Acne and rosacea are chronic inflammatory disorders long thought to be primarily infectious. However, evidence in recent years indicates that far more than microorganisms inflammation plays a key role in the pathogenesis of these disorders.1 Coinciding with recent emphasis on inflammation has been an increased reliance on antibiotic agents, which we now know to confer anti-inflammatory effects. In the last 10 years, prescriptions for oral antibiotics by both dermatologists and non-dermatologists have continued to rise. The most commonly prescribed antibiotics in dermatology are the tetracyclines, of which second-generation molecules doxycycline and minocycline are most prominent. While antibiotics can be used in a variety of dermatologic conditions, doxycycline and minocycline are likely used as much or more for their anti-inflammatory properties as for their antimicrobial effects.

As researchers strive to learn more about the specific role of inflammation in the etiology of acne and rosacea, clinicians should be aware of new developments and prepare to adapt to changing therapeutic conditions. Ahead, I will provide an update of research on antibiotics in acne and rosacea care with a particular focus on the antiinflammatory effects of antibiotics. I will also discuss novel formulations that may be particularly beneficial for patients.

Therapeutic Challenges and Resistance Concerns

Compared to tetracycline, doxycycline and minocycline provide important benefits, including less frequent dosing and improved safety.2 However, certain potential side effects of this class, including GI concerns, staining of developing teeth in children, candidiasis, and photosensitivity, are still a concern.2,3,4 Probably one of the major disadvantages of the use of minocycline is the potential for blue/grey staining of the skin, sclera, teeth, and nails.5 Increasingly, there has been more attention paid to the risk for development of autoantibodies, including antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), and antiphospholipid antibodies, associated with minocycline, with or without associated clinical symptoms.4

While serious side effects associated with secondgeneration tetracyclines are rare, they warrant consideration. All tetracyclines —but especially minocycline— may be associated with benign intracranial hypertension with dizziness, lethargy, headaches, nausea and vomiting associated with photophobia, diplopia, and papilledema. Staining of the teeth can occur with these agents, and they are not recommended in children under the age of eight years.

Although the rates of adverse events were perceived to be similar between doxycycline and minocycline, a review of the published data shows a disadvantage for minocycline.2 In data from clinical trials published from 1966 to 2003, rates of reported adverse events ranged from 0 to 61 percent for doxycycline and 11.7 to 83.3 percent for minocycline. The majority of AEs associated with doxycycline were related to GI complaints, while minocycline had primarily CNS or GI complaints. Similarly, evaluation of FDA MedWatch reports from 1998 to 2003 found a rate of adverse events of 13 per million new prescriptions for doxycycline and 72 per million new prescriptions for minocycline. 2

Minocycline is associated with potentially fatal hypersensitivity syndrome or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).6 A retrospective analysis of 15 ICU-admitted cases of DRESS in France found that minocycline was causative in three cases. All three of those patients experienced renal failure, and two of those three patients died. Based on their analysis of these cases and other databases, the authors recommend that minocycline be considered a “higher risk” medication. 12 Although predictive and prognostic factors are not well-defined, evidence from another recent review of hypersensitivity reactions in African and African-American patients suggests that the risk for DRESS may be associated with prolonged exposure to minocycline and subsequent accumulation of the drug in plasma and skin.7

Antibiotic Resistance. In addition to treatmentassociated adverse events, use of topical and oral antibiotics at standard doses (at or above minimal inhibitory concentration) is associated with the risk of antibiotic resistance. The problem of resistance has been especially well documented in the management of acne and has been linked to resultant treatment failure.8 However, resistance is not limited to Propionibacterium acnes (P acnes). Researchers have identified resistant strains of Staphylococcus epidermidis,9-11 among acne patients treated with oral erythromycin. Another study of acne patients showed that systemic antibiotic therapy was associated with Streptococcus pyogenes colonization and resistance in the oropharynx. While only 20 percent of S pyogenes cultures from individuals not treated with antibiotics were resistant to at least one tetracycline, 85 percent of cultures from antibiotic-treated patients demonstrated resistance.12

Proposed strategies to reduce the risk of resistance are to limit the use of oral and topical antibiotics, to use these agents in combination with adjunctive antimicrobial agents, such as benzoyl peroxide, or to administer antibiotics at levels below the minimal inhibitory concentration or MIC. The MIC is the plasma concentration that must be achieved in order for an antibiotic agent to inhibit or kill bacteria. The MIC is specific to each antibiotic agent. Continuous use of low-dose antibiotics contributes to development of resistance. 13

Anti-Inflammatory Effects

Despite concerns of resistance and adverse effects, antibiotics have proven most useful for the antiinflammatory effects associated with their use. Guidelines from the Global Alliance to Improve Outcomes in Acne Therapy highlight findings the inflammatory component of acne. It has now been shown that immune changes and inflammatory responses precede comedogenesis.14 Recent in vivo research into the pathophysiology of acne and associated scarring found a marked increase in inflammatory cytokine gene transcripts in active acne lesions, including TNF-α and IL-1β.15 These pro-inflammatory cytokines amplify NF-κβ signaling pathways. These reports suggest that acne is a disease mediated not only by bacteria but also by inflammatory processes.

The fact that tetracycline antibiotics confer both antimicrobial and anti-inflammatory effects accounts for their utility in acne management. Both minocycline and doxycycline are lipophilic agents that demonstrate better tissue permeability than tetracycline, adding to their therapeutic benefit. 16

Minocycline and doxycyline appear to offer similar efficacy in the management of acne. A systematic review of clinical trials from 1962 to 2006 failed to identify a significant difference in reduction of inflammatory or non-inflammatory lesions between patients treated with doxycycline and those treated with minocycline.17 In a head-to-head study in which 64 patients were randomized to receive either doxycycline or minocycline 50mg twice daily for four weeks and then once daily for the next eight weeks,18 the two agents had equivalent efficacy. In another comparative trial, this one involving 34 patients randomized to treatment with doxycycline 50mg once daily or minocycline 50mg twice daily, the agents again had similar efficacy. 19

Given their equivalent efficacy, selection of an agent often depends on the specific patient and the prescriber's assessment of the relative risks for development of therapy-associated adverse events. For patients with moderate to severe inflammatory acne, initiation of appropriate systemic therapy should not be delayed. Treatment aimed at reducing inflammation can reduce the risk of scarring and post-inflamamtory hyperpigmention.20

Oral antibiotics have also been used effectively in the treatment of rosacea since the 1960s.21 Doxycycline and other tetracyclines have been shown to produce a number of anti-inflammatory effects that may contribute to their beneficial effects in patients with rosacea. The tetracyclines, generally classified as antibiotics, have a range of therapeutic effects that are independent of antimicrobial mechanisms. In fact, tetracyclines have current or theoretical applications in periodontitis, arthritis, osteoporosis, and cancer.22-24

Doxycycline and other tetracyclines have been shown to reduce the production of interleukin-1 beta (IL-1β) (p <0.05) and tumor necrosis factor alpha (TNF-α)25 and may reduce neutrophil chemotaxis. 26 Tetracyclines also reduce the activity of phospholipase A2, a family of inflammatory enzymes.27 Doxycycline reduces the generation of neutrophil-derived toxic reactive oxygen species, including superoxide anion, hydrogen peroxide, and the hydroxyl ion.28 In vitro studies show that doxycycline can reduce the production of nitric oxide by epithelial cells at concentrations as low as 3μg/ml.29 Doxycycline has also been shown to reduce angiogenesis in animal models.

Appreciation of the anti-inflammatory effects of tetracyclines may be attributed to research with chemically-modified tetracycline (CMT) analogues. There are at least 10 CMTs, modified so that the dimethylamino group from carbon-4 position (the side-chain required for antimicrobial activity) is removed. These analogues provide no antimicrobial effect, but they inhibit synthesis of collagenase and other matrix metalloproteinases and down regulate cytokines in animal models.22-25

Conclusion

While the pathogeneses of acne and roscea are not fully understood, scientific inquiries increasingly articulate the importance of systemic antibiotics as therapeutic agents in the treatment of both conditions. 2-5 In addition, new data indicate that the widespread use of oral antibiotics is associated with a significant decrease in total annual prescription spending.30 As advancements in formulation are undoubtedly paving the way for more efficacious antibiotic agents to play an increased role in acne and rosacea therapy (Table 1), clinicians' abilities to understand and manage these conditions will continue to evolve.

Take-Home Tips

Despite concerns of resistance and adverse effects, antibiotics have proven most useful for the anti-inflammatory effects associated with their use. Given the equivalent efficacy of doxycycline and minocycline, selection of an agent often depends on the specific patient and the prescriber's assessment of the relative risks for development of therapy-associated adverse events. As advancements in formulation are undoubtedly paving the way for more efficacious antibiotic agents to play an increased role in acne and rosacea therapy, clinicians' abilities to understand and manage these conditions will continue to evolve.

Dr. Kircik has served as a researcher, consultant, or speaker for Allergan, Coria, Dermik, Galderma, Stiefel/GSK, Intendis, Medicis, Obagi, OrthoDermatologics, and Triax.

Leon Kircik, MD, FAAD is Director of Derm Research, PLLC and Physicians Skin Care, PLLC. He is Clinical Associate Professor of Dermatology at Mount Sinai Medical Center and Indiana University School of Medicine.