CLINICAL SCIENCE

Oral Azithromycin for Treatment of Posterior Blepharitis

Thais Zamudio Igami, MD,* Ricardo Holzchuh, MD,* Tammy Hentona Osaki, MD, Ruth Miyuki Santo, MD, PhD,* Newton Kara-Jose, MD, PhD,* and Richard Y. Hida, MD*
hronic posterior blepharitis or meibomian gland dysfunction (MGD) is a complex condition that is easily found in our daily general outpatient clinic. According to the International Dry Eye Workshop, it is typically characterized by inammation of the eyelids and meibomian gland obstruction or abnormal secretion causing lipid tear deciency or evaporative dry eye.16 Chronic posterior blepharitis commonly presents nonspecic symptoms like itching, tearing, photophobia, burning, dry eye, and foreign body sensation.3,4 Ocular ndings are related to meibomian gland and eyelid inammation, such as keratitis, neovascularization, corneal opacities, tear lm instability, stasis of meibomian secretion, and conjunctival and eyelid margin hyperemia.3 The tear lm plays a key role in maintaining tear surface tension, retarding evaporation, and providing a smooth optical surface for high-quality vision.7,8 Aqueous layer and mucin also can experience changes with environmental factors.9,10 It is believed that the tear lm lipid layer is a 2-phase layer, a thin polar phase adjacent to the aqueousmucin phase and a thick nonpolar phase associated with both the polar phase and the air interface.11 Meibum lipids are modied in patients with MGD. Meibomian gland abnormalities are related to stasis of the meibomian secretion caused by its inammation, obstruction, or atrophy, resulting in tear instability and evaporative dry eye.2,7,8 This can be a source of considerable visual disability and can cause extreme ocular discomfort.4,1215 The treatment of chronic blepharitis usually involves a continuous regimen of eyelid scrubs to remove debris and warm compresses to provide appropriate meibum secretion. For severe or refractory cases, topical and systemic antibiotics with antiinammatory properties are proposed (tetracycline, doxycycline, and minocycline).2,3 Based on its pharmacological properties and tolerance,1618 previous studies have shown that azithromycin can be a good option in the treatment of chronic inammatory diseases, such as rosacea.16,1826 It is also reported that topical azithromycin can improve posterior blepharitis;2729 however, there are no previous studies describing the benets of oral azithromycin in posterior blepharitis not related to rosacea. The purpose of this study was to evaluate the effects of oral azithromycin in patients with posterior blepharitis.

Purpose: To evaluate the effects of oral azithromycin in patients

with posterior blepharitis.

Methods: Twenty-six eyes of 13 patients with posterior blepharitis diagnosed by a qualied ophthalmologist were enrolled in this study. Patients were instructed to use oral azithromycin 500 mg per day for 3 days in 3 cycles with 7-day intervals. Subjective clinical outcomes were graded and scored 1 day before and 30 days after the end of the treatment (53 days after initiating the treatment) based on severity scores of: (1) eyelid debris; (2) eyelid telangiectasia; (3) swelling of the eyelid margin; (4) redness of the eyelid margin; and (5) ocular mucus secretion. For the assessment of global efcacy, patients were asked by the investigator to rate the subjective symptoms (eyelid itching, ocular itching, eyelid hyperemia, ocular hyperemia, ocular mucus secretion, photophobia, foreign body sensation, and dry eye sensation) on a scale of 0 (no symptoms) to 5 (severe symptoms). Break-up time, Schirmer I test, corneal uorescein staining score, and rose bengal staining score were also performed in all patients. Results: All clinical outcomes scoring showed statistically
signicant improvement after oral azithromycin, except for eyelid swelling. Average subjective symptom grading improved statistically after treatment with oral azithromycin, except for eyelid hyperemia, photophobia, and foreign body sensation. Average tear lm break-up time values showed statistically signicant improvement after the treatment with oral azithromycin. No statistically signicant improvement was observed on average values of Schirmer I test, corneal uorescein staining score, and rose bengal staining score.

Conclusions: The combination of multiple clinical parameters shown in this study supports the clinical efcacy of pulsed oral azithromycin therapy for the management of posterior blepharitis.
Key Words: blepharitis, meibomian glands, dry eye syndrome, macrolides, azithromycin, tear instability (Cornea 2011;30:11451149)

Received for publication June 27, 2010; revision received November 9, 2010; accepted November 17, 2010. From the *Department of Ophthalmology, Hospital das Clnicas of Universidade de Sao Paulo (USP), Sao Paulo, Brazil; and Department of Ophthalmology, Santa Casa de Sao Paulo, Sao Paulo, Brazil. Financial support: None. No authors have any nancial/conicting interests to disclose. Reprints: Richard Yudi Hida, Rua Afonso de Freitas, 488 apt 61, Paraiso, Sao Paulo, Brazil 04006-052 (e-mail: ryhida@gmail.com). Copyright 2011 by Lippincott Williams & Wilkins

MATERIALS AND METHODS

This prospective, noncontrolled, interventional case series adhered to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board (protocol
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number: 0301/08; Ethics Committee of the Hospital das Clnicas da Faculdade de Medicina da Universidade de Sao Paulo; (Comissao de Etica para Analise de Projetos de Pesquisa, CAPPesq). Informed consent was obtained from all the study participants after the nature and possible consequences of the study had been explained to them in detail. Twenty-six eyes of 13 patients [6 men and 7 women; 53.15 6 13.18 (mean 6 SD)] with posterior blepharitis diagnosed by a qualied ophthalmologist were enrolled in this study. All patients were examined at the Ocular Surface Outpatient Clinic of the Department of Ophthalmology, Universidade de Sao Paulo (Hospital das Clnicas of Universidade de Sao Paulo, HC-FMUSP) from January 2008 to August 2009. All patients enrolled in our study met the following criteria: (1) presence of signs and symptoms of posterior blepharitis; (2) daily need of articial tears; and (3) previous unsuccessful blepharitis therapy (eyedrops, ophthalmic ointment, or any oral medication). Using a subjective clinical outcome severity scores of 0 (normal) to 4 (very severe), patients enrolled in our study demonstrated scores of at least 1 for either redness or swelling of the eyelid margin and a score of at least 1 for either eyelid debris or meibomian gland secretion. Subjective clinical outcome was graded and scored by 1 investigator, in a designated order, 1 day before (D0) and 30 days after the end of the treatment (53 days after initiating the treatment) based on severity scores of: (1) eyelid debris; (2) eyelid telangiectasia; (3) swelling of the eyelid margin; (4) redness of the eyelid margin; and (5) ocular mucus secretion. All subjective clinical outcomes and evaluations were graded by the examiner as follows: 0, no signs; 1, mild signs; 2, moderate signs; and 3, severe signs. Meibomian gland secretion was graded from 0 to 3 (0 = clear secretion; 1 = cloudy secretion; 2 = granular or paste-like secretion; and 3 = no expressible secretion). For the assessment of global efcacy, patients were asked, by the investigator, to rate subjective symptoms (eyelid itching, ocular itching, eyelid hyperemia, ocular hyperemia, ocular mucus secretion, photophobia, foreign body sensation, and dry eye sensation) on a scale of 0 (no symptoms) to 5 (severe symptoms). Patients enrolled in our study demonstrated scores of at least 3 for any of the subjective symptoms cited above. Patients with the following were excluded from the study: (1) any topical or systemic antibiotics or antiinammatory drugs 90 days before study entry; (2) previous eye surgery or punctal occlusion; (3) use of any other topical or systemic medication that could interfere in the ocular surface; (4) contact lens use; (5) presence of any corneal diseases (marginal ulcer, opacity, scar, bullous keratopathy, inammation, edema, conjunctivochalasis, symblepharon, and tumor); (6) any eyelid structural abnormalities; (7) any inammation and/or active structural change in the iris or anterior chamber; (8) glaucoma; (9) any side effect with any macrolide antibiotics; (10) irregular use of azithromycin during the study (dose and frequency); (11) known hypersensitivity to azithromycin or any other macrolide antibiotics; (12) pregnancy; and (13) rosacea. Tear lm break-up time (TFBUT), Schirmer I test, corneal uorescein staining score, and rose bengal staining

score were also performed in all patients. Schirmer I test was assessed without anesthesia using Whatman 41 paper strip placed in the lateral lower conjunctival sac, and the measurement after 5 minutes (closed eye) was recorded. TFBUT, rose bengal staining score, and uorescein staining score were performed immediately after the instillation of 3 mL of 1:1 preservative-free solution consisting of 1% rose bengal and 1% uorescein dissolved in saline according to the double-vital staining method described by Toda and Tsubota30 and used in other studies.3133 TFBUT was measured 3 times and averaged. Ocular surface staining score was semiquantitatively assessed using a rating from 0 to 9 (0, no staining; 1, mild staining; 2, moderate staining; and 3, extensive staining) according to the methods described previously.8,30,34 Fluorescein staining score was assessed using a grading scale of 0 to 3 for each one-third of the cornea divided horizontally (total of 9 points). Rose bengal staining score was assessed using a grading scale of 0 to 3 in the cornea, nasal conjunctiva, and temporal conjunctiva (total of 9 points) (Fig. 1). All measurements and grading were performed by 1 examiner (Thais Zamudio Igami) under controlled climate (temperature and humidity variation of 20.4 6 1.28C and 62.6% 6 6.00%, respectively). Patients were instructed to use oral 500 mg azithromycin (1 tablet) per day for 3 days in 3 cycles with 7-day intervals (total treatment of 23 days). Patients were instructed to continue concomitant treatment prior to the study (such as eyelid hygiene and use of articial tears). Data are expressed as mean 6 SD. Comparisons were made using Student t test. The level of signicance was P , 0.05.

RESULTS
Figure 2 shows the subjective clinical outcomes scoring for eyelid debris, eyelid telangiectasia, swelling of the eyelid margin, redness of the eyelid margin, ocular mucus secretion, and meibomian gland secretion. We can observe statistically signicant improvement in most clinical signs analyzed in the present study, except for eyelid swelling (P = 0.999). Average subjective symptom grading (except for eyelid hyperemia, photophobia, and foreign body sensation) improved statistically after treatment with oral azithromycin (Fig. 3). Average TFBUT values improved statistically from 6.64 6 4.58 seconds to 9.75 6 5.83 seconds (P = 0.0005) after the treatment with oral azithromycin. No statistical improvement was observed in average values of Schirmer I test, corneal uorescein, and rose bengal staining score (Fig. 4).

DISCUSSION
Although the pathogenesis of MGD is still unclear, clinical improvement generally is obtained with eyelid scrubs to remove debris and warm compresses to facilitate meibomian excretion. However, when clinical and symptomatic improvement is slow or insufcient, empiric oral antibiotic treatment is proposed, even with the effects not fully understood. It is believed that some antibiotics with antiinammatory properties may help control bacterial ora and eyelid inammation.16,25,3537 Clinical benets of systemic antibiotics
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FIGURE 2. Average and SD of clinical symptom scoring before and after the treatment of oral azithromycin for the treatment of posterior blepharitis.

FIGURE 1. Assessment of ocular surface staining score. Fluorescein staining score was assessed using a grading scale of 0 to 3 for each one-third of the cornea divided horizontally (total of 9 points). Rose bengal staining score was assessed using a grading scale of 0 to 3 in the cornea, nasal conjunctiva, and temporal conjunctiva (total of 9 points). Scoring was rated from 0 to 3 (0, no staining; 1, mild staining; 2, moderate staining; and 3, extensive staining).

aureus for 4 days in the tears and 14 days in the conjunctiva.46 A long half-life (24 days) allows us to prescribe a simple and tolerable treatment.42 It also has afnity for human tissue undergoing an active inammatory process.42 For this reason, azithromycin was chosen for this study. Ocular ora in patients with anterior and posterior blepharitis primarily includes Staphylococcus epidermidis, Propionibacterium acnes, Corynebacterium sp., and S. aureus. It is believed that patients with blepharitis are more heavily colonized with these microorganisms.47,48 They could contribute to abnormalities of the meibomian gland secretion when they synthesize lipolytic enzymes responsible for the production of highly irritating fatty acids and cholesterol, resulting in tear lm instability, inammation, and epithelial toxicity (possibly caused by inammatory response to bacterial toxins).27,28,39,48,49 We believe that oral azithromycin in the treatment of posterior blepharitis may have similar mechanisms as those of oral tetracycline because previous studies have shown that tetracycline can inhibit bacterial lipase production and reduce fatty acids.39 We also hypothesize that the antiinammatory

like tetracycline, doxycycline, and minocycline for the treatment of meibomitis have been described previously by Aronowicz et al,38 Dougherty et al,39 Shine et al,40 and Ta et al.41 However, its side effects, tolerance, and compliance are sometimes inconveniences in completing the treatment. Azithromycin is a semisynthetic macrolide antibiotic chemically related to erythromycin and clarithromycin. It has a good intracellular penetration and half-life long enough to provide a wide and long antimicrobial effect.18,20,25,35,4244 The antiinammatory effect of azithromycin is already welldescribed by many authors.25,37,42,44,45 We believe that the immunomodulatory effect of azithromycin can be therapeutic in addition to its antibacterial properties.36 A single oral dose of 1 g of azithromycin can reach its minimum inhibitory concentration (MIC90) of 0.25 mg/mL for Staphylococcus
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FIGURE 3. Average and SD of clinical outcome scoring before and after the treatment of oral azithromycin for the treatment of posterior blepharitis. www.corneajrnl.com |

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the treatment of rosacea.20,21,51 Our study showed clinical benets using dosages similar to those described by Antonio et al16 and Singhi et al.18 Further randomized double-blind studies must be performed to clarify short-term and/or longterm efcacy, ideal dose, and comparison with other oral medications. In conclusion, the combination of multiple clinical parameters shown in this study supports the clinical efcacy of pulsed oral azithromycin therapy for the management of refractory or severe blepharitis/meibomitis.

FIGURE 4. Average and SD of ocular surface status scoring (rose bengal, uorescein, TFBUT, and Schirmer I) before and after the treatment of oral azithromycin for the treatment of posterior blepharitis.

REFERENCES
1. Research in Dry Eye: report of the Research Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5:179193. 2. Gilbard JP. Dry eye, blepharitis and chronic eye irritation: divide and conquer. J Ophthalmic Nurs Technol. 1999;18:109115. 3. Jackson WB. Blepharitis: current strategies for diagnosis and management. Can J Ophthalmol. 2008;43:170179. 4. Lemp MA, Nichols KK. Blepharitis in the United States 2009: a surveybased perspective on prevalence and treatment. Ocul Surf. 2009;7: S1S14. 5. McCulley JP, Dougherty JM, Deneau DG. Classication of chronic blepharitis. Ophthalmology. 1982;89:11731180. 6. McCulley JP, Shine WE. Changing concepts in the diagnosis and management of blepharitis. Cornea. 2000;19:650658. 7. Driver PJ, Lemp MA. Meibomian gland dysfunction. Surv Ophthalmol. 1996;40:343367. 8. Shimazaki J, Sakata M, Tsubota K. Ocular surface changes and discomfort in patients with meibomian gland dysfunction. Arch Ophthalmol. 1995;113:12661270. 9. Barabino S, Rolando M, Chen L, et al. Exposure to a dry environment induces strain-specic responses in mice. Exp Eye Res. 2007;84:973977. 10. Wieslander G, Norback D, Venge P. Changes of symptoms, tear lm stability and eosinophilic cationic protein in nasal lavage uid after reexposure to a damp ofce building with a history of ooding. Indoor Air. 2007;17:1927. 11. McCulley JP, Shine W. A compositional based model for the tear lm lipid layer. Trans Am Ophthalmol Soc. 1997;95:7988; discussion 8893. 12. Brewitt H, Sistani F. Dry eye disease: the scale of the problem. Surv Ophthalmol. 2001;45(Suppl 2):S199S202. 13. Kaido M, Dogru M, Ishida R, et al. Concept of functional visual acuity and its applications. Cornea. 2007;26:S29S35. 14. Lemp MA. Evaluation and differential diagnosis of keratoconjunctivitis sicca. J Rheumatol Suppl. 2000;61:1114. 15. Shimmura S, Shimazaki J, Tsubota K. Results of a population-based questionnaire on the symptoms and lifestyles associated with dry eye. Cornea. 1999;18:408411. 16. Antonio JR, Pegas JR, Cestari TF, et al. Azithromycin pulses in the treatment of inammatory and pustular acne: efcacy, tolerability and safety. J Dermatolog Treat. 2008;19:210215. 17. Bakar O, Demircay Z, Yuksel M, et al. The effect of azithromycin on reactive oxygen species in rosacea. Clin Exp Dermatol. 2007;32:197200. 18. Singhi MK, Ghiya BC, Dhabhai RK. Comparison of oral azithromycin pulse with daily doxycycline in the treatment of acne vulgaris. Indian J Dermatol Venereol Leprol. 2003;69:274276. 19. Akhyani M, Ehsani AH, Ghiasi M, et al. Comparison of efcacy of azithromycin vs. doxycycline in the treatment of rosacea: a randomized open clinical trial. Int J Dermatol. 2008;47:284288. 20. Bakar O, Demircay Z, Gurbuz O. Therapeutic potential of azithromycin in rosacea. Int J Dermatol. 2004;43:151154. 21. Bakar O, Demircay Z, Toker E, et al. Ocular signs, symptoms and tear function tests of papulopustular rosacea patients receiving azithromycin. J Eur Acad Dermatol Venereol. 2009;23:544549. 22. Fernandez-Obregon A. Oral use of azithromycin for the treatment of acne rosacea. Arch Dermatol. 2004;140:489490. 23. Fernandez-Obregon AC. Azithromycin for the treatment of acne. Int J Dermatol. 1997;36:239240. 24. Fernandez-Obregon AC. Azithromycin for the treatment of acne. Int J Dermatol. 2000;39:4550.

properties of azithromycin can help reduce eyelid and ocular surface inammation in the pathogenesis of blepharitis. However, further studies must be performed to investigate the inuence of azithromycin on ocular and eyelid inammatory factors. The present study showed improvement of clinical signs and symptoms after treatment with oral azithromycin. The main goal of MGD management is stabilization of the tear lm, and it is well-represented by TFBUT analysis, Schirmer I test, uorescein staining score, and rose bengal staining score.8,38 This study showed that oral azithromycin statistically improved TFBUT and meibomian gland secretion patterns of patients with MGD after 30 days of treatment. However, no improvement was observed in the Schirmer I test, uorescein staining score, or rose bengal staining score. This suggests that tear lm stability can be restored in patients with blepharitis, even with abnormal corneal integrity and tear secretion.7,8 Most of the patients (n = 12) studied claimed some benets in the symptoms analyzed (conjunctival congestion, foreign body sensation, and dry eye sensation) after treatment with azithromycin (except for photophobia). It is believed that this benet is related to the reduction of ocular surface inammation. Other studies have shown similar effects with the use of oral minocycline in patients with MGD.38,40,41,50 Luchs29 reported improvement in clinical signs and symptoms of posterior blepharitis after the use of 1% topical azithromycin. Similar results were found in our study after 30 days of systemic azithromycin. Bakar et al17 described benets of systemic azithromycin in symptoms and side effects for 4 weeks in papulopustular rosacea.20,21 Eyelid margin and ocular surface inammation were evaluated in his study; however, no statistical differences were observed in TFBUT, Schirmer test, rose bengal score, and uorescein score. In our study, side effects were not analyzed; however, 1 patient reported mild gastrointestinal side effects that did not interfere with compliance. Our study showed improvement of eyelid redness; however, eyelid swelling did not show improvement. Longer treatment strategies must be analyzed to evaluate the effect of azithromycin on swelling of the eyelid margin. There is no agreement on the ideal dosage of azithromycin. Previous studies have evaluated daily use of 250 or 500 mg per day for

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25. Labro MT. Anti-inammatory activity of macrolides: a new therapeutic potential? J Antimicrob Chemother. 1998;41(Suppl B):3746. 26. Sehgal VN, Sharma S, Sardana K. Rosacea/acne rosacea: efcacy of combination therapy of azithromycin and topical 0.1% tacrolimus ointment. J Eur Acad Dermatol Venereol. 2008;22:13661368. 27. Foulks GN, Borchman D, Yappert M, et al. Topical azithromycin therapy for meibomian gland dysfunction: clinical response and lipid alterations. Cornea. 2010;29:781788. 28. Haque RM, Torkildsen GL, Brubaker K, et al. Multicenter open-label study evaluating the efcacy of azithromycin ophthalmic solution 1% on the signs and symptoms of subjects with blepharitis. Cornea. 2010;29: 871877. 29. Luchs J. Efcacy of topical azithromycin ophthalmic solution 1% in the treatment of posterior blepharitis. Adv Ther. 2008;25:858870. 30. Toda I, Tsubota K. Practical double vital staining for ocular surface evaluation. Cornea. 1993;12:366367. 31. Hikichi T, Yoshida A, Fukui Y, et al. Prevalence of dry eye in Japanese eye centers. Graefes Arch Clin Exp Ophthalmol. 1995;233:555558. 32. Tsubota K, Monden Y, Yagi Y, et al. New treatment of dry eye: the effect of calcium ointment through eyelid skin delivery. Br J Ophthalmol. 1999; 83:767770. 33. Kaido M, Goto E, Dogru M, et al. Punctal occlusion in the management of chronic Stevens-Johnson syndrome. Ophthalmology. 2004;111: 895900. 34. van Bijsterveld OP. Diagnostic tests in the sicca syndrome. Arch Ophthalmol. 1969;82:1014. 35. Giamarellos-Bourboulis EJ. Macrolides beyond the conventional antimicrobials: a class of potent immunomodulators. Int J Antimicrob Agents. 2008;31:1220. 36. Rubin BK. Immunomodulatory properties of macrolides: overview and historical perspective. Am J Med. 2004;117(Suppl 9A):2S4S. 37. Voils SA, Evans ME, Lane MT, et al. Use of macrolides and tetracyclines for chronic inammatory diseases. Ann Pharmacother. 2005;39:8694.

38. Aronowicz JD, Shine WE, Oral D, et al. Short term oral minocycline treatment of meibomianitis. Br J Ophthalmol. 2006;90:856860. 39. Dougherty JM, McCulley JP, Silvany RE, et al. The role of tetracycline in chronic blepharitis. Inhibition of lipase production in staphylococci. Invest Ophthalmol Vis Sci. 1991;32:29702975. 40. Shine WE, McCulley JP, Pandya AG. Minocycline effect on meibomian gland lipids in meibomianitis patients. Exp Eye Res. 2003;76:417420. 41. Ta CN, Shine WE, McCulley JP, et al. Effects of minocycline on the ocular ora of patients with acne rosacea or seborrheic blepharitis. Cornea. 2003; 22:545548. 42. Alvarez-Elcoro S, Enzler MJ. The macrolides: erythromycin, clarithromycin, and azithromycin. Mayo Clin Proc. 1999;74:613634. 43. Gilmans GA. The Pharmacological Basis of Therapeutics. New York: McGraw-Hill Medical Publishing Division, 2006. 44. Ianaro A, Ialenti A, Mafa P, et al. Anti-inammatory activity of macrolide antibiotics. J Pharmacol Exp Ther. 2000;292:156163. 45. Levert H, Gressier B, Moutard I, et al. Azithromycin impact on neutrophil oxidative metabolism depends on exposure time. Inammation. 1998;22: 191201. 46. Tabbara KF, al-Kharashi SA, al-Mansouri SM, et al. Ocular levels of azithromycin. Arch Ophthalmol. 1998;116:16251628. 47. Dougherty JM, McCulley JP. Comparative bacteriology of chronic blepharitis. Br J Ophthalmol. 1984;68:524528. 48. Groden LR, Murphy B, Rodnite J, et al. Lid ora in blepharitis. Cornea. 1991;10:5053. 49. Dougherty JM, Osgood JK, McCulley JP. The role of wax and sterol ester fatty acids in chronic blepharitis. Invest Ophthalmol Vis Sci. 1991;32:19321937. 50. Souchier M, Joffre C, Gregoire S, et al. Changes in meibomian fatty acids and clinical signs in patients with meibomian gland dysfunction after minocycline treatment. Br J Ophthalmol. 2008;92:819822. 51. Modi S, Harting M, Rosen T. Azithromycin as an alternative rosacea therapy when tetracyclines prove problematic. J Drugs Dermatol. 2008;7: 898899.

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