Adjunctive systemic antimicrobials for the non-surgical treatment of periodontitis

Shivi Khattri, Sumanth Kumbargere Nagraj, Ankita Arora, Prashanti Eachempati, Chandan Kumar Kusum, Kishore G Bhat, Trevor M Johnson, Giovanni Lodi, Shivi Khattri, Sumanth Kumbargere Nagraj, Ankita Arora, Prashanti Eachempati, Chandan Kumar Kusum, Kishore G Bhat, Trevor M Johnson, Giovanni Lodi

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.

Conflict of interest statement

Shivi Khattri: no interests to declare.
Sumanth Kumbargere Nagraj: no interests to declare.
Ankita Arora: no interests to declare.
Prashanti Eachempati: no interests to declare.
Chandan Kumar Kusum: no interests to declare.
Kishore G Bhat: no interests to declare.
Trevor M Johnson: no interests to declare.
Giovanni Lodi: no interests to declare.

Figures

1
Etiopathogenesis of periodontal disease.

2
Classification of periodontitis (Armitage 1999; Geurs 2015). AL = attachment loss; PD = pocket depth.

4
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

5
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

**1.1. Analysis**
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 1: Percentage of closed pockets ‐ short‐term (≤ 3 months) improvement

**1.2. Analysis**
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 2: Percentage of closed pockets ‐ intermediate‐term (> 3 months) improvement

**1.3. Analysis**
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 3: Percentage of closed pockets ‐ long‐term (≥ 1 year) improvement

**1.4. Analysis**
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 4: CAL ‐ short‐term (≤ 3 months) improvement

**1.5. Analysis**
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 5: CAL ‐ intermediate‐term (> 3 months) improvement

**1.6. Analysis**
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 6: CAL ‐ long‐term (≥ 1 year) improvement

**1.7. Analysis**
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 7: Pocket depth ‐ short‐term (≤ 3 months) improvement

**1.8. Analysis**
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 8: Pocket depth ‐ intermediate‐term (> 3 months) improvement

**1.9. Analysis**
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 9: Pocket depth ‐ long‐term (≥ 1 year) improvement

**1.10. Analysis**
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 10: BOP ‐ short‐term (≤ 3 months) improvement

**1.11. Analysis**
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 11: BOP ‐ intermediate‐term (> 3 months) improvement

**1.12. Analysis**
Comparison 1: AMOX + MTZ + SRP versus SRP, Outcome 12: BOP ‐ long‐term (≥ 1 year) improvement

**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. Analysis**
Comparison 2: MTZ + SRP versus SRP, Outcome 2: Percentage of closed pockets ‐ intermediate‐term (> 3 months) improvement in chronic periodontitis

**2.3. Analysis**
Comparison 2: MTZ + SRP versus SRP, Outcome 3: Percentage of closed pockets ‐ long‐term (≥ 1 year) improvement

**2.4. Analysis**
Comparison 2: MTZ + SRP versus SRP, Outcome 4: CAL ‐ short‐term (≤ 3 months) improvement

**2.5. Analysis**
Comparison 2: MTZ + SRP versus SRP, Outcome 5: CAL ‐ intermediate‐term (> 3 months) improvement

**2.6. Analysis**
Comparison 2: MTZ + SRP versus SRP, Outcome 6: CAL ‐ long‐term (≥ 1 year) improvement

**2.7. Analysis**
Comparison 2: MTZ + SRP versus SRP, Outcome 7: Pocket depth ‐ short‐term (≤ 3 months) improvement

**2.8. Analysis**
Comparison 2: MTZ + SRP versus SRP, Outcome 8: Pocket depth ‐ intermediate‐term (> 3 months) improvement

**2.9. Analysis**
Comparison 2: MTZ + SRP versus SRP, Outcome 9: Pocket depth ‐ long‐term (≥ 1 year) improvement

**2.10. Analysis**
Comparison 2: MTZ + SRP versus SRP, Outcome 10: BOP ‐ short‐term (≤ 3 months) improvement

**2.11. Analysis**
Comparison 2: MTZ + SRP versus SRP, Outcome 11: BOP ‐ intermediate‐term (> 3 months) improvement

**2.12. Analysis**
Comparison 2: MTZ + SRP versus SRP, Outcome 12: BOP ‐ long‐term (≥ 1 year) improvement

**3.1. Analysis**
Comparison 3: AZT + SRP versus SRP, Outcome 1: Percentage of closed pockets ‐ intermediate‐term (> 3 months) improvement

**3.2. Analysis**
Comparison 3: AZT + SRP versus SRP, Outcome 2: Percentage of closed pockets ‐ long‐term (≥ 1 year) improvement

**3.3. Analysis**
Comparison 3: AZT + SRP versus SRP, Outcome 3: CAL ‐ short‐term (≤ 3 months) improvement

**3.4. Analysis**
Comparison 3: AZT + SRP versus SRP, Outcome 4: CAL ‐ intermediate‐term (> 3 months) improvement

**3.5. Analysis**
Comparison 3: AZT + SRP versus SRP, Outcome 5: CAL ‐ long‐term (≥ 1 year) improvement

**3.6. Analysis**
Comparison 3: AZT + SRP versus SRP, Outcome 6: Pocket depth ‐ short‐term (≤ 3 months) improvement

**3.7. Analysis**
Comparison 3: AZT + SRP versus SRP, Outcome 7: Pocket depth ‐ intermediate‐term (> 3 months) improvement

**3.8. Analysis**
Comparison 3: AZT + SRP versus SRP, Outcome 8: Pocket depth ‐ long‐term (≥ 1 year) improvement

**3.9. Analysis**
Comparison 3: AZT + SRP versus SRP, Outcome 9: BOP ‐ short‐term (≤ 3 months) improvement

**3.10. Analysis**
Comparison 3: AZT + SRP versus SRP, Outcome 10: BOP ‐ intermediate‐term (> 3 months) improvement

**3.11. Analysis**
Comparison 3: AZT + SRP versus SRP, Outcome 11: BOP ‐ long‐term (≥ 1 year) improvement

**4.1. Analysis**
Comparison 4: AMOX + CLAV + SRP versus SRP in chronic periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement

**4.2. Analysis**
Comparison 4: AMOX + CLAV + SRP versus SRP in chronic periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement

**4.3. Analysis**
Comparison 4: AMOX + CLAV + SRP versus SRP in chronic periodontitis, Outcome 3: CAL ‐ long‐term (≥ 1 year) improvement

**4.4. Analysis**
Comparison 4: AMOX + CLAV + SRP versus SRP in chronic periodontitis, Outcome 4: Pocket depth ‐ short‐term (≤ 3 months) improvement

**4.5. Analysis**
Comparison 4: AMOX + CLAV + SRP versus SRP in chronic periodontitis, Outcome 5: Pocket depth ‐ intermediate‐term (> 3 months) improvement

**4.6. Analysis**
Comparison 4: AMOX + CLAV + SRP versus SRP in chronic periodontitis, Outcome 6: Pocket depth ‐ long‐term (≥ 1 year) improvement

**4.7. Analysis**
Comparison 4: AMOX + CLAV + SRP versus SRP in chronic periodontitis, Outcome 7: BOP ‐ short‐term (≤ 3 months) improvement

**4.8. Analysis**
Comparison 4: AMOX + CLAV + SRP versus SRP in chronic periodontitis, Outcome 8: BOP ‐ intermediate‐term (> 3 months) improvement

**4.9. Analysis**
Comparison 4: AMOX + CLAV + SRP versus SRP in chronic periodontitis, Outcome 9: BOP ‐ long‐term (≥ 1 year) improvement

**5.1. Analysis**
Comparison 5: Doxycycline + SRP versus SRP in aggressive periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement

**5.2. Analysis**
Comparison 5: Doxycycline + SRP versus SRP in aggressive periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement

**5.3. Analysis**
Comparison 5: Doxycycline + SRP versus SRP in aggressive periodontitis, Outcome 3: CAL ‐ long‐term (≥ 1 year) improvement

**5.4. Analysis**
Comparison 5: Doxycycline + SRP versus SRP in aggressive periodontitis, Outcome 4: Pocket depth ‐ short‐term (≤ 3 months) improvement

**5.5. Analysis**
Comparison 5: Doxycycline + SRP versus SRP in aggressive periodontitis, Outcome 5: Pocket depth ‐ intermediate‐term (> 3 months) improvement

**5.6. Analysis**
Comparison 5: Doxycycline + SRP versus SRP in aggressive periodontitis, Outcome 6: Pocket depth ‐ long‐term (≥ 1 year) improvement

**5.7. Analysis**
Comparison 5: Doxycycline + SRP versus SRP in aggressive periodontitis, Outcome 7: BOP ‐ short‐term (≤ 3 months) improvement

**5.8. Analysis**
Comparison 5: Doxycycline + SRP versus SRP in aggressive periodontitis, Outcome 8: BOP ‐ intermediate‐term (> 3 months) improvement

**6.1. Analysis**
Comparison 6: Tetracycline + SRP versus SRP in aggressive periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement

**6.2. Analysis**
Comparison 6: Tetracycline + SRP versus SRP in aggressive periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement

**6.3. Analysis**
Comparison 6: Tetracycline + SRP versus SRP in aggressive periodontitis, Outcome 3: CAL ‐ long‐term (≥ 1 year) improvement

**6.4. Analysis**
Comparison 6: Tetracycline + SRP versus SRP in aggressive periodontitis, Outcome 4: Pocket depth ‐ short‐term (≤ 3 months) improvement

**6.5. Analysis**
Comparison 6: Tetracycline + SRP versus SRP in aggressive periodontitis, Outcome 5: BOP ‐ short‐term (≤ 3 months) improvement

**7.1. Analysis**
Comparison 7: Clarithromycin + SRP versus SRP, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement

**7.2. Analysis**
Comparison 7: Clarithromycin + SRP versus SRP, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement

**7.3. Analysis**
Comparison 7: Clarithromycin + SRP versus SRP, Outcome 3: Pocket depth ‐ short‐term (≤ 3 months) improvement

**7.4. Analysis**
Comparison 7: Clarithromycin + SRP versus SRP, Outcome 4: Pocket depth ‐ intermediate‐term (> 3 months) improvement

**7.5. Analysis**
Comparison 7: Clarithromycin + SRP versus SRP, Outcome 5: BOP ‐ short‐term (≤ 3 months) improvement

**7.6. Analysis**
Comparison 7: Clarithromycin + SRP versus SRP, Outcome 6: BOP ‐ intermediate‐term (> 3 months) improvement

**8.1. Analysis**
Comparison 8: Moxifloxacin + SRP versus SRP in aggressive periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement

**8.2. Analysis**
Comparison 8: Moxifloxacin + SRP versus SRP in aggressive periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement

**8.3. Analysis**
Comparison 8: Moxifloxacin + SRP versus SRP in aggressive periodontitis, Outcome 3: Pocket depth ‐ short‐term (≤ 3 months) improvement

**8.4. Analysis**
Comparison 8: Moxifloxacin + SRP versus SRP in aggressive periodontitis, Outcome 4: Pocket depth ‐ intermediate‐term (> 3 months) improvement

**8.5. Analysis**
Comparison 8: Moxifloxacin + SRP versus SRP in aggressive periodontitis, Outcome 5: BOP ‐ short‐term (≤ 3 months) improvement

**8.6. Analysis**
Comparison 8: Moxifloxacin + SRP versus SRP in aggressive periodontitis, Outcome 6: BOP ‐ intermediate‐term (> 3 months) improvement

**9.1. Analysis**
Comparison 9: Levofloxacin + SRP versus SRP in chronic periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement

**9.2. Analysis**
Comparison 9: Levofloxacin + SRP versus SRP in chronic periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement

**9.3. Analysis**
Comparison 9: Levofloxacin + SRP versus SRP in chronic periodontitis, Outcome 3: Pocket depth ‐ short‐term (≤ 3 months) improvement

**9.4. Analysis**
Comparison 9: Levofloxacin + SRP versus SRP in chronic periodontitis, Outcome 4: Pocket depth ‐ intermediate‐term (> 3 months) improvement

**9.5. Analysis**
Comparison 9: Levofloxacin + SRP versus SRP in chronic periodontitis, Outcome 5: BOP ‐ short‐term (≤ 3 months) improvement

**9.6. Analysis**
Comparison 9: Levofloxacin + SRP versus SRP in chronic periodontitis, Outcome 6: BOP ‐ intermediate‐term (> 3 months) improvement

**10.1. Analysis**
Comparison 10: Clindamycin + SRP versus SRP in aggressive periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement

**10.2. Analysis**
Comparison 10: Clindamycin + SRP versus SRP in aggressive periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement

**10.3. Analysis**
Comparison 10: Clindamycin + SRP versus SRP in aggressive periodontitis, Outcome 3: CAL ‐ long‐term (≥ 1 year) improvement

**10.4. Analysis**
Comparison 10: Clindamycin + SRP versus SRP in aggressive periodontitis, Outcome 4: Pocket depth ‐ short‐term (≤ 3 months) improvement

**10.5. Analysis**
Comparison 10: Clindamycin + SRP versus SRP in aggressive periodontitis, Outcome 5: Pocket depth ‐ intermediate‐term (> 3 months) improvement

**10.6. Analysis**
Comparison 10: Clindamycin + SRP versus SRP in aggressive periodontitis, Outcome 6: Pocket depth ‐ long‐term (≥ 1 year) improvement

**11.3. Analysis**
Comparison 11: Cefixime + SRP versus SRP in chronic periodontitis, Outcome 3: BOP ‐ short‐term (≤ 3 months) improvement

**12.1. Analysis**
Comparison 12: MTZ + SRP versus AMOX + MTZ + SRP, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement

**12.2. Analysis**
Comparison 12: MTZ + SRP versus AMOX + MTZ + SRP, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement

**12.3. Analysis**
Comparison 12: MTZ + SRP versus AMOX + MTZ + SRP, Outcome 3: Pocket depth ‐ short‐term (≤ 3 months) improvement

**12.4. Analysis**
Comparison 12: MTZ + SRP versus AMOX + MTZ + SRP, Outcome 4: Pocket depth ‐ intermediate‐term (> 3 months) improvement

**12.5. Analysis**
Comparison 12: MTZ + SRP versus AMOX + MTZ + SRP, Outcome 5: BOP ‐ short‐term (≤ 3 months) improvement

**12.6. Analysis**
Comparison 12: MTZ + SRP versus AMOX + MTZ + SRP, Outcome 6: BOP ‐ intermediate‐term (> 3 months) improvement

**13.1. Analysis**
Comparison 13: Doxycycline + SRP versus AMOX + MTZ + SRP in aggressive periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement

**13.2. Analysis**
Comparison 13: Doxycycline + SRP versus AMOX + MTZ + SRP in aggressive periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement

**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. Analysis**
Comparison 13: Doxycycline + SRP versus AMOX + MTZ + SRP in aggressive periodontitis, Outcome 4: Pocket depth ‐ intermediate‐term (> 3 months) improvement

**14.1. Analysis**
Comparison 14: Doxycycline + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement

**14.2. Analysis**
Comparison 14: Doxycycline + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement

**14.3. Analysis**
Comparison 14: Doxycycline + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 3: CAL ‐ long‐term (≥ 1 year) improvement

**14.4. Analysis**
Comparison 14: Doxycycline + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 4: Pocket depth ‐ short‐term (≤ 3 months) improvement

**14.5. Analysis**
Comparison 14: Doxycycline + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 5: Pocket depth ‐ intermediate‐term (> 3 months) improvement

**14.6. Analysis**
Comparison 14: Doxycycline + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 6: Pocket depth ‐ long‐term (≥ 1 year) improvement

**14.7. Analysis**
Comparison 14: Doxycycline + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 7: BOP ‐ short‐term (≤ 3 months) improvement

**14.8. Analysis**
Comparison 14: Doxycycline + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 8: BOP ‐ intermediate‐term (> 3 months) improvement

**15.1. Analysis**
Comparison 15: Clindamycin + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement

**15.2. Analysis**
Comparison 15: Clindamycin + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement

**15.3. Analysis**
Comparison 15: Clindamycin + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 3: CAL ‐ long‐term (≥ 1 year) improvement

**15.4. Analysis**
Comparison 15: Clindamycin + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 4: Pocket depth ‐ short‐term (≤ 3 months) improvement

**15.5. Analysis**
Comparison 15: Clindamycin + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 5: Pocket depth ‐ intermediate‐term (> 3 months) improvement

**15.6. Analysis**
Comparison 15: Clindamycin + SRP versus MTZ + SRP in aggressive periodontitis, Outcome 6: Pocket depth ‐ long‐term (≥ 1 year) improvement

**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. Analysis**
Comparison 16: AMOX + CLAV + SRP versus tetracycline + SRP in aggressive periodontitis, Outcome 2: BOP ‐ intermediate‐term (> 3 months) improvement

**17.1. Analysis**
Comparison 17: Clindamycin + SRP versus doxycycline + SRP in aggressive periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement

**17.2. Analysis**
Comparison 17: Clindamycin + SRP versus doxycycline + SRP in aggressive periodontitis, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement

**17.3. Analysis**
Comparison 17: Clindamycin + SRP versus doxycycline + SRP in aggressive periodontitis, Outcome 3: CAL ‐ long‐term (≥ 1 year) improvement

**17.4. Analysis**
Comparison 17: Clindamycin + SRP versus doxycycline + SRP in aggressive periodontitis, Outcome 4: Pocket depth ‐ short‐term (≤ 3 months) improvement

**17.5. Analysis**
Comparison 17: Clindamycin + SRP versus doxycycline + SRP in aggressive periodontitis, Outcome 5: Pocket depth ‐ intermediate‐term (> 3 months) improvement

**17.6. Analysis**
Comparison 17: Clindamycin + SRP versus doxycycline + SRP in aggressive periodontitis, Outcome 6: Pocket depth ‐ long‐term (≥ 1 year) improvement

**18.1. Analysis**
Comparison 18: AMOX + MZT versus clarithromycin + SRP, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement

**18.2. Analysis**
Comparison 18: AMOX + MZT versus clarithromycin + SRP, Outcome 2: CAL ‐ intermediate‐term (> 3 months) improvement

**18.3. Analysis**
Comparison 18: AMOX + MZT versus clarithromycin + SRP, Outcome 3: Pocket depth ‐ short‐term (≤ 3 months) improvement

**18.4. Analysis**
Comparison 18: AMOX + MZT versus clarithromycin + SRP, Outcome 4: Pocket depth ‐ intermediate‐term (> 3 months) improvement

**18.5. Analysis**
Comparison 18: AMOX + MZT versus clarithromycin + SRP, Outcome 5: BOP ‐ short‐term (≤ 3 months) improvement

**18.6. Analysis**
Comparison 18: AMOX + MZT versus clarithromycin + SRP, Outcome 6: BOP ‐ intermediate‐term (> 3 months) improvement

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.

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.

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.

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.
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.
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.

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.

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.

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.

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.

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.

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.

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]
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.

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.

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.

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.

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.

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.

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.

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.

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.

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]. (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]

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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]. (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.

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.

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.

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.

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.

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.

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.

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.

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.

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]
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.

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.

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]. (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: ]

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.

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.

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.

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.
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]

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.

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.

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.

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.

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.

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.
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.

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.
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]. (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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Mestnik 2010 {published data only}

1. Lira E, Ramiro F, Chiarelli F, Dias R, Feres M, Figueiredo L, et al. Reduction in prevalence of Archaea after periodontal therapy in subjects with generalized aggressive periodontitis. Australian Dental Journal 2013;58(4):442-7. [DOI: 10.1111/j.1600-051X.2010.01538.x]
1. Mestnik MJ, Feres M, Figueiredo LC, Duarte PM, Lira EAG, 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. Journal of Clinical Periodontology 2010;37(4):353–65.
1. Mestnik MJ, Feres M, Figueiredo LC, Soares G, Teles RP, Fermiano D, et al. The effects of adjunctive metronidazole plus amoxicillin in the treatment of generalized aggressive periodontitis: a 1-year double-blinded, placebo-controlled, randomized clinical trial. Journal of Clinical Periodontology 2012;39(10):955-61. [DOI: 10.1111/j.1600-051X.2012.01932.]

Mombelli 2012 {published data only}

1. Mombelli A, Romano F, Guzzi N, Carnevale G. Full mouth disinfection and systemic antimicrobial therapy in generalized aggressive periodontitis: a randomized, placebo-controlled trial. Journal of Clinical Periodontology 2012;39(3):284-94.

Muller 1986 {published data only}

1. Muller HP, Hartmann J, Jacoby F. Systemic metronidazole therapy and/or subgingival scaling with root planing. I. Clinical results. Deutsche Zahnarztliche Zeitschrift 1986;41(6):573-8.

Murugesan 2018 {published data only}

1. Murugesan G, Sudha KM, Subaramoniam MK, Dutta T, Dhanasekar KR. A comparative study of synbiotic as an add-on therapy to standard treatment in patients with aggressive periodontitis. Journal of Indian Society of Periodontology 2018;22(5):438-41. [PMID: ]

NCT00066066 {unpublished data only}

1. NCT00066066. Effect of three periodontal therapies in current smokers and non-smokers. (first received 5 August 2003).

NCT01499225 {unpublished data only}

1. NCT01499225. A clinical trial of YH14642 in patients with chronic periodontal disease (YH14642) [A double-blind, randomized, parallel, placebo-active controlled, multicenter phase II clinical trial to investigate the efficacy and safety of YH14642 following 12-week oral administration in patients with chronic periodontal disease]. (first received 26 December 2011).

Nepokupnaia 2014 {published data only}

1. Nepokupnaia-Slobodianiuk TS, Skripnikov PN. Clinical efficiency of short and long-term adjuvant therapy of chronic periodontal disease with azithromycin. Stomatologiya 2014;93(6):20.

Oliveira 2012 {published data only}

1. Oliveira AP, Faveri M, Gursky LC, Mestnik MJ, Feres M, Haffajee AD, et al. Effects of periodontal therapy on GCF cytokines in generalized aggressive periodontitis subjects. Journal of Clinical Periodontology 2012;39(3):295-302.

Oteo 2010 {published data only}

1. Oteo A, Herrera D, Figuero E, O’Connor A, González I, Sanz M. Azithromycin as an adjunct to scaling and root planing in the treatment of Porphyromonas gingivalis-associated periodontitis: a pilot study. Journal of Clinical Periodontology 2010;37(11):1005-15.

Preus 2017 {published data only}

1. Preus HR, Gjermo P, Baelum V. A double-masked randomized clinical trial (RCT) comparing four periodontitis treatment strategies: 5-year clinical results. Journal of Clinical Periodontology 2017;44(10):1029–38.
1. Preus HR, Gjermo P, Baelum V. A randomized double-masked clinical trial comparing four periodontitis treatment strategies: 5-year tooth loss results. Journal of Periodontology 2017;88(2):144-52. [PMID: ]
1. Preus HR, Gunleiksrud TM, Sandvik L, Gjermo P, Baelum V. A randomized, double-masked clinical trial comparing four periodontitis treatment strategies: 1-year clinical results. Journal of Periodontology 2013;84(8):1075-86. [PMID: ]

Re 1988 {published data only}

1. Re G, Barbero P, Briccarello MP, Manzon W, Zoccola GC. Oral amoxicillin 1 g b.i.d. vs 1 g t.i.d. in the treatment of oral periodontitis. Randomized and double-blind pilot trial. Minerva Stomatologica 1988;37(6):507-9.

Rooney 2002 {published data only}

1. Rooney J, Wade WG, Sprague SV, Newcombe RG, Addy M. Adjunctive effects to non-surgical periodontal therapy of systemic metronidazole and amoxycillin alone and combined. Journal of Clinical Periodontology 2002;29(4):342-50.

Shayesteh 2004 {published data only}

1. Shayesteh YS, Khorsand A, Salary M, Mehrizy H. Comparison of systemic ciprofloxacin in elimination of A.a from active sites with combination of metronidazole and amoxicillin in patients with aggressive periodontitis: a randomized double-blind controlled trial. Journal of Dentistry of Tehran University of Medical Sciences 2004;1(2):24-8.

Soder 1990 {published data only}

1. Söder P-Ö, Frithiof L, Wikner S, Wouters F, Engström P-E, Rubin B, et al. The effect of systemic metronidazole after non-surgical treatment in moderate and advanced periodontitis in young adults. Journal of Periodontology 1990;61(5):281-8.

Sterry 1985 {published data only}

1. Sterry KA, Langeroudi M, Dolby AE. Metronidazole as an adjunct to periodontal therapy with subgingival curettage. British Dental Journal 1985;158(5):176-8.

Tinoco 1998 {published data only}

1. Tinoco EM, Beldi MI, Campedelli F, Lana M, Loureiro CA, Bellini HT, et al. Clinical and microbiologic effects of adjunctive antibiotics in treatment of localized juvenile periodontitis. A controlled clinical trial. Journal of Periodontology 1998;69(12):1355-63.

Tsarev 1998 {published data only}

1. Tsarev VN, Chernyshova SB, Dmitrieva LA, Raĭnov NA, Nosik AS. The prospects for the use of fluoroquinolone preparations in the combined treatment of chronic generalized periodontitis at a stage of exacerbation [Perspektivy primeneniia preparatov ftorkhinolonovogo riada v kompleksnom lechenii khronicheskogo generalizovannogo parodontita v stadii obostreniia]. Stomatologiia 1998;77(5):13-4.

UMIN000012033 {published data only}

1. UMIN000012033. Development and validation of safety of a new antimicrobial agent therapy to early healing for individual periodontal disease. (first received 1 November 2013).

Wang 1996 {published data only}

1. Wang R, Chen L, Ni K. The effect of tinidazole in the treatment of adult periodontitis. Zhonghua Kou Qiang Yi Xue za Zhi [Chinese Journal of Stomatology] 1996;31(5):303-6.

Watts 1986 {published data only}

1. Watts T, Palmer R, Floyd P. Metronidazole: a double-blind trial in untreated human periodontal disease. Journal of Clinical Periodontology 1986;13(10):939-43.

Zhao 2006 {published data only}

1. Zhao N, Ge S-H, Ding G-Y. Clinical effect of minocycline as adjunctive therapy to scaling and root planning on treatment of chronic periodontitis. Hua Xi Kou Qiang Yi Xue za Zhi [West China Journal of Stomatology] 2006;24(1):32-5.

References to studies awaiting assessment Andronikaki‐Faldami 1985 {published data only}

1. Andronikaki-Faldami A. Drugs in the prevention and therapy of periodontal diseases. II. Systemic administration - antibiotics. Hellenika Stomatologika Chronika [Hellenic Stomatological Annals] 1985;29(2):82-7.

IRCT2014010816141N1 {unpublished data only}

1. IRCT2014010816141N1. Effect of ciprofloxacin versus amoxicillin and metronidazole in recovery of chronic periodontitis [Effect of ciprofloxacin versus amoxicillin and metronidazole as an additional helpful therapy after scaling and root planing in enhancement of periodontal disease clinical parameters of chronic periodontitis]. (first received 14 February 2014).

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]. (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]. (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. (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]. (first received 7 October 2015).

NCT02839421 {unpublished data only}

1. NCT02839421. Efficacy of three antibiotic protocols for aggressive periodontitis treatment [Efficacy of moxifloxacin, amoxicillin + metronidazole for aggressive periodontitis treatment]. (first received 21 July 2016).

Additional references Aitken 1992

1. Aitken S, Birek P, Kulkarni GV, Lee WL, McCulloch CA. Serial doxycycline and metronidazole in prevention of recurrent periodontitis in high-risk patients. Journal of Periodontology 1992;63(2):87-92.

Al‐Joburi 1989

1. Al-Joburi W, Quee TC, Lautar C, Iugovaz I, Bourgouin J, Delorme F, et al. Effects of adjunctive treatment of periodontitis with tetracycline and spiramycin. Journal of Periodontology 1989;60(10):533-9.

Araújo 2010

1. da Silva Araújo AC, Gusmão ES, Batista JEM, Cimões R. Impact of periodontal disease on quality of life. Quintessence International 2010;41(6):e111-8.

Armitage 1999

1. Armitage GC. Development of a classification system for periodontal diseases and conditions. Annals of Periodontology 1999;4(1):1-6.

Atilla 1996

1. Atilla G, Balcan M, Biçakçi N, Kazandi A. The effect of non-surgical periodontal and adjunctive minocycline-HCL treatments on the activity of salivary proteases. Journal of Periodontology 1996;67(1):1-6.

Balshem 2011

1. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. Journal of Clinical Epidemiology 2011;64(4):401-6.

Caton 2018

1. Caton JG, Armitage G, Berglundh T, Chapple ILC, Jepsen S, Kornman KS, et al. A new classification scheme for periodontal and peri-implant diseases and conditions - Introduction and key changes from the 1999 classification. Journal of Clinical Periodontology 2018;45 Suppl 20:S1-8. [PMID: ]

Chapple 2018

1. Chapple ILC, Mealey BL, Dyke TEV, Bartold PM, Dommisch H, Eickholz P, et al. Periodontal health and gingival diseases and conditions on an intact and a reduced periodontium: consensus report of workgroup 1 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. Journal of Clinical Periodontology 2018;45(S20):S68-77. [DOI: 10.1111/jcpe.12940]

Chraif 2014

1. Chraif M, Vasile C, Anitei M, Simona G, Silvia M, Carina B. Quality of life regarding patients with periodontal disease in Iasi, Romania. Procedia - Social and Behavioral Sciences 2014;127:15-20.

Colgan 2001

1. Colgan R, Powers JH. Appropriate antimicrobial prescribing: approaches that limit antibiotic resistance. American Family Physician 2001;64(6):999-1004.

COMET 2019

1. Lamont TJ, Clarkson JE, Ricketts DNJ, Heasman PA, Ramsay CR, Gillies K. Core outcome measures and selective outcome reporting in randomised controlled trials for the prevention and treatment of periodontal disease. (accessed 16 July 2019).

Contreras 1996

1. Contreras A, Slots J. Mammalian viruses in human periodontitis. Oral Microbiology and Immunology 1996;11(6):381-6.

Corbett 2014

1. Corbett MS, Higgins JP, Woolacott NF. Assessing baseline imbalance in randomised trials: implications for the Cochrane risk of bias tool. Research Synthesis Methods 2014;5(1):79-85. [PMID: ]

da Costa 2017

1. da Costa LFNP, Amaral C da SF, Barbirato D da S, Leão ATT, Fogacci MF. Chlorhexidine mouthwash as an adjunct to mechanical therapy in chronic periodontitis. Journal of the American Dental Association 2017;148(5):308-18. [DOI: 10.1016/j.adaj.2017.01.021]

Deas 2016

1. Deas DE, Moritz AJ, Sagun RS, Gruwell SF, Powell CA. Scaling and root planing vs conservative surgery in the treatment of chronic periodontitis. Periodontology 2000 2016;71(1):128-39.

Eickholz 2019

1. Eickholz P, Koch R, Kocher T, Hoffmann T, Kim TS, Meyle J, et al. Clinical benefits of systemic amoxicillin/metronidazole may depend on periodontitis severity and patients' age: an exploratory subanalysis of the ABPARO trial. Journal of Clinical Periodontology 2019;46(4):491-501. [PMID: ]

Eke 2012

1. Eke PI, Thornton-Evans G, Dye B, Genco R. Advances in surveillance of periodontitis: the Centers for Disease Control and Prevention periodontal disease surveillance project. Journal of Periodontology 2012;83(11):1337-42.

Eke 2015

1. Eke PI, Dye BA, Wei L, Slade GD, Thornton-Evans GO, Borgnakke WS, et al. Update on prevalence of periodontitis in adults in the United States: NHANES 2009 to 2012. Journal of Periodontology 2015;86(5):611-22.

Elter 1997

1. Elter JR, Lawrence HP, Offenbacher S, Beck JD. Meta-analysis of the effect of systemic metronidazole as an adjunct to scaling and root planing for adult periodontitis. Journal of Periodontal Research 1997;32(6):487-96.

Feng 2006

1. Feng Z, Weinberg A. Role of bacteria in health and disease of periodontal tissues. Periodontology 2000 2006;40(1):50-76.

Ferreira 2009

1. Ferreira Lopes MW, Gusmão ES, Alves R de V, Cimões R. The impact of chronic periodontitis on quality of life in Brazilian subjects. Acta Stomatologica Croatica 2009;43(2):89-98. [PMID: ]

Gamboa 2014

1. Gamboa F, Acosta A, García D-A, Velosa J, Araya N, Ledergerber R. Occurrence of porphyromonas gingivalis and its antibacterial susceptibility to metronidazole and tetracycline in patients with chronic periodontitis. Acta Odontológica Latinoamericana 2014;27(3):137-44.

Geurs 2015

1. Geurs N, Iacono V, Krayer J, Mealey B, Paquette D, Pearson B, et al. American Academy of Periodontology task force report on the update to the 1999 Classification of Periodontal Diseases and Conditions. Journal of Periodontology 2015;86(7):835-8.

Gordon 1985

1. Gordon J, Walker C, Lamster I, West T, Socransky S, Seiger M, et al. Efficacy of clindamycin hydrochloride in refractory periodontitis: 12-month results. Journal of Periodontology 1985;56(11 Suppl):75-80.

Gordon 1990

1. Gordon J, Walker C, Hovliaras C, Socransky S. Efficacy of clindamycin hydrochloride in refractory periodontitis: 24-month results. Journal of Periodontology 1990;61(11):686-91.

GRADEpro GDT [Computer program]

1. McMaster University (developed by Evidence Prime) GRADEpro GDT. Version accessed 2 February 2017. Hamilton (ON): McMaster University (developed by Evidence Prime), 2015. Available at .

Haffajee 1985

1. Haffajee AD, Socransky SS, Goodson JM, Lindhe J. Intraclass correlations of periodontal measurements. Journal of Clinical Periodontology 1985;12(3):216-24. [DOI: 10.1111/j.1600-051x.1985.tb00919.x]

Haffajee 2005

1. Haffajee AD, Socransky SS. Microbiology of periodontal diseases: introduction. Periodontology 2000 2005;38(1):9-12. [DOI: 10.1111/j.1600-0757.2005.00112.x]

Helldén 1979

1. Helldén 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.

Herrera 2008

1. Herrera D, Alonso B, León R, Roldán S, Sanz M. Antimicrobial therapy in periodontitis: the use of systemic antimicrobials against the subgingival biofilm. Journal of Clinical Periodontology 2008;35(s8):45-66. [DOI: 10.1111/j.1600-051X.2008.01260.x]

Higgins 2011

1. Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from .

How 2016

1. How KY, Song KP, Chan KG. Porphyromonas gingivalis: an overview of periodontopathic pathogen below the gum line. Frontiers in Microbiology 2016;7:53.

Jagannathan 2019

1. Jagannathan N, Acharya A, Yi FO, Li KY, Nibali L, Pelekos G. Disease severity, debridement approach and timing of drug modify outcomes of adjunctive azithromycin in non-surgical management of chronic periodontitis: a multivariate meta-analysis. BMC Oral Health 2019;19(1):65.

Japoni 2011

1. Japoni A, Vasin A, Noushadi S, Kiany F, Japoni S, Alborzi A. Antibacterial susceptibility patterns of Porphyromonas gingivalis isolated from chronic periodontitis patients. Medicina Oral, Patología Oral y Cirugía Bucal 2011;16(7):e1031-5.

Jepsen 2016

1. Jepsen K, Jepsen S. Antibiotics/antimicrobials: systemic and local administration in the therapy of mild to moderately advanced periodontitis. Periodontology 2000 2016;71(1):82-112. [DOI: 10.1111/prd.12121]

Jepsen 2018

1. Jepsen S, Caton JG, Albandar JM, Bissada NF, Bouchard P, Cortellini P, et al. Periodontal manifestations of systemic diseases and developmental and acquired conditions: consensus report of workgroup 3 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. Journal of Clinical Periodontology 2018;45(S20):S219-29. [DOI: 10.1111/jcpe.12951]

Jeske 2017

1. Jeske AH. Mosby's Dental Drug Reference. 12th edition. St. Louis (USA): Elsevier - Health Sciences Division, 2017.

Jorgensen 2000

1. Jorgensen MG, Slots J. Practical antimicrobial periodontal therapy. Compendium of Continuing Education in Dentistry 2000;21(2):111-4.

Keestra 2015

1. Keestra JA, Grosjean I, Coucke W, Quirynen M, Teughels W. Non-surgical periodontal therapy with systemic antibiotics in patients with untreated chronic periodontitis: a systematic review and meta-analysis. Journal of Periodontal Research 2015;50(3):294-314.

Keestra 2015a

1. Keestra JA, Grosjean I, Coucke W, Quirynen M, Teughels W. Non-surgical periodontal therapy with systemic antibiotics in patients with untreated aggressive periodontitis: a systematic review and meta-analysis. Journal of Periodontal Research 2015;50(6):689-706.

Kolakovic 2014

1. Kolakovic M, Held U, Schmidlin PR, Sahrmann P. An estimate of pocket closure and avoided needs of surgery after scaling and root planing with systemic antibiotics: a systematic review. BMC Oral Health 2014;14:159. [PMID: ]

Lefebvre 2020

1. Lefebvre C, Glanville J, Briscoe S, Littlewood A, Marshall C, Metzendorf M-I, et al. Technical Supplement to Chapter 4: Searching for and selecting studies. In: Higgins JPT, Thomas J, Chandler J, Cumpston MS, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions, Version 6.1 (updated September 2020). Cochrane, 2020. Available from .

Lightfoot 2005

1. Lightfoot WS, Hefti A, Mariotti A. Using a Delphi panel to survey criteria for successful periodontal therapy in anterior teeth. Journal of Periodontology 2005;76(9):1508-12. [PMID: ]

Lightfoot 2005a

1. Lightfoot WS, Hefti A, Mariotti A. Using a Delphi panel to survey criteria for successful periodontal therapy in posterior teeth. Journal of Periodontology 2005;76(9):1502-7. [PMID: ]

Lindhe 1983

1. Lindhe J, Haffajee AD, Socransky SS. Progression of periodontal disease in adult subjects in the absence of periodontal therapy. Journal of Clinical Periodontology 1983;10(4):433-42. [DOI: 10.1111/j.1600-051x.1983.tb01292.x]

López 2000

1. López NJ, Gamonal JA, Martinez B. Repeated metronidazole and amoxicillin treatment of periodontitis. A follow-up study. Journal of Periodontology 2000;71(1):79-89.

Magnusson 1984

1. Magnusson I, Lindhe J, Yoneyama T, Liljenberg B. Recolonization of a subgingival microbiota following scaling in deep pockets. Journal of Clinical Periodontology 1984;11(3):193-207. [DOI: 10.1111/j.1600-051x.1984.tb01323.x]

Marsh 2011

1. Marsh PD, Moter A, Devine DA. Dental plaque biofilms: communities, conflict and control. Periodontology 2000 2011;55(1):16-35. [DOI: 10.1111/j.1600-0757.2009.00339.x]

Matisko 1993

1. Matisko MW, Bissada NF. Short-term sequential administration of amoxicillin/clavulanate potassium and doxycycline in the treatment of recurrent/progressive periodontitis. Journal of Periodontology 1993;64(6):553-8.

MECIR 2020

1. Higgins JPT, Lasserson T, Chandler J, Tovey D, Thomas J, Flemyng E, et al. Standards for the conduct of new Cochrane Intervention Reviews. In: Higgins JPT, Lasserson T, Chandler J, Tovey D, Thomas J, Flemyng E, et al. Methodological Expectations of Cochrane Intervention Reviews. Cochrane: London, March 2020. Available from .

Mendes 2020

1. Mendes CL, Assis P de, Annibal H, Oliveira LJR de, Albuquerque MS de, Soares M de L, et al. Metronidazole and amoxicillin association in aggressive periodontitis: a systematic review and meta-analysis. Saudi Dental Journal 2020;32(6):269-75. [DOI: 10.1016/j.sdentj.2020.04.010]

Mombelli 2012a

1. Mombelli A. Antimicrobial advances in treating periodontal diseases. Frontiers of Oral Biology 2012;15:133-48.

Mombelli 2017

1. Mombelli A. Microbial colonization of the periodontal pocket and its significance for periodontal therapy. Periodontology 2000 2018;76(1):85-96. [DOI: 10.1111/prd.12147]

Moore 1994

1. Moore WE, Moore LV. The bacteria of periodontal diseases. Periodontology 2000 1994;5:66-77.

Mühlemann 1971

1. Mühlemann HR, Son S. Gingival sulcus bleeding - a leading symptom in initial gingivitis. Helvetica Odontologica Acta 1971;15(2):107-13.

Müller 1998

1. Müller HP, Heinecke A, Borneff M, Kiencke C, Knopf A, Pohl S. Eradication of Actinobacillus actinomycetemcomitans from the oral cavity in adult periodontitis. Journal of Periodontal Research 1998;33(1):49-58.

Novak 1996

1. Novak MJ, Novak KF. Early-onset periodontitis. Current Opinion in Periodontology 1996;3:45-58.

Noyan 1997

1. Noyan U, Yilmaz S, Kuru B, Kadir T, Acar O, Büget E. A clinical and microbiological evaluation of systemic and local metronidazole delivery in adult periodontitis patients. Journal of Clinical Periodontology 1997;24(3):158-65.

Oh 2018

1. Oh T-J. Adjunctive use of chlorhexidine mouthwash to non-surgical periodontal therapy may enhance periodontal pocket depth reduction. Journal of Evidence Based Dental Practice 2018;18(4):358-9. [DOI: 10.1016/j.jebdp.2018.10.004]

Oliver 1991

1. Oliver RC, Brown LJ, Loe H. Variations in the prevalence and extent of periodontitis. Journal of the American Dental Association 1991;122(6):43-8.

Papapanou 2018

1. Papapanou PN, Sanz M, Buduneli N, Dietrich T, Feres M, Fine DH, et al. Periodontitis: consensus report of workgroup 2 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. Journal of Clinical Periodontology 2018;45(S20):S162-70. [DOI: 10.1111/jcpe.12946]

Petersen 2012

1. Petersen PE, Ogawa H. The global burden of periodontal disease: towards integration with chronic disease prevention and control. Periodontology 2000 2012;60(1):15-39.

Preus 1995

1. Preus HR, Lassen J, Aass AM, Ciancio SG. Bacterial resistance following subgingival and systemic administration of minocycline. Journal of Clinical Periodontology 1995;22(5):380-4.

Purucker 2001

1. Purucker P, Mertes H, Goodson JM, Bernimoulin J-P. Local versus systemic adjunctive antibiotic therapy in 28 patients with generalized aggressive periodontitis. Journal of Periodontology 2001;72(9):1241-5.

Rabelo 2015

1. Rabelo CC, Feres M, Goncalves C, Figueiredo LC, Faveri M, Tu YK, et al. Systemic antibiotics in the treatment of aggressive periodontitis. A systematic review and a Bayesian network meta-analysis. Journal of Clinical Periodontology 2015;42(7):647-57. [PMID: ]

Renatus 2016

1. Renatus A, Herrmann J, Schonfelder A, Schwarzenberger F, Jentsch H. Clinical efficacy of azithromycin as an adjunctive therapy to non-surgical periodontal treatment of periodontitis: a systematic review and meta-analysis. Journal of Clinical and Diagnostic Research 2016;10(7):ZE01-7. [PMID: ]

Review Manager 2020 [Computer program]

1. Nordic Cochrane Centre, The Cochrane Collaboration Review Manager 5 (RevMan 5). Version 5.4. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2020.

Riep 2009

1. Riep B, Edesi-Neuss L, Claessen F, Skarabis H, Ehmke B, Flemmig TF, et al. Are putative periodontal pathogens reliable diagnostic markers? Journal of Clinical Microbiology 2009;47(6):1705-11.

Schünemann 2011

1. Schünemann HJ, Oxman AD, Vist GE, Higgins JPT, Deeks JJ, Glasziou P, et al. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from .

Slots 2002

1. Slots J, Ting M. Systemic antibiotics in the treatment of periodontal disease. Periodontology 2000 2002;28(1):106-76. [PMID: ]

Slots 2004

1. Slots J, Research, Science and Therapy Committee. Systemic antibiotics in periodontics. Journal of Periodontology 2004;75(11):1553-65.

Slots 2007

1. Slots J. Herpesviral-bacterial synergy in the pathogenesis of human periodontitis. Current Opinion in Infectious Diseases 2007;20(3):278-83.

Smiley 2015

1. Smiley CJ, Tracy SL, Abt E, Michalowicz BS, John MT, Gunsolley J, et al. Systematic review and meta-analysis on the non-surgical treatment of chronic periodontitis by means of scaling and root planing with or without adjuncts. Journal of the American Dental Association 2015;146(7):508-24.e5. [PMID: ]

Sundaram 2013

1. Sundaram NS, Narendar R, Dineshkumar P, Ramesh SB, Gokulanathan S. Evaluation of oral health related quality of life in patient with mild periodontitis among young male population of Namakkal district. Journal of Pharmacy and Bioallied Sciences 2013;5(Suppl 1):S30-2.

Teughels 2020

1. Teughels W, Feres M, Oud V, Martín C, Matesanz P, Herrera D. Adjunctive effect of systemic antimicrobials in periodontitis therapy: a systematic review and meta-analysis. Journal of Clinical Periodontology 2020;47(S22):257-81. [DOI: 10.1111/jcpe.13264]

Tonetti 1999

1. Tonetti MS, Mombelli A. Early-onset periodontitis. Annals of Periodontology 1999;4(1):39-53.

Tonetti 2018

1. Tonetti MS, Greenwell H, Kornman KS. Staging and grading of periodontitis: framework and proposal of a new classification and case definition. Journal of Clinical Periodontology 2018;45(S20):S149-61. [DOI: 10.1111/jcpe.12945]

van Winkelhoff 1989

1. Winkelhoff AJ, Rodenburg JP, Goené RJ, Abbas F, Winkel EG, Graaff J. Metronidazole plus amoxycillin in the treatment of Actinobacillus actinomycetemcomitans associated periodontitis. Journal of Clinical Periodontology 1989;16(2):128-31. [DOI: 10.1111/j.1600-051x.1989.tb01626.x]

Walter 2019

1. Walter C, Chapple ILC, Ower P, Tank M, West NX, Needleman I, et al. Periodontal diagnosis in the context of the BSP implementation plan for the 2017 classification system of periodontal diseases and conditions: presentation of a patient with severe periodontitis following successful periodontal therapy and supportive periodontal treatment. British Dental Journal 2019;226(6):411-3. [DOI: 10.1038/s41415-019-0143-8]

Yilmaz 1996

1. Yilmaz S, Kuru B, Noyan U, Kadir T, Acar O, Büget E. A clinical and microbiological evaluation of systemic and local metronidazole delivery in early onset periodontitis patients. Journal of Marmara University Dental Faculty 1996;2(2-3):500-9.

Zandbergen 2016

1. Zandbergen D, Slot DE, Niederman R, Van der Weijden FA. The concomitant administration of systemic amoxicillin and metronidazole compared to scaling and root planing alone in treating periodontitis: a systematic review. BMC Oral Health 2016;16:27. [PMID: ]

References to other published versions of this review Khattri 2017

1. Khattri S, Arora A, Sumanth KN, Prashanti E, Bhat KG, Kusum CK, et al. Adjunctive systemic antimicrobials for the non‐surgical treatment of chronic and aggressive periodontitis. Cochrane Database of Systematic Reviews 2017, Issue 2. Art. No: CD012568. [DOI: 10.1002/14651858.CD012568]

Source: PubMed

Adjunctive systemic antimicrobials for the non-surgical treatment of periodontitis

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