Metanalisis tto PERIODONTITIS AGRESIVA

Journal of Periodontology; Copyright 2011 DOI: 10.1902/jop.2011.110432

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

Fabrizio Sgolastra*, DDS; Ambra Petrucci*, DDS; Roberto Gatto*, MD; Annalisa Monaco*, DDS

*Department of Health Sciences, School of Dentistry, University of L’Aquila, L’Aquila, Italy.

Background: The systemic use of combined amoxicillin and metronidazole (AMX/MET) as an adjunctive treatment to full-mouth scaling root planing (FMSRP) has been proposed for the treatment of generalized aggressive periodontitis (GAgP); however, its effectiveness and clinical safety remain to be defined. The purpose of the present meta-analysis was to assess the effectiveness of FMSRP + AMX/MET compared to FMSRP alone.

Methods: An electronic search of eight databases and a hand-search of ten international dental journals were conducted through September 11, 2011. Gain in clinical attachment level (CAL), reduction in probing depth (PD), secondary outcomes and adverse events were analyzed. A random-effect model was used to pool the extracted data. The weighted mean difference with 95% confidence interval (CI) was calculated for continuous outcomes, while risk difference (RD) with 95% CI was used for dichotomous data; heterogeneity was assessed with the Cochrane χ2 and I2 tests. The level of significance was set at p < 0.05.

Results: After the selection process, six randomized clinical trials were included. Results of the meta-analysis showed significant CAL gain (MD: 0.42; 95% CI: 0.23 -0.61; p < 0.05), PD reduction (MD: 0.58; 95% CI: 0.39-0.77; p < 0.05) in favor of FMSRP + AMX/MET; moreover, no significant RD was found in the occurrence of adverse events (RD: 0.01; 95% CI: -0.02-0.04, p > 0.05).

Conclusion: The findings of the meta-analysis seem to support the effectiveness and the clinical safety of FMSRP + AMX/MET; however, future studies are needed to confirm these results.

KEYWORDS: aggressive periodontitis, root planing, amoxicillin, metronidazole, meta-analysis

Generalized aggressive periodontitis (GAgP) is a complex periodontal disease that is characterized by severe and rapid destruction of the supporting apparatus of the teeth1. Even if GAgP affects a minority of periodontal patients, the disease is still highly significant: if left untreated, GAgP can lead to early edentulism2. Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Tannerella forsythia have been strongly associated with GAgP3,4, although recent studies suggest that other microbial species could be involved5. The treatment of this disease and the maintenance of treatment outcomes represent major challenges for clinicians6.

Modern leanings suggest that, as with chronic periodontitis (CP), the first phase in the treatment of GAgP should be aimed at reducing and/or eliminating the disease-causing pathogenic microorganisms7. Current treatment strategies that are applied in this phase primarily revolve around full-mouth scaling and root planing (FMSRP), which is associated with varying degrees of additional clinical and microbiological benefits8-11, and the adjunctive use of systemic antibiotics2. An emerging approach to maintain the effects of antibiotics suggests the use of a combination of multiple adjunctive antimicrobial agents. This strategy assumes that multiple species can be eliminated or suppressed simultaneously during periodontal therapy, leading to better stability of the microbiota and improved host response12.

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Among the possible antibiotics regimens, the combination of amoxicillin and metronidazole (AMX/MET) has been indicated in the treatment of aggressive forms of periodontal disease12,13. This approach has gained increasing popularity, because of its wide spectrum of activity and effectiveness at suppressing Aggregatibacter actinomycetemcomitans14. However, recent studies6,15,16 comparing FMSRP+AMX/MET and FMSRP alone have reported contrasting clinical and microbiological outcomes in terms of the effectiveness of the combined antimicrobial therapy. Moreover, several important issues related to the therapy have yet to be clarified. For example, there is no clear consensus on the mechanism of action and effectiveness of AMX/MET during the treatment of GAgP. Substantial variations exist in the study design, dosage, and duration of AMX/MET administration6. Furthermore, the possibility that the AMX/MET combined treatment could induce antibiotic resistance in the periodontal microflora, suppress the microflora itself, or enable overgrowth by periodontal or opportunistic pathogens should be addressed. The risk of side effects or adverse events also remains to be analyzed.

Previous metaanalyses12,13 focusing on the effectiveness of several antimicrobial agents in the treatment of CP and GAgP have indicated that combined AMX/MET therapy could provide additional clinical benefits. However, several methodological shortcomings, such as the absence of rigorous inclusion criteria and a high heterogeneity in terms of treatment types and study design, prohibited these analyses from obtaining reliable results. Therefore, the primary aim of the present meta-analysis was to assess the effectiveness of systemic AMX/MET combined therapy as an adjunct to FMSRP in comparison with FMSRP alone, in the treatment of GAgP. A secondary aim was to assess the clinical safety of AMX/MET combined therapy.

MATERIALS AND METHODSThe following meta-analysis was conducted in agreement with the recommendations of the Cochrane Collaboration17 and the principles of the QUOROM statement18.

Focused QuestionThe focused question addressed in this study was: “What is the effectiveness of combined AMX/MET therapy as an adjunct to FMSRP, when compared to FMSRP alone, in the treatment of patients with GAgP?”

Search StrategyThe following databases were searched from their earliest records through 11 September 2011: MEDLINE, Cochrane Controlled Clinical Trial Register, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), CINAHL, Science Direct, ISI Web of Science, and SCOPUS. To minimize the potential for reviewer bias, screening was performed independently by two blinded reviewers (F. S. and A. P.). Inter-reviewer reliability in the study selection process was determined by the Cohen k test, assuming an acceptable threshold value of 0.6119,20. Discrepancies with regard to the inclusion or exclusion of studies were resolved by discussion between the reviewers who selected the studies (F. S. and A. P.).

The databases were searched with the following search algorithm, in which Boolean operators were used and the asterisk symbol (*) indicates truncation: ((("Aggressive Periodontitis"[Mesh] OR juvenile periodon* OR aggressive periodon*

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OR early onset periodon*) AND (therapy OR treatment OR intervention)) OR (periodontal non surgical treatment OR periodontal non surgical therapy OR scaling root planing OR dental scaling OR periodontal treatment OR periodontal therapy OR calculus remov* OR calculus debridement OR dental debridement OR periodontal debridement OR "Dental Scaling"[Mesh] OR "Root Planing"[Mesh] OR "Dental Prophylaxis"[Mesh])) AND ("Amoxicillin"[Mesh] "Metronidazole"[Mesh] OR amoxicillin plus metronidazole OR amoxicillin metronidazole OR (amoxicillin and metronidazole) OR amoxicillin-metronidazole OR amoxicillin metronidazole combination OR amoxicillin metronidazole combined OR amoxicillin/metronidazole OR AMX/MTZ OR AMX MTZ combined OR AMX MTZ combination); in CINAHL, SCOPUS and Science Direct databases, the MeSH terms were not used.

In addition, a manual search was performed of issues of the last 15 years of the following journals: Journal of Periodontology, International Journal of Periodontics and Restorative Dentistry, Journal of Clinical Periodontology, Journal of Dental Research, Journal of Periodontal Research, Periodontology 2000, Journal of Dentistry, Journal of the American Dental Association, Journal of Clinical Dentistry, and Clinical Oral Investigations. To avoid selection bias, no restrictions were applied with regard to language or year; additionally, the references of all selected full-text articles and related reviews were scanned. The corresponding authors were contacted to find unpublished material, obtain missing data, or clarify paramount methodological issues.

Study Inclusion and Exclusion CriteriaThe study selection process was performed by two blinded reviewers (R. G. and A. M.) in 2 phases. In the first phase, the studies were analyzed according to the following inclusion criteria (A): 1) Randomized clinical trials (RCTs), 2) Studies comparing FMSRP with FMSRP + AMX/MET, 3) Patients with aggressive periodontitis, 4) Studies including patients with generalized aggressive periodontitis, 5) Studies involving human adult subjects (age >18 years).

Only studies that met all inclusion criteria in (A) were admitted to the second phase, which consisted of analysis of the preselected studies according to the following exclusion criteria (B): 1) Patients with systemic disease or who, within the last 3 months, have taken antibiotics or medications that are assumed or known to affect periodontal tissue or treatment, 2) Follow-up of <2 months, 3) Duplicate studies, 4) Primary outcome of interest not analyzed

Outcome Variables

Primary outcomes of interest. The primary outcomes were changes in full-mouth clinical attachment level (CAL) gain (mm) and full-mouth probing depth (PD) reduction (mm).

Secondary outcomes of interest. Secondary outcomes were changes at study sites in the following: visible plaque index (VP) (expressed as the percentage of site with plaque accumulation), gingival bleeding index (GB) (expressed as the percentage of site with gingival bleeding by running the probe 2 mm into the gingival crevice), bleeding on probing (BOP) (expressed as the percentage of site with BOP), microbiological changes, adverse events, compliance of patients to AMX/MET administration, and costs/benefits ratio. All outcome variables were analyzed as pre-

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and post-intervention changes, where the preintervention time corresponds to the baseline and the postintervention time corresponds to the end of follow-up.

Data ExtractionData were collected by two independent reviewers (F.S. and M.G.). The following data were extracted from the included studies: year of publication, country, study design, demographic characteristics of participants, number of patients per intervention group, diagnostic criteria, dosage of AMX/MET administration, therapeutic regimen of AMX/MET, frequency and type of AMX/MET-related adverse events, microbiological outcomes, and length of follow-up. If data were presented both numerically (in tables or text) and graphically (in figures), only numeric data were considered for extraction. The reviewers cross-checked all extracted data. Disagreements were resolved by discussion until consensus was reached.

Quality AssessmentThe quality assessment of the methodology of all included studies (Table 1) was performed independently by two blinded reviewers (F. S. and G. M.) according to the revised recommendation of the CONSORT statement21; the level of agreement between reviewers was calculated as reported above. Quality assessment was performed in two phases: during the first phase, quality assessment was based on the published full-text articles; in the second phase, all studies were reconsidered according to the additional information provided by the corresponding authors. After determining the scores at the conclusion of the second phase of quality assessment, an overall estimation of plausible risk of bias (low, moderate, or high) was performed for each selected study. A low risk of bias was estimated when all of the criteria were met, a moderate risk was estimated when one or more criteria were partly met, and a high risk of bias was estimated when one or more criteria were not met17.

Statistical AnalysisData were combined for meta-analysis with a statistical software†. Heterogeneity was assessed by using the χ2-based Q-statistic method and I2 measurement, with significance indicated by P < 0.1; however, because of the moderate insensitivity of the Q statistic22, only an I2 value of 0% was considered reliable to detect the absence of heterogeneity23 For continous data, the effect size was estimated and reported as the mean difference (MD) and the 95% confidence interval was calculated (CI). For dichotomous data, such as adverse events, a risk difference (RD) with the 95% CI was used to pool the results of each treatment group. Due to the expected interstudy heterogeneity, a random effect model24 was used. The pooled effect was considered significant if p was < 0.05. Forest plots for each meta-analysis present the raw data (i.e., means, SDs, and sample sizes, for continous data, and number of events, number of total events for each treatment groups, for dichotomous data), point estimates (displayed as blocks) and CIs (displayed as lines) for the chosen effect, heterogeneity statistic (I2), total number of participants per group, overall average effect (MD and Z-statistics, for continuous data) and overall risk difference (RD and Z-statistics, for dichotomous data) in the random effect model, and percent weight given to each study. The publication bias was investigated for each outcome of interest by using two methods. Visual detection was used to analyze the funnel plot25. Quantitative analysis was performed by using the regression asymmetry test26 and the trim-and-fill method27. Publication bias was assessed with an additional statistical software

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package‡.

RESULTS

Study SelectionA total of 368 potentially relevant titles and abstracts were found during the electronic and manual searches (Table 2). During the first stage of study selection, 342 publications were excluded based on an evaluation of the title and abstract (interreviewer agreement k = 0.79). During the second phase, the complete full-text articles of the remaining 26 publications2,6,7,13,15,16,28-47 were thoroughly evaluated. A total of 17 papers13,29-31,34-43,45-47 were excluded during this second stage because they did not fulfill the inclusion criteria (A) (inter-reviewer agreement k = 0.87). Three full-texts articles7,15,33 of the remaining nine publications were excluded because they met one or more of the exclusion criteria (B) (inter-reviewer agreement k = 0.89); therefore, a total of six studies2,6,16,28,32,44 fulfilled the required selection criteria of both phases and were included in meta-analyses. A flowchart for the study selection process is shown in Figure 1. The main characteristics of the studies included in the meta-analyses are summarized in Table 3.

Description of StudiesThe six included RCTs compared FMSRP + AMX/MET versus FMSRP alone in the treatment of GAgP, which was diagnosed according to the criteria of American Academy of Periodontology (AAP)1 in five out of the six included studies. Three studies2,16,32 used a double-blind design, whereas one study6,44 used a single-blind design; all of the studies had a parallel design. One study32 did not include smokers, whereas five studies2,6,16,28,44 reported no significant difference in the number of smokers between the FMSRP + AMX/MET and FMSRP groups. One study16

performed the so-called “full-mouth disinfection”; two study2,28 performed the FMSRP in one single session of treatment, one study6 accomplished the FMSRP in two consecutive session, whereas in two studies29,41 the FMSRP was concluded in 4 to 6 sessions. Two studies16,32 used VP, three studies16,28,32 used GB indexes; BOP was assessed in three studies16,32,44. The follow-up duration varied from 2 to 6 months.

Quality AssessmentThe quality assessment results of all selected studies before and after contact with the corresponding authors are presented in Table 4. Before contact with author, four studies2,6,16,32 satisfied all of the criteria, whereas one44 did not report a sample size calculation (A), and one28 did not satisfy criteria A, B and F. However, after the authors were contacted, all of the studies fulfilled the required criteria, with the exception of one study28, whose quality assessment remained the same; therefore, five out of the six included studies were considered to be at a low risk of bias (k = 1.0), and one was considered to be at high risk of bias (k=1.0)

Microbiological OutcomesTwo studies32,44 analyzed microbiological outcomes by checkboard DNA-DNA hybridization, whereas one6 used polymerase chain reaction (PCR). Of these studies, one study32 reported a significant decrease from baseline to the end of follow-up in the proportions of Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola in FMSRP + AMX/MET compared to FMSRP alone, as well a significant

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increase in Actinomyces species; the proportion of Aggregatibacter actinomycetemcomitans was significantly reduced only in initially deep sites (PD ≥7 mm). Additionally, a significant difference in the number of subjects positive at baseline for Aggregatibacter actinomycetemcomitans was observed in the FMSRP + AMX/MET group. One study44 reported a significant reduction from baseline to the end of follow-up in the proportions of Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, and Aggregatibacter actinomycetemcomitans in the FMSRP + AMX/MET group, whereas in the FMSRP group, only a difference in the proportions of Porphyromonas gingivalis was maintained; however, no significant differences were observed for those species between groups. Moreover, no significant difference was found in the number of patients positive at baseline for Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, or Aggregatibacter actinomycetemcomitans. One study6 reported significant reduction in Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola; however, at six months no significant differences were observed between FMSRP + AMX/MET and FMSRP groups.

ComplianceAll included studies with the exception of one28 assessed the compliance of the patients to the antibiotic treatment protocol. Full adherence to the treatment protocol was reported four6,16,32,44 out of the six included studies, while one study2 reported that 4 out of the 20 patients in FMSRP + AMX/MET failed to strictly adhere to the prescribed antimicrobial regimen; however, the main reason advocated by the non-compliant patients was the occurrence of diarrhoea and vomiting.

Meta-Analyses

Primary outcomes. The meta-analysis showed that the FMSRP + MET/AMX treatment provided significant CAL gain (MD: 0.42; 95% CI: 0.23 -0.61; p < 0.05) (Fig. 2) and PD reduction (MD: 0.58; 95% CI: 0.39-0.77; p < 0.05) (Fig. 3) between baseline and end of follow-up. No evidence of heterogeneity across the studies was observed for either outcome (χ2 = 2.44; I2 = 0%, P = 0.79 and χ2 = 4.36; I2 = 0%, P = 0.50 respectively).

Secondary outcomes. Significant differences in favor of FMSRP + MET/AMX were also found for BOP changes (MD: 14.95; 95% CI: 6.68 -23.23; p < 0.05) (Fig. 4) and GB changes (MD: 21.44; 95% CI: 3.80-39.08; p < 0.05) (Fig. 5), whereas the differences in VP changes were not significant (MD: 8.28; 95% CI: -8.97-25.53; p > 0.05) (Fig. 6). A meta-analysis on microbiological changes, because the data were not suitable for pooling. Meta-analysis of adverse events showed no significant RD for any investigated event between FMSRP + AMX/MET and FMSRP groups (Fig. 7).

Publication bias. The funnel plots of CAL gain and of the other outcomes of interest did not show asymmetry (Fig. 8). Even if the trim-and-fill method indicated that one study missed in the CAL and PD funnel plot, the regression asymmetry test did not suggest publication biases for the investigated outcomes (Table 5). Furthermore, the difference between the original estimate and the adjusted effect size according to the trim-and-effect procedure was nonsignificant for all outcomes (Fig. 9).

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DISCUSSIONThe present meta-analysis, with a total of 181 patients, was undertaken to address the effect of AMX/MET as an adjunctive treatment to FMSRP. The results suggest that combined AMX/MET treatment could provide additional clinical benefits, in terms of CAL gain and PD reduction, to FMSRP in patients with GAgP. These results are contradictory to those reported by the included studies. Indeed, with the exception of two study28,32 that found significant differences between the baseline and end of follow-up in favor of FMSRP + AMX/MET, no study observed significant differences in full-mouth PD reduction or full-mouth CAL gain between the FMSRP + AMX/MET and FMSRP groups. These contrasting findings may be related to the small sample size adopted in the included studies; however, the four2,6,16,44 studies that failed to retrieve significant difference between FMSRP + AMX/MET and FMSRP reported a sample size calculation, and all had included the minimum sample size necessary to detect significant differences between the FMSRP + AMX/MET and FMSRP groups.

According to the parameters suggested by Van Dyke48, the results of meta-analysis could be considered also clinically relevant. A generally accepted indicator for the detection of clinical significance of treatment outcomes in periodontics49 is the proportion of sites with a PD reduction or CAL gain of ≥2 mm: these parameters were investigated in only two studies2,16, that reported contrasting findings: one study16

failed to show significant differences between baseline and the end of follow-up between FMSRP + AMX/MET and FMSRP, whereas the other study2 observed significant percentage of sites with CAL gain and PD reduction ≥2 mm in the FMSRP + AMX/MET group; however it should be stressed that in one study16 all patients were debrided according to the concept of full-mouth disinfection8; furthermore at 3 months, the patients underwent an additional staged quadrant 1-h session of SRP, which was completed within 4-6 weeks. It is reasonable to assume that the full-mouth debridement at 24 h and SRP reinstrumentation at 3 months may have had effects that overshadowed those by the adjunctive AMX/MET.

The included studies used different dosages and administration regimens in the AMX/MET combined treatment (Table 3). It is difficult to state whether such differences could have influenced the clinical outcomes, because no comparative data are available to define the most effective dosage and administration regimen16. Even if differences were observed among the studies in terms of antimicrobial regimens, follow-up times, and treatment designs, the I2 test for interstudy heterogeneity did not provide evidence for heterogeneity for primary outcomes or changes in BOP, while significant heterogeneity was found for GB and VP changes: for these two outcomes, it is difficult to identify the source of heterogeneity, since these indexes were reported in only two studies, and, therefore, no sensitivity analysis could be performed; however, considering the small number of studies that were pooled and the presence of heterogeneity in GB and VP changes, the results of meta-analysis for those secondary outcomes should be interpreted with caution.

Smoking is a well-known risk factor for chronic periodontitis and GAgP50, and it has been proven to exert a negative influence on nonsurgical conventional therapy51,52. Differences in the included studies were also observed for the distribution of smokers in the FMSRP + AMX/MET and FMSRP groups. One study44 reported an equal distribution of smokers between the treatment arms, while four studies2,6,16,28 reported no significant differences in the distribution of smoking patients. Two of these two

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studies2,16 included a stratified analysis for smoking that revealed no significant influence on the study results. Another study did not include smokers32. Considering that the influence of smoking was assessed and substantially excluded by the included studies, it is reasonable to hypothesize that the confounding effect of smoking status was mitigated on the results of the meta-analysis.

Microbiological outcomes and patient compliance could not be pooled, because the data were not reported as the mean and standard deviation. Three6,32,44 of the six included studies analyzed microbiological outcomes, with contradictory results. Only one study32 supported the effectiveness of adjunctive AMX/MET combined treatment, on the basis of a reduction between the baseline and end of follow-up proportions of Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, and Aggregatibacter actinomycetemcomitans compared to FMSRP alone. These differences in microbiological outcomes between the studies could be explained by several factors, such as the susceptibility profiles of periodontal pathogens related to different geographical areas, antibiotic misuse, and patient noncompliance53. Nevertheless, because AMX/MET combined treatment has been proposed in the treatment of GAgP for its supposed ability to eliminate Aggregatibacter actinomycetemcomitans14, which represents one of the most involved pathogens for GAgP3, the microbiological results of adjunctive AMX/MET combined treatment and the possibility of antimicrobial resistance acquisition by other periodontal pathogens are paramount issues that should be addressed in future studies.

Most of patients were reported to be in full compliance to the administration and dosage regimens in the included studies. However, the methods used to assess compliance, such as patient self-report44, interviews16 and counting tablets32, are not always objective and reliable54,55. Such methodologies, especially self-reporting, could overestimate the results56. No serious adverse events were reported in any of the included studies and meta-analysis revealed that there was no significant RD in gastrointestinal symptoms (such as diarrhoea, nausea or vomiting), dizziness, metallic taste or intra-oral tissue alterations (such as ulceration); those results are in agreement with those of the included studies. However, since adverse events could influence the compliance rate2 and clinical outcomes, adverse events should be assessed in future large studies.

No cost-effectiveness analysis could be performed in the present meta-analysis, because none of the included studies assessed this issue. Interestingly, a recent meta-analysis57 indicated that adjunctive systemic antimicrobials are more cost-effective than local antimicrobials. In particular, combined AMX/MET was reported to have a low incremental cost and an adjunctive clinical benefit compared to nonsurgical periodontal therapy alone; however, this analysis did not consider the risk of side-effects or the potential development of antimicrobial resistance, which could compromise successive episodes of periodontal treatment with antimicrobials. Because the costs-benefits ratio (including the occurrence of adverse events and development of antimicrobial resistance) represents an important issue for clinicians and patients and could influence the need for future nonsurgical treatment sessions, this issue needs to be addressed in future studies.

The results of the present meta-analysis seem to support the clinical effectiveness of systemic adjunctive AMX/MET treatment. These findings are in agreement with previous meta-analyses12,13 that hypothesized some clinical benefit, but did not quantify the clinical effect. However, with respect to previous studies12,13, the present

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meta-analysis, based on the recommendations of the Cochrane Collaboration17 and on the principles of the QUOROM statement18, focused only on one type of systemic antimicrobial, included a specific and appropriate search strategy, and used a target type of periodontitis. Moreover, the present meta-analysis included a CONSORT-based quality assessment for RCTs. This assessment revealed that, after contact with the authors, five out of six of the included studies were at low risk of bias. An additional qualitative and quantitative publication bias analysis did not suggest the presence of publication bias, even if publication bias could be excluded, considering that only six studies were entered into the meta-analysis.

Despite the high quality and rigorous methodology, the present meta-analysis had an important limitation: indeed, even if WMD was used to pool the data, none of the included studies reported a proved normal distribution of data; therefore, the normal distribution of data was only supposed; therefore, this issue should be considered when interpreting the results of the present meta-analysis. Future large, well-designed RCTs are needed to confirm these results. Such studies should also address the effect of adjunctive AMX/MET combined therapy on the microbiological profile of pathogens involved in the pathogenesis of GAgP, the possibility of antimicrobial resistance acquisition, the occurrence of adverse events, and should include a cost-effectiveness analysis.

CONCLUSIONThe findings of this meta-analysis support the effectiveness of the systemic use of combined AMX/MET treatment as an adjunctive therapy to FMSRP in patients with GAgP; furthermore, the results of meta-analysis seem to indicate that the use of combined AMX/MET therapy is not associated with the occurrence of serious adverse events; however, considering the small number of included studies, future well-designed, multicenter and large studies with standardized study designs are needed to confirm these results.

ACKNOWLEDGMENTSThe authors appreciate the additional information provided by Dr. Dimitra Sakellari (Department of Preventive Dentistry, Periodontology and Implant Biology, Dental School, Aristotle University of Thessaloniki, Thessaloniki, Greece) and Serdar Cintan (Department of Periodontology, Faculty of Dentistry, Istanbul University, Istanbul, Turkey) during the authors’ contact process. The authors report no conflicts of interest related to this meta-analysis.

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29. Silva MP, Feres M, Oliveira Sirotto TA, Silva Soares GM, Velloso Mendes JA, Faveri M, Figueiredo LC. 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.

30. Mombelli A, Décaillet F, Almaghlouth A, Wick P, Cionca N. Efficient, minimally invasive periodontal therapy. An evidence based treatment concept. Schweiz Monatsschr Zahnmed 2011;121:145-157.

31. Zafiropoulos GG, di Prisco MO, Deli G, Hoffmann O, Kasaj A. Maintenance after a complex orthoperio treatment in a case of generalized aggressive periodontitis: 7-year result. J Int Acad Periodontol 2010;12:112-22.

32. 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.

33. Buchmann R, Conrads G, Sculean A. Short-term effects of systemic antibiotics during periodontal healing. Quintessence Int 2010;41:303-312.

34. Van Winkelhoff AJ, Winkel EG. Antibiotics in periodontics: right or wrong? J Periodontol 2009;80:1555-1558.

35. Valenza G, Veihelmann S, Peplies J, Tichy D, 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.

36. 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.

37. Johnson JD, Chen R, Lenton PA, Zhang G, Hinrichs JE, Rudney JD. Persistence of extracrevicular bacterial reservoirs after treatment of aggressive periodontitis. J Periodontol 2008;79:2305-2312.

38. Akincibay H, Orsal SO, Sengün D, Tözüm TF. Systemic administration of doxycycline versus metronidazole plus amoxicillin in the treatment of localized aggressive periodontitis: a clinical and microbiologic study. Quintessence Int 2008;39:33-39.

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

40. 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.

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

42. 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.

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43. 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.

44. 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.

45. Buchmann R, Müller RF, Van Dyke TE, Lange DE. Change of antibiotic susceptibility following periodontal therapy. A pilot study in aggressive periodontal disease. J Clin Periodontol 2003;30:222-229.

46. Buchmann R, Nunn ME, Van Dyke TE, Lange DE. Aggressive periodontitis: 5-year follow-up of treatment. J Periodontol 2002;73:675-683.

47. 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.

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periodontal disease. J Int Acad Periodontol 2005;7(Suppl. 4):191-196.

49. Sgolastra F., Petrucci A., Giannoni M., Gatto R., Monaco A. 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;March 14 [Epub ahead of print].

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51. Ah MK, Johnson GK, Kaldahl WB, Patil KB, Kalkwarf KL. The effect of smoking on the response to periodontal therapy. J Clin Periodontol 1994;21:91-97.

52. McGuire MK, Nunn ME. Prognosis versus actual outcome. III. The effectiveness of clinical parameters in accurately predicting tooth survival. J Periodontol 1996;67:666-674.

53. Van Winkelhoff AJ, Herrera D, Oteo A, Sanz M. Antimicrobial profiles of periodontal pathogens isolated from periodontitis patients in the Netherlands and Spain. J Clin Periodontol 2005;32:893-898.

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56. Bachmann LH, Stephens J, Richey CM, Hook EW 3rd. Measured versus self-reported compliance with doxycycline therapy for chlamydia-associated syndromes: high therapeutic success rates despite poor compliance. Sex Transm Dis 1999;26:272-278.

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Correspondence: Dr. Fabrizio Sgolastra, School of Dentistry, Dental Clinic, University of L’Aquila, San Salvatore 1, Building Delta 6, 67100 L’Aquila, Italy,

Phone: 0390862434816, Fax: 0390862434815 Italy, E-mail: [email protected]

Submitted July 27, 2011; accepted for publication September 11, 2011.

Figure 1.

Flowchart of the search strategy.

Figure 2.

Forest plot of CAL gain.

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Figure 3.

Forest plot of PD reduction.

Figure 4.

Forest plot of changes in BOP.

Figure 5.

Forest plot of changes in GB.

Figure 6.

Forest plot of changes in VP.

Figure 7.

Forest plot of adverse events.

Figure 8.

Funnel plot for CAL gain.

Figure 9.

Funnel plot for CAL gain, adjusted with the trim-and-fill method.

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Table 1. Categories used to assess the quality of selected studies.

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Category Description Grading

A Sample size calculation, estimating the minimum number of participants required to detect a significant difference among compared groups

0 = did not exist/not mentioned/not clear

1 = was reported, but not confirmed

2 = reported and confirmed

B Randomization and allocation concealment methods

0 = clearly inadequate

1 = possibly adequate

2 = clearly adequate

C Clear definition of inclusion and/or exclusion criteria

0 = no

1 = yes

D Completeness of follow-up (specified reasons for withdrawals and dropouts in each study group)

0 = no/not mentioned/ not clear

1 = yes/no withdrawals or dropouts occurred

E Experimental and control groups comparable at study baseline for important prognostic factors

0 = no

1 = unclear/possibly not comparable for one or more important prognostic factors

2 = clearly adequate

F Presence of masking 0 = no

1 = unclear/not complete

2 = yes

G Appropriate statistical analysis 0 = no

1 = unclear/possibly not the best method applied

2 = yes


Table 2. Abstracts retrieved by electronic, manual and reference searching.Database Overall number of

search outcomesNumber of search

outcomes without overlapPubmed (Basis) 148 148

Science Direct 6 6

Cochrane Controlled Clinical Trials Register 39 3

Cochrane Database of Systematic Reviews 7 5

Database of Abstracts of Reviews of Effects 1 1

CINAHL 41 18

ISI Web of Science 125 23

Scopus 1 0

Hand-search 1 1

Reference review articles 1 1

Reference selected articles 0 0

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Table 3. Characteristics of included studiesStudy Population Female/Male

AgeDesign Intervention Follow-up Adverse

eventsMicrobiological changes

Xajigeorgiou et al., 200641

21 patients with GagP diagnosed according to AAP criteria

Thessaloniki, Greece

5/5 (38.88 ± 8.74)

5/6 (37 ± 5.59)

Parallel, single-blind

Test: FMSRP within 24 h + 7 days 500 mg MET/500 mg AMX (t.i.d.)

Control: FMSRP within 24 h + SRP 6 weeks after FMSRP

6 weeks after SRP, 6 months from baseline

No statistical analysis

No significant differences between test and control groups

Mestnik et al., 201029


Guarulhos, Saõ Paulo, Brazil

9/6 (26.8 ± 3.9)

11/4 (27.6 ± 3.5)

Parallel, double-blind, placebo-controlled

Test: FMSRP + 14 days 400 mg MET/500 mg AMX (t.i.d.)

Control: FMSRP + 14 days placebos (t.i.d.)

3 months from baseline


Significant reduction of red complex species and of the mean percentage of sites colonized by A. actinomycetemcomitans and red complex species in favor of SRP+MET/AMX

Varela et al., 201116


10/8 (33.1 ± 5.1)

13/4 (32.1 ± 3.9)


Test: FMSRP + 10 days 250 mg MET/500 mg AMX (t.i.d.) + quadrant staged SRP

3, 6 months after therapy

No significant differences between test and control groups

Not analyzed

Rio de Janeiro, Brazil

Control: FMSRP + 10 days placebos (t.i.d.) + quadrant staged SRP

Yek et al. 20106

28 30 patients with GagP

Istanbul, Turkey

10/2 (33.7 ± 6.9)

9/7 (28.9 ± 7.4)

Parallel, single-blind


Control: FMSRP



Significant reduction of red complex species in test and control group, but no significant differences between the groups was observed

Baltacioğlu et al., 201128


Trabzon, Turkey

7/7 (29.6 ± 6.7)

6/6 (30.8 ± 8.4)

Parallel Test: FMSRP + 10 days 250 mg MET/250 mg AMX (t.i.d.)

Control: FMSRP

2 months after therapy

No adverse events

Not analyzed

Guerrero et al., 20052


London, UK

16/4 (31.3 ± 5.2)

12/9 (31.7 ± 5.1)



Control: FMSRP + 7 days placebos (t.i.d.)



Not analyzed

Legend: t.i.d. ter in die.

Table 4. Quality assessment of selected studies prior to and after contact (parentheses) with corresponding authors.Study *A (0 – 2) *B (0 – 2) *C (0 – 1) *D (0 – 1) *E (0 – 2) *F (0 – 2) *G (0 – 2) Estimated risk of bias

Xajigeorgiou et al., 200644 0 (2) 2 (2) 1 (1) 1 (1) 2 (2) 2 (2) 2 (2) High (Low)

Mestnik et al., 201032 2 (2) 2 (2) 1 (1) 1 (1) 2 (2) 2 (2) 2 (2) Low (Low)

Varela et al., 201116 2 (2) 2 (2) 1 (1) 1 (1) 2 (2) 2 (2) 2 (2) Low (Low)

Yek et al., 20106 2 (2) 2 (2) 1 (1) 1 (1) 2 (2) 2 (2) 2 (2) Low (Low)

Baltacioğlu et al., 201128 0 (0) 0 (0) 1 (1) 1 (1) 2 (2) 0 (0) 2 (2) High (High)

Guerrero et al., 20052 2 (2) 2 (2) 1 (1) 1 (1) 2 (2) 2 (2) 2 (2) Low (Low)

* Letters refer to quality assessment categories illustrated in Table 1.

Table 5. Quantitative analysis for publication bias assessments.

Original Meta-analysis Trim-and-Fill Analysis

Outcome MD (95% CI) P MD (95% CI) Studies Trimmed/ Total Studies

Egger Regression P

CAL gain 0.42 (0.23 to 0.61) <0.0001 0.37 (0.19 to 0.54) 1/6 0.72

PD reduction 0.71 (0.37 to 1.05) <0.0001 0.70 (0.36 to 1.05) 1/6 0.83

BOP changes 14.95 (6.68 to 23.23) 0.0004 14.95 (6.67 to 23.23) 0/3 0.32

VP changes 8.28 (-8.97 to 25.53) 0.35 8.28 (-8.97 to 25.53) 0/2 -

GB changes 21.44 (3.8 to 39.08) 0.02 21.44 (3.80 to 39.08) 0/3 0.41† Review Manager (RevMan), Version 5, 2008, The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark‡ Stata IC version 10.1, StataCorp, College Station, Texas


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