Volume 85 • Number 3
Letters to the Editor To the Editor: Re: The Clinical Effect of Scaling and Root Planing and the Concomitant Administration of Systemic Amoxicillin and Metronidazole: A Systematic Review. Zandbergen D, Slot DE, Cobb CM, Van der Weijden FA. (J Periodontol 2013;84:332351.) 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. Sgolastra F, Gatto R, Petrucci A, Monaco A. (J Periodontol 2012;83:1257-1269.) 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. Sgolastra F, Petrucci A, Gatto R, Monaco A. (J Periodontol 2012;83:731-743.) Combined Antibiotics and Periodontal Therapy We have with great interest read the systematic review by Zandbergen et al.,1 and also the earlier reviews by Sgolastra et al.2,3 These are extensive reviews that support the additional benefit of combining systemic amoxicillin (AMOX) and metronidazole (MET) in the treatment of periodontitis. Even so, there are some crucial issues that need to be addressed before these systematic reviews may be used to encourage the use of this combination therapy (CT) in the treatment of periodontitis. Scaling and root planing (SRP), with or without surgical intervention, is the main component of any successful treatment of periodontitis.4-8 However, occasionally this therapy fails when the periodontal destruction continues after treatment or recurs after periods of remission.9,10 This frustrating observation has led to the introduction of adjunct systemic antibiotics in periodontal therapy, and clinical tests have indicated varying success.11-14 However, it is generally agreed that antibiotic treatment, if used, must be an adjunct to SRP15 and that CT is the more effective antimicrobial strategy,16-19 just as the three extensive systematic reviews1-3 testify to its clinical effectiveness. The synergistic effect of combining penicillin with metronidazole has been known for decades,20 but CT was not introduced to periodontics until van Winkelhoff and coworkers in 1989 reported its effectiveness 374
against Actinobacillus actinomycetemcomitans.21 Since then, CT has gradually been integrated in periodontal therapy, often replacing other antibiotics when an adjunct antimicrobial is considered. Thereby, the use of this broad-spectrum combination has gained increasing popularity despite the general knowledge that the subgingival microflora associated with periodontitis mostly consists of anaerobes, which are susceptible to metronidazole alone.22 More seriously, the increasing popularity of CT contravenes the general recommendations for the use of antibiotics by the World Health Organization (WHO)23 and the European Union (EU).24,25 To prevent development of resistant bacterial strains, WHO and EU recommend that: 1) unnecessary use of any antibiotic be avoided; 2) narrow-spectrum antibiotics be used whenever possible; and 3) broad-spectrum or combination antibiotics be avoided except in cases of severe infections that do not respond otherwise. In corroboration with these recommendations, microbiological diagnosis is advised before selecting an antibiotic against infectious diseases in general,23-25 and periodontal diseases in particular.26-28 Consequently, both WHO and EU recommend their member nations to develop high-quality, accessible and affordable microbiological diagnostic laboratories.23-25 Systematic reviews are potent tools for the provision of answers regarding clinical questions on efficacy and effectiveness, but their outcomes are dependent on the quality of the original research and the methodological rigor exerted when conducting the reviews. The said systematic reviews1-3 all agree that adjunct CT is beneficial for the outcome of periodontal therapy in general,1 chronic,3 and aggressive2 periodontitis. However, in our opinion there are four general issues related to these reviews and to the studies on antibiotics in periodontics in general that need to be addressed as caveats: the heterogeneity of results of systematic reviews; the very short follow-up time; the criteria for selecting the antibiotic; and the overall clinical treatment strategy. The Heterogeneity of Results of Systematic Reviews It is troubling to note that the estimates provided in the three systematic reviews1-3 of the clinical effectiveness of CT were quite variable, even if the reviews, judged from their publication dates, were carried out at approximately the same time. The
J Periodontol • March 2014
estimates of the additional probing depth (PD) reduction obtained with CT ranged from 0.21 mm3 to 1.41 mm,1 while the additional clinical attachment level (CAL) gain from CT ranged from 0.42 mm2 to 0.94 mm.1 Zandbergen et al.1 were able to include 19 studies (outcomes: PD reduction and CAL gain) in the evaluation of the adjunct effect of CT in periodontal treatment, whereas Sgolastra et al. were able to include six2 and four3 studies in their reviews. This methodological heterogeneity only serves to underline what is generally known about the quality of systematic reviews, particularly those that are not Cochrane reviews.29,30 In any case, systematic reviews are of limited value if their outcomes are not trustworthy, and we interpret the rather variable efficacy estimates reviewed above as suggestions of considerable room for improvement. Systematic reviews have gained substantial popularity, and in view of the frequent observation of an absence of high-quality studies on which the review is based, we would suggest more emphasis be placed on the production of high-quality research to fill the obvious knowledge gaps. The Short Follow-Up Time Most of the studies included in the three systematic reviews1-3 had a follow-up time of 6 months or less (Table 1). Moreover, the comparatively low number of participants in most of the included studies is of concern (Table 1). While it sometimes may be relevant to assess the microbiological response to the antibiotics administered within the first 6 months after administration, it is clearly of no interest to record the clinical outcomes with such a short follow-up. Therefore, recording clinical data before 12 months has questionable value although an initial clinical PD reduction may be observed directly after treatment.31-33 Zandbergen et al.1 found 35 papers (representing 28 studies) out of 526 unique titles for the evaluation of the adjunct effect of CT in periodontal treatment, but only five studies (six papers) had a follow-up exceeding 12 months.34-39 Sgolastra and coworkers identified 368 unique titles in their systematic review on CT in the treatment of aggressive periodontitis2 and 517 unique titles in their review of CT in the treatment of chronic periodontitis,3 and included six and four studies, respectively. None of these had a follow-up of more than 6 months. We would therefore conclude that although there seems to be some very short-term (
Letters to the Editor To the Editor: Re: The Clinical Effect of Scaling and Root Planing and the Concomitant Administration of Systemic Amoxicillin and Metronidazole: A Systematic Review. Zandbergen D, Slot DE, Cobb CM, Van der Weijden FA. (J Periodontol 2013;84:332351.) 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. Sgolastra F, Gatto R, Petrucci A, Monaco A. (J Periodontol 2012;83:1257-1269.) 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. Sgolastra F, Petrucci A, Gatto R, Monaco A. (J Periodontol 2012;83:731-743.) Combined Antibiotics and Periodontal Therapy We have with great interest read the systematic review by Zandbergen et al.,1 and also the earlier reviews by Sgolastra et al.2,3 These are extensive reviews that support the additional benefit of combining systemic amoxicillin (AMOX) and metronidazole (MET) in the treatment of periodontitis. Even so, there are some crucial issues that need to be addressed before these systematic reviews may be used to encourage the use of this combination therapy (CT) in the treatment of periodontitis. Scaling and root planing (SRP), with or without surgical intervention, is the main component of any successful treatment of periodontitis.4-8 However, occasionally this therapy fails when the periodontal destruction continues after treatment or recurs after periods of remission.9,10 This frustrating observation has led to the introduction of adjunct systemic antibiotics in periodontal therapy, and clinical tests have indicated varying success.11-14 However, it is generally agreed that antibiotic treatment, if used, must be an adjunct to SRP15 and that CT is the more effective antimicrobial strategy,16-19 just as the three extensive systematic reviews1-3 testify to its clinical effectiveness. The synergistic effect of combining penicillin with metronidazole has been known for decades,20 but CT was not introduced to periodontics until van Winkelhoff and coworkers in 1989 reported its effectiveness 374
against Actinobacillus actinomycetemcomitans.21 Since then, CT has gradually been integrated in periodontal therapy, often replacing other antibiotics when an adjunct antimicrobial is considered. Thereby, the use of this broad-spectrum combination has gained increasing popularity despite the general knowledge that the subgingival microflora associated with periodontitis mostly consists of anaerobes, which are susceptible to metronidazole alone.22 More seriously, the increasing popularity of CT contravenes the general recommendations for the use of antibiotics by the World Health Organization (WHO)23 and the European Union (EU).24,25 To prevent development of resistant bacterial strains, WHO and EU recommend that: 1) unnecessary use of any antibiotic be avoided; 2) narrow-spectrum antibiotics be used whenever possible; and 3) broad-spectrum or combination antibiotics be avoided except in cases of severe infections that do not respond otherwise. In corroboration with these recommendations, microbiological diagnosis is advised before selecting an antibiotic against infectious diseases in general,23-25 and periodontal diseases in particular.26-28 Consequently, both WHO and EU recommend their member nations to develop high-quality, accessible and affordable microbiological diagnostic laboratories.23-25 Systematic reviews are potent tools for the provision of answers regarding clinical questions on efficacy and effectiveness, but their outcomes are dependent on the quality of the original research and the methodological rigor exerted when conducting the reviews. The said systematic reviews1-3 all agree that adjunct CT is beneficial for the outcome of periodontal therapy in general,1 chronic,3 and aggressive2 periodontitis. However, in our opinion there are four general issues related to these reviews and to the studies on antibiotics in periodontics in general that need to be addressed as caveats: the heterogeneity of results of systematic reviews; the very short follow-up time; the criteria for selecting the antibiotic; and the overall clinical treatment strategy. The Heterogeneity of Results of Systematic Reviews It is troubling to note that the estimates provided in the three systematic reviews1-3 of the clinical effectiveness of CT were quite variable, even if the reviews, judged from their publication dates, were carried out at approximately the same time. The
J Periodontol • March 2014
estimates of the additional probing depth (PD) reduction obtained with CT ranged from 0.21 mm3 to 1.41 mm,1 while the additional clinical attachment level (CAL) gain from CT ranged from 0.42 mm2 to 0.94 mm.1 Zandbergen et al.1 were able to include 19 studies (outcomes: PD reduction and CAL gain) in the evaluation of the adjunct effect of CT in periodontal treatment, whereas Sgolastra et al. were able to include six2 and four3 studies in their reviews. This methodological heterogeneity only serves to underline what is generally known about the quality of systematic reviews, particularly those that are not Cochrane reviews.29,30 In any case, systematic reviews are of limited value if their outcomes are not trustworthy, and we interpret the rather variable efficacy estimates reviewed above as suggestions of considerable room for improvement. Systematic reviews have gained substantial popularity, and in view of the frequent observation of an absence of high-quality studies on which the review is based, we would suggest more emphasis be placed on the production of high-quality research to fill the obvious knowledge gaps. The Short Follow-Up Time Most of the studies included in the three systematic reviews1-3 had a follow-up time of 6 months or less (Table 1). Moreover, the comparatively low number of participants in most of the included studies is of concern (Table 1). While it sometimes may be relevant to assess the microbiological response to the antibiotics administered within the first 6 months after administration, it is clearly of no interest to record the clinical outcomes with such a short follow-up. Therefore, recording clinical data before 12 months has questionable value although an initial clinical PD reduction may be observed directly after treatment.31-33 Zandbergen et al.1 found 35 papers (representing 28 studies) out of 526 unique titles for the evaluation of the adjunct effect of CT in periodontal treatment, but only five studies (six papers) had a follow-up exceeding 12 months.34-39 Sgolastra and coworkers identified 368 unique titles in their systematic review on CT in the treatment of aggressive periodontitis2 and 517 unique titles in their review of CT in the treatment of chronic periodontitis,3 and included six and four studies, respectively. None of these had a follow-up of more than 6 months. We would therefore conclude that although there seems to be some very short-term (
