Azithromycin in periodontal treatment: More than an antibiotic

Journal of Periodontal Research

Volumn 47, Issue 2, 2012, Pages 137-148

  Hirsch, R ^a   Deng, H ^a   Laohachai, M N ^a  

^a UNIVERSITY OF ADELAIDE   (Australia)

Author keywords

Azithromycin; Gingival overgrowth; Periodontal therapy; Periodontitis

Indexed keywords

ANTIINFECTIVE AGENT; ANTIINFLAMMATORY AGENT; AZITHROMYCIN; IMMUNOLOGIC FACTOR;

FIBROBLAST; GINGIVA OVERGROWTH; HUMAN; MACROPHAGE; METABOLISM; PERIODONTAL DISEASE; PERIODONTITIS; REVIEW;

ANTI-BACTERIAL AGENTS; ANTI-INFLAMMATORY AGENTS; AZITHROMYCIN; FIBROBLASTS; GINGIVAL OVERGROWTH; HUMANS; IMMUNOLOGIC FACTORS; MACROPHAGES; PERIODONTAL DISEASES; PERIODONTITIS;

EID: 84857452314     PISSN: 00223484     EISSN: 16000765     Source Type: Journal    
DOI: 10.1111/j.1600-0765.2011.01418.x     Document Type: Review

References (93)

1. Hoepelman IM, Schneider MM. Azithromycin: the first of the tissue-selective azalides. Int J Antimicrob Agents 1995;5:145-167.
2. Greenwood D. Antimicrobial Drugs: Chronicle of a Twentieth Century Medical Triumph. Oxford: Oxford University Press, 2008:xxix, 429.
3. Miller RS, Wongsrichanalai C, Buathong N et al. Effective treatment of uncomplicated Plasmodium falciparum malaria with azithromycin-quinine combinations: a randomized, dose-ranging study. Am J Trop Med Hyg 2006;74:401-406.
4. Noedl H, Krudsood S, Chalermratana K et al. Azithromycin combination therapy with artesunate or quinine for the treatment of uncomplicated Plasmodium falciparum malaria in adults: a randomized, phase 2 clinical trial in Thailand. Clin Infect Dis 2006;43:1264-1271.
5. Gomi K, Yashima A, Iino F et al. Drug concentration in inflamed periodontal tissues after systemically administered azithromycin. J Periodontol 2007;78:918-923.
6. Haffajee AD, Torresyap G, Socransky SS. Clinical changes following four different periodontal therapies for the treatment of chronic periodontitis: 1-year results. J Clin Periodontol 2007;34:243-253.
7. Glasheen JJ, Fugit RV, Prochazka AV. The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens. J Gen Intern Med 2005;20:653-656.
8. Anon. Pfizer azithromycin prescribing guide. URL: [accessed on 20 July 2011]
9. Lopez-Boado YS, Rubin BK. Macrolides as immunomodulatory medications for the therapy of chronic lung diseases. Curr Opin Pharmacol 2008;8:286-291.
10. Shinkai M, Henke MO, Rubin BK. Macrolide antibiotics as immunomodulatory medications: proposed mechanisms of action. Pharmacol Ther 2008;117:393-405.
11. Gomi K, Yashima A, Nagano T, Kanazashi M, Maeda N, Arai T. Effects of full-mouth scaling and root planing in conjunction with systemically administered azithromycin. J Periodontol 2007;78:422-429.
12. Corey EJ, CzakoÌ B, Kürti L. Molecules and Medicine, 'Part IV: Antibiotics'. Hoboken, NJ: John Wiley & Sons, 2007, p. 134.
13. Foulds G, Shepard RM, Johnson RB. The pharmacokinetics of azithromycin in human serum and tissues. J Antimicrob Chemother 1990;25(suppl A):73-82.
14. Wolter J, Seeney S, Bell S, Bowler S, Masel P, McCormack J. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Thorax 2002;57:212-216.
15. Solomon AW, Holland MJ, Alexander ND et al. Mass treatment with single-dose azithromycin for trachoma. N Engl J Med 2004;351:1962-1971.
16. Arguedas A, Emparanza P, Schwartz RH et al. A randomized, multicenter, double blind, double dummy trial of single dose azithromycin versus high dose amoxicillin for treatment of uncomplicated acute otitis media. Pediatr Infect Dis J 2005;24:153-161.
17. Haggerty CL, Ness RB. Newest approaches to treatment of pelvic inflammatory disease: a review of recent randomized clinical trials. Clin Infect Dis 2007;44:953-960.
18. Chico RM, Pittrof R, Greenwood B, Chandramohan D. Azithromycin-chloroquine and the intermittent preventive treatment of malaria in pregnancy. Malar J 2008;7:255.
19. Bosnar M, Bosnjak B, Cuzic S et al. Azithromycin and clarithromycin inhibit lipopolysaccharide-induced murine pulmonary neutrophilia mainly through effects on macrophage-derived granulocyte-macrophage colony-stimulating factor and interleukin-1beta. J Pharmacol Exp Ther 2009;331:104-113.
20. Hardy DJ, Hensey DM, Beyer JM, Vojtko C, McDonald EJ, Fernandes PB. Comparative in vitro activities of new 14-, 15-, and 16-membered macrolides. Antimicrob Agents Chemother 1988;32:1710-1719.
21. Pallasch TJ. Antibacterial and antibiotic drugs. In: Yagiela JA, Dowd FJ, Johnson BS, Mariotti AJ, Neidle EA, eds. Pharmacology and Therapeutics for Dentistry, 6th edition. St. Louis, MO: Mosby, 2011:618-621.
22. Tamura A, Ara T, Imamura Y, Fujii T, Wang PL. The effects of antibiotics on in vitro biofilm model of periodontal disease. Eur J Med Res 2008;13:439-445.
23. Kitzis MD, Goldstein FW, Miegi M, Acar JF. In-vitro activity of azithromycin against various Gram-negative bacilli and anaerobic bacteria. J Antimicrob Chemother 1990;25(suppl A):15-18.
24. Pajukanta R. In vitro antimicrobial susceptibility of Porphyromonas gingivalis to azithromycin, a novel macrolide. Oral Microbiol Immunol 1993;8:325-326.
25. Haffajee AD, Patel M, Socransky SS. Microbiological changes associated with four different periodontal therapies for the treatment of chronic periodontitis. Oral Microbiol Immunol 2008;23:148-157.
26. Wang PL. Roles of oral bacteria in cardiovascular diseases - from molecular mechanisms to clinical cases: treatment of periodontal disease regarded as biofilm infection: systemic administration of azithromycin. J Pharmacol Sci 2010;113:126-133.
27. Morozumi T, Kubota T, Abe D, Shimizu T, Komatsu Y, Yoshie H. Effects of irrigation with an antiseptic and oral administration of azithromycin on bacteremia caused by scaling and root planing. J Periodontol 2010;81:1555-1563.
28. Lai PC, Ho W, Jain N, Walters JD. Azithromycin Concentrations in Blood and Gingival Crevicular Fluid After Systemic Administration. J Periodontol 2011 Mar 21 [Epub ahead of print].
29. Tateda K, Comte R, Pechere JC, Kohler T, Yamaguchi K, Van Delden C. Azithromycin inhibits quorum sensing in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2001;45:1930-1933.
30. Tateda K, Standiford TJ, Pechere JC, Yamaguchi K. Regulatory effects of macrolides on bacterial virulence: potential role as quorum-sensing inhibitors. Curr Pharm Des 2004;10:3055-3065.
31. Nalca Y, Jansch L, Bredenbruch F, Geffers R, Buer J, Haussler S. Quorum-sensing antagonistic activities of azithromycin in Pseudomonas aeruginosa PAO1: a global approach. Antimicrob Agents Chemother 2006;50:1680-1688.
32. Bala A, Kumar R, Harjai K. Inhibition of quorum sensing in Pseudomonas aeruginosa by azithromycin and its effectiveness in urinary tract infections. J Med Microbiol 2011;60:300-306.
33. Goossens H. Antibiotic consumption and link to resistance. Clin Microbiol Infect 2009;15(suppl 3):12-15.
34. Malhotra-Kumar S, Lammens C, Martel A et al. Oropharyngeal carriage of macrolide-resistant viridans group streptococci: a prevalence study among healthy adults in Belgium. J Antimicrob Chemother 2004;53:271-276.
35. Malhotra-Kumar S, Lammens C, Coenen S, Van Herck K, Goossens H. Effect of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: a randomised, double-blind, placebo-controlled study. Lancet 2007;369:482-490.
36. van Winkelhoff AJ, Herrera D, Oteo A, Sanz M. Antimicrobial profiles of periodontal pathogens isolated from periodontitis patients in The Netherlands and Spain. J Clin Periodontol 2005;32:893-898.
37. Yousef AA, Jaffe A. The role of azithromycin in patients with cystic fibrosis. Paediatr Respir Rev 2010;11:108-114.
38. Pressler T. Targeting airway inflammation in cystic fibrosis in children: past, present, and future. Paediatr Drugs 2011;13:141-147.
39. Tamaoki J, Kadota J, Takizawa H. Clinical implications of the immunomodulatory effects of macrolides. Am J Med 2004;117(suppl 9A):5S-11S.
40. Giamarellos-Bourboulis EJ. Macrolides beyond the conventional antimicrobials: a class of potent immunomodulators. Int J Antimicrob Agents 2008;31:12-20.
41. Gladue RP, Bright GM, Isaacson RE, Newborg MF. In vitro and in vivo uptake of azithromycin (CP-62, 993) by phagocytic cells: possible mechanism of delivery and release at sites of infection. Antimicrob Agents Chemother 1989;33:277-282.
42. Gladue RP, Snider ME. Intracellular accumulation of azithromycin by cultured human fibroblasts. Antimicrob Agents Chemother 1990;34:1056-1060.
43. McDonald PJ, Pruul H. Phagocyte uptake and transport of azithromycin. Eur J Clin Microbiol Infect Dis 1991;10:828-833.
44. Bosnar M, Kelneric Z, Munic V, Erakovic V, Parnham MJ. Cellular uptake and efflux of azithromycin, erythromycin, clarithromycin, telithromycin, and cethromycin. Antimicrob Agents Chemother 2005;49:2372-2377.
45. Schentag JJ, Ballow CH. Tissue-directed pharmacokinetics. Am J Med 1991;91:5S-11S.
46. Culic O, Erakovic V, Cepelak I et al. Azithromycin modulates neutrophil function and circulating inflammatory mediators in healthy human subjects. Eur J Pharmacol 2002;450:277-289.
47. Hodge S, Hodge G, Brozyna S, Jersmann H, Holmes M, Reynolds PN. Azithromycin increases phagocytosis of apoptotic bronchial epithelial cells by alveolar macrophages. Eur Respir J 2006;28:486-495.
48. Cigana C, Nicolis E, Pasetto M, Assael BM, Melotti P. Anti-inflammatory effects of azithromycin in cystic fibrosis airway epithelial cells. Biochem Biophys Res Commun 2006;350:977-982.
49. Murphy BS, Sundareshan V, Cory TJ, Hayes D Jr, Anstead MI, Feola DJ. Azithromycin alters macrophage phenotype. J Antimicrob Chemother 2008;61:554-560.
50. Feola DJ, Garvy BA, Cory TJ et al. Azithromycin alters macrophage phenotype and pulmonary compartmentalization during lung infection with Pseudomonas. Antimicrob Agents Chemother 2010;54:2437-2447.
51. Cheung PS, Si EC, Hosseini K. Anti-inflammatory activity of azithromycin as measured by its NF-kappaB, inhibitory activity. Ocul Immunol Inflamm 2010;18:32-37.
52. Kamemoto A, Ara T, Hattori T, Fujinami Y, Imamura Y, Wang PL. Macrolide antibiotics like azithromycin increase lipopolysaccharide-induced IL-8 production by human gingival fibroblasts. Eur J Med Res 2009;14:309-314.
53. Matsumura Y, Mitani A, Suga T et al. Azithromycin may inhibit interleukin-8 through the suppression of Rac1 and a nuclear factor kappaB pathway in KB cells stimulated with lipopolysaccharide. J Periodontol 2011 Mar 21 [Epub ahead of print].
54. Ho W, Eubank T, Leblebicioglu B, Marsh C, Walters J. Azithromycin decreases crevicular fluid volume and mediator content. J Dent Res 2010;89:831-835.
55. Blandizzi C, Malizia T, Lupetti A et al. Periodontal tissue disposition of azithromycin in patients affected by chronic inflammatory periodontal diseases. J Periodontol 1999;70:960-966.
56. Malizia T, Batoni G, Ghelardi E et al. Interaction between piroxicam and azithromycin during distribution to human periodontal tissues. J Periodontol 2001;72:1151-1156.
57. Sefton AM, Maskell JP, Beighton D et al. Azithromycin in the treatment of periodontal disease. Effect on microbial flora. J Clin Periodontol 1996;23:998-1003.
58. Schmidt EF, Bretz WA. Benefits of additional courses of systemic azithromycin in periodontal disease case report. N Y State Dent J 2007;73:40-45.
59. Hirsch R. Periodontal healing and bone regeneration in response to azithromycin. Aust Dent J 2010;55:193-199.
60. Wahlstrom E, Zamora JU, Teichman S. Improvement in cyclosporine-associated gingival hyperplasia with azithromycin therapy. N Engl J Med 1995;332:753-754.
61. Nowicki M, Kokot F, Wiecek A. Partial regression of advanced cyclosporin-induced gingival hyperplasia after treatment with azithromycin. A case report. Ann Transplant 1998;3:25-27.
62. Wong W, Hodge MG, Lewis A, Sharpstone P, Kingswood JC. Resolution of cyclosporin-induced gingival hypertrophy with metronidazole. Lancet 1994;343:986.
63. Gomez E, Sanchez-Nunez M, Sanchez JE et al. Treatment of cyclosporin-induced gingival hyperplasia with azithromycin. Nephrol Dial Transplant 1997;12:2694-2697.
64. Paik JW, Kim CS, Cho KS, Chai JK, Kim CK, Choi SH. Inhibition of cyclosporin A-induced gingival overgrowth by azithromycin through phagocytosis: an in vivo and in vitro study. J Periodontol 2004;75:380-387.
65. Kim JY, Park SH, Cho KS et al. Mechanism of azithromycin treatment on gingival overgrowth. J Dent Res 2008;87:1075-1079.
66. Slots J, Ting M. Systemic antibiotics in the treatment of periodontal disease. Periodontol 2000 2002;28:106-176.
67. Mombelli A, Cionca N, Almaghlouth A. Does adjunctive antimicrobial therapy reduce the perceived need for periodontal surgery? Periodontol 2000 2011;55:205-216.
68. Heller D, Varela VM, Silva-Senem MX, Torres MC, Feres-Filho EJ, Colombo AP. Impact of systemic antimicrobials combined with anti-infective mechanical debridement on the microbiota of generalized aggressive periodontitis: a 6-month RCT. J Clin Periodontol 2011;38:355-364.
69. Varela VM, Heller D, Silva-Senem MX, Torres MC, Colombo AP, Feres-Filho EJ. Systemic antimicrobials adjunctive to A repeated mechanical and antiseptic therapy for aggressive periodontitis: a 6-month randomized controlled trial. J Periodontol 2011;82:1121-1130.
70. Li JZ, Winston LG, Moore DH, Bent S. Efficacy of short-course antibiotic regimens for community-acquired pneumonia: a meta-analysis. Am J Med 2007;120:783-790.
71. Griffiths GS, Ayob R, Guerrero A et al. Amoxicillin and metronidazole as an adjunctive treatment in generalized aggressive periodontitis at initial therapy or re-treatment: a randomized controlled clinical trial. J Clin Periodontol 2011;38:43-49.
72. Rizzo A, Paolillo R, Guida L, Annunziata M, Bevilacqua N, Tufano MA. Effect of metronidazole and modulation of cytokine production on human periodontal ligament cells. Int Immunopharmacol 2010;10:744-750.
73. Sloan B, Scheinfeld N. The use and safety of doxycycline hyclate and other second-generation tetracyclines. Expert Opin Drug Saf 2008;7:571-577.
74. Mencarelli A, Distrutti E, Renga B et al. Development of non-antibiotic macrolide that corrects inflammation-driven immune dysfunction in models of inflammatory bowel diseases and arthritis. Eur J Pharmacol 2011;665:29-39.
75. Smith SR, Foyle DM, Daniels J et al. A double-blind placebo-controlled trial of azithromycin as an adjunct to non-surgical treatment of periodontitis in adults: clinical results. J Clin Periodontol 2002;29:54-61.
76. Fujii T, Wang P-L, Hosokawa Y et al. Effect of systemically administered azithromycin in early onset aggressive periodontitis. Periodontol 2000 2004;1:321-325.
77. Mascarenhas P, Gapski R, Al-Shammari K et al. Clinical response of azithromycin as an adjunct to non-surgical periodontal therapy in smokers. J Periodontol 2005;76:426-436.
78. Dastoor SF, Travan S, Neiva RF, Rayburn LA, Giannobile WV, Wang HL. Effect of adjunctive systemic azithromycin with periodontal surgery in the treatment of chronic periodontitis in smokers: a pilot study. J Periodontol 2007;78:1887-1896.
79. Pradeep AR, Sagar SV, Daisy H. Clinical and microbiologic effects of subgingivally delivered 0.5% azithromycin in the treatment of chronic periodontitis. J Periodontol 2008;79:2125-2135.
80. Haas AN, de Castro GD, Moreno T et al. Azithromycin as an adjunctive treatment of aggressive periodontitis: 12-months randomized clinical trial. J Clin Periodontol 2008;35:696-704.
81. Yashima A, Gomi K, Maeda N, Arai T. One-stage full-mouth versus partial-mouth scaling and root planing during the effective half-life of systemically administered azithromycin. J Periodontol 2009;80:1406-1413.
82. Oteo A, Herrera D, Figuero E, O'Connor A, Gonzalez I, Sanz M. Azithromycin as an adjunct to scaling and root planing in the treatment of Porphyromonas gingivalis-associated periodontitis: a pilot study. J Clin Periodontol 2010;37:1005-1015.
83. Puig JM, Lloveras J, Bosch JM et al. Treatment of gingival hyperplasia secondary to cyclosporine by the new macrolide azithromycin. Transplant Proc 1997;29:2379-2380.
84. Jucgla A, Moreso F, Sais G et al. The use of azithromycin for cyclosporin-induced gingival overgrowth. Br J Dermatol 1998;138:198-199.
85. Nash MM, Zaltzman JS. Efficacy of azithromycin in the treatment of cyclosporine-induced gingival hyperplasia in renal transplant recipients. Transplantation 1998;65:1611-1615.
86. Wirnsberger GH, Pfragner R, Mauric A, Zach R, Bogiatzis A, Holzer H. Effect of antibiotic treatment with azithromycin on cyclosporine A-induced gingival hyperplasia among renal transplant recipients. Transplant Proc 1998;30:2117-2119.
87. Citterio F, Di Pinto A, Borzi MT et al. Azithromycin treatment of gingival hyperplasia in kidney transplant recipients is effective and safe. Transplant Proc 2001;33:2134-2135.
88. Nafar M, Ataie R, Einollahi B, Nematizadeh F, Firoozan A, Poorrezagholi F. A comparison between the efficacy of systemic and local azithromycin therapy in treatment of cyclosporine induced gingival overgrowth in kidney transplant patients. Transplant Proc 2003;35:2727-2728.
89. Mesa FL, Osuna A, Aneiros J et al. Antibiotic treatment of incipient drug-induced gingival overgrowth in adult renal transplant patients. J Periodontal Res 2003;38:141-146.
90. Tokgoz B, Sari HI, Yildiz O et al. Effects of azithromycin on cyclosporine-induced gingival hyperplasia in renal transplant patients. Transplant Proc 2004;36:2699-2702.
91. Chand DH, Quattrocchi J, Poe SA, Terezhalmy GT, Strife CF, Cunningham RJ. Trial of metronidazole vs. azithromycin for treatment of cyclosporine-induced gingival overgrowth. Pediatr Transplant 2004;8:60-64.
92. Argani H, Pourabbas R, Hassanzadeh D, Masri M, Rahravi H. Treatment of cyclosporine-induced gingival overgrowth with azithromycin-containing toothpaste. Exp Clin Transplant 2006;4:420-424.
93. Ramalho VL, Ramalho HJ, Cipullo JP, Azoubel R, Burdmann EA. Comparison of azithromycin and oral hygiene program in the treatment of cyclosporine-induced gingival hyperplasia. Ren Fail 2007;29:265-270.