High sensitive- C reactive protein, periodontal parameters and periodontal microbiota after scaling-root planning plus Azithromycin as treatment of Chronic Periodontitis: A Randomized Clinical Trial
Chronic periodontitis azitromycin randomized clinical trial C reactive protein
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Objective: This single blind randomized clinical trial (RCT) determined the effect of scaling and root planning plus azithromycin (SRP+Azi) in serum C reactive protein levels and other blood biomarkers, clinical periodontal parameters and subgingival microbial composition three months after periodontal therapy.
Materials and Methods: Forty-nine chronic periodontitis patients participatedin the study and were randomly assignedsession of scaling and root planning plus oral azithromycin 500 mg daily for five days (SRP+Azi) while, 27 patients in the control group received the same single session of scaling and root planning plus placebo (SRP+Pb). A group of 25 subjects presenting periodontal health-gingivitis were included as a comparison group and in them was determined clinical periodontal parameters, blood parameters and microbiota at baseline. Periodontitis groups received a full mouth periodontal examination, blood test and microbiological cultures at baseline, and three months after therapy.
Primary outcome variable was the variation in serum high sensitive C- reactive protein (hs-CRP). Secondary outcome variables were variation of triglycerides, High density Cholesterol (HDL), low density Cholesterol (LDL), fasting glucose, pocket depth and microbial composition.
Results: Therapy with SRP+Azi do not significantly reduce the plasmatic levels of hs-CRP however, a positive trend was notice (4,33 to 2,99 mg/l). This group obtained also greater reduction of pocket depth (PD), artery index and P. gingivalis and P intermedia detection frequency when compared to the SRP placebo group (p<0.05). Other blood biochemistry parameters did not changed significantly in the test group. In contrast, the control group increased the hs- CRP levels after therapy and in some cases a increase of pocket depth was detected.
Conclusions: Combined SRP+Azi therapy in chronic periodontitis did not reduced hs- CRP serum level significantly after three months. However, this group reduced significantly their probing pocket depth, reduced P. gingivalis and P intermedia frequency and increased clinical attachment gain.
Key words: Chronic periodontitis, Creactive protein, azithromycin, randomized clinical trial.
Soto-Franco, J.-E., Aldana, H.-F., Navia, J.-M., Peláez, M., Quisoboni, J., O’Meara, M.-A., & Contreras, A. (2017). High sensitive- C reactive protein, periodontal parameters and periodontal microbiota after scaling-root planning plus Azithromycin as treatment of Chronic Periodontitis: A Randomized Clinical Trial. Revista Estomatología, 24(2). https://doi.org/10.25100/re.v24i2.5798
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2. Levi F, Chatenoud L, Bertuccio P, Lucchini F, Negri E, La Vecchia C. Mortality from cardiovascular and cerebrovascular
diseases in Europe and other areas of the world: an update. Eur J Cardiovasc Prev Rehabil. 2009; 16(3):333-50.
3. Wood D. Established and emerging cardiovascular risk factors. Am Heart J 2001; 141(2 Suppl):S49-57.
4. Mukamal KJ, Kronmal RA, Tracy RP, Cushman M, Siscovick DS. Traditional and novel risk factors in older adults: cardiovascular risk assessment late in life. Am J Geriatr Cardiol. 2004; 13(2):69-80.
5. H a n s s o n G K . I n f l amma t i o n , atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352(16): 1685-95.
6. Papapanou PN. Periodontal diseases: epidemiology. Ann Periodontol. 1996; 1(1):1-36.
7. Kassebaum NJ, Bernabé E, et al. Global burden of severe periodontitis in 1990- 2010: a systematic review and metaregression
J Dent Res. 2014; 93(11): 1045-53.
8. Eke PI, Dye BA, Wei L, Thornton-Evans GO, Genco RJ. Prevalence of periodontitis in adults in the United States: 2009 and
2010. J Dent Res 2012; 91(10): 914-920.
9. Ministerio de Salud. República de Colombia. IV Estudio Nacional de Salud Bucal ENSAB-IV 2013-2014. Situación en Salud Bucal, 2015: 78.
10. Ebersole JL, Machen RL, Steffen MJ, Willmann DE. Systemic acutephase reactants, C-reactive protein and haptoglobin, in adult periodontitis. Clin Exp Immunol. 1997; 107(2):347-52.
11. D’Aiuto F, Nibali L, Parkar M, Suvan J, Tonetti MS. Short-term effects of intensive periodontal therapy on serum inflammatory
markers and cholesterol. J Dent Res. 2005; 84(3):269-73.
12. Paraskevas S, Huizinga JD, Loos BG. A systematic review and meta-analyses on C-reactive protein in relation to periodontitis. J Clin Periodontol. 2008; 35(4):277-90.
13. Sorsa T. Tjäderhane T., Salo T. Matrix metalloproteinases (MMPs) in oral diseases. Oral Diseases. 2004; 10(6): 311-8.
14. Sorsa T, Mantyla P, Tervahartiala T, Pussinen PJ, Gamonal J, Hernandez M. MMP activation in diagnostics of periodontitis and systemic inflammation. J Clin Periodontol. 2011; 38(9): 817-9.
15. Tonetti MS, D’Aiuto F, Nibali L, et al. Treatment of periodontitis and endothelial function. N Engl J Med. 2007; 356(9): 911-20.
16. Amar S, Gokce N, Morgan S, Loukideli M, Van Dyke TE, Vita JA. Periodontal disease is associated with brachial artery endothelial dysfunction and systemic inflammation. Arterioscler Thromb Vasc Biol. 2003; 23(7):1245-9.
17. Blaizot A, Vergnes JN, Nuwwareh S, Amar J, Sixou M. Periodontal diseases and cardiovascular events: meta-analysis
of observational studies. Int Dent J. 2009; 59(4):197-209.
18. Mattila KJ, Nieminen MS, Valtonen VV, et al. Association between dental health and acute myocardial infarction. BMJ. 1989;
298(6676):779-81.
19. Meurman JH, Sanz M, Janket SJ. Oral health, atherosclerosis, and cardiovascular disease. Crit Rev Oral Biol Med. 2004;
15(6):403-13.
20. Lafaurie GI, Mayorga-Fayad I, Torres MF, Castillo DM, Aya MR, Baron A, Hurtado PA. Periodontopathic microorganisms in peripheric blood after scaling and root planing. J Clin Periodontol 2007; 34(10): 873-9.
21. Chou HH, Yumoto H, Davey M, et al. Porphyromonas gingivalis fimbriadependent activation of inflammatory genes in human aortic endothelial cells. Infect Immun. 2005; 73(9):5367-78.
22. Desvarieux M, Demmer RT, Rundek T, et al. Periodontal microbiota and carotid intima-media thickness: the Oral Infections
and Vascular Disease Epidemiology Study (INVEST). Circulation. 2005; 111(5): 576- 82.
23. Spahr A, Klein E, Khuseyinova N, et al. Periodontal infections and coronary heart disease: role of periodontal bacteria and importance of total pathogen burden in the Coronary Event and Periodontal Disease (CORODONT) study. Arch Intern Med.
2006; 166(5):554-9.
24. Nonnenmacher C, Stelzel M, Susin C. Periodontal Microbiota in Patients With Coronary Artery Disease Measured by Real-Time Polymerase Chain Reaction: A Case-Control Study. J Periodontol. 2007; 78 (9): 1724-30.
25. Joshipura KJ, Wand HC, Merchant AT, Rimm EB. Periodontal disease and biomarkers related to cardiovascular disease. J Dent Res 2004; 83(2): 151-5.
26. Elter JR, Hinderliter AL, Offenbacher S, Beck JD, Caughey M, Brodala N, et al. The effects of periodontal therapy on vascular endothelial function: a pilot trial. Am Heart. J 2006; 151(1):47-e1
27. Mustapha IZ, Debrey S, Oladubu M, Ugarte R. Markers of systemic bacterial exposure in periodontal disease and cardiovascular disease risk: a systematic review and meta-analysis. J Periodontol. 2007; 78(12):2289-302
28. Bahekar AA, Singh S,Saha S,Molnar J, Arora R. The prevalence and incidence of coronary heart disease is significantly
increased in periodontitis: A meta-analysis. Am Heart Journal 2007; 154 (5): 830-7.
29. Loos BG. Sys t emi c Ma rke r s of Inflammation in Periodontitis Systemic Markers of Inflammation in Periodontitis. J Periodontol 2005; 76(11-s): 2106-15.
30. I de M, McPartlin D, Coward PY, Crook M. Effect of treatment of chronic periodontitis on levels of serum markers of acute-phase inflammatory and vascular responses. J Clinic periodontol. 2003;
30(4): 334-340
31. D’Aiuto F, Ready D, Tonetti MS. Periodontal disease and C-reactive protein-associated cardiovascular risk. J Periodontal Res. 2004; 39(4): 236-241.
32. Yamazaki K, Ohsawa Y, Itoh H, Ueki K, Tabeta K, Oda T, et al. T-cell clonality to Porphyromonas gingivalis and human heat shock protein 60s in patients with atherosclerosis and periodontitis. Oral Microbiol Immunol. 2004; 19(3):160-7.
33. Behle JH, Sedaghatfar MH, Demmer RT. Heterogeneity of systemic inflammatory responses to periodontal therapy. J Clinic
Periodontol 2009; 36(4): 287-294
34. Armitage, G. C. Development of a classification system for periodontal diseases and conditions. Annals of periodontal 1999; 4(1):1-6.
35. Jaramillo A, Lafaurie GI, Millan LV, et al. Association between periodontal disease and plasma levels of cholesterol and triglycerides. Colomb Med 2013; 44(2): 80-86.
36. Lopez NJ, Quintero A, Casanova PA, Ibieta CI, Baelum V, Lopez R. Effects of periodontal therapy on systemic markers of inflammation in patients with metabolic syndrome: a controlled clinical trial. J Periodontol. 2012; 83(3):267-78
37. Quirynen M, Bollen CML. Full-Vs. Partial-mouth desinfection in the treatment of periodontal infections: short-term clinical and microbiological observations. J Dent Res. 1995; 74(8):1459-67
38. Paraskevas S, Huizinga JD, Loos BG. A systematic review and meta-analyses on C-reactive protein in relation to periodontitis. J Clinic Periodontol. 2008; 35(4):277-290
39. Ianaro A, Ialenti A, Maffia P, Sautebin L, Rombolà L, Carnuccio R, Iuvone T, D’Acquisto F, Di Rosa M. Antiinflammatory activity of macrolide antibiotics. J Pharmacol Exp Ther. 2000; 292(1):156-63.
40. Pussinen PJ, Mattila K. Periodontal infections and atherosclerosis: mere associations? Curr Opin Lipidol. 2004;15(5):583-8.
41. Pejcic A, Kesic L, Brkic Z, Pesic Z, Mirkovic D. Effect of periodontal treatment on lipoproteins levels in plasma in patients with periodontitis. South Med J. 2011; 104(8):547-52
42. Ribeiro CMP, Hurd H, Wu Y, Martino MEB, Jones L, et al. (2009) Azithromycin Treatment Alters Gene Expression in Inflammatory, Lipid Metabolism, and Cell Cycle Pathways in Well-Differentiated Human Airway Epithelia. PLoS ONE 4(6): e5806
43. Elisa Kallio KA, Hyvärinen K, Kovanen PT, Pussinen PJ. Very low density lipoproteins derived from periodontitis patients facilitate macrophage activation via lipopolysaccharide function. Metabol Clinic Exp. 2013; 62(5):661-8.
44. Herrera D, Sanz M, Jepsen S, Needleman I, Roldan S. A systematic review on the effect of systemic antimicrobials as an adjunct to scaling and root planing in periodontitis patients. J Clin Periodontol. 2002; 29(Suppl 3):136-59
45. Guerrero A, Griffiths GS, Nibali L, et al. Adjunctive benefits of systemic amoxicillin and metronidazole in non-surgical treatment of generalized aggressive periodontitis: a randomized placebo-controlled clinical trial. J Clin Periodontol. 2005; 32(10):1096-107
46. 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(3):243-53.
47. 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(8):696-704.
48. Yashima A, Gomi K, Maeda N, Arai T. One-stage full-mouth versus partialmouth scaling and root planing during the effective half-life of systemically administered azithromycin. J Periodontol. 2009; 80(9):1406-13.
49. 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(3):422-9.
50. 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(3):426-36.
51. 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(1):54-61.
52. 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(11): 2125-35.
53. Gomi K, Yashima A, Iino F, et al. Drug concentration in inflamed periodontal tissues after systemically administered azithromycin. J Periodontol. 2007; 78(5): 918-23.
54. Herrera D, Alonso B, Leon R, Roldan S, Sanz M. Antimicrobial therapy in periodontitis: the use of systemic antimicrobials against the subgingival biofilm. J Clin Periodontol. 2008; 35(s8): 45-66.
55. Sanz M, Teughels W. Innovations in nonsurgical periodontal therapy: Consensus Report of the Sixth European Workshop on Periodontology. J Clin Periodontol. 2008; 35(s8):3-7
56. Contopoulos-Ioannidis DG, Ioannidis JP, Chew P, Lau J. Meta-analysis of randomized controlled trials on the comparative efficacy and safety of azithromycin against other antibiotics for lower respiratory tract infections. J Antimicrob Chemother. 2001; 48(5):691-703.
57. Casey JR, Pichichero ME. Higher dosages of azithromycin are more effective in treatment of group A streptococcal tonsillopharyngitis. Clin Infect Dis. 2005; 40(12):1748-55.
58. 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(10):1887-96
59. Veloo AC, Seme K, Raangs E, et al. Antibiotic susceptibility profiles of oral pathogens. Int J Antimicrob Agents. 2012; 40(5): 450-4.
60. 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(8): 893-8.
61. Sefton AM, Maskell JP, Beighton D, et al. Azithromycin in the treatment of periodontal disease. Effect on microbial flora. J Clin Periodontol. 1996; 23(11): 998-1003.
62. Jaramillo Echeverri A, Betancourth Quiroz M, Mayorga-Fayad I, et al. Perfiles Antimicrobianos de Bacterias Subgingival es en Pa ci ent e s con Periodontitis en Colombia. Revista Clínica de Periodoncia, Implantología y Rehabilitación Oral. 2008; 1(2):61-5.
2. Levi F, Chatenoud L, Bertuccio P, Lucchini F, Negri E, La Vecchia C. Mortality from cardiovascular and cerebrovascular
diseases in Europe and other areas of the world: an update. Eur J Cardiovasc Prev Rehabil. 2009; 16(3):333-50.
3. Wood D. Established and emerging cardiovascular risk factors. Am Heart J 2001; 141(2 Suppl):S49-57.
4. Mukamal KJ, Kronmal RA, Tracy RP, Cushman M, Siscovick DS. Traditional and novel risk factors in older adults: cardiovascular risk assessment late in life. Am J Geriatr Cardiol. 2004; 13(2):69-80.
5. H a n s s o n G K . I n f l amma t i o n , atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352(16): 1685-95.
6. Papapanou PN. Periodontal diseases: epidemiology. Ann Periodontol. 1996; 1(1):1-36.
7. Kassebaum NJ, Bernabé E, et al. Global burden of severe periodontitis in 1990- 2010: a systematic review and metaregression
J Dent Res. 2014; 93(11): 1045-53.
8. Eke PI, Dye BA, Wei L, Thornton-Evans GO, Genco RJ. Prevalence of periodontitis in adults in the United States: 2009 and
2010. J Dent Res 2012; 91(10): 914-920.
9. Ministerio de Salud. República de Colombia. IV Estudio Nacional de Salud Bucal ENSAB-IV 2013-2014. Situación en Salud Bucal, 2015: 78.
10. Ebersole JL, Machen RL, Steffen MJ, Willmann DE. Systemic acutephase reactants, C-reactive protein and haptoglobin, in adult periodontitis. Clin Exp Immunol. 1997; 107(2):347-52.
11. D’Aiuto F, Nibali L, Parkar M, Suvan J, Tonetti MS. Short-term effects of intensive periodontal therapy on serum inflammatory
markers and cholesterol. J Dent Res. 2005; 84(3):269-73.
12. Paraskevas S, Huizinga JD, Loos BG. A systematic review and meta-analyses on C-reactive protein in relation to periodontitis. J Clin Periodontol. 2008; 35(4):277-90.
13. Sorsa T. Tjäderhane T., Salo T. Matrix metalloproteinases (MMPs) in oral diseases. Oral Diseases. 2004; 10(6): 311-8.
14. Sorsa T, Mantyla P, Tervahartiala T, Pussinen PJ, Gamonal J, Hernandez M. MMP activation in diagnostics of periodontitis and systemic inflammation. J Clin Periodontol. 2011; 38(9): 817-9.
15. Tonetti MS, D’Aiuto F, Nibali L, et al. Treatment of periodontitis and endothelial function. N Engl J Med. 2007; 356(9): 911-20.
16. Amar S, Gokce N, Morgan S, Loukideli M, Van Dyke TE, Vita JA. Periodontal disease is associated with brachial artery endothelial dysfunction and systemic inflammation. Arterioscler Thromb Vasc Biol. 2003; 23(7):1245-9.
17. Blaizot A, Vergnes JN, Nuwwareh S, Amar J, Sixou M. Periodontal diseases and cardiovascular events: meta-analysis
of observational studies. Int Dent J. 2009; 59(4):197-209.
18. Mattila KJ, Nieminen MS, Valtonen VV, et al. Association between dental health and acute myocardial infarction. BMJ. 1989;
298(6676):779-81.
19. Meurman JH, Sanz M, Janket SJ. Oral health, atherosclerosis, and cardiovascular disease. Crit Rev Oral Biol Med. 2004;
15(6):403-13.
20. Lafaurie GI, Mayorga-Fayad I, Torres MF, Castillo DM, Aya MR, Baron A, Hurtado PA. Periodontopathic microorganisms in peripheric blood after scaling and root planing. J Clin Periodontol 2007; 34(10): 873-9.
21. Chou HH, Yumoto H, Davey M, et al. Porphyromonas gingivalis fimbriadependent activation of inflammatory genes in human aortic endothelial cells. Infect Immun. 2005; 73(9):5367-78.
22. Desvarieux M, Demmer RT, Rundek T, et al. Periodontal microbiota and carotid intima-media thickness: the Oral Infections
and Vascular Disease Epidemiology Study (INVEST). Circulation. 2005; 111(5): 576- 82.
23. Spahr A, Klein E, Khuseyinova N, et al. Periodontal infections and coronary heart disease: role of periodontal bacteria and importance of total pathogen burden in the Coronary Event and Periodontal Disease (CORODONT) study. Arch Intern Med.
2006; 166(5):554-9.
24. Nonnenmacher C, Stelzel M, Susin C. Periodontal Microbiota in Patients With Coronary Artery Disease Measured by Real-Time Polymerase Chain Reaction: A Case-Control Study. J Periodontol. 2007; 78 (9): 1724-30.
25. Joshipura KJ, Wand HC, Merchant AT, Rimm EB. Periodontal disease and biomarkers related to cardiovascular disease. J Dent Res 2004; 83(2): 151-5.
26. Elter JR, Hinderliter AL, Offenbacher S, Beck JD, Caughey M, Brodala N, et al. The effects of periodontal therapy on vascular endothelial function: a pilot trial. Am Heart. J 2006; 151(1):47-e1
27. Mustapha IZ, Debrey S, Oladubu M, Ugarte R. Markers of systemic bacterial exposure in periodontal disease and cardiovascular disease risk: a systematic review and meta-analysis. J Periodontol. 2007; 78(12):2289-302
28. Bahekar AA, Singh S,Saha S,Molnar J, Arora R. The prevalence and incidence of coronary heart disease is significantly
increased in periodontitis: A meta-analysis. Am Heart Journal 2007; 154 (5): 830-7.
29. Loos BG. Sys t emi c Ma rke r s of Inflammation in Periodontitis Systemic Markers of Inflammation in Periodontitis. J Periodontol 2005; 76(11-s): 2106-15.
30. I de M, McPartlin D, Coward PY, Crook M. Effect of treatment of chronic periodontitis on levels of serum markers of acute-phase inflammatory and vascular responses. J Clinic periodontol. 2003;
30(4): 334-340
31. D’Aiuto F, Ready D, Tonetti MS. Periodontal disease and C-reactive protein-associated cardiovascular risk. J Periodontal Res. 2004; 39(4): 236-241.
32. Yamazaki K, Ohsawa Y, Itoh H, Ueki K, Tabeta K, Oda T, et al. T-cell clonality to Porphyromonas gingivalis and human heat shock protein 60s in patients with atherosclerosis and periodontitis. Oral Microbiol Immunol. 2004; 19(3):160-7.
33. Behle JH, Sedaghatfar MH, Demmer RT. Heterogeneity of systemic inflammatory responses to periodontal therapy. J Clinic
Periodontol 2009; 36(4): 287-294
34. Armitage, G. C. Development of a classification system for periodontal diseases and conditions. Annals of periodontal 1999; 4(1):1-6.
35. Jaramillo A, Lafaurie GI, Millan LV, et al. Association between periodontal disease and plasma levels of cholesterol and triglycerides. Colomb Med 2013; 44(2): 80-86.
36. Lopez NJ, Quintero A, Casanova PA, Ibieta CI, Baelum V, Lopez R. Effects of periodontal therapy on systemic markers of inflammation in patients with metabolic syndrome: a controlled clinical trial. J Periodontol. 2012; 83(3):267-78
37. Quirynen M, Bollen CML. Full-Vs. Partial-mouth desinfection in the treatment of periodontal infections: short-term clinical and microbiological observations. J Dent Res. 1995; 74(8):1459-67
38. Paraskevas S, Huizinga JD, Loos BG. A systematic review and meta-analyses on C-reactive protein in relation to periodontitis. J Clinic Periodontol. 2008; 35(4):277-290
39. Ianaro A, Ialenti A, Maffia P, Sautebin L, Rombolà L, Carnuccio R, Iuvone T, D’Acquisto F, Di Rosa M. Antiinflammatory activity of macrolide antibiotics. J Pharmacol Exp Ther. 2000; 292(1):156-63.
40. Pussinen PJ, Mattila K. Periodontal infections and atherosclerosis: mere associations? Curr Opin Lipidol. 2004;15(5):583-8.
41. Pejcic A, Kesic L, Brkic Z, Pesic Z, Mirkovic D. Effect of periodontal treatment on lipoproteins levels in plasma in patients with periodontitis. South Med J. 2011; 104(8):547-52
42. Ribeiro CMP, Hurd H, Wu Y, Martino MEB, Jones L, et al. (2009) Azithromycin Treatment Alters Gene Expression in Inflammatory, Lipid Metabolism, and Cell Cycle Pathways in Well-Differentiated Human Airway Epithelia. PLoS ONE 4(6): e5806
43. Elisa Kallio KA, Hyvärinen K, Kovanen PT, Pussinen PJ. Very low density lipoproteins derived from periodontitis patients facilitate macrophage activation via lipopolysaccharide function. Metabol Clinic Exp. 2013; 62(5):661-8.
44. Herrera D, Sanz M, Jepsen S, Needleman I, Roldan S. A systematic review on the effect of systemic antimicrobials as an adjunct to scaling and root planing in periodontitis patients. J Clin Periodontol. 2002; 29(Suppl 3):136-59
45. Guerrero A, Griffiths GS, Nibali L, et al. Adjunctive benefits of systemic amoxicillin and metronidazole in non-surgical treatment of generalized aggressive periodontitis: a randomized placebo-controlled clinical trial. J Clin Periodontol. 2005; 32(10):1096-107
46. 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(3):243-53.
47. 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(8):696-704.
48. Yashima A, Gomi K, Maeda N, Arai T. One-stage full-mouth versus partialmouth scaling and root planing during the effective half-life of systemically administered azithromycin. J Periodontol. 2009; 80(9):1406-13.
49. 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(3):422-9.
50. 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(3):426-36.
51. 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(1):54-61.
52. 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(11): 2125-35.
53. Gomi K, Yashima A, Iino F, et al. Drug concentration in inflamed periodontal tissues after systemically administered azithromycin. J Periodontol. 2007; 78(5): 918-23.
54. Herrera D, Alonso B, Leon R, Roldan S, Sanz M. Antimicrobial therapy in periodontitis: the use of systemic antimicrobials against the subgingival biofilm. J Clin Periodontol. 2008; 35(s8): 45-66.
55. Sanz M, Teughels W. Innovations in nonsurgical periodontal therapy: Consensus Report of the Sixth European Workshop on Periodontology. J Clin Periodontol. 2008; 35(s8):3-7
56. Contopoulos-Ioannidis DG, Ioannidis JP, Chew P, Lau J. Meta-analysis of randomized controlled trials on the comparative efficacy and safety of azithromycin against other antibiotics for lower respiratory tract infections. J Antimicrob Chemother. 2001; 48(5):691-703.
57. Casey JR, Pichichero ME. Higher dosages of azithromycin are more effective in treatment of group A streptococcal tonsillopharyngitis. Clin Infect Dis. 2005; 40(12):1748-55.
58. 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(10):1887-96
59. Veloo AC, Seme K, Raangs E, et al. Antibiotic susceptibility profiles of oral pathogens. Int J Antimicrob Agents. 2012; 40(5): 450-4.
60. 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(8): 893-8.
61. Sefton AM, Maskell JP, Beighton D, et al. Azithromycin in the treatment of periodontal disease. Effect on microbial flora. J Clin Periodontol. 1996; 23(11): 998-1003.
62. Jaramillo Echeverri A, Betancourth Quiroz M, Mayorga-Fayad I, et al. Perfiles Antimicrobianos de Bacterias Subgingival es en Pa ci ent e s con Periodontitis en Colombia. Revista Clínica de Periodoncia, Implantología y Rehabilitación Oral. 2008; 1(2):61-5.
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