Non-surgical periodontal therapy with systemic antibiotics in patients with untreated aggressive periodontitis: A systematic review and meta-analysis

Journal of Periodontal Research

Volumn 50, Issue 6, 2015, Pages 689-706

  Keestra, J A J ^a,b   Grosjean, I ^a,b   Coucke, W ^c   Quirynen, M ^a,b   Teughels, W ^a,b,d  

^a UNIVERSITY OF LEUVEN   (Belgium)

^b UNIVERSITY HOSPITALS LEUVEN   (Belgium)

^c SCIENTIFIC INSTITUTE OF PUBLIC HEALTH   (Belgium)

^d RESEARCH FOUNDATION FLANDERS FWO   (Belgium)

Author keywords

Aggressive periodontitis; Non surgical periodontal therapy; Systemic antibiotics

Indexed keywords

AMOXICILLIN; ANTIINFECTIVE AGENT; METRONIDAZOLE;

AGGRESSIVE PERIODONTITIS; COMBINATION DRUG THERAPY; HUMAN; META ANALYSIS; TREATMENT OUTCOME;

AGGRESSIVE PERIODONTITIS; AMOXICILLIN; ANTI-BACTERIAL AGENTS; DRUG THERAPY, COMBINATION; HUMANS; METRONIDAZOLE; TREATMENT OUTCOME;

EID: 84945467095     PISSN: 00223484     EISSN: 16000765     Source Type: Journal    
DOI: 10.1111/jre.12252     Document Type: Review

References (127)

1. Socransky SS, Haffajee AD. The bacterial etiology of destructive periodontal disease: current concepts. J Periodontol 1992;63:322-331.
2. Armitage GC. Development of a classification system for periodontal diseases and conditions. Ann Periodontol 1999;4:1-6.
3. Lang NP, Tonetti MS. Periodontal risk assessment (PRA) for patients in supportive periodontal therapy (SPT). Oral Health Prev Dent 2003;1:7-16.
4. Armitage GC. Periodontal diagnoses and classification of periodontal diseases. Periodontol 2000 2004;34:9-21.
5. Albandar JM. Aggressive periodontitis: case definition and diagnostic criteria. Periodontol 2000 2014;65:13-26.
6. Teughels W, Dhondt R, Dekeyser C et al. Treatment of aggressive periodontitis. Periodontol 2000 2014;65:107-133.
7. AAP. Systemic antibiotics in periodontics. J Periodontol 1996;67:831-838.
8. Haffajee AD, Socransky SS, Gunsolley JC. Systemic anti-infective periodontal therapy. A systematic review. Ann Periodontol 2003;8:115-181.
9. Sanz M, Teughels W. Innovations in non-surgical periodontal therapy: Consensus Report of the Sixth European Workshop on Periodontology. J Clin Periodontol 2008;35:3-7.
10. Sgolastra F, Petrucci A, Gatto R et al. Effectiveness of systemic amoxicillin/metronidazole as an adjunctive therapy to full-mouth scaling and root planing in the treatment of aggressive periodontitis: a systematic review and meta-analysis. J Periodontol 2012;83:731-743.
11. Preus HR, Scheie AA, Baelum V. Letter to the editor: re: the clinical effect of scaling and root planing and the concomitant administration of systemic amoxicillin and metronidazole: a systematic review; re: effectiveness of systemic amoxicillin/metronidazole as adjunctive therapy to scaling and root planing in the treatment of chronic periodontitis: a systematic review and meta-analysis; re: effectiveness of systemic amoxicillin/metronidazole as an adjunctive therapy to full-mouth scaling and root planing in the treatment of aggressive periodontitis: a systematic review and meta-analysis. J Periodontol 2014;85:374-384.
12. Bronzwaer S, Lonnroth A, Haigh R. The European Community strategy against antimicrobial resistance. Euro Surveill 2004;9:30-34.
13. European Centre for Disease Prevention and Control. Strategies for Disease-Specific Programs: 2010-2013. Stockholm: European Centre for Disease Prevention and Control, 2010.
14. World Health Organization. The Evolving Threat of Antimicrobial Resistance: Options for Action. Geneva, Switzerland: World Health Organization, 2012.
15. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Accessed November 23, 2013.
16. Moher D, Liberati A, Tetzlaff J et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 2009;62:1006-1012.
17. Schulz KF, Altman DG, Moher D et al. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol 2010;63:834-840.
18. Verhagen AP, de Vet HC, de Bie RA et al. The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus. J Clin Epidemiol 1998;51:1235-1241.
19. Van der Weijden F, Dell'Acqua F, Slot DE. Alveolar bone dimensional changes of post-extraction sockets in humans: a systematic review. J Clin Periodontol 2009;36:1048-1058.
20. The Cochrane Collaboration. Review Manager (RevMan) [Computer program]. Version 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012.
21. Preus HR, Gunleiksrud TM, Sandvik L et al. A randomized, double-masked clinical trial comparing four periodontitis treatment strategies: 1-year clinical results. J Periodontol 2013;84:2075-2086.
22. Rodrigues AS, Lourencao DS, Lima Neto LG et al. Clinical and microbiologic evaluation, by real-time polymerase chain reaction, of non-surgical treatment of aggressive periodontitis associated with amoxicillin and metronidazole. J Periodontol 2012;83:744-752.
23. Haas AN, Silva-Boghossian CM, Colombo AP et al. Adjunctive azithromycin in the treatment of aggressive periodontitis: microbiological findings of a 12-month randomized clinical trial. J Dent 2012;40:556-563.
24. Haas AN, Seleme F, Segatto P et al. Azithromycin as an adjunctive treatment of aggressive periodontitis: radiographic findings of a 12-month randomized clinical trial. Am J Dent 2012;25:215-219.
25. Basegmez C, Berber L, Yalcin F. Clinical and biochemical efficacy of minocycline in nonsurgical periodontal therapy: a randomized controlled pilot study. J Clin Pharmacol 2011;51:915-922.
26. Schmidt E, Kaciroti N, Loesche W. Benefits of additional courses of systemic azithromycin in periodontal therapy. Gen Dent 2011;59:180-187.
27. Varela VM, Heller D, Silva-Senem MX et al. 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.
28. Serrano C, Torres N, Bejarano A et al. Clinical and microbiological comparison of three non-surgical protocols for the initial treatment of chronic periodontitis. J Int Acad Periodontol 2011;13:17-26.
29. Tüter G, Serdar M, Kurtis B et al. Effects of scaling and root planing and subantimicrobial dose doxycycline on gingival crevicular fluid levels of matrix metalloproteinase-8, -13 and serum levels of HsCRP in patients with chronic periodontitis. J Periodontol 2010;81:1132-1139.
30. Mestnik MJ, Feres M, Figueiredo LC et al. Short-term benefits of the adjunctive use of metronidazole plus amoxicillin in the microbial profile and in the clinical parameters of subjects with generalized aggressive periodontitis. J Clin Periodontol 2010;37:353-365.
31. Cionca N, Giannopoulou C, Ugolotti G et al. Microbiologic testing and outcomes of full-mouth scaling and root planing with or without amoxicillin/metronidazole in chronic periodontitis. J Periodontol 2010;81:15-23.
32. Valenza G, Veihelmann S, Peplies J et al. Microbial changes in periodontitis successfully treated by mechanical plaque removal and systemic amoxicillin and metronidazole. Int J Med Microbiol 2009;299:427-438.
33. Machtei EE, Younis MN. The use of 2 antibiotic regimens in aggressive periodontitis: comparison of changes in clinical parameters and gingival crevicular fluid biomarkers. Quintessence Int 2008;39:811-819.
34. Akincibay H, Orsal SO, Sengun D et al. Systemic administration of doxycycline versus metronidazole plus amoxicillin in the treatment of localized aggressive periodontitis: a clinical and microbiologic study. Quintessence Int 2008;39:e33-e39.
35. Novak MJ, Dawson DR 3rd, Magnusson I et al. Combining host modulation and topical antimicrobial therapy in the management of moderate to severe periodontitis: a randomized multicenter trial. J Periodontol 2008;79:33-41.
36. Moreira RM, Feres-Filho EJ. Comparison between full-mouth scaling and root planing and quadrant-wise basic therapy of aggressive periodontitis: 6-month clinical results. J Periodontol 2007;78:1683-1688.
37. Kaner D, Christan C, Dietrich T et al. Timing affects the clinical outcome of adjunctive systemic antibiotic therapy for generalized aggressive periodontitis. J Periodontol 2007;78:1201-1208.
38. Moeintaghavi A, Talebi-Ardakani MR, Haerian-Ardakani A et al. Adjunctive effects of systemic amoxicillin and metronidazole with scaling and root planing: a randomized, placebo controlled clinical trial. J Contemp Dent Pract 2007;8:51-59.
39. Emingil G, Gurkan A, Atilla G et al. Adjunctive low-dose doxycycline therapy effect on clinical parameters and gingival crevicular fluid tissue plasminogen activator levels in chronic periodontitis. Inflamm Res 2006;55:550-558.
40. 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;32:1096-1107.
41. Vergani SA, Silva EB, Vinholis AH et al. Systemic use of metronidazole in the treatment of chronic periodontitis: a pilot study using clinical, microbiological, and enzymatic evaluation. Braz Oral Res 2004;18:121-127.
42. Blandino G, Lo Bue AM, Milazzo I et al. Comparison of systemic flurithromycin therapy and clinical procedures in the treatment of periodontal diseases. J Chemother 2004;16:151-155.
43. Emingil G, Atilla G, Sorsa T et al. The effect of adjunctive low-dose doxycycline therapy on clinical parameters and gingival crevicular fluid matrix metalloproteinase-8 levels in chronic periodontitis. J Periodontol 2004;75:106-115.
44. Kamma JJ, Nakou M, Mitsis FJ. The clinical and microbiological effects of systemic ornidazole in sites with and without subgingival debridement in early-onset periodontitis patients. J Periodontol 2000;71:1862-1873.
45. Palmer RM, Matthews JP, Wilson RF. Non-surgical periodontal treatment with and without adjunctive metronidazole in smokers and non-smokers. J Clin Periodontol 1999;26:158-163.
46. Tinoco EM, Beldi MI, Campedelli F et al. Clinical and microbiological effects of adjunctive antibiotics in treatment of localized juvenile periodontitis. A controlled clinical trial. J Periodontol 1998;69:1355-1363.
47. Flemmig TF, Milian E, Karch H et al. Differential clinical treatment outcome after systemic metronidazole and amoxicillin in patients harboring Actinobacillus actinomycetemcomitans and/or Porphyromonas gingivalis. J Clin Periodontol 1998;25:380-387.
48. Noyan U, Yilmaz S, Kuru B et al. A clinical and microbiological evaluation of systemic and local metronidazole delivery in adult periodontitis patients. J Clin Periodontol 1997;24:158-165.
49. 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.
50. Yilmaz S, Kuru B, Noyan U et al. A clinical and microbiological evaluation of systemic and local metronidazole delivery in early onset periodontitis patients. J Marmara Univ Dent Fac 1996;2:500-509.
51. Haffajee AD, Dibart S, Kent RL Jr et al. Clinical and microbiological changes associated with the use of 4 adjunctive systemically administered agents in the treatment of periodontal infections. J Clin Periodontol 1995;22:618-627.
52. Saxen L, Asikainen S. Metronidazole in the treatment of localized juvenile periodontitis. J Clin Periodontol 1993;20:166-171.
53. Loesche WJ, Giordano JR, Hujoel P et al. Metronidazole in periodontitis: reduced need for surgery. J Clin Periodontol 1992;19:103-112.
54. Loesche WJ, Schmidt E, Smith BA et al. Effects of metronidazole on periodontal treatment needs. J Periodontol 1991;62:247-257.
55. Chin QT, Al-Joburi W, Lautar-Lemay C et al. Comparison of spiramycin and tetracycline used adjunctively in the treatment of advanced chronic periodontitis. J Antimicrob Chemother 1988;22:171-177.
56. Quee TC, Chan EC, Clark C et al. The role of adjunctive Rodogyl therapy in the treatment of advanced periodontal disease. A longitudinal clinical and microbiologic study. J Periodontol 1987;58:594-601.
57. Joyston-Bechal S, Smales FC, Duckworth R. A follow-up study 3 years after metronidazole therapy for chronic periodontal disease. J Clin Periodontol 1986;13:944-949.
58. Loesche WJ, Syed SA, Morrison EC et al. Metronidazole in periodontitis. I. Clinical and bacteriological results after 15 to 30 weeks. J Periodontol 1984;55:325-335.
59. Joyston-Bechal S, Smales FC, Duckworth R. Effect of metronidazole on chronic periodontal disease in subjects using a topically applied chlorhexidine gel. J Clin Periodontol 1984;11:53-62.
60. Lindhe J, Liljenberg B, Adielson B et al. Use of metronidazole as a probe in the study of human periodontal disease. J Clin Periodontol 1983;10:100-112.
61. Lindhe J, Liljenberg B, Adielsson B. Effect of long-term tetracycline therapy on human periodontal disease. J Clin Periodontol 1983;10:590-601.
62. Loesche WJ, Syed SA, Morrison EC et al. Treatment of periodontal infections due to anaerobic bacteria with short-term treatment with metronidazole. J Clin Periodontol 1981;8:29-44.
63. Hellden LB, Listgarten MA, Lindhe J. The effect of tetracycline and/or scaling on human periodontal disease. J Clin Periodontol 1979;6:222-230.
64. Listgarten MA, Lindhe J, Hellden L. Effect of tetracycline and/or scaling on human periodontal disease. Clinical, microbiological, and histological observations. J Clin Periodontol 1978;5:246-271.
65. Pradeep AR, Kalra N, Priyanka N et al. Systemic ornidazole as an adjunct to non-surgical periodontal therapy in the treatment of chronic periodontitis: a randomized, double-masked, placebo-controlled clinical trial. J Periodontol 2012;83:1149-1154.
66. Feres M, Soares GM, Mendes JA et al. Metronidazole alone or with amoxicillin as adjuncts to non-surgical treatment of chronic periodontitis: a 1-year double-blinded, placebo-controlled, randomized clinical trial. J Clin Periodontol 2012;39:1149-1158.
67. Goodson JM, Haffajee AD, Socransky SS et al. Control of periodontal infections: a randomized controlled trial I. The primary outcome attachment gain and pocket depth reduction at treated sites. J Clin Periodontol 2012;39:526-536.
68. Han B, Emingil G, Ozdemir G et al. Azithromycin as an adjunctive treatment of generalized severe chronic periodontitis: clinical, microbiologic, and biochemical parameters. J Periodontol 2012;83:1480-1491.
69. Sampaio E, Rocha M, Figueiredo LC et al. Clinical and microbiological effects of azithromycin in the treatment of generalized chronic periodontitis: a randomized placebo-controlled clinical trial. J Clin Periodontol 2011;38:838-846.
70. Silva MP, Feres M, Sirotto TA et al. Clinical and microbiological benefits of metronidazole alone or with amoxicillin as adjuncts in the treatment of chronic periodontitis: a randomized placebo-controlled clinical trial. J Clin Periodontol 2011;38:828-837.
71. Pradeep AR, Kathariya R. Clarithromycin, as an adjunct to non surgical periodontal therapy for chronic periodontitis: a double blinded, placebo controlled, randomized clinical trial. Arch Oral Biol 2011;56:1112-1119.
72. Emingil G, Gurkan A, Atilla G et al. Subantimicrobial-dose doxycycline and cytokine-chemokine levels in gingival crevicular fluid. J Periodontol 2011;82:452-461.
73. Oteo A, Herrera D, Figuero E et al. 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.
74. Deo V, Gupta S, Bhongade ML et al. Evaluation of subantimicrobial dose doxycycline as an adjunct to scaling and root planing in chronic periodontitis patients with diabetes: a randomized, placebo-controlled clinical trial. J Contemp Dent Pract 2010;11:009-016.
75. Yashima A, Gomi K, Maeda N et al. 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.
76. Ribeiro EP, Bittencourt S, Zanin IC et al. Full-mouth ultrasonic debridement associated with amoxicillin and metronidazole in the treatment of severe chronic periodontitis. J Periodontol 2009;80:1254-1264.
77. Cionca N, Giannopoulou C, Ugolotti G et al. Amoxicillin and metronidazole as an adjunct to full-mouth scaling and root planing of chronic periodontitis. J Periodontol 2009;80:364-371.
78. Guentsch A, Jentsch H, Pfister W et al. Moxifloxacin as an adjunctive antibiotic in the treatment of severe chronic periodontitis. J Periodontol 2008;79:1894-1903.
79. Matarazzo F, Figueiredo LC, Cruz SE et al. Clinical and microbiological benefits of systemic metronidazole and amoxicillin in the treatment of smokers with chronic periodontitis: a randomized placebo-controlled study. J Clin Periodontol 2008;35:885-896.
80. Emingil G, Atilla G, Sorsa T et al. The effect of adjunctive subantimicrobial dose doxycycline therapy on GCF EMMPRIN levels in chronic periodontitis. J Periodontol 2008;79:469-476.
81. Preshaw PM, Novak MJ, Mellonig J et al. Modified-release subantimicrobial dose doxycycline enhances scaling and root planing in subjects with periodontal disease. J Periodontol 2008;79:440-452.
82. Gomi K, Yashima A, Nagano T et al. Effects of full-mouth scaling and root planing in conjunction with systemically administered azithromycin. J Periodontol 2007;78:422-429.
83. Needleman I, Suvan J, Gilthorpe MS et al. A randomized-controlled trial of low-dose doxycycline for periodontitis in smokers. J Clin Periodontol 2007;34:325-333.
84. 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.
85. Gorska R, Nedzi-Gora M. The effects of the initial treatment phase and of adjunctive low-dose doxycycline therapy on clinical parameters and MMP-8, MMP-9, and TIMP-1 levels in the saliva and peripheral blood of patients with chronic periodontitis. Arch Immunol Ther Exp (Warsz) 2006;54:419-426.
86. Llambes F, Silvestre FJ, Hernandez-Mijares A et al. Effect of non-surgical periodontal treatment with or without doxycycline on the periodontium of type 1 diabetic patients. J Clin Periodontol 2005;32:915-920.
87. Ehmke B, Moter A, Beikler T et al. Adjunctive antimicrobial therapy of periodontitis: long-term effects on disease progression and oral colonization. J Periodontol 2005;76:749-759.
88. 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.
89. Gurkan A, Cinarcik S, Huseyinov A. Adjunctive subantimicrobial dose doxycycline: effect on clinical parameters and gingival crevicular fluid transforming growth factor-beta levels in severe, generalized chronic periodontitis. J Clin Periodontol 2005;32:244-253.
90. Lee JY, Lee YM, Shin SY et al. Effect of subantimicrobial dose doxycycline as an effective adjunct to scaling and root planing. J Periodontol 2004;75:1500-1508.
91. Emingil G, Atilla G, Sorsa T et al. Effectiveness of adjunctive low-dose doxycycline therapy on clinical parameters and gingival crevicular fluid laminin-5 gamma2 chain levels in chronic periodontitis. J Periodontol 2004;75:1387-1396.
92. Carvalho LH, D'Avila GB, Leao A et al. Scaling and root planing, systemic metronidazole and professional plaque removal in the treatment of chronic periodontitis in a Brazilian population. I. clinical results. J Clin Periodontol 2004;31:1070-1076.
93. Preshaw PM, Hefti AF, Novak MJ et al. Subantimicrobial dose doxycycline enhances the efficacy of scaling and root planing in chronic periodontitis: a multicenter trial. J Periodontol 2004;75:1068-1076.
94. Akalin FA, Baltacioglu E, Sengun D et al. A comparative evaluation of the clinical effects of systemic and local doxycycline in the treatment of chronic periodontitis. J Oral Sci 2004;46:25-35.
95. Alptekin NO, Kurtoglu F, Serpek B et al. Effects on the clinical indices and gingival crevicular fluid enzyme activities of the cyclical regimen of low-dose doxycycline therapy for adult periodontitis. J Int Acad Periodontol 2000;2:3-8.
96. Novak MJ, Johns LP, Miller RC et al. Adjunctive benefits of subantimicrobial dose doxycycline in the management of severe, generalized, chronic periodontitis. J Periodontol 2002;73:762-769.
97. Rooney J, Wade WG, Sprague SV et al. Adjunctive effects to non-surgical periodontal therapy of systemic metronidazole and amoxycillin alone and combined. A placebo controlled study. J Clin Periodontol 2002;29:342-350.
98. 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.
99. Ramberg P, Rosling B, Serino G et al. The long-term effect of systemic tetracycline used as an adjunct to non-surgical treatment of advanced periodontitis. J Clin Periodontol 2001;28:446-452.
100. Winkel EG, van Winkelhoff AJ, Timmerman MF et al. Amoxicillin plus metronidazole in the treatment of adult periodontitis patients. A double-blind placebo-controlled study. J Clin Periodontol 2001;28:296-305.
101. Caton JG, Ciancio SG, Blieden TM et al. Treatment with subantimicrobial dose doxycycline improves the efficacy of scaling and root planing in patients with adult periodontitis. J Periodontol 2000;71:521-532.
102. Feres M, Haffajee AD, Goncalves C et al. Systemic doxycycline administration in the treatment of periodontal infections (I). Effect on the subgingival microbiota. J Clin Periodontol 1999;26:775-783.
103. Winkel EG, van Winkelhoff AJ, Barendregt DS et al. Clinical and microbiological effects of initial periodontal therapy in conjunction with amoxicillin and clavulanic acid in patients with adult periodontitis. A randomised double-blind, placebo-controlled study. J Clin Periodontol 1999;26:461-468.
104. Palmer RM, Matthews JP, Wilson RF. Adjunctive systemic and locally delivered metronidazole in the treatment of periodontitis: a controlled clinical study. Br Dent J 1998;184:548-552.
105. Berglundh T, Krok L, Liljenberg B et al. The use of metronidazole and amoxicillin in the treatment of advanced periodontal disease. A prospective, controlled clinical trial. J Clin Periodontol 1998;25:354-362.
106. Bain CA, Beagrie GS, Bourgoin J et al. The effects of spiramycin and/or scaling on advanced periodontitis in humans. J Can Dent Assoc 1994;60:209, 212-09, 217.
107. Al-Joburi W, Quee TC, Lautar C et al. Effects of adjunctive treatment of periodontitis with tetracycline and spiramycin. J Periodontol 1989;60:533-539.
108. Silva-Senem MX, Heller D, Varela VM et al. Clinical and microbiological effects of systemic antimicrobials combined to an anti-infective mechanical debridement for the management of aggressive periodontitis: a 12-month randomized controlled trial. J Clin Periodontol 2013;40:242-251.
109. Emingil G, Han B, Ozdemir G et al. Effect of azithromycin, as an adjunct to nonsurgical periodontal treatment, on microbiological parameters and gingival crevicular fluid biomarkers in generalized aggressive periodontitis. J Periodontal Res 2012;47:729-739.
110. Beliveau D, Magnusson I, Bidwell JA et al. Benefits of early systemic antibiotics in localized aggressive periodontitis: a retrospective study. J Clin Periodontol 2012;39:1075-1081.
111. Mestnik MJ, Feres M, Figueiredo LC et al. The effects of adjunctive metronidazole plus amoxicillin in the treatment of generalized aggressive periodontitis: a 1-year double-blinded, placebo-controlled, randomized clinical trial. J Clin Periodontol 2012;39:955-961.
112. Casarin RC, Peloso Ribeiro ED, Sallum EA et al. The combination of amoxicillin and metronidazole improves clinical and microbiologic results of one-stage, full-mouth, ultrasonic debridement in aggressive periodontitis treatment. J Periodontol 2012;83:988-998.
113. Aimetti M, Romano F, Guzzi N et al. Full-mouth disinfection and systemic antimicrobial therapy in generalized aggressive periodontitis: a randomized, placebo-controlled trial. J Clin Periodontol 2012;39:284-294.
114. de Lima Oliveira AP, de Faveri M, Gursky LC et al. Effects of periodontal therapy on GCF cytokines in generalized aggressive periodontitis subjects. J Clin Periodontol 2012;39:295-302.
115. Baltacioglu E, Aslan M, Sarac O et al. Analysis of clinical results of systemic antimicrobials combined with nonsurgical periodontal treatment for generalized aggressive periodontitis: a pilot study. J Can Dent Assoc 2011;77:b97.
116. Heller D, Varela VM, Silva-Senem MX et al. 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.
117. 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.
118. Yek EC, Cintan S, Topcuoglu N et al. Efficacy of amoxicillin and metronidazole combination for the management of generalized aggressive periodontitis. J Periodontol 2010;81:964-974.
119. 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.
120. Xajigeorgiou C, Sakellari D, Slini T et al. Clinical and microbiological effects of different antimicrobials on generalized aggressive periodontitis. J Clin Periodontol 2006;33:254-264.
121. Palmer RM, Watts TL, Wilson RF. A double-blind trial of tetracycline in the management of early onset periodontitis. J Clin Periodontol 1996;23:670-674.
122. Keestra JAJ, Grosjean I, Coucke W et al. Non-surgical therapy with systemic antibiotics in untreated chronic periodontitis patients: a systematic review and meta-analysis. J Periodontal Res 2014 (in press) doi: 10.1111/jre.12221.
123. Zandbergen D, Slot DE, Cobb CM et al. The clinical effect of scaling and root planing and the concomitant administration of systemic amoxicillin and metronidazole: a systematic review. J Periodontol 2013;84:332-351.
124. Sgolastra F, Petrucci A, Gatto R et al. Long-term efficacy of subantimicrobial-dose doxycycline as an adjunctive treatment to scaling and root planing: a systematic review and meta-analysis. J Periodontol 2011;82:1570-1581.
125. Sgolastra F, Gatto R, Petrucci A et al. Effectiveness of systemic amoxicillin/metronidazole as adjunctive therapy to scaling and root planing in the treatment of chronic periodontitis: a systematic review and meta-analysis. J Periodontol 2012;83:1257-1269.
126. van Winkelhoff AJ, Herrera D, Oteo A et al. Antimicrobial profiles of periodontal pathogens isolated from periodontitis patients in the Netherlands and Spain. J Clin Periodontol 2005;32:893-898.
127. 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;29:136-159.