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Meta-Analysis
. 2020 Nov 16;11(11):CD012568.
doi: 10.1002/14651858.CD012568.pub2.

Adjunctive systemic antimicrobials for the non-surgical treatment of periodontitis

Shivi Khattri  1 , Sumanth Kumbargere Nagraj  2 , Ankita Arora  3 , Prashanti Eachempati  4 , Chandan Kumar Kusum  5 , Kishore G Bhat  6 , Trevor M Johnson  7 , Giovanni Lodi  8
Affiliations
Meta-Analysis

Adjunctive systemic antimicrobials for the non-surgical treatment of periodontitis

Shivi Khattri et al. Cochrane Database Syst Rev. .

Abstract

Background: Systemic antimicrobials can be used as an adjunct to mechanical debridement (scaling and root planing (SRP)) as a non-surgical treatment approach to manage periodontitis. A range of antibiotics with different dosage and combinations are documented in the literature. The review follows the previous classification of periodontitis as all included studies used this classification.

Objectives: To assess the effects of systemic antimicrobials as an adjunct to SRP for the non-surgical treatment of patients with periodontitis.

Search methods: Cochrane Oral Health's Information Specialist searched the following databases to 9 March 2020: Cochrane Oral Health's Trials Register, CENTRAL, MEDLINE, and Embase. The US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials.

Selection criteria: We included randomized controlled trials (RCTs) which involved individuals with clinically diagnosed untreated periodontitis. Trials compared SRP with systemic antibiotics versus SRP alone/placebo, or with other systemic antibiotics.

Data collection and analysis: We selected trials, extracted data, and assessed risk of bias in duplicate. We estimated mean differences (MDs) for continuous data, with 95% confidence intervals (CIs). We assessed the certainty of the evidence using GRADE.

Main results: We included 45 trials conducted worldwide involving 2664 adult participants. 14 studies were at low, 8 at high, and the remaining 23 at unclear overall risk of bias. Seven trials did not contribute data to the analysis. We assessed the certainty of the evidence for the 10 comparisons which reported long-term follow-up (≥ 1 year). None of the studies reported data on antimicrobial resistance and patient-reported quality of life changes. Amoxicillin + metronidazole + SRP versus SRP in chronic/aggressive periodontitis: the evidence for percentage of closed pockets (MD -16.20%, 95% CI -25.87 to -6.53; 1 study, 44 participants); clinical attachment level (CAL) (MD -0.47 mm, 95% CI -0.90 to -0.05; 2 studies, 389 participants); probing pocket depth (PD) (MD -0.30 mm, 95% CI -0.42 to -0.18; 2 studies, 389 participants); and percentage of bleeding on probing (BOP) (MD -8.06%, 95% CI -14.26 to -1.85; 2 studies, 389 participants) was of very low certainty. Only the results for closed pockets and BOP showed a minimally important clinical difference (MICD) favouring amoxicillin + metronidazole + SRP. Metronidazole + SRP versus SRP in chronic/aggressive periodontitis: the evidence for percentage of closed pockets (MD -12.20%, 95% CI -29.23 to 4.83; 1 study, 22 participants); CAL (MD -1.12 mm, 95% CI -2.24 to 0; 3 studies, 71 participants); PD (MD -1.11 mm, 95% CI -2.84 to 0.61; 2 studies, 47 participants); and percentage of BOP (MD -6.90%, 95% CI -22.10 to 8.30; 1 study, 22 participants) was of very low certainty. Only the results for CAL and PD showed an MICD favouring the MTZ + SRP group. Azithromycin + SRP versus SRP for chronic/aggressive periodontitis: we found no evidence of a difference in percentage of closed pockets (MD 2.50%, 95% CI -10.19 to 15.19; 1 study, 40 participants); CAL (MD -0.59 mm, 95% CI -1.27 to 0.08; 2 studies, 110 participants); PD (MD -0.77 mm, 95% CI -2.33 to 0.79; 2 studies, 110 participants); and percentage of BOP (MD -1.28%, 95% CI -4.32 to 1.76; 2 studies, 110 participants) (very low-certainty evidence for all outcomes). Amoxicillin + clavulanate + SRP versus SRP for chronic periodontitis: the evidence from 1 study, 21 participants for CAL (MD 0.10 mm, 95% CI -0.51 to 0.71); PD (MD 0.10 mm, 95% CI -0.17 to 0.37); and BOP (MD 0%, 95% CI -0.09 to 0.09) was of very low certainty and did not show a difference between the groups. Doxycycline + SRP versus SRP in aggressive periodontitis: the evidence from 1 study, 22 participants for CAL (MD -0.80 mm, 95% CI -1.49 to -0.11); and PD (MD -1.00 mm, 95% CI -1.78 to -0.22) was of very low certainty, with the doxycycline + SRP group showing an MICD in PD only. Tetracycline + SRP versus SRP for aggressive periodontitis: we found very low-certainty evidence of a difference in long-term improvement in CAL for the tetracycline group (MD -2.30 mm, 95% CI -2.50 to -2.10; 1 study, 26 participants). Clindamycin + SRP versus SRP in aggressive periodontitis: we found very low-certainty evidence from 1 study, 21 participants of a difference in long-term improvement in CAL (MD -1.70 mm, 95% CI -2.40 to -1.00); and PD (MD -1.80 mm, 95% CI -2.47 to -1.13) favouring clindamycin + SRP. Doxycycline + SRP versus metronidazole + SRP for aggressive periodontitis: there was very low-certainty evidence from 1 study, 27 participants of a difference in long-term CAL (MD 1.10 mm, 95% CI 0.36 to 1.84); and PD (MD 1.00 mm, 95% CI 0.30 to 1.70) favouring metronidazole + SRP. Clindamycin + SRP versus metronidazole + SRP for aggressive periodontitis: the evidence from 1 study, 26 participants for CAL (MD 0.20 mm, 95% CI -0.55 to 0.95); and PD (MD 0.20 mm, 95% CI -0.38 to 0.78) was of very low certainty and did not show a difference between the groups. Clindamycin + SRP versus doxycycline + SRP for aggressive periodontitis: the evidence from 1 study, 23 participants for CAL (MD -0.90 mm, 95% CI -1.62 to -0.18); and PD (MD -0.80 mm, 95% CI -1.58 to -0.02) was of very low certainty and did not show a difference between the groups. Most trials testing amoxicillin, metronidazole, and azithromycin reported adverse events such as nausea, vomiting, diarrhoea, mild gastrointestinal disturbances, and metallic taste. No serious adverse events were reported.

Authors' conclusions: There is very low-certainty evidence (for long-term follow-up) to inform clinicians and patients if adjunctive systemic antimicrobials are of any help for the non-surgical treatment of periodontitis. There is insufficient evidence to decide whether some antibiotics are better than others when used alongside SRP. None of the trials reported serious adverse events but patients should be made aware of the common adverse events related to these drugs. Well-planned RCTs need to be conducted clearly defining the minimally important clinical difference for the outcomes closed pockets, CAL, PD, and BOP.

Trial registration: ClinicalTrials.gov NCT02969928 NCT02125812 NCT02735395 NCT00805558 NCT00707369 NCT02829983 NCT02954393 NCT02223702 NCT00066066 NCT01499225.

PubMed Disclaimer

Conflict of interest statement

  1. Shivi Khattri: no interests to declare.

  2. Sumanth Kumbargere Nagraj: no interests to declare.

  3. Ankita Arora: no interests to declare.

  4. Prashanti Eachempati: no interests to declare.

  5. Chandan Kumar Kusum: no interests to declare.

  6. Kishore G Bhat: no interests to declare.

  7. Trevor M Johnson: no interests to declare.

  8. Giovanni Lodi: no interests to declare.

Figures

1
1
Etiopathogenesis of periodontal disease.
2
2
Classification of periodontitis (Armitage 1999; Geurs 2015).
AL = attachment loss; PD = pocket depth.
3
3
Study flow diagram.
4
4
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
5
5
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
1.1
1.1. Analysis
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 1: Percentage of closed pockets ‐ short‐term (≤ 3 months) improvement
1.2
1.2. Analysis
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 2: Percentage of closed pockets ‐ intermediate‐term (> 3 months) improvement
1.3
1.3. Analysis
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 3: Percentage of closed pockets ‐ long‐term (≥ 1 year) improvement
1.4
1.4. Analysis
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 4: CAL ‐ short‐term (≤ 3 months) improvement
1.5
1.5. Analysis
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 5: CAL ‐ intermediate‐term (> 3 months) improvement
1.6
1.6. Analysis
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 6: CAL ‐ long‐term (≥ 1 year) improvement
1.7
1.7. Analysis
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 7: Pocket depth ‐ short‐term (≤ 3 months) improvement
1.8
1.8. Analysis
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 8: Pocket depth ‐ intermediate‐term (> 3 months) improvement
1.9
1.9. Analysis
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 9: Pocket depth ‐ long‐term (≥ 1 year) improvement
1.10
1.10. Analysis
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 10: BOP ‐ short‐term (≤ 3 months) improvement
1.11
1.11. Analysis
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 11: BOP ‐ intermediate‐term (> 3 months) improvement
1.12
1.12. Analysis
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 12: BOP ‐ long‐term (≥ 1 year) improvement
2.1
2.1. Analysis
Comparison 2: MTZ + SRP versus SRP, Outcome 1: Percentage of closed pockets ‐ short‐term (≤ 3 months) improvement in chronic periodontitis
2.2
2.2. Analysis
Comparison 2: MTZ + SRP versus SRP, Outcome 2: Percentage of closed pockets ‐ intermediate‐term (> 3 months) improvement in chronic periodontitis
2.3
2.3. Analysis
Comparison 2: MTZ + SRP versus SRP, Outcome 3: Percentage of closed pockets ‐ long‐term (≥ 1 year) improvement
2.4
2.4. Analysis
Comparison 2: MTZ + SRP versus SRP, Outcome 4: CAL ‐ short‐term (≤ 3 months) improvement
2.5
2.5. Analysis
Comparison 2: MTZ + SRP versus SRP, Outcome 5: CAL ‐ intermediate‐term (> 3 months) improvement
2.6
2.6. Analysis
Comparison 2: MTZ + SRP versus SRP, Outcome 6: CAL ‐ long‐term (≥ 1 year) improvement
2.7
2.7. Analysis
Comparison 2: MTZ + SRP versus SRP, Outcome 7: Pocket depth ‐ short‐term (≤ 3 months) improvement
2.8
2.8. Analysis
Comparison 2: MTZ + SRP versus SRP, Outcome 8: Pocket depth ‐ intermediate‐term (> 3 months) improvement
2.9
2.9. Analysis
Comparison 2: MTZ + SRP versus SRP, Outcome 9: Pocket depth ‐ long‐term (≥ 1 year) improvement
2.10
2.10. Analysis
Comparison 2: MTZ + SRP versus SRP, Outcome 10: BOP ‐ short‐term (≤ 3 months) improvement
2.11
2.11. Analysis
Comparison 2: MTZ + SRP versus SRP, Outcome 11: BOP ‐ intermediate‐term (> 3 months) improvement
2.12
2.12. Analysis
Comparison 2: MTZ + SRP versus SRP, Outcome 12: BOP ‐ long‐term (≥ 1 year) improvement
3.1
3.1. Analysis
Comparison 3: AZT + SRP versus SRP, Outcome 1: Percentage of closed pockets ‐ intermediate‐term (> 3 months) improvement
3.2
3.2. Analysis
Comparison 3: AZT + SRP versus SRP, Outcome 2: Percentage of closed pockets ‐ long‐term (≥ 1 year) improvement
3.3
3.3. Analysis
Comparison 3: AZT + SRP versus SRP, Outcome 3: CAL ‐ short‐term (≤ 3 months) improvement
3.4
3.4. Analysis
Comparison 3: AZT + SRP versus SRP, Outcome 4: CAL ‐ intermediate‐term (> 3 months) improvement
3.5
3.5. Analysis
Comparison 3: AZT + SRP versus SRP, Outcome 5: CAL ‐ long‐term (≥ 1 year) improvement
3.6
3.6. Analysis
Comparison 3: AZT + SRP versus SRP, Outcome 6: Pocket depth ‐ short‐term (≤ 3 months) improvement
3.7
3.7. Analysis
Comparison 3: AZT + SRP versus SRP, Outcome 7: Pocket depth ‐ intermediate‐term (> 3 months) improvement
3.8
3.8. Analysis
Comparison 3: AZT + SRP versus SRP, Outcome 8: Pocket depth ‐ long‐term (≥ 1 year) improvement
3.9
3.9. Analysis
Comparison 3: AZT + SRP versus SRP, Outcome 9: BOP ‐ short‐term (≤ 3 months) improvement
3.10
3.10. Analysis
Comparison 3: AZT + SRP versus SRP, Outcome 10: BOP ‐ intermediate‐term (> 3 months) improvement
3.11
3.11. Analysis
Comparison 3: AZT + SRP versus SRP, Outcome 11: BOP ‐ long‐term (≥ 1 year) improvement
4.1
4.1. Analysis
Comparison 4: AMOX + CLAV + SRP versus SRP in chronic periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement
4.2
4.2. Analysis
Comparison 4: AMOX + CLAV + SRP versus SRP in chronic periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement
4.3
4.3. Analysis
Comparison 4: AMOX + CLAV + SRP versus SRP in chronic periodontitis, Outcome 3: CAL ‐ long‐term (≥ 1 year) improvement
4.4
4.4. Analysis
Comparison 4: AMOX + CLAV + SRP versus SRP in chronic periodontitis, Outcome 4: Pocket depth ‐ short‐term (≤ 3 months) improvement
4.5
4.5. Analysis
Comparison 4: AMOX + CLAV + SRP versus SRP in chronic periodontitis, Outcome 5: Pocket depth ‐ intermediate‐term (> 3 months) improvement
4.6
4.6. Analysis
Comparison 4: AMOX + CLAV + SRP versus SRP in chronic periodontitis, Outcome 6: Pocket depth ‐ long‐term (≥ 1 year) improvement
4.7
4.7. Analysis
Comparison 4: AMOX + CLAV + SRP versus SRP in chronic periodontitis, Outcome 7: BOP ‐ short‐term (≤ 3 months) improvement
4.8
4.8. Analysis
Comparison 4: AMOX + CLAV + SRP versus SRP in chronic periodontitis, Outcome 8: BOP ‐ intermediate‐term (> 3 months) improvement
4.9
4.9. Analysis
Comparison 4: AMOX + CLAV + SRP versus SRP in chronic periodontitis, Outcome 9: BOP ‐ long‐term (≥ 1 year) improvement
5.1
5.1. Analysis
Comparison 5: Doxycycline + SRP versus SRP in aggressive periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement
5.2
5.2. Analysis
Comparison 5: Doxycycline + SRP versus SRP in aggressive periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement
5.3
5.3. Analysis
Comparison 5: Doxycycline + SRP versus SRP in aggressive periodontitis, Outcome 3: CAL ‐ long‐term (≥ 1 year) improvement
5.4
5.4. Analysis
Comparison 5: Doxycycline + SRP versus SRP in aggressive periodontitis, Outcome 4: Pocket depth ‐ short‐term (≤ 3 months) improvement
5.5
5.5. Analysis
Comparison 5: Doxycycline + SRP versus SRP in aggressive periodontitis, Outcome 5: Pocket depth ‐ intermediate‐term (> 3 months) improvement
5.6
5.6. Analysis
Comparison 5: Doxycycline + SRP versus SRP in aggressive periodontitis, Outcome 6: Pocket depth ‐ long‐term (≥ 1 year) improvement
5.7
5.7. Analysis
Comparison 5: Doxycycline + SRP versus SRP in aggressive periodontitis, Outcome 7: BOP ‐ short‐term (≤ 3 months) improvement
5.8
5.8. Analysis
Comparison 5: Doxycycline + SRP versus SRP in aggressive periodontitis, Outcome 8: BOP ‐ intermediate‐term (> 3 months) improvement
6.1
6.1. Analysis
Comparison 6: Tetracycline + SRP versus SRP in aggressive periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement
6.2
6.2. Analysis
Comparison 6: Tetracycline + SRP versus SRP in aggressive periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement
6.3
6.3. Analysis
Comparison 6: Tetracycline + SRP versus SRP in aggressive periodontitis, Outcome 3: CAL ‐ long‐term (≥ 1 year) improvement
6.4
6.4. Analysis
Comparison 6: Tetracycline + SRP versus SRP in aggressive periodontitis, Outcome 4: Pocket depth ‐ short‐term (≤ 3 months) improvement
6.5
6.5. Analysis
Comparison 6: Tetracycline + SRP versus SRP in aggressive periodontitis, Outcome 5: BOP ‐ short‐term (≤ 3 months) improvement
7.1
7.1. Analysis
Comparison 7: Clarithromycin + SRP versus SRP, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement
7.2
7.2. Analysis
Comparison 7: Clarithromycin + SRP versus SRP, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement
7.3
7.3. Analysis
Comparison 7: Clarithromycin + SRP versus SRP, Outcome 3: Pocket depth ‐ short‐term (≤ 3 months) improvement
7.4
7.4. Analysis
Comparison 7: Clarithromycin + SRP versus SRP, Outcome 4: Pocket depth ‐ intermediate‐term (> 3 months) improvement
7.5
7.5. Analysis
Comparison 7: Clarithromycin + SRP versus SRP, Outcome 5: BOP ‐ short‐term (≤ 3 months) improvement
7.6
7.6. Analysis
Comparison 7: Clarithromycin + SRP versus SRP, Outcome 6: BOP ‐ intermediate‐term (> 3 months) improvement
8.1
8.1. Analysis
Comparison 8: Moxifloxacin + SRP versus SRP in aggressive periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement
8.2
8.2. Analysis
Comparison 8: Moxifloxacin + SRP versus SRP in aggressive periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement
8.3
8.3. Analysis
Comparison 8: Moxifloxacin + SRP versus SRP in aggressive periodontitis, Outcome 3: Pocket depth ‐ short‐term (≤ 3 months) improvement
8.4
8.4. Analysis
Comparison 8: Moxifloxacin + SRP versus SRP in aggressive periodontitis, Outcome 4: Pocket depth ‐ intermediate‐term (> 3 months) improvement
8.5
8.5. Analysis
Comparison 8: Moxifloxacin + SRP versus SRP in aggressive periodontitis, Outcome 5: BOP ‐ short‐term (≤ 3 months) improvement
8.6
8.6. Analysis
Comparison 8: Moxifloxacin + SRP versus SRP in aggressive periodontitis, Outcome 6: BOP ‐ intermediate‐term (> 3 months) improvement
9.1
9.1. Analysis
Comparison 9: Levofloxacin + SRP versus SRP in chronic periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement
9.2
9.2. Analysis
Comparison 9: Levofloxacin + SRP versus SRP in chronic periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement
9.3
9.3. Analysis
Comparison 9: Levofloxacin + SRP versus SRP in chronic periodontitis, Outcome 3: Pocket depth ‐ short‐term (≤ 3 months) improvement
9.4
9.4. Analysis
Comparison 9: Levofloxacin + SRP versus SRP in chronic periodontitis, Outcome 4: Pocket depth ‐ intermediate‐term (> 3 months) improvement
9.5
9.5. Analysis
Comparison 9: Levofloxacin + SRP versus SRP in chronic periodontitis, Outcome 5: BOP ‐ short‐term (≤ 3 months) improvement
9.6
9.6. Analysis
Comparison 9: Levofloxacin + SRP versus SRP in chronic periodontitis, Outcome 6: BOP ‐ intermediate‐term (> 3 months) improvement
10.1
10.1. Analysis
Comparison 10: Clindamycin + SRP versus SRP in aggressive periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement
10.2
10.2. Analysis
Comparison 10: Clindamycin + SRP versus SRP in aggressive periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement
10.3
10.3. Analysis
Comparison 10: Clindamycin + SRP versus SRP in aggressive periodontitis, Outcome 3: CAL ‐ long‐term (≥ 1 year) improvement
10.4
10.4. Analysis
Comparison 10: Clindamycin + SRP versus SRP in aggressive periodontitis, Outcome 4: Pocket depth ‐ short‐term (≤ 3 months) improvement
10.5
10.5. Analysis
Comparison 10: Clindamycin + SRP versus SRP in aggressive periodontitis, Outcome 5: Pocket depth ‐ intermediate‐term (> 3 months) improvement
10.6
10.6. Analysis
Comparison 10: Clindamycin + SRP versus SRP in aggressive periodontitis, Outcome 6: Pocket depth ‐ long‐term (≥ 1 year) improvement
11.1
11.1. Analysis
Comparison 11: Cefixime + SRP versus SRP in chronic periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement
11.2
11.2. Analysis
Comparison 11: Cefixime + SRP versus SRP in chronic periodontitis, Outcome 2: Pocket depth ‐ short‐term (≤ 3 months) improvement
11.3
11.3. Analysis
Comparison 11: Cefixime + SRP versus SRP in chronic periodontitis, Outcome 3: BOP ‐ short‐term (≤ 3 months) improvement
12.1
12.1. Analysis
Comparison 12: MTZ + SRP versus AMOX + MTZ + SRP, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement
12.2
12.2. Analysis
Comparison 12: MTZ + SRP versus AMOX + MTZ + SRP, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement
12.3
12.3. Analysis
Comparison 12: MTZ + SRP versus AMOX + MTZ + SRP, Outcome 3: Pocket depth ‐ short‐term (≤ 3 months) improvement
12.4
12.4. Analysis
Comparison 12: MTZ + SRP versus AMOX + MTZ + SRP, Outcome 4: Pocket depth ‐ intermediate‐term (> 3 months) improvement
12.5
12.5. Analysis
Comparison 12: MTZ + SRP versus AMOX + MTZ + SRP, Outcome 5: BOP ‐ short‐term (≤ 3 months) improvement
12.6
12.6. Analysis
Comparison 12: MTZ + SRP versus AMOX + MTZ + SRP, Outcome 6: BOP ‐ intermediate‐term (> 3 months) improvement
13.1
13.1. Analysis
Comparison 13: Doxycycline + SRP versus AMOX + MTZ + SRP in aggressive periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement
13.2
13.2. Analysis
Comparison 13: Doxycycline + SRP versus AMOX + MTZ + SRP in aggressive periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement
13.3
13.3. Analysis
Comparison 13: Doxycycline + SRP versus AMOX + MTZ + SRP in aggressive periodontitis, Outcome 3: Pocket depth ‐ short‐term (≤ 3 months) improvement
13.4
13.4. Analysis
Comparison 13: Doxycycline + SRP versus AMOX + MTZ + SRP in aggressive periodontitis, Outcome 4: Pocket depth ‐ intermediate‐term (> 3 months) improvement
14.1
14.1. Analysis
Comparison 14: Doxycycline + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement
14.2
14.2. Analysis
Comparison 14: Doxycycline + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement
14.3
14.3. Analysis
Comparison 14: Doxycycline + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 3: CAL ‐ long‐term (≥ 1 year) improvement
14.4
14.4. Analysis
Comparison 14: Doxycycline + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 4: Pocket depth ‐ short‐term (≤ 3 months) improvement
14.5
14.5. Analysis
Comparison 14: Doxycycline + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 5: Pocket depth ‐ intermediate‐term (> 3 months) improvement
14.6
14.6. Analysis
Comparison 14: Doxycycline + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 6: Pocket depth ‐ long‐term (≥ 1 year) improvement
14.7
14.7. Analysis
Comparison 14: Doxycycline + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 7: BOP ‐ short‐term (≤ 3 months) improvement
14.8
14.8. Analysis
Comparison 14: Doxycycline + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 8: BOP ‐ intermediate‐term (> 3 months) improvement
15.1
15.1. Analysis
Comparison 15: Clindamycin + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement
15.2
15.2. Analysis
Comparison 15: Clindamycin + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement
15.3
15.3. Analysis
Comparison 15: Clindamycin + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 3: CAL ‐ long‐term (≥ 1 year) improvement
15.4
15.4. Analysis
Comparison 15: Clindamycin + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 4: Pocket depth ‐ short‐term (≤ 3 months) improvement
15.5
15.5. Analysis
Comparison 15: Clindamycin + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 5: Pocket depth ‐ intermediate‐term (> 3 months) improvement
15.6
15.6. Analysis
Comparison 15: Clindamycin + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 6: Pocket depth ‐ long‐term (≥ 1 year) improvement
16.1
16.1. Analysis
Comparison 16: AMOX + CLAV + SRP versus tetracycline + SRP in aggressive periodontitis, Outcome 1: Pocket depth ‐ intermediate‐term (> 3 months) improvement
16.2
16.2. Analysis
Comparison 16: AMOX + CLAV + SRP versus tetracycline + SRP in aggressive periodontitis, Outcome 2: BOP ‐ intermediate‐term (> 3 months) improvement
17.1
17.1. Analysis
Comparison 17: Clindamycin + SRP versus doxycycline + SRP in aggressive periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement
17.2
17.2. Analysis
Comparison 17: Clindamycin + SRP versus doxycycline + SRP in aggressive periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement
17.3
17.3. Analysis
Comparison 17: Clindamycin + SRP versus doxycycline + SRP in aggressive periodontitis, Outcome 3: CAL ‐ long‐term (≥ 1 year) improvement
17.4
17.4. Analysis
Comparison 17: Clindamycin + SRP versus doxycycline + SRP in aggressive periodontitis, Outcome 4: Pocket depth ‐ short‐term (≤ 3 months) improvement
17.5
17.5. Analysis
Comparison 17: Clindamycin + SRP versus doxycycline + SRP in aggressive periodontitis, Outcome 5: Pocket depth ‐ intermediate‐term (> 3 months) improvement
17.6
17.6. Analysis
Comparison 17: Clindamycin + SRP versus doxycycline + SRP in aggressive periodontitis, Outcome 6: Pocket depth ‐ long‐term (≥ 1 year) improvement
18.1
18.1. Analysis
Comparison 18: AMOX + MZT versus clarithromycin + SRP, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement
18.2
18.2. Analysis
Comparison 18: AMOX + MZT versus clarithromycin + SRP, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement
18.3
18.3. Analysis
Comparison 18: AMOX + MZT versus clarithromycin + SRP, Outcome 3: Pocket depth ‐ short‐term (≤ 3 months) improvement
18.4
18.4. Analysis
Comparison 18: AMOX + MZT versus clarithromycin + SRP, Outcome 4: Pocket depth ‐ intermediate‐term (> 3 months) improvement
18.5
18.5. Analysis
Comparison 18: AMOX + MZT versus clarithromycin + SRP, Outcome 5: BOP ‐ short‐term (≤ 3 months) improvement
18.6
18.6. Analysis
Comparison 18: AMOX + MZT versus clarithromycin + SRP, Outcome 6: BOP ‐ intermediate‐term (> 3 months) improvement
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Abu Fanas 1991 {published data only}
    1. Abu Fanas SH, Drucker DB, Hull PS. Amoxycillin with clavulanic acid and tetracycline in periodontal therapy. Journal of Dentistry 1991;19(2):97-9. - PubMed
Akincibay 2008 {published data only}
    1. Akincibay H, Örsal SÖ, Şengün D, Tözüm TF. Systemic administration of doxycycline versus metronidazole plus amoxicillin in the treatment of localized aggressive periodontitis: a clinical and microbiologic study. Quintessence International 2008;39(2):e33-e39. - PubMed
Araujo 2019 {published and unpublished data}
    1. Araujo CF, Andere NMRB, Santos NCC dos, Mathias‐Santamaria IF, Reis AA, Oliveira LD de, et al. Two different antibiotic protocols as adjuncts to one-stage full-mouth ultrasonic debridement to treat generalized aggressive periodontitis: a pilot randomized controlled clinical trial. Journal of Periodontology 2019;90(12):1431-40. - PubMed
Ardila 2015 {published data only}
    1. Ardila CM, Guzmán IC. Benefits of adjunctive moxifloxacin in generalized aggressive periodontitis: a subgroup analyses in Aggregatibacter actinomycetemcomitans-positive/negative patients from a clinical trial. Journal of Investigative and Clinical Dentistry 2015;8(2):e12197. - PubMed
    1. Ardila CM, Guzmán IC. Clinical factors influencing the efficacy of systemic moxifloxacin in the therapy of patients with generalized aggressive periodontitis: a multilevel analysis from a clinical trial. Global Journal of Health Science 2016;8(3):80. - PMC - PubMed
    1. Ardila CM, Martelo-Cadavid JF, Boderth-Acosta G, Ariza-Garcés AA, Guzmán IC. Adjunctive moxifloxacin in the treatment of generalized aggressive periodontitis patients: clinical and microbiological results of a randomized, triple-blind and placebo-controlled clinical trial. Journal of Clinical Periodontology 2015;42(2):160-8. - PubMed
Basegmez 2011 {published data only}
    1. Basegmez C, Berber L, Yalcin F. Clinical and biochemical efficacy of minocycline in non-surgical periodontal therapy: a randomized controlled pilot study. Journal of Clinical Pharmacology 2011;51(6):915-22. - PubMed
Boia 2019 {published data only}
    1. Boia S, Boariu M, Baderca F, Rusu D, Muntean D, Horhat F, et al. Clinical, microbiological and oxidative stress evaluation of periodontitis patients treated with two regimens of systemic antibiotics, adjunctive to non-surgical therapy. A placebo-controlled randomized clinical trial. Experimental and Therapeutic Medicine 2019;18(6):5001-15. - PMC - PubMed
Borges 2017 {published data only}
    1. Borges I, Faveri M, Figueiredo LC, Duarte PM, Retamal-Valdes B, Montenegro SCL, et al. Different antibiotic protocols in the treatment of severe chronic periodontitis: a 1-year randomized trial. Journal of Clinical Periodontology 2017;44(8):822–32. - PubMed
Carvalho 2004 {published data only}
    1. Carvalho LH, D’Avila GB, Leao A, Haffajee AD, Socransky SS, Feres M. Scaling and root planing, systemic metronidazole and professional plaque removal in the treatment of chronic periodontitis in a Brazilian population. I. Clinical results. Journal of Clinical Periodontology 2004;31(12):1070-6. - PubMed
Casarin 2012 {published data only}
    1. Casarin RCV, Peloso Ribeiro ÉD, Sallum EA, Nociti FH, Gonçalves RB, Casati MZ. The combination of amoxicillin and metronidazole improves clinical and microbiologic results of one-stage, full-mouth, ultrasonic debridement in aggressive periodontitis treatment. Journal of Periodontology 2012;83(8):988-98. - PubMed
Chin Quee 1988 {published data only}
    1. Chin Quee T, Al-Joburi W, Lautar-Lemay C, Chan ECS, Iugovaz I, Bourgouin J, et al. Comparison of spiramycin and tetracycline used adjunctively in the treatment of advanced chronic periodontitis. Journal of Antimicrobial Chemotherapy 1988;22(Supplement B):171-7. - PubMed
Cosgarea 2016 {published and unpublished data}ISRCTN17605083
    1. Cosgarea R, Heumann C, Juncar R, Tristiu R, Lascu L, Salvi GE, et al. One year results of a randomized controlled clinical study evaluating the effects of non-surgical periodontal therapy of chronic periodontitis in conjunction with three or seven days systemic administration of amoxicillin/metronidazole. PLOS One 2017;12(6):e0179592. [DOI: 10.1371/journal.pone.0179592] - DOI - PMC - PubMed
    1. Cosgarea R, Juncar R, Heumann C, Tristiu R, Lascu L, Arweiler N, et al. Non-surgical periodontal treatment in conjunction with 3 or 7 days systemic administration of amoxicillin and metronidazole in severe chronic periodontitis patients. A placebo-controlled randomized clinical study. Journal of Clinical Periodontology 2016;43(9):767-77. - PubMed
D'avila 2005 {published data only}
    1. D’avila GB, Carvalho LH, Feres-Filho EJ, Feres M, Leão A. Oral health impacts on daily living related to four different treatment protocols for chronic periodontitis. Journal of Periodontology 2005;76(10):1751-7. - PubMed
Dukic 2016 {published data only}
    1. Dukic S, Matijevic S, Dakovic D, Cutovic T. Comparison of cefixime and amoxicillin plus metronidazole in the treatment of chronic periodontitis. Vojnosanitetski Pregled 2016;73(6):526-30. - PubMed
Emingil 2012 {published data only}
    1. Emingil G, Han B, Özdemir G, Tervahartiala T, Vural C, Atilla G, et al. Effect of azithromycin, as an adjunct to non-surgical periodontal treatment, on microbiological parameters and gingival crevicular fluid biomarkers in generalized aggressive periodontitis. Journal of Periodontal Research 2012;47(6):729-39. - PubMed
Gomi 2007 {published data only}
    1. Gomi K, Yashima A, Nagano T, Kanazashi M, Maeda N, Arai T. Effects of full-mouth scaling and root planing in conjunction with systemically administered azithromycin. Journal of Periodontology 2007;78(3):422-9. - PubMed
Guzman 2011 {published data only}
    1. Guzmán IC, Grisales Romero H, Ardila Medina CM. Adjunctive systemic administration of moxifloxacin versus ciprofloxacin plus metronidazole in the treatment of chronic periodontitis harboring Gram-negative enteric rods: I. Microbiological and clinical effects [Administración sistémica adjunta de moxifloxacina versus ciprofloxacina más metronidazol en el tratamiento de periodontitis crónica con presencia de bacilos entéricos Gram negativos: I. Efectos clínicos y microbiológicos]. Revista Facultad de Odontología Universidad de Antioquia 2011;23(1):92-110.
    1. Guzmán IC, Grisales Romero H, Medina A, Martín C. Adjunctive systemic administration of moxifloxacin versus ciprofloxacin plus metronidazole in the treatment of chronic periodontitis harboring Gram-negative enteric rods: II. A multilevel analysis. Revista Facultad de Odontología Universidad de Antioquia 2012;23(2):207-24.
Haas 2008 {published data only}
    1. Haas AN, Castro GD, Moreno T, Susin C, Albandar JM, Oppermann RV, et al. Azithromycin as an adjunctive treatment of aggressive periodontitis: 12-month randomized clinical trial. Journal of Clinical Periodontology 2008;35(8):696-704. - PubMed
Han 2012 {published data only}
    1. Han B, Emingil G, Özdemir G, Tervahartiala T, Vural C, Atilla G, et al. Azithromycin as an adjunctive treatment of generalized severe chronic periodontitis: clinical, microbiologic, and biochemical parameters. Journal of Periodontology 2012;83(12):1480-91. - PubMed
Harks 2015 {published data only}ISRCTN64254080
    1. Harks I, Koch R, Eickholz P, Hoffmann T, Kim T-S, Kocher T, et al. Is progression of periodontitis relevantly influenced by systemic antibiotics? A clinical randomized trial. Journal of Clinical Periodontology 2015;42(9):832-42. - PMC - PubMed
Li 2015 {published data only}
    1. Li Y, Xu L, Lu RF, An YB, Wang XE, Song WL, et al. Clinical effect of different sequences of debridement-antibiotic therapy in treatment of severe chronic periodontitis. Beijing Da Xue Xue Bao Yi Xue Ban [Journal of Peking University Health sciences] 2015;47(1):27-31. - PubMed
Liaw 2019 {published data only}
    1. ACTRN12618000957291. The clinical efficacy of non-surgical periodontal debridement alone, adjunctive systemic azithromycin, or amoxicillin-metronidazole therapy in patients with chronic moderate-to-advanced periodontitis [Comparing the periodontal tissue response to non-surgical scaling and root planing alone, adjunctive azithromycin, or adjunctive amoxicillin plus metronidazole in generalised chronic moderate-to-severe periodontitis: a preliminary randomised controlled trial]. www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375168 (first received 2 June 2018).
    1. Liaw A, Miller C, Nimmo A. Comparing the periodontal tissue response to non-surgical scaling and root planing alone, adjunctive azithromycin, or adjunctive amoxicillin plus metronidazole in generalized chronic moderate-to-severe periodontitis: a preliminary randomized controlled trial. Australian Dental Journal 2019;64(2):145-52. [DOI: 10.1111/adj.12674] - DOI - PubMed
Loesche 1991 {published data only}
    1. Loesche WJ, Schmidt E, Smith BA, Morrison EC, Caffesse R, Hujoel PP. Effects of metronidazole on periodontal treatment needs. Journal of Periodontology 1991;62(4):247-57. - PubMed
Lu 2012 {published data only}
    1. Lu R, Xu L, Feng X, Meng H. Short term effect of combined use of amoxicillin and metronidazole at different time of non-surgical periodontal treatment for aggressive periodontitis. Zhonghua Kou Qiang Yi Xue Za Zhi [Chinese Journal of Stomatology] 2012;47(11):666-70. - PubMed
Martande 2016 {published data only}
    1. Martande SS, Pradeep AR, Singh SP, Kumari M, Naik SB, Suke DK, et al. Clinical and microbiological effects of systemic azithromycin in adjunct to non-surgical periodontal therapy in treatment of Aggregatibacter actinomycetemcomitans associated periodontitis: a randomized placebo-controlled clinical trial. Journal of Investigative and Clinical Dentistry 2016;7(1):72-80. - PubMed
Mascarenhas 2005 {published data only}
    1. Mascarenhas P, Gapski R, Al-Shammari K, Hill R, Soehren S, Fenno JC, et al. Clinical response of azithromycin as an adjunct to non-surgical periodontal therapy in smokers. Journal of Periodontology 2005;76(3):426-36. - PubMed
Matarazzo 2008 {published data only}
    1. Matarazzo F, Figueiredo LC, Cruz SEB, 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. Journal of Clinical Periodontology 2008;35(10):885-96. - PubMed
Moeintaghavi 2007 {published data only}
    1. Moeintaghavi A, Talebi-Ardakani MR, Haerian-Ardakani A, Zandi H, Taghipour S, Fallahzadeh H, et al. Adjunctive effects of systemic amoxicillin and metronidazole with scaling and root planing: a randomized, placebo-controlled clinical trial. Journal of Contemporary Dental Practice 2007;8(5):51-9. - PubMed
Mombelli 2013 {published data only}
    1. Mombelli A, Cionca N, Almaghlouth A, Décaillet F, Courvoisier DS, Giannopoulou C. Are there specific benefits of amoxicillin plus metronidazole in Aggregatibacter actinomycetemcomitans-associated periodontitis? Double-masked, randomized clinical trial of efficacy and safety. Journal of Periodontology 2013;84(6):715–24. - PubMed
Palmer 1996 {published data only}
    1. Palmer RM, Watts TLP, Wilson RF. A double-blind trial of tetracycline in the management of early onset periodontitis. Journal of Clinical Periodontology 1996;23(7):670–4. - PubMed
Pradeep 2011 {published data only}
    1. Pradeep AR, Kathariya R. Clarithromycin, as an adjunct to non-surgical periodontal therapy for chronic periodontitis: a double-blinded, placebo-controlled, randomized clinical trial. Archives of Oral Biology 2011;56(10):1112-9. - PubMed
Pradeep 2014 {published data only}
    1. Pradeep AR, Singh SP, Martande SS, Naik SB, Kalra N, Priyanka N. Clinical and microbiological effects of levofloxacin in the treatment of Aggregatibacter actinomycetemcomitans-associated periodontitis: a randomized placebo-controlled clinical trial. Journal of the International Academy of Periodontology 2014;16(3):67-77. - PubMed
Pradeep 2015 {published data only}
    1. Pradeep AR, Singh SP, Martande SS, Naik SB, N P, Kalra N, et al. Clinical and microbiological effects of levofloxacin in the treatment of chronic periodontitis: a randomized, placebo-controlled clinical trial. Journal of Investigative and Clinical Dentistry 2015;6(3):170-8. - PubMed
Rebelatto 2017 {published data only}
    1. Rebelatto Bechara Andere NM, Castro Dos Santos NC, Araujo CF, Mathias IF, Taiete T, Casarin RCV, et al. Clarithromycin as an adjunct to one-stage full mouth ultrasonic periodontal debridement in generalized aggressive periodontitis: a randomized controlled clinical trial. Journal of Periodontology 2017;03:1-15. - PubMed
Ribeiro 2009 {published data only}
    1. Ribeiro ÉDP, Bittencourt S, Zanin ICJ, Bovi Ambrosano GM, Sallum EA, Nociti FH, et al. Full-mouth ultrasonic debridement associated with amoxicillin and metronidazole in the treatment of severe chronic periodontitis. Journal of Periodontology 2009;80(8):1254-64. - PubMed
Sampaio 2011 {published data only}
    1. NCT03629288. Efficacy of azithromycin as an adjunct to non-surgical periodontal treatment [Clinical and microbiological efficacy of a azithromycin as an adjunct to non-surgical periodontal treatment: a randomized controlled clinical trial]. clinicaltrials.gov/show/NCT03629288 (first received 14 August 2018).
    1. Sampaio E, Rocha M, Figueiredo LC, Faveri M, Duarte PM, Gomes Lira EA, et al. Clinical and microbiological effects of azithromycin in the treatment of generalized chronic periodontitis: a randomized placebo-controlled clinical trial. Journal of Clinical Periodontology 2011;38(9):838-46. - PubMed
Sigusch 2000 {published data only}
    1. Sigusch B, Pfister W, Klinger G, Glockmann E. Adjuvant antibiotic therapy as a 2-step treatment concept in early-onset periodontitis: a strategy for eradication of bacteria that cause periodontitis. Deutsche Medizinische Wochenschrift 2000;125(40):1186-91. - PubMed
Sigusch 2001 {published data only}
    1. Sigusch B, Beier M, Klinger G, Pfister W, Glockmann E. A 2-step non-surgical procedure and systemic antibiotics in the treatment of rapidly progressive periodontitis. Journal of Periodontology 2001;72(3):275-83. - PubMed
Silva 2011 {published data only}
    1. Silva MP, Feres M, Oliveira Sirotto TA, Silva Soares GM, Velloso Mendes JA, Faveri M, 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. Journal of Clinical Periodontology 2011;38(9):828-37. - PubMed
Smith 2002 {published data only}
    1. Smith SR, Foyle DM, Daniels J, Joyston-Bechal S, Smales FC, Sefton A, et al. A double-blind placebo-controlled trial of azithromycin as an adjunct to non-surgical treatment of periodontitis in adults: clinical results. Journal of Clinical Periodontology 2002;29(1):54-61. - PubMed
Taiete 2016 {published data only}
    1. Taiete T, Casati MZ, Ribeiro Édel P, Sallum EA, Nociti Júnior FH, Casarin RC. Amoxicillin/metronidazole associated with non-surgical therapy did not promote additional benefits in immunologic parameters in generalized aggressive periodontitis: a randomized controlled clinical trial. Quintessence International 2015;47(4):281-92. - PubMed
Winkel 1999 {published data only}
    1. Winkel EG, Van Winkelhoff AJ, Barendregt DS, Van der Weijden GA, Timmerman MF, Van der Velden U. Clinical and microbiological effects of initial periodontal therapy in conjunction with amoxicillin and clavulanic acid in patients with adult periodontitis. Journal of Clinical Periodontology 1999;26(7):461-8. - PubMed
Winkel 2001 {published data only}
    1. 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. Journal of Clinical Periodontology 2001;28(4):296-305. - PubMed
Xajigeorgiou 2006 {published data only}
    1. Xajigeorgiou C, Sakellari D, Slini T, Baka A, Konstantinidis A. Clinical and microbiological effects of different antimicrobials on generalized aggressive periodontitis. Journal of Clinical Periodontology 2006;33(4):254-64. - PubMed
Yek 2010 {published data only}
    1. Cifcibasi E, Kantarci A, Badur S, Issever H, Cintan S. Impact of metronidazole and amoxicillin combination on matrix metalloproteinases-1 and tissue inhibitors of matrix metalloproteinases balance in generalized aggressive periodontitis. European Journal of Dentistry 2015;9(1):53-9. [DOI: 10.4103/1305-7456.149642] - DOI - PMC - PubMed
    1. Yek EC, Cintan S, Topcuoglu N, Kulekci G, Halim İssever, Kantarci A. Efficacy of amoxicillin and metronidazole combination for the management of generalized aggressive periodontitis. Journal of Periodontology 2010;81(7):964-74. - PubMed
Zhang 2006 {published data only}
    1. Zhang X, Xie M, Zhang H, Huang S, Zhang Y. Mechanical periodontal treatment combined with tetracycline for aggressive periodontitis. Nan Fang Yi Ke Da Xue Xue Bao 2006;26(4):509-11, 514. - PubMed

References to studies excluded from this review

ACTRN12617000531314 {unpublished data only}
    1. ACTRN12617000531314. Clinical and microbiological evaluation of non-surgical treatment of chronic periodontitis with systemically administered azithromycin [Clinical and microbiological evaluation of one-stage full mouth disinfection in conjunction with systemically administered azithromycin: a randomised controlled clinical trial in patients with moderate to advanced chronic periodontitis]. www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372552 (first received 11 April 2017).
Boia 2018 {published data only}
    1. Boia S, Stratul SI, Boariu M, Ursoniu S, Gotia SL, Boia ER, et al. Evaluation of antioxidant capacity and clinical assessment of patients with chronic periodontitis treated with non-surgical periodontal therapy and adjunctive systemic antibiotherapy. Romanian Journal of Morphology and Embryology 2018;59(4):1107-13. [PMID: ] - PubMed
Carvalho 2005 {published data only}
    1. Carvalho LH, D’Avila GB, Leão A, Gonçalves C, Haffajee AD, Socransky SS, et al. Scaling and root planing, systemic metronidazole and professional plaque removal in the treatment of chronic periodontitis in a Brazilian population II – microbiological results. Journal of Clinical Periodontology 2005;32(4):406-11. - PubMed
Caton 1997 {published data only}
    1. Caton JG. An orally administered drug for treatment of periodontal disease. Practical Periodontics and Aesthetic Dentistry 1997;9(4):465-66. - PubMed
Ciancio 1981 {published data only}
    1. Ciancio SG. Clinical and microbiological evaluation of minocycline in treatment of periodontal disease. Journal of Dental Research 1981;60(Issue 1_Suppl):527 (Abstract no 871).
Ciancio 1984 {published data only}
    1. Ciancio SG. A comparison of tetracycline and minocycline as adjunctive antimicrobial agents in the treatment of adult periodontitis. Journal of Dental Research 1984;63(Spec Iss):267 (Abstract no 870).
Cigana 1989 {published data only}
    1. Cigana F, Doumenjou F. The evaluation of the efficacy of antibiotic therapy in human periodontal disease. Bulletin du Groupement International pour la Recherche Scientifique en Stomatologie et Odontologie 1989;32(4):227-37. - PubMed
Cionca 2009 {published data only}
    1. Cionca N, Giannopoulou C, Ugolotti G, Mombelli A. Amoxicillin and metronidazole as an adjunct to full mouth scaling and root planing of chronic periodontitis. Journal of Periodontology 2009;80(3):364-71. - PubMed
    1. 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. Journal of Periodontology 2010;81(1):15-23. [DOI: 10.1902/jop.2009.090390] - DOI - PubMed
Clark 1983 {published data only}
    1. Clark DC, Shenker S, Stulginski P, Schwartz S. Effectiveness of routine periodontal treatment with and without adjunctive metronidazole therapy in a sample of mentally retarded adolescents. Journal of Periodontology 1983;54(11):658-65. - PubMed
Counsell 1972 {published data only}
    1. Counsell LA. Studies in dental health education: I. Effect of antibiotic prophylaxis on the oral hygiene and periodontal health of young men. Journal of Dental Research 1972;51(6):1619-23. - PubMed
Di Murro 1986 {published data only}
    1. Di Murro C, Pantosti A, Paoloantonio M, Berti L, Pedrazzoli V, Martino P. Clinical and microbiological evaluation of the use of bacampicillin and tetracycline in periodontal therapy. Mondo Odontostomatologico 1986;28(6):53-61. - PubMed
Ehmke 2005 {published data only}
    1. Ehmke B, Moter A, Beikler T, Milian E, Flemmig TF. Adjunctive antimicrobial therapy of periodontitis: long-term effects on disease progression and oral colonization. Journal of Periodontology 2005;76(5):749-59. - PubMed
Eisenberg 1991 {published data only}
    1. Eisenberg L, Suchow R, Coles RS, Deasy MJ. The effects of metronidazole administration on clinical and microbiologic parameters of periodontal disease. Clinical Preventive Dentistry 1991;13(1):28-34. - PubMed
El‐Fadl 2015 {published data only}
    1. El-Fadl DA, Sabri NA, Abuel-Ela HA. A clinical study on the impact of different treatment modalities on improving the clinical outcomes in chronic periodontitis patients. International Journal of Pharmaceutical Sciences and Research 2015;6(10):4198.
Feres 1999 {published data only}
    1. Feres M, Haffajee AD, Goncalves C, Allard KA, Som S, Smith C, et al. Systemic doxycycline administration in the treatment of periodontal infections (I). Effect on the subgingival microbiota. Journal of Clinical Periodontology 1999;26(12):775-83. - PubMed
    1. Haffajee AD, Feres M, Goncalves C, Allard KA, Som S, Goodson JM, et al. Systemic doxycycline administration I. Effect on composition of subgingival microbiota. Journal of Dental Research 1998;77(Spec Iss A):195 (Abstract no 719).
Feres 2012 {published data only}
    1. Feres M, Soares GMS, Mendes JAV, Silva MP, Faveri M, Teles R, et al. Metronidazole alone or with amoxicillin as adjuncts to non-surgical treatment of chronic periodontitis: a 1-year double-blinded, placebo-controlled, randomized clinical trial. Journal of Clinical Periodontology 2012;39(12):1149-58. - PubMed
Feres 2017 {published data only}
    1. Feres M, Retamal-Valdes B, Mestnik MJ, Figueiredo LC, Faveri M, Duarte PM, et al. The ideal time of systemic metronidazole and amoxicillin administration in the treatment of severe periodontitis: study protocol for a randomized controlled trial. Trials 2018;19(1):201. - PMC - PubMed
    1. NCT02954393. Amoxicillin and metronidazole during periodontal treatment (MOMENT) [Influence of moment of systemic metronidazole and amoxicillin administration in the treatment of chronic periodontitis: a randomized clinical trial]. clinicaltrials.gov/ct2/show/NCT02954393 (first received 3 November 2016).
Flemmig 1998 {published data only}
    1. Flemmig TF, Milián E, Karch H, Klaiber B. Differential clinical treatment outcome after systemic metronidazole and amoxicillin in patients harboring Actinobacillus actinomycetemcomitans and/or Porphyromonas gingivalis. Journal of Clinical Periodontology 1998;25(5):380-7. - PubMed
Giannopoulou 2006 {published data only}
    1. Giannopoulou C, Andersen E, Brochut P, Plagnat D, Mombelli A. Enamel matrix derivative and systemic antibiotics as adjuncts to non-surgical periodontal treatment: biologic response. Journal of Periodontology 2006;77(4):707-13. - PubMed
Guentsch 2008 {published data only}
    1. Guentsch A, Jentsch H, Pfister W, Hoffmann T, Eick S. Moxifloxacin as an adjunctive antibiotic in the treatment of severe chronic periodontitis. Journal of Periodontology 2008;79(10):1894-903. - PubMed
Guerrero 2005 {published data only}ISRCTN19566213
    1. Guerrero A, Griffiths GS, Nibali L, Suvan J, Moles DR, Laurell L, et al. Adjunctive benefits of systemic amoxicillin and metronidazole in non-surgical treatment of generalized aggressive periodontitis: a randomized placebo-controlled clinical trial. Journal of Clinical Periodontology 2005;32(10):1096-107. - PubMed
Guerrero 2014 {published data only}
    1. Guerrero A, Nibali L, Lambertenghi R, Ready D, Suvan J, Griffiths GS, et al. Impact of baseline microbiological status on clinical outcomes in generalized aggressive periodontitis patients treated with or without adjunctive amoxicillin and metronidazole: an exploratory analysis from a randomized controlled clinical trial. Journal of Clinical Periodontology 2014;41(11):1080-9. - PubMed
Guzeldemir 2015 {published data only}
    1. Guzeldemir-Akcakanat E, Gurgan C. Systemic moxifloxacin vs amoxicillin/metronidazole adjunct to non-surgical treatment in generalized aggressive periodontitis. Medicina Oral, Patologia Oral y Cirugia Bucal 2015;20(4):e441–9. - PMC - PubMed
Haas 2012 {published data only}
    1. Haas AN, Silva-Boghossian CM, Colombo AP, Susin C, Albandar JM, Oppermann RV, et al. Adjunctive azithromycin in the treatment of aggressive periodontitis: microbiological findings of a 12-month randomized clinical trial. Journal of Dentistry 2012;40(7):556–63. - PubMed
Hartmann 1986 {published data only}
    1. Hartmann J, Muller HP, Jacoby F. Systemic metronidazole therapy and/or subgingival scaling and root planing. II. Development of clinical parameters in relation to the changes in the composition of the associated subgingival microflora. Deutsche Zahnarztliche Zeitschrift 1986;41(6):579-84. - PubMed
Helldean 1979 {published data only}
    1. Helldéan LB, Listgarten MA, Lindhe J. The effect of tetracycline and/or scaling on human periodontal disease. Journal of Clinical Periodontology 1979;6(4):222-30. - PubMed
Heller 2011 {published data only}
    1. Heller D, Varela VM, Silva-Senem MX, Torres MCB, Feres-Filho EJ, Colombo APV. Impact of systemic antimicrobials combined with anti-infective mechanical debridement on the microbiota of generalized aggressive periodontitis: a 6-month RCT. Journal of Clinical Periodontology 2011;38(4):355-64. - PubMed
Helovuo 1989 {published data only}
    1. Helovuo H, Paunio K. Effects of penicillin and erythromycin on the clinical parameters of the periodontium. Journal of Periodontology 1989;60(8):467-72. - PubMed
Javed 2014 {published data only}
    1. Javed F, Ahmed HB, Mehmood A, Bain C, Romanos GE. Effect of non-surgical periodontal therapy (with or without oral doxycycline delivery) on glycemic status and clinical periodontal parameters in patients with prediabetes: a short-term longitudinal randomized case–control study. Clinical Oral Investigations 2014;18(8):1963-8. - PubMed
Jenkins 1989 {published data only}
    1. Jenkins WMM, MacFarlane TW, Gilmour WH, Ramsay I, MacKenzie D. Systemic metronidazole in the treatment of periodontitis. Journal of Clinical Periodontology 1989;16(7):443-50. - PubMed
Jentsch 2016 {published data only}
    1. Jentsch HFR, Buchmann A, Friedrich A, Eick S. Non-surgical therapy of chronic periodontitis with adjunctive systemic azithromycin or amoxicillin/metronidazole. Clinical Oral Investigations 2016;20(7):1765-73. - PubMed
Joyston 1986 {published data only}
    1. Joyston-Bechal S, Smales FC, Duckworth R. A follow-up study 3 years after metronidazole therapy for chronic periodontal disease. Journal of Clinical Periodontology 1986;13(10):944-9. - PubMed
Kaner 2011 {published data only}
    1. Kaner D, Bernimoulin J-P, Dietrich T, Kleber B-M, Friedmann A. Calprotectin levels in gingival crevicular fluid predict disease activity in patients treated for generalized aggressive periodontitis: calprotectin predicts periodontal disease activity. Journal of Periodontal Research 2011;46(4):417-26. - PubMed
Kone 2005 {published data only}
    1. Kone D, Kamagate A. Comparative study of 2 antibiotic combinations in the treatment of rapidly progressing periodontitis. Odonto-stomatologie Tropicale [Tropical Dental Journal] 2005;28(110):41-4. - PubMed
Kunihira 1985 {published data only}
    1. Kunihira DM, Caine FA, Palcanis KG, Best AM, Ranney RR. A clinical trial of phenoxymethyl penicillin for adjunctive treatment of juvenile periodontitis. Journal of Periodontology 1985;56(6):352-8. - PubMed
Listgarten 1978 {published data only}
    1. Listgarten MA, Lindhe J, Hellden L. Effect of tetracycline and/or scaling on human periodontal disease. Journal of Clinical Periodontology 1978;5(4):246-71. - PubMed
Loesche 1992 {published data only}
    1. Loesche WJ, Giordano JR, Hujoel P, Schwarcz J, Smith BA. Metronidazole in periodontitis: reduced need for surgery. Journal of Clinical Periodontology 1992;19(2):103-12. - PubMed
Mestnik 2010 {published data only}
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NCT01499225 {unpublished data only}
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Nepokupnaia 2014 {published data only}
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References to studies awaiting assessment

Andronikaki‐Faldami 1985 {published data only}
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IRCT2014010816141N1 {unpublished data only}
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IRCT2014071518493N1 {unpublished data only}
    1. IRCT2014071518493N1. Azithromycin's effect on periodontitis [Effect of systemic administration of azithromycin following non-surgical treatment in patients with moderate chronic periodontitis]. en.irct.ir/trial/16759 (first received 6 March 2015).
IRCT2015052510304N2 {unpublished data only}
    1. IRCT2015052510304N2. Survey of prescription of azithromycin in treatment of patients with chronic periodontitis [Survey of systemic prescription of azithromycin using salivary occult blood test (SOBT) and periodontal parameters in non-surgical treatment of patients with moderate to severe chronic periodontitis]. www.irct.ir/trial/10762 (first received 10 June 2015).
Li 2003 {published data only}
    1. Li, Xu L, Lu R, An Y, Wang X, Song W, et al. Observing clinical effects of azithromycin on treating periodontitis. Chinese Journal of Modern Medicine 2003;13(7):82.
Tramontina 2000 {published data only}
    1. Tramontina RG. Clinical and Microbiological Effects of Short Term Systemic Administration of Azithromycin as an Adjunct to Mechanical Adult Periodontitis Treatment [Thesis]. Sao Paulo (Brazil): University of Sao Paulo, 2000.

References to ongoing studies

2015‐004306‐42 {unpublished data only}
    1. 2015-004306-42. Comparison of the efficacy of treatment of chronic periodontitis with scaling and root planing alone or in combination with azithromycin - a prospective, double-blind, randomized clinical trial. www.clinicaltrialsregister.eu/ctr-search/search?query=2015-004306-42 (first received 27 January 2016).
ACTRN12615001047583 {unpublished data only}
    1. ACTRN12615001047583. Adjunctive systemic azithromycin versus amoxycillin and metronidazole in non-surgical mechanical therapy of periodontitis [Efficacy of adjunctive azithromycin versus amoxycillin and medtronidazole, and placebo in the treatment of chronic periodontitis in adults]. www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12615001047583 (first received 7 October 2015).
NCT02839421 {unpublished data only}
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