The use of adjunctive systemic metronidazole and amoxicillin in the treatment of periodontal infections

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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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