Skip to main content

Advertisement

SpringerLink
Log in

Non-surgical periodontal therapy supplemented with systemically administered azithromycin: a systematic review of RCTs

  • Review
  • Published:
Clinical Oral Investigations Aims and scope Submit manuscript

Abstract

Background

Azithromycin may be an alternative adjunctive systemic antibiotic in non-surgical periodontal therapy.

Objective

This study aims to identify randomized controlled trials evaluating non-surgical periodontal treatment of chronic and/or aggressive periodontitis supplemented with systemically administered azithromycin.

Materials and methods

A systematic literature search was performed for publications published by 31 March 2014 using electronic databases and hand search. Randomized controlled trials published in English or German language, with a follow-up ≥6 months were included. From 231 titles identified, nine publications were eligible for inclusion.

Results

Among the studies included, showing some risk of bias, seven reported on patients with chronic periodontitis and two with aggressive periodontitis. Minor adverse events were described in five studies. A synthesis of results using a vote counting method was applied. Significant (p < 0.05) beneficial effects of azithromycin were shown in six studies for probing depth changes and in five studies for clinical attachment level changes.

Conclusion

In contrast to aggressive periodontitis patients, data from this analysis indicate a potential benefit of systemic azithromycin as adjunctive to non-surgical periodontal therapy in chronic periodontitis patients.

Clinical relevance

When contraindications for the standard antibiotics are present, azithromycin (AZM) may be considered as alternative systemically administered antibiotic drug in selected cases of chronic periodontitis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Haffajee AD, Socransky SS, Gunsolley JC (2003) Systemic anti-infective periodontal therapy. A systematic review. Ann Periodontol 8:115–181

    Article  PubMed  Google Scholar 

  2. Herrera D, Alonso B, Leon R, Roldan S, Sanz M (2008) Antimicrobial therapy in periodontitis: the use of systemic antimicrobials against the subgingival biofilm. J Clin Periodontol 35:45–66

    Article  PubMed  Google Scholar 

  3. Herrera D, Matesanz P, Bascones-Martinez A, Sanz M (2012) Local and systemic antimicrobial therapy in periodontics. J Evid Based Dent Pract 12:50–60

    Article  PubMed  Google Scholar 

  4. Keestra JA, Grosjean I, Coucke W, Quirynen M, Teughels W (2014) Non-surgical periodontal therapy with systemic antibiotics in patients with untreated aggressive periodontitis: a systematic review and meta-analysis. J Periodontal Res. doi:10.1111/jre.12252

    Google Scholar 

  5. Keestra JA, Grosjean I, Coucke W, Quirynen M, Teughels W (2014) Non-surgical periodontal therapy with systemic antibiotics in patients with untreated chronic periodontitis: a systematic review and meta-analysis. J Periodontal Res. doi:10.1111/jre.12221

    Google Scholar 

  6. Astasov-Frauenhoffer M, Braissant O, Hauser-Gerspach I, Weiger R, Walter C, Zitzmann NU, Waltimo T (2014) Microcalorimetric determination of the effects of amoxicillin, metronidazole, and their combination on in vitro biofilm. J Periodontol 85:349–357

    Article  PubMed  Google Scholar 

  7. Kulik Kunz EM, Lenkeit K, Waltimo T, Weiger R, Walter C (2014) Combinatorial effects of amoxicillin and metronidazole on selected periodontal bacteria and whole plaque samples. Arch Oral Biol 59:608–615

    Article  PubMed  Google Scholar 

  8. Walter C, Kulik EM, Weiger R, Zitzmann NU, Waltimo T (2011) Additive or synergistic antimicrobial effects of amoxicillin and metronidazole on whole plaque samples: a preliminary report. J Int Acad Periodontol 13:11–16

    PubMed  Google Scholar 

  9. Pavicic MJ, van Winkelhoff AJ, Douque NH, Steures RW, de Graaff J (1994) Microbiological and clinical effects of metronidazole and amoxicillin in Actinobacillus actinomycetemcomitans-associated periodontitis. A 2-year evaluation. J Clin Periodontol 21:107–112

    Article  PubMed  Google Scholar 

  10. Pavicic MJ, van Winkelhoff AJ, Pavicic-Temming YA, de Graaff J (1994) Amoxycillin causes an enhanced uptake of metronidazole in Actinobacillus actinomycetemcomitans: a mechanism of synergy. J Antimicrob Chemother 34:1047–1050

    Article  PubMed  Google Scholar 

  11. Guerrero A, Griffiths GS, Nibali L, Suvan J, Moles DR, Laurell L, Tonetti MS (2005) Adjunctive benefits of systemic amoxicillin and metronidazole in non-surgical treatment of generalized aggressive periodontitis: a randomized placebo-controlled clinical trial. J Clin Periodontol 32:1096–1107

    Article  PubMed  Google Scholar 

  12. Kaner D, Bernimoulin JP, Hopfenmuller W, Kleber BM, Friedmann A (2007) Controlled-delivery chlorhexidine chip versus amoxicillin/metronidazole as adjunctive antimicrobial therapy for generalized aggressive periodontitis: a randomized controlled clinical trial. J Clin Periodontol 34:880–891

    Article  PubMed  Google Scholar 

  13. Rodrigues AS, Lourencao DS, Lima Neto LG, Pannuti CM, Hirata RD, Hirata MH, Lotufo RF, De Micheli G (2012) Clinical and microbiologic evaluation, by real-time polymerase chain reaction, of non-surgical treatment of aggressive periodontitis associated with amoxicillin and metronidazole. J Periodontol 83:744–752

    Article  PubMed  Google Scholar 

  14. Xajigeorgiou C, Sakellari D, Slini T, Baka A, Konstantinidis A (2006) Clinical and microbiological effects of different antimicrobials on generalized aggressive periodontitis. J Clin Periodontol 33:254–264

    Article  PubMed  Google Scholar 

  15. Cionca N, Giannopoulou C, Ugolotti G, Mombelli A (2010) Microbiologic testing and outcomes of full-mouth scaling and root planing with or without amoxicillin/metronidazole in chronic periodontitis. J Periodontol 81:15–23

    Article  PubMed  Google Scholar 

  16. Feres M, Soares GM, Mendes JA, Silva MP, Faveri M, Teles R, Socransky SS, Figueiredo LC (2012) 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 39:1149–1158

    Article  PubMed  Google Scholar 

  17. Albandar JM (2012) Adjunctive antibiotics with nonsurgical periodontal therapy improve the clinical outcome of chronic periodontitis in current smokers. J Evid Based Dent Pract 12:63–66

    Article  PubMed  Google Scholar 

  18. Matarazzo F, Figueiredo LC, Cruz SE, Faveri M, Feres M (2008) 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 35:885–896

    Article  PubMed  Google Scholar 

  19. Schmidt JC, Walter C, Rischewski JR, Weiger R (2013) Treatment of periodontitis as a manifestation of neutropenia with or without systemic antibiotics: a systematic review. Pediatr Dent 35:E54–63

    PubMed  Google Scholar 

  20. Walter C, Buset S, Thillainathan L, Weiger R, Zitzmann NU (2013) Evaluation of periodontal therapy in undergraduate courses of the University of Basle. A retrospective study. Schweiz Monatsschr Zahnmed 123:861–877

    PubMed  Google Scholar 

  21. Mombelli A, Cionca N, Almaghlouth A (2011) Does adjunctive antimicrobial therapy reduce the perceived need for periodontal surgery? Periodontol 2000 55:205–216

    Article  PubMed  Google Scholar 

  22. van Winkelhoff AJ, Rodenburg JP, Goene RJ, Abbas F, Winkel EG, de Graaff J (1989) Metronidazole plus amoxycillin in the treatment of Actinobacillus actinomycetemcomitans associated periodontitis. J Clin Periodontol 16:128–131

    Article  PubMed  Google Scholar 

  23. Cosgarea J, Juncar R, Tristiu R, Arweiler N, Heumann C, Lascu L, Sculean A (2014) Nicht – chirurgische parodontale Therapie mit adjunktiver Gabe von Amoxicillin und Metronidazol für unterschiedliche Zeitabstände in Patienten mit schwerer chronischer Parodontitis. Parodontologie 23:344–345

    Google Scholar 

  24. Moreira RM, Feres-Filho EJ (2007) Comparison between full-mouth scaling and root planing and quadrant-wise basic therapy of aggressive periodontitis: 6-month clinical results. J Periodontol 78:1683–1688

    Article  PubMed  Google Scholar 

  25. Silva-Senem MX, Heller D, Varela VM, Torres MC, Feres-Filho EJ, Colombo AP (2013) 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 40:242–251

    Article  PubMed  Google Scholar 

  26. Lopez NJ, Socransky SS, Da Silva I, Japlit MR, Haffajee AD (2006) Effects of metronidazole plus amoxicillin as the only therapy on the microbiological and clinical parameters of untreated chronic periodontitis. J Clin Periodontol 33:648–660

    Article  PubMed  Google Scholar 

  27. Mombelli A (2005) Antimicrobial profiles of periodontal pathogens and systemic antimicrobial therapy. J Clin Periodontol 32:891–892

    Article  PubMed  Google Scholar 

  28. van Winkelhoff AJ, Herrera D, Oteo A, Sanz M (2005) Antimicrobial profiles of periodontal pathogens isolated from periodontitis patients in The Netherlands and Spain. J Clin Periodontol 32:893–898

    Article  PubMed  Google Scholar 

  29. Walter C, Weiger R (2006) Antibiotics as the only therapy of untreated chronic periodontitis: a critical commentary. J Clin Periodontol 33:938–939, author reply 940-1

    Article  PubMed  Google Scholar 

  30. Rams TE, Feik D, Mortensen JE, Degener JE, van Winkelhoff AJ (2014) Antibiotic susceptibility of periodontal Streptococcus constellatus and Streptococcus intermedius clinical isolates. J Periodontol 85:1792–1798

    Article  PubMed  Google Scholar 

  31. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM (2012) Azithromycin and the risk of cardiovascular death. N Engl J Med 366:1881–1890

    Article  PubMed Central  PubMed  Google Scholar 

  32. WHO (2014) Antibiotic resistance: global report on surveillance. ISBN: 978 92 4 156474 8

  33. Sgolastra F, Gatto R, Petrucci A, Monaco A (2012) 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 83:1257–1269

    Article  PubMed  Google Scholar 

  34. Guerrero A, Echeverria JJ, Tonetti MS (2007) Incomplete adherence to an adjunctive systemic antibiotic regimen decreases clinical outcomes in generalized aggressive periodontitis patients: a pilot retrospective study. J Clin Periodontol 34:897–902

    Article  PubMed  Google Scholar 

  35. Llor C, Sierra N, Hernandez S, Moragas A, Hernandez M, Bayona C, Miravitlles M (2009) The higher the number of daily doses of antibiotic treatment in lower respiratory tract infection the worse the compliance. J Antimicrob Chemother 63:396–399

    Article  PubMed  Google Scholar 

  36. Muniz FW, de Oliveira CC, de Sousa arvalho CR, Moreira MM, de Moraes ME, Martins RS (2013) Azithromycin: a new concept in adjuvant treatment of periodontitis. Eur J Pharmacol 705:135–139

    Article  PubMed  Google Scholar 

  37. Bartold PM, du Bois AH, Gannon S, Haynes DR, Hirsch RS (2013) Antibacterial and immunomodulatory properties of azithromycin treatment implications for periodontitis. Inflammopharmacology 21:321–238

    Article  PubMed  Google Scholar 

  38. Hand WL, Hand DL (2001) Characteristics and mechanisms of azithromycin accumulation and efflux in human polymorphonuclear leukocytes. Int J Antimicrob Agents 18:419–425

    Article  PubMed  Google Scholar 

  39. McDonald PJ, Pruul H (1991) Phagocyte uptake and transport of azithromycin. Eur J Clin Microbiol Infect Dis 10:828–833

    Article  PubMed  Google Scholar 

  40. Wildfeuer A, Laufen H, Zimmermann T (1994) Distribution of orally administered azithromycin in various blood compartments. Int J Clin Pharmacol Ther 32:356–360

    PubMed  Google Scholar 

  41. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 62:e1–34

    Article  PubMed  Google Scholar 

  42. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097.

  43. Hopkins S (1991) Clinical toleration and safety of azithromycin. Am J Med 91:40S–45S

    Article  PubMed  Google Scholar 

  44. Martinez MA, Vuppalanchi R, Fontana RJ, Stolz A, Kleiner DE, Hayashi PH, Gu J, Hoofnagle JH, Chalasani N (2014) Clinical and histologic features of azithromycin-induced liver injury. Clin Gastroenterol Hepatol. doi:10.1016/j.cgh.2014.07.054

    Google Scholar 

  45. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:d5928

    Article  PubMed Central  PubMed  Google Scholar 

  46. Graziani F, Figuero E, Herrera D (2012) Systematic review of quality of reporting, outcome measurements and methods to study efficacy of preventive and therapeutic approaches to peri-implant diseases. J Clin Periodontol 39(Suppl 12):224–244

    Article  PubMed  Google Scholar 

  47. Haas AN, de Castro GD, Moreno T, Susin C, Albandar JM, Oppermann RV, Rosing CK (2008) Azithromycin as an adjunctive treatment of aggressive periodontitis: 12-months randomized clinical trial. J Clin Periodontol 35:696–704

    Article  PubMed  Google Scholar 

  48. Haffajee AD, Torresyap G, Socransky SS (2007) Clinical changes following four different periodontal therapies for the treatment of chronic periodontitis: 1-year results. J Clin Periodontol 34:243–253

    Article  PubMed  Google Scholar 

  49. Yashima A, Gomi K, Maeda N, Arai T (2009) One-stage full-mouth versus partial-mouth scaling and root planing during the effective half-life of systemically administered azithromycin. J Periodontol 80:1406–1413

    Article  PubMed  Google Scholar 

  50. Oteo A, Herrera D, Figuero E, O’Connor A, Gonzalez I, Sanz M (2010) Azithromycin as an adjunct to scaling and root planing in the treatment of Porphyromonas gingivalis-associated periodontitis: a pilot study. J Clin Periodontol 37:1005–1015

    Article  PubMed  Google Scholar 

  51. Mascarenhas P, Gapski R, Al-Shammari K, Hill R, Soehren S, Fenno JC, Giannobile WV, Wang HL (2005) Clinical response of azithromycin as an adjunct to non-surgical periodontal therapy in smokers. J Periodontol 76:426–436

    Article  PubMed  Google Scholar 

  52. Emingil G, Han B, Ozdemir G, Tervahartiala T, Vural C, Atilla G, Baylas H, Sorsa T (2012) 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 47:729–739

    Article  PubMed  Google Scholar 

  53. Gomi K, Yashima A, Nagano T, Kanazashi M, Maeda N, Arai T (2007) Effects of full-mouth scaling and root planing in conjunction with systemically administered azithromycin. J Periodontol 78:422–429

    Article  PubMed  Google Scholar 

  54. Han B, Emingil G, Ozdemir G, Tervahartiala T, Vural C, Atilla G, Baylas H, Sorsa T (2012) Azithromycin as an adjunctive treatment of generalized severe chronic periodontitis: clinical, microbiologic, and biochemical parameters. J Periodontol 83:1480–1491

    Article  PubMed  Google Scholar 

  55. Sampaio E, Rocha M, Figueiredo LC, Faveri M, Duarte PM, Gomes Lira EA, Feres M (2011) Clinical and microbiological effects of azithromycin in the treatment of generalized chronic periodontitis: a randomized placebo-controlled clinical trial. J Clin Periodontol 38:838–846

    Article  PubMed  Google Scholar 

  56. Farman M, Joshi RI (2008) Full-mouth treatment versus quadrant root surface debridement in the treatment of chronic periodontitis: a systematic review. Br Dent J 205, E18, discussion 496-497

    Article  PubMed  Google Scholar 

  57. Matthews DC (2009) No difference between full-mouth and quadrant-wise treatment of chronic periodontitis. Evid Based Dent 10:17

    Article  PubMed  Google Scholar 

  58. Principi N, Esposito S (1999) Comparative tolerability of erythromycin and newer macrolide antibacterials in paediatric patients. Drug Saf 20:25–41

    Article  PubMed  Google Scholar 

  59. Almalki ZS, Guo JJ (2014) Cardiovascular events and safety outcomes associated with azithromycin therapy: a meta-analysis of randomized controlled trials. Am Health Drug Benefits 7:318–328

    PubMed Central  PubMed  Google Scholar 

  60. Panteix G, Guillaumond B, Harf R, Desbos A, Sapin V, Leclercq M, Perrin-Fayolle M (1993) In-vitro concentration of azithromycin in human phagocytic cells. J Antimicrob Chemother 31(Suppl E):1–4

    Article  PubMed  Google Scholar 

  61. Jaruratanasirikul S, Hortiwakul R, Tantisarasart T, Phuenpathom N, Tussanasunthornwong S (1996) Distribution of azithromycin into brain tissue, cerebrospinal fluid, and aqueous humor of the eye. Antimicrob Agents Chemother 40:825–826

    PubMed Central  PubMed  Google Scholar 

  62. Gomi K, Yashima A, Iino F, Kanazashi M, Nagano T, Shibukawa N, Ohshima T, Maeda N, Arai T (2007) Drug concentration in inflamed periodontal tissues after systemically administered azithromycin. J Periodontol 78:918–923

    Article  PubMed  Google Scholar 

  63. Malizia T, Tejada MR, Ghelardi E, Senesi S, Gabriele M, Giuca MR, Blandizzi C, Danesi R, Campa M, Del Tacca M (1997) Periodontal tissue disposition of azithromycin. J Periodontol 68:1206–1209

    Article  PubMed  Google Scholar 

  64. Loos B, Nylund K, Claffey N, Egelberg J (1989) Clinical effects of root debridement in molar and non-molar teeth. A 2-year follow-up. J Clin Periodontol 16:498–504

    Article  PubMed  Google Scholar 

  65. Nordland P, Garrett S, Kiger R, Vanooteghem R, Hutchens LH, Egelberg J (1987) The effect of plaque control and root debridement in molar teeth. J Clin Periodontol 14:231–236

    Article  PubMed  Google Scholar 

  66. Walter C, Weiger R, Zitzmann NU (2011) Periodontal surgery in furcation-involved maxillary molars revisited—an introduction of guidelines for comprehensive treatment. Clin Oral Investig 15:9–20

    Article  PubMed  Google Scholar 

  67. Matuliene G, Pjetursson BE, Salvi GE, Schmidlin K, Bragger U, Zwahlen M, Lang NP (2008) Influence of residual pockets on progression of periodontitis and tooth loss: results after 11 years of maintenance. J Clin Periodontol 35:685–695

    Article  PubMed  Google Scholar 

  68. Badersten A, Nilveus R, Egelberg J (1984) Effect of nonsurgical periodontal therapy. II. Severely advanced periodontitis. J Clin Periodontol 11:63–76

    Article  PubMed  Google Scholar 

  69. Warnakulasuriya S, Dietrich T, Bornstein MM, Casals Peidro E, Preshaw PM, Walter C, Wennstrom JL, Bergstrom J (2010) Oral health risks of tobacco use and effects of cessation. Int Dent J 60:7–30

    PubMed  Google Scholar 

  70. Michalowicz BS, Gustafsson A, Thumbigere-Math V, Buhlin K (2013) The effects of periodontal treatment on pregnancy outcomes. J Clin Periodontol 40(Suppl 14):S195–208

    PubMed  Google Scholar 

Download references

Acknowledgments

Parts of this research were conducted by S. L. Buset in partial fulfilment of the requirements for an MD degree from the University of Basel, Switzerland.

Conflict of interest

The authors declare that they have no conflict of interests.

Author information

Authors and Affiliations

  1. Department of Periodontology, Endodontology and Cariology, University of Basel, Hebelstrasse 3, CH-4056, Basel, Switzerland

    Sabrina L. Buset, Nicola U. Zitzmann, Roland Weiger & Clemens Walter

Authors
  1. Sabrina L. Buset
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicola U. Zitzmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roland Weiger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Clemens Walter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Clemens Walter.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 81 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Buset, S.L., Zitzmann, N.U., Weiger, R. et al. Non-surgical periodontal therapy supplemented with systemically administered azithromycin: a systematic review of RCTs. Clin Oral Invest 19, 1763–1775 (2015). https://doi.org/10.1007/s00784-015-1499-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00784-015-1499-z

Keywords

Search

Navigation