance and risk converting MDR-TB to total drug- or extended drug-resistant TB.6 Expanded-spectrum cephalosporin-resistant Neisseria gonorrhea H041 and F89 strains isolated in Japan and France, respectively, may soon become a worldwide superbug responsible for truly untreatable gonorrhea.7,8 The plasmid IP1202 in MDR Yersinia pestis gives it high-level resistance to streptomycin, tetracycline, chloramphenicol and sulfonamides—drugs recommended for plague prophylaxis and therapy.9 These various superbugs, and others, constitute a significant public health and biodefense threat which, in part, stems from indiscriminate, inappropriate, irrational and profligate use of antibiotics. Any healthcare provider who doubts the global threat posed by emerging trends toward antibiotic resistance should review the data compiled and literature produced by the World Health Organization in conjunction with World Health Day 2011, available at: http://www.who.int/world-health-day/2011/en/index.html.
Mechanisms of Resistance
Antibiotic resistance genes are acquired via four major mechanisms—spontaneous mutation, conjugation (transfer of plasmid), transformation (transfer of free DNA), or transduction (transfer by viral delivery). Spread may be vertical (i.e., generation to generation of the same species) or horizontal (i.e., across species or even genera). With prolonged or inappropriate antibiotic use, antimicrobial-resistant strains are selected for survival compared to non-resistant strains, leading to a dominance of the former within the micro-environment.
The genetic elements endow the bacterium with a number of resistance modalities. Some genes encode enzymes that alter or destroy the antibiotic. Others upregulate or modify the target enzyme or metabolic process that the antibiotic attacks. This allows the bacterium to go unrecognized in the presence of the antibiotic. Other genetic elements decrease the permeability of the organism for the antibiotic (decreased uptake) or encode efflux pumps that extrude the antibiotic once it has entered the organism.
Parties Responsible for Antibiotic Resistance
There are four main contributors to the development of bacterial antibiotic resistance: the pharmaceutical industry, the agriculture and animal husbandry industry, patients, and healthcare providers. Due to the rise in antibiotic resistance, new drugs must be developed to treat highly virulent pathogens; however, the number of new antibacterials receiving US FDA approval has dramatically decreased. There has been a staggering 75% decrease in systemic antibacterial drugs approved by the FDA from 1983 to 2007.2 In part, the astounding cost of new drug development inhibits pharmaceutical industry investment. The cost to develop one systemic drug can range anywhere between $3.7-$11.8 billion dollars, including years of basic research, preclinical development, and clinical trials.10 The significant decrease in novel antibiotic introduction parallels a considerable decrease in anti-infective drug discovery and development. Of the 13 pharmaceutical leaders in the world, only 5 have antibacterial discovery programs and the number of antibacterials in Phase 2 or 3 development is distressingly low.2
The agriculture and animal husbandry industry routinely use prophylactic antibiotics in livestock and fruit. Use of antibacterial compounds in these settings leads to constant selective pressure toward survival of resistant strains and contributes to a larger global resistance reservoir.11
Patients and healthcare providers also contribute to the problem. Patients, who often save unused antibiotics, share these agents with friends, relatives, neighbors and co-workers, or inappropriately use them – serve to expand the microbial resistance reservoir. It is not uncommon for healthcare providers to prescribe antibiotics when they are not indicated, use the wrong dose or duration for treatment, and frequently treat chronic conditions with antibiotics for extended periods of time. All of these practices can increase the risk of resistant organisms.
In dermatology, acne and rosacea are the two major conditions for which antibiotics are regularly used. Especially in the treatment of acne and rosacea, antibiotics are frequently prescribed for prolonged periods of time, often greater than 6 months. However, many non-infectious conditions, such as Hailey-Hailey disease, pityriasis lichenoides et varioliformis acuta (PLEVA), pityriasis rosea, pityriasis lichenoides chronica, hidradenitis suppurativa, and Gougerot-Carteaud syndrome are also treated with antibiotics. Although there are admittedly many contributing factors, dermatologists can control the part they play in propagating antimicrobial resistance.
Rationale for Eliminating Antibiotic Use for Acne
Success against antimicrobial resistance requires a comprehensive and multifaceted approach, including increased microbial surveillance; more judicious use of antimicrobials in human medicine, agriculture, and animal husbandry; increased research on the biology of microbes and mechanisms of resistance; development of novel antibiotics and vaccines as well as rapid, point-of-care diagnostics; and, most importantly pertinent to this manuscript, alteration of old prescribing habits.12 For the dermatologist, the latter point particularly means eliminating the use of antibiotics to treat acne (and rosacea). This statement might appear to be hyperbolic and extreme in scope. But, at the very least, dermatologists should consider carefully each and every prescription for antibiotics dispensed for acne (or rosacea) in light of the apocalyptic threat posed by the mounting crescendo of antimicrobial resistance. Let us also note additional points relevant to the consideration of eliminating antibiotics in the management of acne.
Antibiotics and Side Effects
Antibiotics have serious side effects, and even brief treatment can have long-lasting effects. Pseudomembranous colitis, infamously associated with antibiotic use, alters the colonic flora and enables Clostridium difficile (C. difficile) to proliferate and produce toxins with cytopathic effects on the colonic mucosa; acute peritonitis, toxic megacolon, and colonic perforation may ensue.13 However, these changes in bowel flora are neither temporary nor limited to the treated patient. Evidence suggests that even a 7-day course of clindamycin shows resistance patterns in gut flora up to 2 years after therapy has been discontinued.11 Studies have also shown that changes in bowel flora after tetracycline use are not limited to the patient, but can also lead to resistance patterns in the gastrointestinal flora of close personal contacts.1
Overgrowth of gram-negative microbes on the skin such as Escherichia coli (E. coli), Klebsiella, Proteus, or Enterobacter, is another potential side effect of long-term antibacterial treatment.14 A rather dramatic gram-negative folliculitis, replete with painful, boggy nodules, may result.14 Side effects including hypersensitivity reactions like urticaria and DRESS (drug rash with eosinophilia and systemic symptoms) syndrome; dyschromia of skin, teeth, gums, palate, conjunctiva, or sclera from tetracyclines;15-18 pseudotumor cerebri; and adverse hepatic, renal and hematological effects may also occur. Although controversial, literature exists to suggest that antibiotic use may be associated with development of inflammatory bowel disease, particularly among those with a familial predisposition.19-21 Does the risk-benefit ratio really warrant the routine use of antibiotics, especially in light of alternate therapies which offer similar outcomes without this litany of potential adverse events?
Prevalence of Propionibacterium acnes Resistance
In the last few decades Propionibacterium acnes (P. acnes) has become resistant to many different antibiotics, making them less efficacious in treating acne.1,22 In a topical benzoyl peroxide study, 100% of patients had pre-treatment high-level erythromycinresistant organisms and intermediate- to high-level resistance to tetracycline, doxycycline, minocycline, and clindamycin.22
Moreover, the prevalence of P. acnes resistance worldwide highlights the near futility of oral antibiotic treatment. In countries like Mexico,23 Sweden,24 France,25 Japan,26 and Singapore27 there is already a high level of resistance to antibiotics like azithromycin, trimethoprim/sulfamethoxazole, erythromycin, and clindamycin. Additionally, patients who harbor resistant P. acnes may be clinically more treatment refractory due to higher bacterial counts; the limited, direct experimental evidence for this assertion is nicely summarized in a recent manuscript by Patel and co-authors.1
Worsening of the Overall Resistance Problem
Antibiotic use for acne can worsen the already serious overall antimicrobial resistance dilemma. Studies have shown that Streptococcus pyogenes colonization and resistance in the oropharynx is associated with antibiotic therapy in patients with acne.28 Moreover, the problem of resistant bacteria is not limited to patients receiving therapy. Contacts of acne patients being treated with antibiotics demonstrate significant increased prevalence and density of resistant strains of coagulase-negative Staphylococcus (CNS) compared to those with no contact with acne patients.29 CNS can horizontally transfer resistance genes to coagulasepositive staphylococci such as S. aureus, further emphasizing the concern that dermatologists might induce resistance against the arsenal for MRSA. This puts not only patients, but potentially the whole community at risk; the longer the resistant CNS colonizes the skin, the greater the opportunity it has to spread resistant genes to other bacteria.1
BPO Monotherapy Non-Inferior to Antibiotics
Benzoyl peroxide (BPO) has been used since the 1930s due to its antibacterial, keratolytic, and comedolytic properties.30 Studies done on patients with mild to moderate acne have shown no statistically significant difference between 5% topical BPO twice daily and oral doxycycline 100 mg 4 times daily, or to other tetracyclines like oxytetracycline and minocycline.30,31 In fact, BPO was actually shown to be the most cost-effective treatment in these investigations.31 In the study done by Leyden et al., 6% BPO cleanser effectively reduced tetracycline-resistant P. acnes populations 1 week after treatment—reductions were >1 log after 2 weeks and ≥2 log after 3 weeks.22 With the anticipated decreased efficacy of tetracyclines due to pre-existing P. acnes resistance, an aggressive BPO regimen may prove to be useful therapy for controlling both acne and antibiotic resistance prevalent in P. acnes at baseline.22,31
Alternatives to Antibiotic Treatment
There are many alternate therapies available that are convenient and effective in treating acne aside from topical monotherapy with BPO, including physical therapeutic modalities such as high intensity light,32 photodynamic therapy,33 and thermotherapy34; hormonal therapy with oral contraceptive pills35 or spironolactone36; subantimicrobial doses of doxycycline which exploit the non-antimicrobial, anti-inflammatory properties of the antibiotic37; dapsone38; isotretinoin; zinc plus or minus nicotinamide39; and topical bleach. These modalities have varying mechanisms of action but have been shown to significantly reduce both inflammatory and/or non-inflammatory acne lesions. Although more experimental and clinical evidence is needed, creative application of these alternative modalities may allow many, if not most, patients to be well managed without ever receiving an antibiotic.
As bacterial antibiotic resistance continues to emerge as a serious global threat, it is crucial that all clinicians re-examine their use of antibiotics, remaining cognizant of the potential deleterious consequences enumerated above. For dermatologists, eliminating all antibiotic use for the treatment of acne (and rosacea) is a first step in assuming responsibility for helping combat the serious problem of antibiotic resistance. Taking into consideration the numerous possible side effects of antibiotics; existing prevalence of P. acnes resistance worldwide; worsening of the overall resistance problem; and ready availability of BPO along with many other alternative therapeutic interventions, the idea of “no more antibiotics for acne” should seem less extreme to some of our colleagues, and should at least provoke thoughtful self-appraisal of current prescribing habits for many others.
- Patel M, Bowe WP, Heughebaert C, et al. The development of antimicrobial resistance due to the antibiotic treatment of acne vulgaris: a review. J Drugs Dermatol. 2012 Jun;9(6):655-64.
- Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 2009 Jan;48(1):1-12.
- Elemam A, Rahimian J, Mandell W. Infection with panresistant Klebsiella pneumoniae: a report of 2 cases and a brief review of the literature. Clin Infect Dis. 2009 Jul;49(2):271-4.
- Model dies after amputations. Seattle Times. http://seattletimes.com/html/ nationworld/2008667914_wdig25.html. Last updated January 25, 2009. Accessed June 19, 2013.
- Whiteman H, de Moura H. Brazilian amputee model dead at 20. CNN. http:// www.cnn.com/2009/WORLD/americas/01/24/brazil.amputee.model/index. html. Last updated January 24, 2009. Accessed June 19, 2013.
- Udwadia ZF, Amale RA, Ajbani KK et al. Totally drug-resistant tuberculosis in India. Clin Infect Dis. 2012 Feb;54(4):579-81.
- Ohnishi M, Golparian D, Shimuta K, et al. Is Neisseria gonorrhoeae initiating a future era of untreatable gonorrhea?: detailed characterization of the first strain with high-level resistance to ceftriaxone. Antimicrob Agents Chemother. 2011 Jul;55(7):3538-45.
- Unemo M, Golparian D, Nicholas R, et al. High-level cefixime- and ceftriaxoneresistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother. 2012 Mar;56(3):1273-80.
- Welch TJ, Fricke WF, McDermott PF, et al. Multiple antimicrobial resistance in plague: an emerging public health risk. PLoS One. 2007 Mar;2(3):e309.
- Herper M. The truly staggering cost of inventing new drugs. Forbes. http:// www.forbes.com/sites/matthewherper/2012/02/10/the-truly-staggering-costof- inventing-new-drugs/. Last updated February 2, 2010. Accessed June 19, 2013.
- Jernberg C, Löfmark S, Edlund C, et al. Long-term impacts of antibiotic exposure on the human intestinal microbiota. Microbiology. 2010 Nov;156 (Pt 11):3216-23.
- Peters NK, Dixon DM, Holland SM, et al. The research agenda of the National Institute of Allergy and Infectious Diseases for antimicrobial resistance. J Infect Dis. 2008 Apr; 197(8):1087-93.
- Andréjak, M, Schmit JL, Tondriaux A. The clinical significance of antibioticassociated pseudomembranous colitis in the 1990s. Drug Saf. 1991 Sep-Oct;6(5):339-49
- Boni R, Nehrhoff B. Treatmeat of gram-negative folliculitis in patients with acne. Am J Clin Dermatol. 2003 Apr;4(4):273-6.
- Rosen T, Hoffman TJ. Minocycline-induced discoloration of the permanent teeth. J Am Acad Dermatol. 1989 Sep;21(3Pt1):569.
- Katz J, Barak S, Shemer J, et al. Black tongue associated with minocycline therapy. Arch Dermatol. 1995 May;131(5):620.
- McAllum P, Slomovic A. Scleral and conjunctival pigmentation following minocycline therapy. Can J Ophthalmol. 2007 Aug;42(4):626-7.
- Wasel NR, Schloss EH, Lin AN. Minocycline-induced cutaneous pigmentation. J Cut Med Surg. 1998 Oct;3(2):105-8.
- Kronman MP, Zaoutis TE, Haynes K, et al. Antibiotic exposure and IBD development among children: a population-based cohort study. Pediatrics. 2012 Oct;130(4):e794-803.
- Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics and new diagnoses of Crohn’s disease and ulcerative colitis. Am J Gastroenterol. 2011 Dec;106(12):2133-42.
- Margolis DJ, Fanelli M, Hoffstad O, et al. Potential association between the oral tetracycline class of antimicrobials used to treat acne and inflammatory bowel disease. Am J Gastroenterol. 2010 Dec;105(12):2610-16.
- Leyden JJ, Wortzman M, Baldwin EK. Antibiotic-resistant Propionibacterium acnes suppressed by a benzoyl peroxide cleanser 6%. Cutis. 2008 Dec;82(6): 417-21.
- González R, Welsh O, Ocampo J, et al. In vitro antimicrobial susceptibility of Propionibacterium acnes isolated from acne patients in northern Mexico. Int J Dermatol. 2010 Sep;49(9):1003-7.
- Oprica C, Emtestam L, Lapins J, et al. Antibiotic-resistant Propionibacterium acnes on the skin of patients with moderate to severe acne in Stockholm. Anaerobe. 2004 Jun;10(3):155-64.
- Dumont-Wallon G, Moyse D, Blouin E, et al. Bacterial resistance in French acne patients. Int J Dermatol. 2010 Mar;49(3):283-8.
- Ishida N, Nakaminami H, Noguchi N, et al. Antimicrobial susceptibilities of Propionibacterium acnes isolated from patients with acne vulgaris. Microbiol Immunol. 2008 Dec;52(12):621-4.
- Tan HH, Tan AW, Barkham T, et al. Community-based study of acne vulgaris in adolescents in Singapore. Br J Dermatol. 2007 Sep;157(3):547-51.
- Levy RM, Huang EY, Roling D, et al. Effect of antibiotics on the oropharyngeal flora in patients with acne. Arch Dermatol. 2003 Apr;139(4):467-71.
- Miller YW, Eady EA, Lacey RW, et al. Sequential antibiotic therapy for acne promotes the carriage of resistant staphylococci on the skin of contacts. J Antimicrob Chemother. 1996 Nov;38(5):829-37.
- Mareledwane NG. A randomized, open-label, comparative study of oral doxycycline 100 mg vs. 5% topical benzoyl peroxide in the treatment of mild to moderate acne vulgaris. Int J Dermatol. 2006 Dec;45(12):1438-9.
- Ozolins M, Eady EA, Avery AJ, et al. Comparison of five antimicrobial regimens for treatment of mild to moderate inflammatory facial acne vulgaris in the community: randomised controlled trial. Lancet. 2004 Dec;364(9452): 2188-95.
- Hamilton FL, Car J, Lyons C, et al. Laser and other light therapies for the treatment of acne vulgaris: systematic review. Br J Dermatol. 2009 Jun;160(6):1273-85.
- Sakamoto FH, Lopes JD, Anderson RR. Photodynamic therapy for acne vulgaris: a critical review from basics to clinical practice: part I. Acne vulgaris: when and why consider photodynamic therapy? J Amer Acad Dermatol. 2010 Aug;63(2):183-93.
- Badgwell Doherty C, Doherty SD, Rosen T. Thermotherapy in dermatologic infections. J Amer Acad Dermatol. 2010 Jun;62(6):909-27.
- Arowojolu AO, Gallo MF, Lopez LM, et al. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD004425.
- Saint-Jean M, Ballanger F, Nguyen JM, et al. Importance of spironolactone in the treatment of acne in adult women. J Eur Acad Dermatol Venereol. 2011 Dec; 25(12):1480-1.
- Toossi P, Farshchian M, Malekzad F, et al. Subantimicrobial-dose doxycycline in the treatment of moderate facial acne. J Drugs Dermatol. 2008 Dec;7(12): 1149-52.
- Kaminsky A. Less common methods to treat acne. Dermatology. 2003; 206(1):68-73.
- James KA, Burkhart CN, Morrell DS. Emerging drugs for acne. Expert Opin Emerg Drugs. 2009 Dec;14(4):649-59.