With the continuing rise in clinical reports

Transcription

1 With the continuing rise in clinical reports of cutaneous MRSA (Methicillin-resistant Staphylococcus aureus) infections in the community and public health officials issuing consistent warnings about the risks of antibiotic overuse and misuse, dermatologists well know the importance of selective and appropriate use of oral antibiotics. Yet dermatologists continue to depend on systemic antibiotics to manage acne and rosacea. Despite compelling evidence of the danger of resistance, antibiotics remain a safe, effective, and very efficient treatment for certain patients with acne and rosacea. In ongoing efforts to capitalize on the therapeutic benefits of oral antibiotics in acne and rosacea while minimizing the risks associated with long-term use, interest has focused on the potential benefits associated with the use of subantimicrobial-dose antibiotics, specifically doxycycline. Though not approved for the treatment of acne or rosacea, subantimicrobial-dose doxycycline (SDD) demonstrates effectiveness in both conditions. 1,2,3,4 I ll review what we know about SDD and how that knowledge may influence the provision of dermatologic care right now. An Historical Perspective Systemic antibiotics, particularly those of the tetracycline class, are well known for their efficacy in treating acne and rosacea. In the case of acne, early interest in the use of systemic antibiotics aimed at diminishing P acnes colonization. While the role of P acnes in the pathogenesis of acne vulgaris is well documented and universally accepted, research and clinical experience have established the importance of other pathogenic 38 Practical Dermatology June 2005

2 By Joseph B. Bikowski, MD Sewickley, PA June 2005 Practical Dermatology 39

3 Subantimicrobial Dose Doxycycline factors, including inflammation, sebum production, and faulty keratinization. The fact that antibiotics confer anti-inflammatory benefits in addition to their antimicrobial action against P acnes further supported their use in acne management. The first reports of P acnes resistance to antibiotics emerged in the 1980s with subsequent reports drawing worldwide attention to the issue. 5,6 Working on the assumption that rosacea once termed acne rosacea was related to acne vulgaris, clinicians began to use antibiotics with good results in managing this condition. We now believe that the clinical benefit that results from the use of antibiotics in rosacea is due at least in part to the antiinflammatory action of these agents. Some have proposed a bacterial etiology in rosacea, speculating that rosacea may be related to helicobacter pylori infection, P acnes, or bacteria from Demodex mites. 7,8,31,32,33 Several studies fail to support the proposed link between H. pylori and rosacea. 9,10 In fact, one study found the prevalence of H. pylori was similar between rosacea patients and controls and showed that treatment with amoxicillin, clarithromycin, or omeprazole failed to significantly Inflammatory Response: A Thumbnail Sketch Inflammatory response has been implicated in the pathogenesis of both acne and rosacea. Though our understanding of the inflammatory process at the molecular level is not complete, research has elucidated many of the key steps of the inflammatory cascade. A general explanation of chronic inflammation as it relates to acne, rosacea, and SDD follows. In response to inflammatory stimuli, the body recruits activated neutrophils and macrophages to the area. Stimuli may include bacteria (proposed in both acne and rosacea) or infestation by other micro-organisms (such as Demodex in rosacea). Additionally, elastic and collagen tissue damage may initiate inflammatory processes in rosacea. Other unproven or as yet unidentified inflammatory instigators may also play a role in both diseases. Activated neutrophils may express matrix metalloproteinases (MMPs). Cytokines or T-helper cells are also produced in the early stages of inflammatory response. The activity of hydrolytic MMPs produces tissue destruction and is suspected to lead to free-radical generation that can in turn produce further inflammation. A number of MMPs have been identified, and they are necessary for normal development and wound healing. But MMPs are also implicated in a number of pathological processes, including the spread of metastatic cancer cells, arthritic conditions, atherosclerosis, and neuroinflammation. Two types of MMPs collagenases and gelatinases have been implicated in the inflammatory processes of acne and rosacea. Tetracyclines and tetracycline analogs demonstrate an ability to interfere with MMPs and down-regulate cytokines. In the case of rosacea, inhibition of gelatinases may protect capillary wall leakage, reduce swelling, and improve connective tissue integrity. Perhaps the greatest body of evidence for this anti-inflammatory effect of tetracyclines and tetracycline analogs comes from the study of periodontal disease. Collagenase and gelatinase are implicated in the inflammation and bone loss associated with periodontitis. Studies demonstrate that various nonantimicrobial tetracycline analogs inhibit collagenase and gelatinase and lead to decreased expression of cytokines, including TNF, IL-1, and IL-6. This activity accounts for the clinical effect of Periostat (doxycycline 20mg BID, CollaGenex) in decreasing the inflammation associated with periodontitis and delaying progression of the disease. 1. Mandal M, Mandal A, Das S, et al. Clinical implications of matrix metalloproteinases. Molecular and Cellular Biochemistry : Rifkin BR, Vernillo AT, Golub LM. Blocking periodontal disease progression by inhibiting tissue-destructive enzymes: a potential therapeutic role for tetracyclines and their chemically-modified analogs. J Periodontol Aug;64(8 Suppl): Milliken L. The Proposed Inflammatory Pathophysiology of Rosacea: Implications for Treatment. SKINmed 2(1):43-47, Bikowski JB. Subantimicrobial dose doxycycline for acne and rosacea. Skinmed (4): Golub LM, Ramamurthy NS, Llavaneras A, et al. A chemically modified nonantimicrobial tetracycline (CMT- 8) inhibits gingival matrix metalloproteinases, periodontal breakdown, and extra-oral bone loss in ovariectomized rats. Ann N Y Acad Sci ;878: Ramamurthy NS, Rifkin BR, Greenwald RA, et al. Inhibition of matrix metalloproteinase-mediated periodontal bone loss in rats: a comparison of 6 chemically modified tetracyclines. J Periodontol Jul;73(7): Practical Dermatology June 2005

4 decrease erythema or provide more than temporary improvement in papulopustules in rosacea patients. 9 There is indirect evidence for a link between P acnes and rosacea. Studies show that once-daily benzoyl peroxide/clindamycin topical gel reduces the papulopustular component of rosacea. 32,33 The Trouble with Antibiotics Despite their utility, oral antibiotics at standard doses (at or above minimal inhibitory concentration) pose challenges in the management of acne and rosacea. Most notable is the risk of antibiotic resistance. Studies document the phenomenon of antibiotic resistant acne and, increasingly, resultant treatment failure. 11 Concerns about resistance have prompted new guidelines in acne management that emphasize topical antimicrobials and retinoids as well as shortened courses of systemic antibiotics in efforts to diminish dependence on oral antibiotics and thus limit risk of developing resistance. 12 Importantly, resistance is not limited to P acnes. Researchers have identified resistant strains of Staphylococcus epidermidis, 13,14,15 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. 16 Concern about long-term antibiotic use and subsequent resistance risk is especially high in light of the increase in reports of community-acquired MRSA (Methicillin-resistant Staphylococcus aureus) skin and soft-tissue infections. 17,18 Price et al report that MRSA accounted for just 1.5 percent of all strains of S. aureus at select dermatology outpatient clinics in In 1998 at these same clinics, 11.9 percent of all S. aureus strains were Methicillin-resistant. 19 A published report linking long-term antibiotic use by women with increasing risk of breast cancer 20 has engendered additional concern among patients regarding systemic antibiotic therapy. Of interest, the authors write that, Among women with the highest levels of tetracycline or macrolide use, risk of breast cancer was not elevated in those using these antibiotics exclusively for acne and rosacea. Due to flaws in this epidemiological study, any conclusions whether favorable or unfavorable are unreliable. Nonetheless, there was wide reporting of the study, and dermatologists may field questions from anxious patients. Finally, systemic antibiotics (erythromycin, tetracycline class) may be associated with changes in normal flora, GI upset, and Candida vaginitis. In addition to these general concerns related to antibiotic use, there are specific drawbacks associated with each of the agents administered systemically for acne and rosacea. P acnes resistance, as noted above, has led to general abandonment of erythromycin in favor of the tetracycline class for the Dermatologists may minimize but not obviate the risks associated with standard antibiotic therapy by varying: the dose, administration schedule, and formulation of antibiotic used. management of acne. 21 However, tetracycline has also been associated with high rates of resistant acne, increasing dependence on minocycline and doxycycline. 22 At standard doses, doxycycline is associated with more GI upset than is minocycline. But minocycline is associated with CNS side-effects, i.e. vertigo, while doxycycline is not. Minocycline poses the additional risk of bluish hyperpigmentation of the sclera, nails, teeth, mucous membranes, and skin. There is a dose-dependent risk of phototoxicity related to doxycycline. Dermatologists may minimize but not obviate the risks associated with standard antibiotic therapy by varying: the dose, administration schedule, and formulation of antibiotic used. For example, slowrelease minocycline (Dynacin, Medicis) may produce fewer CNS side effects than standard formulations, and administering doxycycline in the morning with food or administering doxycycline pellets (Doryx, Warner-Chilcott) can minimize GI side effects without hindering absorption. Seeking Alternatives In light of the concerns associated with standard-dose systemic antibiotics and the specific side effects of each of the commonly-used agents, dermatologists are naturally interested in effective alternatives. Topical antimicrobials particularly benzoyl peroxide and/or benzoyl peroxide combination products for June 2005 Practical Dermatology 41

5 Subantimicrobial Dose Doxycycline acne are obvious alternatives to systemic antibiotics in both acne and rosacea. Furthermore, use of topical retinoids to regulate keratinization and inflammation in acne is standard, and there is growing use of topical retinoids in rosacea management. Nonetheless, there remains a subset of patients with moderate to severe inflammatory acne or rosacea for whom topical therapy alone is insufficient and who are not candidates for or will not pursue oral isotretinoin therapy. For these individuals, subantimicrobial dose doxycycline may be an effective and convenient option with fewer side effects than standard dose antibiotics. The Theoretical Bases. Sub-antimicrobial does not mean sub-therapeutic. 3 In fact, though the tetracyclines are generally classified as antibiotics, they demonstrate a range of therapeutic effects independent of antimicrobial mechanisms. As such, these agents have current or theoretical applications in periodontitis, arthritis, osteoporosis, and cancer. 25,26,27 Chemically-modified tetracycline (CMT) analogs, of which there are at least 10, provide no antimicrobial effect. These analogs, modified so that the dimethylamino group from carbon-4 position (the side-chain required for antimicrobial activity) is removed, inhibit synthesis of collagenase and matrix metalloproteinases and down-regulate cytokines in animal models. 25,26,27 Based on this evidence that CMTs confer anti-inflammatory benefits even when no antibiotic effect is possible, researchers investigated subantimicrobial dose doxycycline for the management of periodontal disease, which was shown to involve an increase in matrix metalloproteinases. A 20mg dose of doxycycline hyclate is below the minimum inhibitory concentration; there is no antibiotic action. 28 Yet, twice-daily dosing of doxycycline hyclate (Periostat, CollaGenex) is widely and effectively used for the management of periodontitis. Its action is exclusively antiinflammatory and long-term SDD therapy (up to 18 months) produced no changes in antimicrobial susceptibility in patients during the treatment period or up to six months post-treat- A 20mg dose of doxycycline hyclate is below the minimum inhibitory concentration; there is no antibiotic action...its action is exclusively anti-inflammatory. ment. 28,29 Periostat received FDA approval in 1998 for treatment of adult periodontitis and has been widely used for that indication. Applications in Dermatology. The efficacy of subantimicrobial dose doxycycline in reducing the inflammation of periodontitis without simultaneously providing an antibacterial effect naturally prompted interest in the potential for SDD to treat inflammatory acne and rosacea. The ability to reduce inflammatory lesions and target the inflammatory component of either disease without the side effects of standard dose antibiotics or risk of resistance would be clearly beneficial. Data from 40 patients in a six-month double-blind, randomized, placebo-controlled study assessing the efficacy of twice daily dosing of 20mg doxycycline in moderate facial acne show that SDD (20mg per dose) significantly reduced the number of inflammatory and non-inflammatory lesions over six months. 4 Importantly, SDD was well-tolerated, and there was no detectable antimicrobial effect on skin flora or increase in the number or severity of resistant organisms. There was no decrease in P acnes counts from the start of the study through its conclusion. Inflammatory lesion counts decreased by 50.1 percent in the treatment group, comedones decreased by 53.6 percent, and overall lesion counts were reduced by 52.3 percent. Clearance rates in the placebo group were 10.3 percent, 10.6 percent, and 17.5 percent, respectively. Results of an open-label study involving 50 patients with all stages of rosacea receiving 20mg doxycycline BID show a 80 to 100 percent reduction in inflammatory lesions and a 50 percent reduction in erythema after an average duration of four weeks of therapy. 3 One hundred thirty-four patients participated in a doubleblind, randomized, placebo-controlled study that confirmed the safety and efficacy of SDD in the treatment of rosacea. 2 Treatment consisted of 20mg doxycycline twice daily for 16 weeks. At the close of the study, 13.1 percent of treated patients demonstrated complete clearing versus 1.5 percent of those in the placebo group. 30 There is also evidence to support the combination of SDD with topical therapy, with the oral agent enhancing the efficacy of the topical treatment. A double-blind, randomized, placebo-controlled study involving 40 patients with rosacea with eight to 30 total inflammatory lesions compared SDD plus topical metronidazole lotion 0.75% to placebo plus topical metronidazole lotion 0.75%. The results document clinically 42 Practical Dermatology June 2005

6 significant differences in Clinician s Global Severity Scores between individuals in the SDD/topical metronidazole group and those in the placebo/topical metronidazole group by week four of treatment. 1 These differences became statistically significant by week 12, at which time the topical agent was withdrawn and patients continued either oral therapy or placebo treatment. SDD-treated patients maintained changes through monotherapy. Current Implications While the surge in reports of antibiotic resistance and mounting concerns about community-acquired MRSA infections force all dermatologists to judiciously consider the use of systemic antibiotics, no other FDA approved agent has yet proven able to fully replace these agents in the treatment of certain cases of acne and rosacea. The cumulative evidence from research studies and clinical practice continues to suggest that the primary benefit of oral antibiotics in the management of acne and rosacea comes via their anti-inflammatory rather than their antimicrobial actions. 3,30,34 Evidence thus far indicates that subantimicrobial dose doxycycline safely and effectively treats acne and rosacea but without the risks of developing resistance or the side effects associated with standard doses. Currently Periostat is approved only for the treatment of adult periodontitis, but CollaGenex has completed enrollment for phase three trials of once-daily Oracea (40mg doxycycline hyclate) and could file a new drug application before year s end. Whenever possible, treatment for mild to moderate disease should begin with topical agents alone or in combination, based on the particular characteristics of the patient and the presentation. If topical therapy proves insufficient, consider systemic therapy with SDD. SDD is preferable to standarddose antibiotics based on the numerous benefits described above documented efficacy, few if any side effects, and obviated risk of resistance. If necessary, SDD may be effectively combined with topical therapy. If after three months SDD therapy does not yield improvement, consider switching patients to minocycline or higher doses of doxycycline. 1. Sanchez J, Somolinoas AL, Almodovar PA, et al. Combined effect of doxycycline hyclate 20mg tablets and metronidazole 0.75 % topical lotion in the treatment of rosacea nd Annual Meeting of the AAD, Washington, DC. 2. Thiboutot D, Skidmore R, Fowler J, et al. Efficacy and Safety of subantimicrobial-dose doxycycline for the treatment of rosacea rd Annual Meeting of the AAD, New Orleans, LA. 3. Bikowski JB. Subantimicrobial dose doxycycline for acne and rosacea. Skinmed (4): Skidmore R, Kovach R, Walker C, et al. Effects of subantimicrobial-dose doxycycline in the treatment of moderate acne. Arch Dermatol (4): Leyden JJ, McGinley KJ, Cavalieri S, et al. Propionibacterium acnes resistance to antibiotics in acne patients. J Am Acad Dermatol (1): Eady EA, Gloor M, Leyden JJ. Propionibacterium acnes resistance: a worldwide problem. Dermatology. 2003;206(1): Diaz C, O Callaghan CJ, Khan A, et al. Rosacea: a cutaneous marker of Helicobacter pylori infection? Results of a pilot study. Acta Derm Venereol. 2003;83(4): Utas S, Ozbakir O, Turasan, et al. Helicobacter pylori eradication treatment reduces the severity of rosacea. J Am Acad Dermatol Mar;40(3): Herr H, You CH. Relationship between Helicobacter pylori and rosacea: it may be a myth.j Korean Med Sci Oct;15(5): Bamford JT, Tilden RL, Blankush JL, et al. Effect of treatment of Helicobacter pylori infection on rosacea. Arch Dermatol Jun;135(6): Eady AE, 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;4(12): Gollnick H, Cunliffe W, Berson D, et al. Global Alliance to Improve Outcomes in Acne. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol Jul;49(1 Suppl):S Nishijima S, Akamatsu H, Akamatsu M, et al. The antibiotic susceptibility of Propionibacterium acnes and Staphylococcus epidermidis isolated from acne. J Dermatol Mar;21(3): Nishijima S, Kurokawa I, Katoh N, Watanabe K. The bacteriology of acne vulgaris and antimicrobial susceptibility of Propionibacterium acnes and Staphylococcus epidermidis isolated from acne lesions. J Dermatol May;27(5): Dreno B, Reynaud A, Moyse D, et al. Erythromycin-resistance of cutaneous bacterial flora in acne. Eur J Dermatol Nov-Dec;11(6): Levy RM, Huang EY, Roling D, et al. Effect of antibiotics on the oropharyngeal flora in patients with acne. Arch Dermatol Apr;139(4): Frazee BW, Lynn J, Charlebois ED, et al. High prevalence of methicillin-resistant Staphylococcus aureus in emergency department skin and soft tissue infections. Ann Emerg Med Mar;45(3): Fridkin SK, Hageman JC, Morrison M, et al. Methicillin-resistant Staphylococcus aureus disease in three communities. N Engl J Med Apr 7;352(14): Price MF, McBride ME, Wolf JE Jr. Prevalence of methicillin-resistant Staphylococcus aureus in a dermatology outpatient population. South Med J Apr;91(4): Velicer CM, Heckbert SR, Lampe JW et al. Antibiotic use in relation to the risk of breast cancer. JAMA ;291(7): Eady EA, et al. Erythromycin resistant in antibiotic treated acne patients: Association with therapeutic failure. Br J Dermatol 1989;121: Eady EA, Jones C, Gardner K, et al. Tetracycline-resistant propionibacteria from acne patients are cross-resistant to doxycycline but sensitivie to minocycline. Br J Dermatol 1993;128: Golub LM, Lee HM, Ryan ME, et al. Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res Nov;12(2): Lokeshwar BL. MMP inhibition in prostate cancer. ANN NY Sci 1999;878: Golub LM, Ramamurthy NS, Llavaneras A, et al. A chemically modified nonantimicrobial tetracycline (CMT-8) inhibits gingival matrix metalloproteinases, periodontal breakdown, and extra-oral bone loss in ovariectomized rats. Ann N Y Acad Sci ;878: Ramamurthy NS, Rifkin BR, Greenwald RA, et al. Inhibition of matrix metalloproteinase-mediated periodontal bone loss in rats: a comparison of 6 chemically modified tetracyclines. J Periodontol Jul;73(7): Lokeshwar BL, Selzer MG, Zhu BQ, et al. Inhibition of cell proliferation, invasion, tumor growth and metastasis by an oral non-antimicrobial tetracycline analog (COL-3) in a metastatic prostate cancer model. Int J Cancer ;98(2): Walker C, Thomas J, Nango S, Lennon J, Wetzel J, Powala C. Long-term treatment with subantimicrobial dose doxycycline exerts no antibacterial effect on the subgingival microflora associated with adult periodontitis. J Periodontol. 2000;71(9): Thomas J, Walker C, Bradshaw M. Long-term use of subantimicrobial dose doxycycline does not lead to changes in antimicrobial susceptibility. J Periodontol Sep;71(9): 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(8): Powell FC. Rosacea and the pilosebaceous follicle. Cutis Sep;74(3 Suppl):9-12, Breneman D, Savin R, VandePol C, et al. Double-blind, randomized, vehicle-controlled clinical trial of once-daily benzoyl peroxide/clindamycin topical gel in the treatment of patients with moderate to severe rosacea. Int J Dermatol May;43(5): Leyden JJ, Thiboutot D, Shalita A. Photographic review of results from a clinical study comparing benzoyl peroxide 5%/clindamycin 1% topical gel with vehicle in the treatment of rosacea. Cutis Jun;73(6 Suppl): Milliken L. The Proposed Inflammatory Pathophysiology of Rosacea: Implications for Treatment. SKINmed 2(1):43-47, June 2005 Practical Dermatology 43