Ricardo Teles
Senior Member of the Staff Department of Applied Oral Science, Center for Periodontology, the Forsyth Institute
Flavia R. Teles
Assistant Member of the Staff Department of Applied Oral Science, Center of Periodontology, the Forsyth Institute
The use of adjunctive systemic antibiotics in the treatment of periodontal diseases has always been somewhat controversial. Opposition to the systematic use of these agents in periodontal therapy was based on several grounds, including: lack of superior outcome compared to conventional mechanical therapy; high rate of recolonization of the subgingival microbiota, potentially requiring several rounds of antibiotics to maintain the clinical gains obtained; induction of bacterial resistance.
Despite these concerns, different systemic antibiotics have been tested as adjuncts to mechanical debridement in the treatment of periodontal infections since the late 1970s with mixed results. Eventually, serendipitous scientific discoveries have led to the development of a highly efficacious antimicrobial therapy to treat periodontal diseases, namely the use of the combination of systemic metronidazole and amoxicillin. Serendipity happened when it was observed that the use of metronidazole to treat vaginal infections resulted in the improvement of the gingival condition of treated subjects 1. That observation led eventually to the use of this nitroimidazole, highly active against strict anaerobic bacteria, to be tested in the treatment of periodontal diseases2-4. Many years later, the use of this drug was combined with amoxicillin in an attempt to treat Aggregatibacter actinomycetemcomitans infections in adult subjects5, 6. These studies launched a new era in the use of systemic antibiotics to treat periodontal infections.
However, they were probably based on erroneous assumptions regarding the relevance of A. actinomycetemcomitans as the etiological agent in the reported cases and the specific effects of the combination of antibiotics on this target. Since these early reports, several clinical trials have tested the adjunctive use of this combination of antimicrobial agents in the treatment of aggressive periodontitis7-13 and moderate to severe forms of chronic periodontitis14-20. The data accumulated by these studies are overwhelmingly in favor of the use of systemic antibiotics. In this paper, we review the most relevant data that support the use of systemic metronidazole and amoxicillin in the treatment of periodontal diseases and make recommendations regarding their proper use.
Clinical effects
The clinical superiority of adjunctive systemic metronidazole and amoxicillin therapy over scaling and root planning (SRP) was not always apparent. The use of full-mouth mean values of pocket depth (PD) and clinical attachment level (CAL) changes gave the impression that the small differences encountered were of little clinical relevance. However, examination of the effects of this therapy on different PD categories revealed that systemic metronidazole and amoxicillin resulted in statistically significant and clinically relevant changes in deeper sites7, 19-21. In recent years, researchers have favored to report the number and or percentage of residual deep sites (i.e. PD ≥ 5 mm) obtained after adjunctive systemic metronidazole and amoxicillin compared to SRP alone7, 15, 19, 22. This clinical outcome is particularly relevant because the indication for periodontal surgery is determined by the number of residual pockets after anti-infective therapy. In addition, recent studies have suggested that the number of residual pockets can give clinicians an estimate of the risk for future disease progression and tooth loss23, 24. By decreasing the number of residual pockets, systemic metronidazole and amoxicillin might reduce the need for periodontal surgery25 and result in long term stability of the remaining periodontium. In fact, the use of these adjunctive systemic antibiotics has been associated with a lower rate of disease progression for 6 months7 and for up to 2 years20 after a single course of the antibiotics. A recent longitudinal study by Goodson et al.26 also indicated that the gains obtained with a single regimen of adjunctive systemic metronidazole and amoxicillin might last for up to 2 years even in the absence of an intensive supportive periodontal therapy. Although most of the initial clinical benefits are more evident in deep sites, this therapy also seems to have an impact in shallow sites. This is suggested by a decrease in the % of sites with additional loss of attachment during maintenance. Since loss of attachment in subjects under supportive periodontal therapy occurs primarily at shallow sites27, it seems that these sites also benefit from the use of these systemic antimicrobials.
Timing of drug administration in reference to mechanical therapy
In 2004, The American Academy of Periodontology (AAP) recommended that systemic antibiotic therapy should be used in patients with unresolved and/or progressing sites after conventional mechanical periodontal treatment28. That implies that a re-examination of the outcome of mechanical therapy should be obtained prior to any decision on the use of systemic antibiotics. That would delay the use of systemic antibiotics up to 3 months after initial therapy. This notion has been challenged by recent studies that demonstrated that systemic antibiotics resulted in improved clinical outcomes when administered immediately after mechanical therapy rather than 3 to 6 months post SRP9, 13. It is possible that delaying the beginning of antibiotic therapy might result in a return of the subgingival biofilm to its original complexity, diminishing the benefits offered by a recent mechanical disruption of its structure. The smaller reduction in the number of subgingival bacteria might also compromise the healing of the periodontal pockets13. In addition, this period of healing might decrease the amount of antibiotics being delivered to the site due to a decrease in the perfusion and the permeability of capillaries associated with inflammation13, lower GCF flow and enhanced epithelial barrier. Therefore, systemic antibiotic therapy should start during the initial anti-infective therapy either after the first session of SRP or immediately after the completion of the final SRP and not as an alternative re-treatment.
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Who should be treated with adjunctive systemic metronidazole and amoxicillin?
The use of systemic antibiotics can be hazardous; therefore, researchers have tried to identify subjects who would benefit the most from this therapy in an attempt to limit their use. It has been suggested that certain patient categories considered to have a higher risk for periodontal disease progression such as aggressive periodontitis should be preferably treated with systemic antibiotics29. Further, several studies have tried to tailor the choice of the antimicrobial agent to the presence of specific periodontal pathogens and some have suggested that systemic metronidazole and amoxicillin would be particularly beneficial when A. actinomycetemcomitans was present at high levels5,6,30. Later, the same group recommended the use of this combination to treat “adult periodontitis” associated with Porphyromonas gingivalis22. Others have suggested that this regimen would adversely affect subjects infected with P. gingivalis but not A. Actinomycetemcomitans31. A recent study recommended the use of systemic metronidazole and amoxicillin as an adjunct to mechanical therapy in patients with moderate to severe chronic periodontitis harboring subgingival A. actinomycetemcomitans and/or P. gingivalis20. Recent evidence challenges the relevance of the clinical diagnosis of aggressive or chronic periodontitis and of any microbiological testing to guide the use of this antimicrobial combination25,32-34.
It has been suggested that even in the absence of detectable A. actinomycetemcomitans and/or P. gingivalis, periodontitis subjects responded positively to adjunct systemic amoxicillin and metronidazole32. In addition, it seems that patients respond well to the use of systemic metronidazole and amoxicillin irrespective of the clinical diagnosis of chronic33 or aggressive periodontitis34 and that the severity and extent of the disease are more relevant in that decision. Precise clinical guidelines that would trigger the need for systemic metronidazole and amoxicillin are still lacking in the literature. However, due to their remarkable effect on reducing the number of residual pockets, for cases in which the clinician suspects there will be a sizeable number of residual deep sites, this combination of antimicrobials should be prescribed.
Dose and dosage
The literature shows no consistency regarding the dose (the quantity of antibiotic to be administered at one time), dosage (the frequency and quantity of antibiotic administered to a patient) and duration of the course of systemic metronidazole and amoxicillin. The different regimens were somewhat arbitrarily defined and no scientific basis for their choice was presented in the manuscripts, making it difficult to make a definitive recommendation. In addition, only a few clinical trials reported the incidence of adverse events associated with the use of antibiotics, making it hard to estimate whether longer courses resulted in a higher incidence of adverse events. The only way to determine the best regimen for this combination of antibiotics would be through a randomized clinical trial (RCT) assessing not only the impact of different regimens on periodontal parameters but also on the incidence of adverse effects. In the absence of this information, the clinician should opt for a conservative approach and use the lowest dosage and shortest duration reported in the literature with an additional benefit over SRP alone. In addition, a shorter course of antibiotics decreases the chances of selecting for resistant species35. We recommend 250 mg of metronidazole and 500 mg of amoxicillin, three times a day for 7 days16,20.
Cost-benefit ratio
As mentioned above, the use of systemic antibiotics is not without risks. Clinicians should weight the costbenefit ratio before prescribing these powerful drugs. We highlighted the clinical benefits that can be achieve with the adjunctive use of systemic metronidazole and amoxicillin, including changes that might mitigate the need for additional costly treatments such as periodontal surgeries and replacement of lost teeth. Further, these drugs are readily available and add very little to the overall costs of periodontal anti-infective therapy36. These drugs have been used widely for over 3 decades and have, for the most, a well documented track record of safety25. However, in assessing the cost-benefit ratio of this therapy, it is important to examine the side effects associated with these drugs. Several studies employing this combination of systemic antimicrobials have reported on the adverse events experienced by study participants7, 8, 10-12, 15, 19-21, 37. The vast majority of side effects were mild gastrointestinal symptoms and the frequency of reporting of other adverse events such as dizziness, metallic taste and intra-oral tissue alteration was not significantly higher in the antibiotics groups compared to the placebo groups34. A few instances of subjects discontinuing medication due to moderate to severe side effects have also been reported9,20. Bacterial resistance is probably the single most important reason why clinicians should refrain from the indiscriminate use of systemic antibiotics to treat periodontal infections. However, concerns regarding antibiotic resistance should not preclude clinicians from using these drugs to treat periodontal diseases when indicated. There are guidelines in the medical literature to the prudent use of antibiotics in order to minimize the risk of antibiotic resistance; these include: use antibiotics only when patient outcome can be improved; use of narrow-spectrum antibiotics whenever possible; save last generation antibiotics for serious, life threatening infections; antibiotic therapy should be stopped as soon as possible38. Periodontists can easily abide by these guidelines while still offering their patients the clinical benefits of the adjunctive use of metronidazole and amoxicillin. Further, the use of a combination of antimicrobial drugs with different modes of action might decrease the chances of inducing bacterial resistance.
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Conclusions
Hitherto, every published study comparing the use of adjunctive systemic metronidazole and amoxicillin to mechanical therapy alone reported a significant clinical benefit associated with the use of this combination. This information coupled with their safety profile should suffice to recommend them as the first drugs of choice in the treatment of periodontal infections. It took the field of periodontology over 40 years of research on adjunctive systemic antibiotics to come up with this regimen and most of the RCTs that support their indication were published within the past decade. That implies that we might be decades away from a more efficacious anti-infective therapy. Until it has been demonstrated that another approach results in superior clinical results with an equal or better safety profile; this combination should be considered the standard of care for patients with moderate to severe generalized forms of periodontitis.
Correspondence:
Ricardo Palmier Teles
Department of Applied Oral Sciences, Center for Periodontology - The Forsyth Institute 245 First Street, Cambridge, MA 02142, USA
Tel. 617-892-8556
rteles@forsyth.org
1. Shinn DLS. Metronidazole in acute ulcerative gingivitis. Lancet 1962;279:1191.
2. Loesche WJ, Giordano JR, Hujoel P, Schwarcz J, Smith BA. Metronidazole in periodontitis: reduced need for surgery. J Clin Periodontol 1992;19:103-112.
3. Loesche WJ, Giordano JR. Metronidazole in periodontitis V: debridement should precede medication. Compendium 1994;15:1198, 1201, 1203 passim; quiz 1218.
4. Loesche WJ, Schmidt E, Smith BA, Caffessee R, Stoll J. Metronidazole therapy for periodontitis. J Periodontal Res 1987;22:224-226.
5. van Winkelhoff AJ, Rodenburg JP, Goene RJ, Abbas F, Winkel EG, de Graaff J. Metronidazole plus amoxycillin in the treatment of Actinobacillus actinomycetemcomitans associated periodontitis. J Clin Periodontol 1989;16:128-131.
6. van Winkelhoff AJ, Tijhof CJ, de Graaff J. Microbiological and clinical results of metronidazole plus amoxicillin therapy in Actinobacillus actinomycetemcomitans-associated periodontitis. J Periodontol 1992;63:52-57.
7. 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 placebocontrolled clinical trial. J Clin Periodontol 2005;32:1096-1107.
8. Yek EC, Cintan S, Topcuoglu N, Kulekci G, Issever H, Kantarci A. Efficacy of amoxicillin and metronidazole combination for the management of generalized aggressive periodontitis. J Periodontol 2010;81:964-974.
9. 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.
10. 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.
11. Baltacioglu E, Aslan M, Sarac O, Saybak A, Yuva P. 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.
12. Mestnik MJ, Feres M, Figueiredo LC, Duarte PM, Lira EA, Faveri M. 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.
13. Kaner D, Christan C, Dietrich T, Bernimoulin JP, Kleber BM, Friedmann A. Timing affects the clinical outcome of adjunctive systemic antibiotic therapy for generalized aggressive periodontitis. J Periodontol 2007;78:1201-1208.
14. Berglundh T, Krok L, Liljenberg B, Westfelt E, Serino G, Lindhe J. 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.
15. Cionca N, Giannopoulou C, Ugolotti G, Mombelli A. Amoxicillin and metronidazole as an adjunct to full-mouth scaling and root planing of chronic periodontitis. J Periodontol 2009;80:364-371.
16.Ribeiro Edel P, 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.
17.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.
18.Rooney J, Wade WG, Sprague SV, Newcombe RG, Addy M. 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.
19.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.
20.Ehmke B, Moter A, Beikler T, Milian E, Flemmig TF. Adjunctive antimicrobial therapy of periodontitis: long-term effects on disease progression and oral colonization. J Periodontol 2005;76:749-759.
21.Matarazzo F, Figueiredo LC, Cruz SE, Faveri M, Feres M. 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.
22.Winkel EG, Van Winkelhoff AJ, Timmerman MF, Van der Velden U, Van der Weijden GA. Amoxicillin plus metronidazole in the treatment of adult periodontitis patients. A doubleblind placebo-controlled study. J Clin Periodontol 2001;28:296-305.
23.Matuliene G, Pjetursson BE, Salvi GE, et al. Influence of residual pockets on progression of periodontitis and tooth loss: results after 11 years of maintenance. J Clin Periodontol 2008;35:685-695.
24.Matuliene G, Studer R, Lang NP, et al. Significance of Periodontal Risk Assessment in the recurrence of periodontitis and tooth loss. J Clin Periodontol 2010;37:191-199.
25. Mombelli A, Cionca N, Almaghlouth A. Does adjunctive antimicrobial therapy reduce the perceived need for periodontal surgery? Periodontol 2000 2011;55:205-216.
26.Goodson JM, Haffajee A, Socransky S, 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(6):526-36.
27. Teles RP, Patel M, Socransky SS, Haffajee AD. Disease progression in periodontally healthy and maintenance subjects. J Periodontol 2008;79:784-794.
28.Slots J. Systemic antibiotics in periodontics. J Periodontol 2004;75:1553-1565.
29. van Winkelhoff AJ, Rams TE, Slots J. Systemic antibiotic therapy in periodontics. Periodontol 2000 1996;10:45-78.
30. Winkel EG, van Winkelhoff AJ, van der Velden U. Additional clinical and microbiological effects of amoxicillin and metronidazole after initial periodontal therapy. J Clin Periodontol 1998;25:857-864.
31. Flemmig TF, Milian E, Karch H, Klaiber B. 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.
32. Cionca N, Giannopoulou C, Ugolotti G, Mombelli A. 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.
33.Sgolastra F, Gatto R, Petrucci A, Monaco A. 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 .
34. Sgolastra F, Petrucci A, Gatto R, Monaco A. 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 2011 .
35.Pallasch TJ. Pharmacokinetic principles of antimicrobial therapy. Periodontol 2000 1996;10:5-11.
36.Heasman PA, Vernazza CR, Gaunt FL, Pennington MW. Cost-effectiveness of adjunctive antimicrobials in the treatment of periodontitis. Periodontol 2000 2011;55:217-230.
37. Xajigeorgiou C, Sakellari D, Slini T, Baka A, Konstantinidis A. Clinical and microbiological effects of different antimicrobials on generalized aggressive periodontitis. J Clin Periodontol 2006;33:254-264.
38. Collignon PJ. 11: Antibiotic resistance. Med J Aust 2002;177:325-329.
