Current Treatment

The Antibiotic Paradox: Benefits and Risks of Using Antimicrobial Oral Antibiotics for The Systemic Treatment of Rosacea

By Dr.James Del Rosso

James Q. Del Rosso, D.O., FAOCD
Clinical Assistant Professor
Department of Dermatology
University of Nevada School of Medicine
Las Vegas, Nevada
Las Vegas Skin & Cancer Clinics
Las Vegas, Nevada

What is rosacea? In answering this question, the reply is likely to spring forward akin to a "knee jerk reflex." The typical response is, "Rosacea is a chronic facial eruption, most commonly seen in Caucasian adults, characterized by erythema of the central face, papules, pustules, telangiectasias and periods of exacerbation and remission." What causes rosacea? This question is much more likely to be followed by a pause, or a response of, "No one really knows, but..." The limited understanding of the pathogenesis of rosacea is a major reason for the slow progression and development of therapeutic agents and modalities.1-3

Despite availability of several therapeutic options, topical metronidazole and topical azelaic acid are the only agents approved for the treatment of rosacea by the US Food & Drug Administration based on pivotal phase III clinical trials. Oral antibiotics—especially the tetracyclines agents tetracycline, doxycycline and minocycline—have been the mainstay of systemic therapy for rosacea for several years based on limited study, widespread clinical experience and observation; the recommended doses of the tetracycline agents have been within the range of what produces antibiotic activity, thereby contributing to antibacterial selection pressure.1,4,5-7 Based on single-dose pharmacokinetics, conventional formulations of doxycycline (50 mg or higher and non-controlled release) achieve serum levels which may produce selection pressure against sensitive bacterial strains based on minimum inhibitory concentration (MIC) evaluation.6,7

Multiple pathophysiologic mechanisms have been associated with the development of rosacea, including structural alterations of cutaneous vasculature, changes in cutaneous blood flow, altered vascular response to ambient and oral heat exposure, immune response to microbial organisms such as follicular Demodex mites, temperature-dependent bacterial protein production, degeneration of dermal matrix, abnormalities of the pilosebaceous unit, and impairment of epidermal barrier function involving predominantly centrofacial skin.2,8-21 Many of the mechanisms associated with the pathogenesis of rosacea have also been correlated with photoaging, including loss of vascular integrity, increased angiogenesis, formation of telangiectasias, altered cutaneous oxidation/antioxidant balance, increased generation of reactive species (ROS), and increased production of reactive nitrogen species (RNS).2,8,9,22-27 Tetracycline antibiotics, including doxycycline, exhibit several anti-inflammatory (biologic) effects unrelated to antibiotic activity.6,28,29 Many of these effects correlate with mechanisms that are advantageous in the treatment of rosacea such as reduced expression of pro-inflammatory cytokines, inhibition of expression of nitric oxide synthetase, accelerated degradation of nitric oxide synthetase, reduced activity of reactive oxygen species, decreased activity of several matrix metalloproteinase enzymes involved in dermal matrix degradation, inhibition of angiogenesis, and reduced pro-inflammatory activity of phospholipase A2.6,28,29

As anti-inflammatory dose doxycycline (doxycycline monohydrate 40 mg controlled-release capsule once daily) provides the aforementioned anti-inflammatory effects but is devoid of antibiotic activity, it offers the advantages of clinical efficacy without antibiotic selection pressure.6 As rosacea is a chronic disorder, prolonged therapy with an oral antibiotic such as a tetracycline agent (using a dosage range that exerts antibiotic activity) would be expected to exert selection pressure against sensitive bacterial strains and contribute to emergence of antibiotic resistant organisms. Although the full clinical impact of selection pressure related to chronic administration of antibiotic doses of tetracyclines may not be entirely clear at present, the potential for adverse sequelae related to chronic antibiotic therapy should not be overlooked.30-35 As the pathogenesis of rosacea has not been correlated with any bacterial organisms, and effective treatment does not appear to relate to reduction or eradication of a bacterium, the availability of an oral agent that has demonstrated efficacy and safety without exertion of antibiotic activity is a welcome addition to the therapeutic armamentarium.6 In addition, once daily administration of anti-inflammatory dose doxycycline is likely to optimize compliance, especially with prolonged administration.36

Overall, the safety profile of tetracycline antibiotics has been highly favorable; phototoxicity has been reported in association with the use of some tetracyclines such as doxycycline, and is dose related, occurring more commonly at doses of 100 mg or higher.37 Vaginal candidiasis is a well-recognized potential adverse consequence of antibiotic therapy in females related to alteration of the normal vaginal flora with overgrowth of yeast organisms.37 In the two pivotal phase III trials of anti-inflammatory dose doxycycline, none of the patients treated with this approach developed photoxicity (n=269) or vaginal candidiasis (n=185).

In summary, systemic treatment of rosacea using conventional doses of oral tetracyclines and other antibiotics has been utilized for several years based primarily on clinical experience, as no oral antibiotic is approved by the FDA for treatment of rosacea. At present, there does not appear to be a bacterium definitively involved with or responsible for the pathogenesis of rosacea. As a result, the efficacy of systemic tetracycline therapy appears to relate to multiple anti-inflammatory mechanisms established with these agents. As an antibiotic effect does not appear to be needed for treatment of rosacea, and is not advantageous due to the potential for emergence of antibiotic resistant bacterial strains, the use of a safe and effective oral anti-inflammatory therapy for rosacea is scientifically rational based on the available body of evidence. Anti-inflammatory dose doxycycline is a major first step in this direction, providing favorable efficacy and safety in a convenient once daily dosing form based on pivotal phase III trials.

References

  1. Del Rosso JQ. Medical treatment of rosacea with emphasis on topical therapies. Exp Opin Pharmacother. 2004;5(1):5-13.
  2. Crawford GH, Pelle MT, James WD. Rosacea: I. Etiology, pathogenesis, and subtype classification. J Am Acad Dermatol. 2004;51:327-341.
  3. Bikowski JB. Rosacea: a tiered approach to therapy.Cutis. 2000;66:S3-S6.
  4. Bikowski JB, Goldman MP. Rosacea: where are we now? J Drugs Dermatol. 2004;3:251-261.
  5. Pelle MT, Crawford GH, James WD. Rosacea: II. Therapy. J Am Acad Dermatol. 2004;51:499-512.
  6. Del Rosso JQ, Bikowski JB. Multicenter, double-blind, randomized, placebo-controlled, parallel-group trial results evaluating the effects of 40 mg doxycycline monohydrate controlled-release capsules in the treatment of rosacea. Poster presentation (P-164), 64th Annual American Academy of Dermatology Meeting, San Francisco, California, March 3-7, 2006 (submitted for publication).
  7. Skidmore RA, Walker C, Kovach R, et al. Effects of a subantimicrobial dose of doxycycline in the treatment of moderate acne. Arch Dermatol. 2003;139:459-464.
  8. Powell FC. Rosacea. N Engl J Med. 2005;352:793-803.
  9. Dahl MV. Pathogenesis of rosacea. Adv Dermatol.2001;17:29-45.
  10. Bamford JTM. Rosacea: current thoughts on origin. Sem Cut Med Surg. 2001;20:199-206.
  11. Aroni K, Tsagroni E, Lazaris A, et al. Rosacea: a clinicopathological approach. Dermatology. 2004;209:177-182.
  12. Wilkin JK. Rosacea: pathophysiology and treatment. Arch Dermatol. 1994;130:359-362.
  13. Wilkin JK. Oral-thermal flushing in erythematotelangiectatic rosacea. J Invest Dermatol. 1981;76:15-18.
  14. Soybe P. Aetiology and pathogenesis of rosacea. Acta Derm Venereol. 1950;30:137-153.
  15. Neumann E, Frithz A. Capillaropathy and capillaroneogenesis in the pathogenesis of rosacea. Int J Dermatol. 1998;37:263-266.
  16. Helm KF, Menz J, Gibson LE, et al. Clinical and histopathologic study of granulomatous rosacea.J Am Acad Dermatol.1991;25:1038-1043.
  17. Schmidt NF, Gans EH. Demodex and rosacea, I: the prevalence and numbers of Demodex mites in rosacea.Cosm Dermatol.2004;17:497-502.
  18. Schmidt NF, Gans EH. Demodex and rosacea, II: Demodex mites and rosacea inflammation.Cosm Dermatol.2004;17:575-580.
  19. Forton F, Germaux MA, Brasseur T, et al. Democidosis and rosacea: epidemiology and significance in daily dermatologic practice.J Am Acad Dermatol.2005;52:74-87.
  20. Dahl MV, Ross AJ, Schlievert PM. Temperature regulates bacterial protein production: possible role in rosacea.J Am Acad Dermatol.2004;50:266-272.
  21. Dirschka T, Tronnier H, Folster-Holst R. Epithelial barrier function and atopic diathesis in rosacea and perioral dermatitis.Br J Dermatol. 2004:150(6):1136-1141.
  22. Jones D. Reactive oxygen species and rosacea.Cutis.2004;74(Suppl 3):17-20.
  23. Oztas MO, Balk M, Ogus E, et al. The role of free oxygen radicals in the aetiopathogenesis of rosacea.Clin Exp Dermatol. 2003;28:188-192.
  24. Miyachi Y. Potential antioxidant mechanism of action for metronidazole: implications for rosacea management.Adv Ther. 2001;18:237-243.
  25. Miyachi Y, Yoshioka A, Imamura S, et al. Effect of antibiotics on the generation of reactive oxygen species.J Invest Dermatol. 1986;86:449-453.
  26. Jain A, Sangal L, Basal E, et al. Anti-inflammatory effects of erythromycin and tetracycline on Propionibacterium acnes induced production of chemotactic factors and reactive oxygen species by human neutrophils (abstract). Dermatol Online J. 2002;8:2.
  27. Akamatsu H, Komura J, Asada Y, et al. Inhibitory effect of azelaic acid on neutrophil functions: a possible cause for its efficacy in treating pathogentically unrelated diseases. Arch Dermatol Res. 1991;283:162-166.
  28. Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol. 2006;54:258-265.
  29. Golub LM, Lee HM, Ryan ME. Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res. 1998;12:12-26.
  30. 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;38:829-837.
  31. Marples RR, Kligman AM. Ecological effect of oral antibiotics on the microflora of human skin. Arch Dermatol. 1971;103:148-153.
  32. Adams SJ, Cunliffe WJ, Cooke EM. Long-term antibiotic therapy for acne vulgaris: effects on the bowel flora of patients and their relatives. J Invest Dermatol.1985;85:35-37.
  33. Levy RM, Huang EY, Roling D, et al. Effect of antibiotics on the oropharyngeal flora in patients with acne. Arch Dermatol. 2003;139:467-471.
  34. Del Rosso JQ. A status report on the use of subantimicrobial-dose doxycycline: a review of the biologic and antimicrobial effects of the tetracyclines. Cutis. 2004;74:118-122.
  35. Eady AH, Cove JH, Layton AM. Is antibiotic resistance in cutaneous propionibacteria clinically relevant? Implications of resistance for acne patients and prescribers. Am J Clin Dermatol. 2003;12:813-831.
  36. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther. 2001;23:1296-1310.
  37. Del Rosso JQ. Systemic therapy for rosacea: focus on oral antibiotic therapy and safety. Cutis. 2000;66:S7-S13.