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

doi:10.1002/14651858.CD012568.pub2

Cochrane Database of Systematic Reviews

Adjunctive systemic antimicrobials for the non‐surgical treatment of periodontitis

Información

DOI:

https://doi.org/10.1002/14651858.CD012568.pub2 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

16 noviembre 2020see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Salud oral

Copyright:

Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Contraer

Autores

Shivi Khattri

Correspondencia a: Department of Periodontics, Subharti Dental College and Hospital, Meerut, India

[email protected]
Sumanth Kumbargere Nagraj

Department of Oral Medicine and Oral Radiology, Faculty of Dentistry, Melaka-Manipal Medical College, Manipal Academy of Higher Education (MAHE), Melaka, Malaysia
Ankita Arora

Department of Pedodontics and Preventive Dentistry, Faculty of Dentistry, Melaka-Manipal Medical College, Melaka, Malaysia
Prashanti Eachempati

Department of Prosthodontics, Faculty of Dentistry, Melaka-Manipal Medical College, Manipal Academy of Higher Education (MAHE), Melaka, Malaysia
Chandan Kumar Kusum

Department of Prosthodontics, Subharti Dental College and Hospital, Meerut, India
Kishore G Bhat

Department of Molecular Biology and Immunology, Maratha Mandal's NGH Institute of Dental Sciences and Research Centre, Belgaum, India
Trevor M Johnson

Faculty of General Dental Practice (UK), RCS England, London, UK
Giovanni Lodi

Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy

Contributions of authors

Shivi Khattri: drafting the protocol, screening the titles and abstracts, selection of studies, data extraction, entering data into Review Manager, drafting the final review, and updating the review.
Sumanth Kumbargere Nagraj: screening the titles and abstracts, statistical analysis and interpretation of results, discussion, drafting the final review, updating the review and arbiter.
Ankita Arora: drafting the protocol, screening the titles and abstracts, selection of studies and drafting the final review.
Prashanti Eachempati: screening the titles and abstracts, statistical analysis, interpretation of results, discussion and updating the review.
Chandan Kumar Kusum: data extraction and entering data into Review Manager.
Kishore G Bhat: content expert and drafting protocol.
Trevor M Johnson: drafting the final review.
Giovanni Lodi: arbiter, drafting the final review.

Sources of support

Internal sources

No sources of support supplied

External sources

National Institute for Health Research (NIHR), UK

This project was supported by the NIHR, via Cochrane Infrastructure funding to Cochrane Oral Health. The views and opinions expressed herein are those of the review authors and do not necessarily reflect those of the Evidence Synthesis Programme, the NIHR, the NHS, or the Department of Health and Social Care.
Cochrane Oral Health Global Alliance, Other

The production of Cochrane Oral Health reviews has been supported financially by our Global Alliance since 2011 (oralhealth.cochrane.org/partnerships-alliances). Contributors in the last 2 years have been the American Association of Public Health Dentistry, USA; AS‐Akademie, Germany; the British Association for the Study of Community Dentistry, UK; the British Society of Paediatric Dentistry, UK; the Canadian Dental Hygienists Association, Canada; the Centre for Dental Education and Research at All India Institute of Medical Sciences, India; the National Center for Dental Hygiene Research & Practice, USA; New York University College of Dentistry, USA; and Swiss Society of Endodontology, Switzerland.

Declarations of interest

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.

Acknowledgements

The authors thank Ms Anne Littlewood (Information Specialist), Ms Janet Lear (Administrator), and Ms Luisa Fernandez Mauleffinch (Managing Editor and Copy Editor) from Cochrane Oral Health. We thank Nicole Pitcher for her help with the preparation of the plain language summary. The authors also wish to thank Professor Dr Jaspal Singh Sahota, CE, Melaka‐Manipal Medical College and Professor Dr Abdul Rashid Haji Ismail, Dean, for supporting this work, and Professor Dr Rajesh Hosadurga and Associate Professor Dr Vijendra Pal Singh, Department of Periodontics, Faculty of Dentistry, Melaka‐Manipal Medical College for their timely suggestions. We thank Ms Shazana MS, Chief Librarian, Melaka‐Manipal Medical College, for all the help rendered during the protocol preparation.

We express gratitude to Adrien Boillot for French translations, May Wong and Dominic Ho for Chinese translations, Toru Naitu for Japanese translations, Stanislav Iakhno for Russian translations, Gemma Villanueva for Spanish translations, Kai Nitschke and Ubai Al Sharif for German translations, Maddalena Manfredi and Valeria Mercandante for Italian translations, and Dawid Storman and Malgorzata Bala for Polish translations.

We also thank peer reviewers Helen Worthington, Thomas Lamont, Ian Needleman, Philip Riley, Jennifer Hilgart, Roos Leroy (senior researcher at the Belgian Health Care Knowledge Centre (KCE)), Professor Kevin Seymour (The University of Manchester), and Pia‐Merete Jervøe‐Storm (University of Bonn), for their helpful feedback.

Version history

Published

Title

Stage

Authors

Version

2020 Nov 16

Adjunctive systemic antimicrobials for the non‐surgical treatment of periodontitis

Review

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

https://doi.org/10.1002/14651858.CD012568.pub2

2017 Feb 23

Adjunctive systemic antimicrobials for the non‐surgical treatment of chronic and aggressive periodontitis

Protocol

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

https://doi.org/10.1002/14651858.CD012568

Differences between protocol and review

We intended to use change scores for probing pocket depth and clinical attachment level analysis. However, the majority of the included trials did not report change scores and thus we used end scores for the analysis.
We planned to combine groups to create a single pairwise comparison in any trial with multiple treatment groups. However, none of the trials had similar groups to combine.
We performed subgroup analyses based on participant smoking status and severity of disease (chronic and aggressive periodontitis). We intended to use other factors like age, socioeconomic status, and oral hygiene practices but we could not get such data to perform subgroup analyses.
We intended not to perform meta‐analysis, if the heterogeneity was considerable. However, we performed the meta‐analysis in such cases and downgraded the certainty of the evidence by an additional one level in GRADE.
Instead of creating 'Summary of findings' tables for each comparison included in the review, we assessed the certainty of the evidence for those comparisons which reported long‐term follow‐up (≥1 year).

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Adult; Humans;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Etiopathogenesis of periodontal disease.

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Figure 2

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

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Figure 3

Study flow diagram.

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Figure 4

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

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Figure 5

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

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Analysis 1.1

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

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Analysis 1.2

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

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Analysis 1.3

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

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Analysis 1.4

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

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Analysis 1.5

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

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Analysis 1.6

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

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Analysis 1.7

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

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Analysis 1.8

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

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Analysis 1.9

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

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Analysis 1.10

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

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Analysis 1.11

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

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Analysis 1.12

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

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Analysis 2.1

Comparison 2: MTZ + SRP versus SRP, Outcome 1: Percentage of closed pockets ‐ short‐term (≤ 3 months) improvement in chronic periodontitis

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Analysis 2.2

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

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Analysis 2.3

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

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Analysis 2.4

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

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Analysis 2.5

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

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Analysis 2.6

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

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Analysis 2.7

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

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Analysis 2.8

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

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Analysis 2.9

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

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Analysis 2.10

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

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Analysis 2.11

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

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Analysis 2.12

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

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Analysis 3.1

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

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Analysis 3.2

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

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Analysis 3.3

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

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Analysis 3.4

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

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Analysis 3.5

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

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Analysis 3.6

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

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Analysis 3.7

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

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Analysis 3.8

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

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Analysis 3.9

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

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Analysis 3.10

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

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Analysis 3.11

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

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Analysis 4.1

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

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Analysis 4.2

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

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Analysis 4.3

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

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Analysis 4.4

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

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Analysis 4.5

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

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Analysis 4.6

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

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Analysis 4.7

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

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Analysis 4.8

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

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Analysis 4.9

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

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Analysis 5.1

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

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Analysis 5.2

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

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Analysis 5.3

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

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Analysis 5.4

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

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Analysis 5.5

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

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Analysis 5.6

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

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Analysis 5.7

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

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Analysis 5.8

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

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Analysis 6.1

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

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Analysis 6.2

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

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Analysis 6.3

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

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Analysis 6.4

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

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Analysis 6.5

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

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Analysis 7.1

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

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Analysis 7.2

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

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Analysis 7.3

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

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Analysis 7.4

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

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Analysis 7.5

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

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Analysis 7.6

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

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Analysis 8.1

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

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Analysis 8.2

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

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Analysis 8.3

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

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Analysis 8.4

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

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Analysis 8.5

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

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Analysis 8.6

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

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Analysis 9.1

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

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Analysis 9.2

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

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Analysis 9.3

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

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Analysis 9.4

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

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Analysis 9.5

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

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Analysis 9.6

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

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Analysis 10.1

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

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Analysis 10.2

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

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Analysis 10.3

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

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Analysis 10.4

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

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Analysis 10.5

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

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Analysis 10.6

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

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Analysis 11.1

Comparison 11: Cefixime + SRP versus SRP in chronic periodontitis, Outcome 1: CAL ‐ short‐term (≤ 3 months) improvement

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Analysis 11.2

Comparison 11: Cefixime + SRP versus SRP in chronic periodontitis, Outcome 2: Pocket depth ‐ short‐term (≤ 3 months) improvement

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Analysis 11.3

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

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Analysis 12.1

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

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Analysis 12.2

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

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Analysis 12.3

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

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Analysis 12.4

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

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Analysis 12.5

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

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Analysis 12.6

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

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Analysis 13.1

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

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Analysis 13.2

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

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Analysis 13.3

Comparison 13: Doxycycline + SRP versus AMOX + MTZ + SRP in aggressive periodontitis, Outcome 3: Pocket depth ‐ short‐term (≤ 3 months) improvement

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Analysis 13.4

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

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Analysis 14.1

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

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Analysis 14.2

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

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Analysis 14.3

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

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Analysis 14.4

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

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Analysis 14.5

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

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Analysis 14.6

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

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Analysis 14.7

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

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Analysis 14.8

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

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Analysis 15.1

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

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Analysis 15.2

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

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Analysis 15.3

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

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Analysis 15.4

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

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Analysis 15.5

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

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Analysis 15.6

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

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Analysis 16.1

Comparison 16: AMOX + CLAV + SRP versus tetracycline + SRP in aggressive periodontitis, Outcome 1: Pocket depth ‐ intermediate‐term (> 3 months) improvement

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Analysis 16.2

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

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Analysis 17.1

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

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Analysis 17.2

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

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Analysis 17.3

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

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Analysis 17.4

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

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Analysis 17.5

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

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Analysis 17.6

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

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Analysis 18.1

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

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Analysis 18.2

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

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Analysis 18.3

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

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Analysis 18.4

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

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Analysis 18.5

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

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Analysis 18.6

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

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Summary of findings 1. Amoxicillin + metronidazole + SRP compared to SRP for the non‐surgical treatment of periodontitis

Amoxicillin + metronidazole + SRP compared to SRP for the non‐surgical treatment of periodontitis
Patient or population: adults with periodontitis (chronic/aggressive) Setting: outpatient Intervention: amoxicillin + metronidazole + SRP Comparison: SRP Follow‐up: ≥1 year
Outcomes	Number of participants (studies)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**		Certainty of the evidence (GRADE)	Comments
Outcomes	Number of participants (studies)	Relative effect (95% CI)	Risk with control (SRP)	Risk difference with amoxicillin + metronidazole + SRP	Certainty of the evidence (GRADE)	Comments
Percentage of closed pockets (Long‐term improvement in chronic periodontitis)	44 (1 RCT^a)	‐	The mean percentage of closed pockets was 49.30%	MD 16.20% lower (25.87 lower to 6.53 lower)	⊕⊝⊝⊝ VERY LOW^c,d	Based on our definition of minimally important clinical difference (MICD)^f, only the results for percentage of closed pockets and of BOP showed an MICD favouring amoxicillin + metronidazole + SRP
CAL (Long‐term improvement in chronic and aggressive periodontitis) Assessed with: periodontal probe in mm	389 (2 RCTs^a,b)	‐	The mean CAL was 3.85 mm	MD 0.47 mm lower (0.90 lower to 0.05 lower )	⊕⊝⊝⊝ VERY LOW^d,e
Probing pocket depth (Long‐term improvement in chronic and aggressive periodontitis) Assessed with: periodontal probe in mm	389 (2 RCTs^a,b)	‐	The mean probing pocket depth was 2.75 mm	MD 0.30 mm lower (0.42 lower to 0.18 lower )	⊕⊝⊝⊝ VERY LOW^d,e
Percentage of BOP (Long‐term improvement in chronic and aggressive periodontitis) Assessed with: periodontal probe	389 (2 RCTs^a,b)	‐	The mean percentage of BOP was 29.45%	MD 8.06% lower (14.26 lower to 1.85 lower)	⊕⊝⊝⊝ VERY LOW^d,e
Antimicrobial resistance	Included studies have not reported this outcome
Adverse events	389 (2 RCTs^a,b)	Most common adverse events were mild gastrointestinal disturbances, nausea and vomiting, metallic taste, and diarrhoea in the intervention group. Control group reported adverse events like hypothermia, mild gastrointestinal symptoms, diarrhoea, vomiting, cramps, rashes, and weakness. Nausea after alcohol intake was reported in 1 participant from the intervention group			⊕⊝⊝⊝ VERY LOW^d,e
Patient‐reported quality of life changes	Included studies have not reported this outcome
^*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) BOP: bleeding on probing; CAL: clinical attachment level; CI: confidence interval; MD: mean difference; MICD: minimally important clinical difference; RCT: randomized controlled trial; SRP: scaling and root planing
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^aBorges 2017. ^bHarks 2015. ^cDowngraded by 1 level due to unclear risk of bias. ^dDowngraded by 2 levels due to imprecision. ^eDowngraded by 2 levels due to risk of bias as studies showed unclear or high risk of bias. ^fWe decided to use an MD of 1 mm as the MICD for CAL and probing pocket depth, and 5% for percentage of closed pockets and percentage of BOP, and respective 95% CI not to cross the line of no effect.

Summary of findings 1. Amoxicillin + metronidazole + SRP compared to SRP for the non‐surgical treatment of periodontitis

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Summary of findings 2. Metronidazole + SRP compared to SRP for the non‐surgical treatment of periodontitis

Metronidazole + SRP compared to SRP for the non‐surgical treatment of periodontitis
Patient or population: adults with periodontitis (chronic/aggressive) Setting: outpatient Intervention: metronidazole + SRP Comparison: SRP Follow‐up: ≥1 year
Outcomes	Number of participants (studies)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**		Certainty of the evidence (GRADE)	Comments
Outcomes	Number of participants (studies)	Relative effect (95% CI)	Risk with control (SRP)	Risk difference with metronidazole + SRP	Certainty of the evidence (GRADE)	Comments
Percentage of closed pockets (Long‐term improvement in chronic periodontitis)	22 (1 RCT^a)	‐	The mean percentage of closed pockets was 52.80%	MD 12.20% lower (29.23 lower to 4.83 higher)	⊕⊝⊝⊝ VERY LOW^d,e	Based on our definition of minimally important clinical difference (MICD)^h, only the results for CAL and probing pocket depth showed an MICD favouring metronidazole + SRP
CAL (Long‐term improvement in chronic and aggressive periodontitis) Assessed with: periodontal probe in mm	71 (3 RCTs^a,b,c)	‐	‐	MD 1.12 mm lower (2.24 lower to 0)	⊕⊝⊝⊝ VERY LOW^e,f,g
Probing pocket depth (Long‐term improvement in aggressive periodontitis) Assessed with: periodontal probe in mm	47 (2 RCTs^a,c)	‐	The mean probing pocket depth was 4.11 mm	MD 1.11 mm lower (2.84 lower to 0.61 higher)	⊕⊝⊝⊝ VERY LOW^d,e,g
Percentage of BOP (Long‐term improvement in chronic periodontitis) Assessed with: periodontal probe	22 (1 RCT^a)	‐	The mean percentage of BOP was 44.92%	MD 6.90% lower (22.10 lower to 8.30 higher)	⊕⊝⊝⊝ VERY LOW^d,e,g
Antimicrobial resistance	Included studies have not reported this outcome
Adverse events	71 (3 RCTs^a,b,c)	No severe adverse effects were reported by any of the participants in 1 study. 2 studies have not reported adverse events			⊕⊝⊝⊝ VERY LOW^e,f
Patient‐reported quality of life changes	Included studies have not reported this outcome
^*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) BOP: bleeding on probing; CAL: clinical attachment level; CI: confidence interval; MD: mean difference; MICD: minimally important clinical difference; RCT: randomized controlled trial; SRP: scaling and root planing
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^aCarvalho 2004. ^bSigusch 2000. ^cSigusch 2001. ^dDowngraded by 1 level due to unclear risk of bias. ^eDowngraded by 2 levels due to imprecision. ^fDowngraded by 2 levels due to risk of bias as studies showed unclear or high risk of bias. ^gDowngraded by 1 level for inconsistency. ^hWe decided to use an MD of 1 mm as the MICD for CAL and probing pocket depth, and 5% for percentage of closed pockets and percentage of BOP, and respective 95% CI not to cross the line of no effect.

Summary of findings 2. Metronidazole + SRP compared to SRP for the non‐surgical treatment of periodontitis

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Summary of findings 3. Azithromycin + SRP compared to SRP for the non‐surgical treatment of periodontitis

Azithromycin + SRP compared to SRP for the non‐surgical treatment of periodontitis
Patient or population: adults with periodontitis (chronic/aggressive) Setting: outpatient Intervention: azithromycin + SRP Comparison: SRP Follow‐up: ≥1 year
Outcomes	Number of participants (studies)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**		Certainty of the evidence (GRADE)	Comments
Outcomes	Number of participants (studies)	Relative effect (95% CI)	Risk with control (SRP)	Risk difference with azithromycin + SRP	Certainty of the evidence (GRADE)	Comments
Percentage of closed pockets (Long‐term improvement in chronic periodontitis)	40 (1 RCT^a)	‐	The mean percentage of closed pockets was 51.50%	MD 2.50% higher (10.19 lower to 15.19 higher)	⊕⊝⊝⊝ VERY LOW^c,d,e	Based on our definition of minimally important clinical difference (MICD)^g, we found no evidence of a difference between intervention and control
CAL (Long‐term improvement in chronic and aggressive periodontitis) Assessed with: periodontal probe in mm	110 (2 RCTs^a,b)	‐	The mean CAL was 5.30 mm	MD 0.59 mm lower (1.27 lower to 0.08 higher)	⊕⊝⊝⊝ VERY LOW^c,e,f
Probing pocket depth (Long‐term improvement in chronic and aggressive periodontitis) Assessed with: periodontal probe in mm	110 (2 RCTs^a,b)	‐	The mean probing pocket depth was 4.29 mm	MD 0.77 mm lower (2.33 lower to 0.79 higher)	⊕⊝⊝⊝ VERY LOW^c,e,f
Percentage of BOP (Long‐term improvement in chronic and aggressive periodontitis) Assessed with: periodontal probe	110 (2 RCTs^a,b)	‐	The mean percentage of BOP was 16.96%	MD 1.28% lower (4.32 lower to 1.76 higher)	⊕⊝⊝⊝ VERY LOW^c,d,e
Antimicrobial resistance	Included studies have not reported this outcome
Adverse events	110 (2 RCTs^a,b)	1 study reported diarrhoea, headache or dizziness, metallic taste, and general unwellness by 4 participants from the intervention group and 3 from the control group. In 1 study none of the participants reported any adverse effects			⊕⊝⊝⊝ VERY LOW^c,e
Patient‐reported quality of life changes	Included studies have not reported this outcome
^*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) BOP: bleeding on probing; CAL: clinical attachment level; CI: confidence interval; MD: mean difference; MICD: minimally important clinical difference; RCT: randomized controlled trial; SRP: scaling and root planing
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^aSampaio 2011. ^bMartande 2016. ^cDowngraded by 1 level due to unclear risk of bias. ^dDowngraded by 1 level due to inconsistency. ^eDowngraded by 2 levels due to imprecision. ^fDowngraded by 2 levels due to inconsistency. ^gWe decided to use an MD of 1 mm as the MICD for CAL and probing pocket depth, and 5% for percentage of closed pockets and percentage of BOP, and respective 95% CI not to cross the line of no effect.

Summary of findings 3. Azithromycin + SRP compared to SRP for the non‐surgical treatment of periodontitis

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Summary of findings 4. Amoxicillin + clavulanate + SRP compared to SRP for the non‐surgical treatment of periodontitis

Amoxicillin + clavulanate + SRP compared to SRP for the non‐surgical treatment of periodontitis
Patient or population: adults with periodontitis (chronic) Setting: outpatient Intervention: amoxicillin + clavulanate + SRP Comparison: SRP Follow‐up: ≥1 year
Outcomes	Number of participants (studies)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**		Certainty of the evidence (GRADE)	Comments
Outcomes	Number of participants (studies)	Relative effect (95% CI)	Risk with control (SRP)	Risk difference with amoxicillin + clavulanate + SRP	Certainty of the evidence (GRADE)	Comments
Percentage of closed pockets	Included study has not reported this outcome					Based on our definition of minimally important clinical difference (MICD)^d, we found no evidence of a difference between intervention and control
CAL (Long‐term improvement in chronic periodontitis) Assessed with: periodontal probe in mm	21 (1 RCT^a)	‐	The mean CAL was 6.80 mm	MD 0.10 mm higher (0.51 lower to 0.71 higher)	⊕⊝⊝⊝ VERY LOW^b,c
Probing pocket depth (Long‐term improvement in chronic periodontitis) Assessed with: periodontal probe in mm	21 (1 RCT^a)	‐	The mean probing pocket depth was 2.80 mm	MD 0.10 mm higher (0.17 lower to 0.37 higher)	⊕⊝⊝⊝ VERY LOW^b,c
Percentage of BOP (Long‐term improvement in chronic periodontitis) Assessed with: periodontal probe	21 (1 RCT^a)	‐	The mean percentage of BOP was 0.20%	MD 0% (0.09 lower to 0.09 higher)	⊕⊝⊝⊝ VERY LOW^b,c
Antimicrobial resistance	Included study has not reported this outcome
Adverse events	21 (1 RCT^a)	Included study reported diarrhoea in 2 participants from both groups			⊕⊝⊝⊝ VERY LOW^b,c
Patient‐reported quality of life changes	Included study has not reported this outcome
^*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) BOP: bleeding on probing; CAL: clinical attachment level; CI: confidence interval; MD: mean difference; MICD: minimally important clinical difference; RCT: randomized controlled trial; SRP: scaling and root planing
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^aWinkel 1999. ^bDowngraded by 1 level due to unclear risk of bias. ^cDowngraded by 2 levels due to imprecision (single study with limited number of participants). ^dWe decided to use an MD of 1 mm as the MICD for CAL and probing pocket depth, and 5% for percentage of closed pockets and percentage of BOP, and respective 95% CI not to cross the line of no effect.

Summary of findings 4. Amoxicillin + clavulanate + SRP compared to SRP for the non‐surgical treatment of periodontitis

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Summary of findings 5. Doxycycline + SRP compared to SRP for the non‐surgical treatment of periodontitis

Doxycycline + SRP compared to SRP for the non‐surgical treatment of periodontitis
Patient or population: adults with periodontitis (aggressive) Setting: outpatient Intervention: doxycycline + SRP Comparison: SRP Follow‐up: ≥1 year
Outcomes	Number of participants (studies)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**		Certainty of the evidence (GRADE)	Comments
Outcomes	Number of participants (studies)	Relative effect (95% CI)	Risk with control (SRP)	Risk difference with doxycycline + SRP	Certainty of the evidence (GRADE)	Comments
Percentage of closed pockets	Included study has not reported this outcome					Based on our definition of minimally important clinical difference (MICD)^d, only the results for probing pocket depth showed an MICD favouring doxycycline + SRP
CAL (Long‐term improvement in aggressive periodontitis) Assessed with: periodontal probe in mm	22 (1 RCT^a)	‐	The mean CAL was 5.90 mm	MD 0.80 mm lower (1.49 lower to 0.11 lower)	⊕⊝⊝⊝ VERY LOW^b,c
Probing pocket depth (Long‐term improvement in aggressive periodontitis) Assessed with: periodontal probe in mm	22 (1 RCT^a)	‐	The mean probing pocket depth was 5.20 mm	MD 1 mm lower (1.78 lower to 0.22 lower)	⊕⊝⊝⊝ VERY LOW^b,c
Percentage of BOP	Included study has not reported this outcome
Antimicrobial resistance	Included study has not reported this outcome
Adverse events	Included study has not reported adverse events
Patient‐reported quality of life changes	Included study has not reported this outcome
^*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) BOP: bleeding on probing; CAL: clinical attachment level; CI: confidence interval; MD: mean difference; MICD: minimally important clinical difference; RCT: randomized controlled trial; SRP: scaling and root planing
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^aSigusch 2001. ^bDowngraded by 1 level due to unclear risk of bias. ^cDowngraded by 2 levels due to imprecision (single study with limited number of participants). ^dWe decided to use an MD of 1 mm as the MICD for CAL and probing pocket depth, and 5% for percentage of closed pockets and percentage of BOP, and respective 95% CI not to cross the line of no effect.

Summary of findings 5. Doxycycline + SRP compared to SRP for the non‐surgical treatment of periodontitis

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Summary of findings 6. Tetracycline + SRP compared to SRP for the non‐surgical treatment of periodontitis

Tetracycline + SRP compared to SRP for the non‐surgical treatment of periodontitis
Patient or population: adults with periodontitis (aggressive) Setting: outpatient Intervention: tetracycline + SRP Comparison: SRP Follow‐up: ≥1 year
Outcomes	Number of participants (studies)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**		Certainty of the evidence (GRADE)	Comments
Outcomes	Number of participants (studies)	Relative effect (95% CI)	Risk with control (SRP)	Risk difference with tetracycline + SRP	Certainty of the evidence (GRADE)	Comments
Percentage of closed pockets	Included study has not reported this outcome					Based on our definition of minimally important clinical difference (MICD)^d, the results for CAL showed an MICD favouring tetracycline + SRP
CAL (Long‐term improvement in aggressive periodontitis) Assessed with: periodontal probe in mm	26 (1 RCT^a)	‐	The mean CAL was 4.40 mm	MD 2.30 mm lower (2.50 lower to 2.10 lower)	⊕⊝⊝⊝ VERY LOW^b,c
Probing pocket depth	Included study has not reported this outcome
Percentage of BOP	Included study has not reported this outcome
Antimicrobial resistance	Included study has not reported this outcome
Adverse events	Included study has not reported adverse events
Patient‐reported quality of life changes	Included study has not reported this outcome
^*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) BOP: bleeding on probing; CAL: clinical attachment level; CI: confidence interval; MD: mean difference; MICD: minimally important clinical difference; RCT: randomized controlled trial; SRP: scaling and root planing
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^aZhang 2006. ^bDowngraded by 1 level due to unclear risk of bias. ^cDowngraded by 2 levels due to imprecision (single study with limited number of participants). ^dWe decided to use an MD of 1 mm as the MICD for CAL and probing pocket depth, and 5% for percentage of closed pockets and percentage of BOP, and respective 95% CI not to cross the line of no effect.

Summary of findings 6. Tetracycline + SRP compared to SRP for the non‐surgical treatment of periodontitis

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Summary of findings 7. Clindamycin + SRP compared to SRP for the non‐surgical treatment of periodontitis

Clindamycin + SRP compared to SRP for the non‐surgical treatment of periodontitis
Patient or population: adults with periodontitis (aggressive) Setting: outpatient Intervention: clindamycin + SRP Comparison: SRP Follow‐up: ≥1 year
Outcomes	Number of participants (studies)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**		Certainty of the evidence (GRADE)	Comments
Outcomes	Number of participants (studies)	Relative effect (95% CI)	Risk with control (SRP)	Risk difference with clindamycin + SRP	Certainty of the evidence (GRADE)	Comments
Percentage of closed pockets	Included study has not reported this outcome					Based on our definition of minimally important clinical difference (MICD)^d, the results for CAL and probing pocket depth showed an MICD favouring clindamycin + SRP
CAL (Long‐term improvement in aggressive periodontitis) Assessed with: periodontal probe in mm	21 (1 RCT^a)	‐	The mean CAL was 5.90 mm	MD 1.70 mm lower (2.40 lower to 1.00 lower)	⊕⊝⊝⊝ VERY LOW^b,c
Probing pocket depth (Long‐term improvement in aggressive periodontitis) Assessed with: periodontal probe in mm	21 (1 RCT^a)	‐	The mean probing pocket depth was 5.20 mm	MD 1.80 mm lower (2.47 lower to 1.13 lower)	⊕⊝⊝⊝ VERY LOW^b,c
Percentage of BOP	Included study has not reported this outcome
Antimicrobial resistance	Included study has not reported this outcome
Adverse events	Included study has not reported adverse events
Patient‐reported quality of life changes	Included study has not reported this outcome
^*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) BOP: bleeding on probing; CAL: clinical attachment level; CI: confidence interval; MD: mean difference; MICD: minimally important clinical difference; RCT: randomized controlled trial; SRP: scaling and root planing
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^aSigusch 2001. ^bDowngraded by 1 level due to unclear risk of bias. ^cDowngraded by 2 levels due to imprecision (single study with limited number of participants). ^dWe decided to use an MD of 1 mm as the MICD for CAL and probing pocket depth, and 5% for percentage of closed pockets and percentage of BOP, and respective 95% CI not to cross the line of no effect.

Summary of findings 7. Clindamycin + SRP compared to SRP for the non‐surgical treatment of periodontitis

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Summary of findings 8. Doxycycline + SRP compared to metronidazole + SRP for the non‐surgical treatment of periodontitis

Doxycycline + SRP compared to metronidazole + SRP for the non‐surgical treatment of periodontitis
Patient or population: adults with periodontitis (aggressive) Setting: outpatient Intervention: doxycycline + SRP Comparison: metronidazole + SRP Follow‐up: ≥1 year
Outcomes	Number of participants (studies)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**		Certainty of the evidence (GRADE)	Comments
Outcomes	Number of participants (studies)	Relative effect (95% CI)	Risk with metronidazole + SRP	Risk difference with doxycycline + SRP	Certainty of the evidence (GRADE)	Comments
Percentage of closed pockets	Included study has not reported this outcome					Based on our definition of minimally important clinical difference (MICD)^d, the results for CAL and probing pocket depth showed an MICD favouring metronidazole + SRP
CAL (Long‐term improvement in aggressive periodontitis) Assessed with: periodontal probe in mm	27 (1 RCT^a)	‐	The mean CAL was 4 mm	MD 1.10 mm higher (0.36 higher to 1.84 higher)	⊕⊝⊝⊝ VERY LOW^b,c
Probing pocket depth (Long‐term improvement in aggressive periodontitis) Assessed with: periodontal probe in mm	27 (1 RCT^a)	‐	The mean probing pocket depth was 3.20 mm	MD 1 mm higher (0.30 higher to 1.70 higher)	⊕⊝⊝⊝ VERY LOW^b,c
Percentage of BOP	Included study has not reported this outcome
Antimicrobial resistance	Included study has not reported this outcome
Adverse events	Included study has not reported adverse events
Patient‐reported quality of life changes	Included study has not reported this outcome
^*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) BOP: bleeding on probing; CAL: clinical attachment level; CI: confidence interval; MD: mean difference; MICD: minimally important clinical difference; RCT: randomized controlled trial; SRP: scaling and root planing
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^aSigusch 2001. ^bDowngraded by 1 level due to unclear risk of bias. ^cDowngraded by 2 levels due to imprecision (single study with limited number of participants). ^dWe decided to use an MD of 1 mm as the MICD for CAL and probing pocket depth, and 5% for percentage of closed pockets and percentage of BOP, and respective 95% CI not to cross the line of no effect.

Summary of findings 8. Doxycycline + SRP compared to metronidazole + SRP for the non‐surgical treatment of periodontitis

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Summary of findings 9. Clindamycin + SRP compared to metronidazole + SRP for the non‐surgical treatment of periodontitis

Clindamycin + SRP compared to metronidazole + SRP for the non‐surgical treatment of periodontitis
Patient or population: adults with periodontitis (aggressive) Setting: outpatient Intervention: clindamycin + SRP Comparison: metronidazole + SRP Follow‐up: ≥1 year
Outcomes	Number of participants (studies)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**		Certainty of the evidence (GRADE)	Comments
Outcomes	Number of participants (studies)	Relative effect (95% CI)	Risk with metronidazole + SRP	Risk difference with clindamycin + SRP	Certainty of the evidence (GRADE)	Comments
Percentage of closed pockets	Included study has not reported this outcome					Based on our definition of minimally important clinical difference (MICD)^d, we found no evidence of a difference between the groups
CAL (Long‐term improvement in aggressive periodontitis) Assessed with: periodontal probe in mm	26 (1 RCT^a)	‐	The mean CAL was 4 mm	MD 0.20 mm higher (0.55 lower to 0.95 higher)	⊕⊝⊝⊝ VERY LOW^b,c
Probing pocket depth (Long‐term improvement in aggressive periodontitis) Assessed with: periodontal probe in mm	26 (1 RCT^a)	‐	The mean probing pocket depth was 3.20 mm	MD 0.20 mm higher (0.38 lower to 0.78 higher)	⊕⊝⊝⊝ VERY LOW^b,c
Percentage of BOP	Included study has not reported this outcome
Antimicrobial resistance	Included study has not reported this outcome
Adverse events	Included study has not reported adverse events
Patient‐reported quality of life changes	Included study has not reported this outcome
^*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) BOP: bleeding on probing; CAL: clinical attachment level; CI: confidence interval; MD: mean difference; MICD: minimally important clinical difference; RCT: randomized controlled trial; SRP: scaling and root planing
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^aSigusch 2001. ^bDowngraded by 1 level due to unclear risk of bias. ^cDowngraded by 2 levels due to imprecision (single study with limited number of participants). ^dWe decided to use an MD of 1 mm as the MICD for CAL and probing pocket depth, and 5% for percentage of closed pockets and percentage of BOP, and respective 95% CI not to cross the line of no effect.

Summary of findings 9. Clindamycin + SRP compared to metronidazole + SRP for the non‐surgical treatment of periodontitis

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Summary of findings 10. Clindamycin + SRP compared to doxycycline + SRP for the non‐surgical treatment of periodontitis

Clindamycin + SRP compared to doxycycline + SRP for the non‐surgical treatment of periodontitis
Patient or population: adults with periodontitis (aggressive) Setting: outpatient Intervention: clindamycin + SRP Comparison: doxycycline + SRP Follow‐up: ≥1 year
Outcomes	Number of participants (studies)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**		Certainty of the evidence (GRADE)	Comments
Outcomes	Number of participants (studies)	Relative effect (95% CI)	Risk with doxycycline + SRP	Risk difference with clindamycin + SRP	Certainty of the evidence (GRADE)	Comments
Percentage of closed pockets	Included study has not reported this outcome					Based on our definition of minimally important clinical difference (MICD)^d, we found no evidence of a difference between the groups
CAL (Long‐term improvement in aggressive periodontitis) Assessed with: periodontal probe in mm	23 (1 RCT^a)	‐	The mean CAL was 5.10 mm	MD 0.90 mm lower (1.62 lower to 0.18 lower)	⊕⊝⊝⊝ VERY LOW^b,c
Probing pocket depth (Long‐term improvement in aggressive periodontitis) Assessed with: periodontal probe in mm	23 (1 RCT^a)	‐	The mean probing pocket depth was 4.20 mm	MD 0.80 mm lower (1.58 lower to 0.02 lower)	⊕⊝⊝⊝ VERY LOW^b,c
Percentage of BOP	Included study has not reported this outcome
Antimicrobial resistance	Included study has not reported this outcome
Adverse events	Included study has not reported adverse events
Patient‐reported quality of life changes	Included study has not reported this outcome
^*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) BOP: bleeding on probing; CAL: clinical attachment level; CI: confidence interval; MD: mean difference; MICD: minimally important clinical difference; RCT: randomized controlled trial; SRP: scaling and root planing
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^aSigusch 2001. ^bDowngraded by 1 level due to unclear risk of bias. ^cDowngraded by 2 levels due to imprecision (single study with limited number of participants). ^dWe decided to use an MD of 1 mm as the MICD for CAL and probing pocket depth, and 5% for percentage of closed pockets and percentage of BOP, and respective 95% CI not to cross the line of no effect.

Summary of findings 10. Clindamycin + SRP compared to doxycycline + SRP for the non‐surgical treatment of periodontitis

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Table 1. Characteristics of interventions

Serial number	Antibiotic prescribed	Type of periodontitis	Included studies
1.	AMOX + MTZ	Chronic periodontitis	Boia 2019; Borges 2017; Cosgarea 2016; Dukic 2016; Liaw 2019; Li 2015; Matarazzo 2008; Moeintaghavi 2007; Mombelli 2013; Ribeiro 2009; Silva 2011; Winkel 2001
		Aggressive periodontitis	Casarin 2012; Lu 2012; Taiete 2016; Xajigeorgiou 2006; Yek 2010
		Both chronic and aggressive periodontitis	Harks 2015
2.	MTZ	Chronic periodontitis	Carvalho 2004; D'avila 2005; Loesche 1991; Matarazzo 2008; Sigusch 2000; Silva 2011
2.	MTZ	Aggressive periodontitis	Sigusch 2001; Xajigeorgiou 2006
3.	AZT	Chronic periodontitis	Gomi 2007; Han 2012; Liaw 2019; Martande 2016; Mascarenhas 2005; Sampaio 2011; Smith 2002
3.	AZT	Aggressive periodontitis	Emingil 2012; Haas 2008
4.	AMOX + CLAV	Chronic periodontitis	Winkel 1999
4.	AMOX + CLAV versus tetracycline	Aggressive periodontitis	Abu Fanas 1991
5.	Minocycline	Chronic periodontitis	Basegmez 2011
6.	Spiramycin	Chronic periodontitis	Chin Quee 1988
7.	Tetracycline	Aggressive periodontitis	Palmer 1996
8.	Cefixime	Chronic periodontitis	Dukic 2016
9 .	Doxycycline	Aggressive periodontitis	Sigusch 2000; Sigusch 2001; Xajigeorgiou 2006
10.	Clindamycin	Aggressive periodontitis	Sigusch 2001
11.	MTZ versus AMOX + MTZ	Both chronic and aggressive periodontitis	Matarazzo 2008; Silva 2011; Xajigeorgiou 2006
12.	Doxycycline versus AMOX + MTZ	Aggressive periodontitis	Akincibay 2008; Xajigeorgiou 2006
13.	Doxycycline versus MTZ	Aggressive periodontitis	Sigusch 2000; Sigusch 2001; Xajigeorgiou 2006
14.	Moxifloxacin	Aggressive periodontitis	Ardila 2015
15.	Levofloxacin	Chronic periodontitis	Pradeep 2014; Pradeep 2015
16.	Doxycycline versus clindamycin	Aggressive periodontitis	Sigusch 2001
17.	Clarithromycin	Both chronic and aggressive periodontitis	Pradeep 2011; Rebelatto 2017
18.	Clindamycin versus MTZ	Aggressive periodontitis	Sigusch 2001
19.	AMOX+MTZ versus clarithromycin	Aggressive periodontitis	Araujo 2019
AMOX = amoxicillin; AZT = azithromycin; CLAV = clavulanate; MTZ = metronidazole.

Table 1. Characteristics of interventions

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Table 2. Dosing regimens of antibiotics

Serial number	Dosage	Number of days	Included studies
1. AMOX + MTZ
i.	500 mg AMOX and 500 mg MTZ	3	Boia 2019
ii.	500 mg AMOX and 500 mg MTZ	4	Cosgarea 2016
iii.	500 mg AMOX and 500 mg MTZ	7	Boia 2019; Cosgarea 2016; Xajigeorgiou 2006; Yek 2010
iv.	500 mg AMOX and 400 mg MTZ	7	Araujo 2019; Borges 2017; Dukic 2016; Harks 2015; Liaw 2019
v.	375 mg AMOX and 500 mg MTZ	7	Casarin 2012; Mombelli 2013
vi.	375 mg AMOX and 250 mg MTZ	7	Ribeiro 2009; Taiete 2016; Winkel 2001
vii.	500 mg AMOX and 200 mg MTZ	7	Li 2015; Lu 2012
viii.	500 mg AMOX and 250 mg MTZ	7	Borges 2017
ix.	500 mg AMOX and 400 mg MTZ	14	Borges 2017; Matarazzo 2008; Silva 2011
x.	500 mg AMOX and 250 mg MTZ	14	Borges 2017
2. MTZ alone
i.	500 mg thrice/day	7	Xajigeorgiou 2006
ii.	500 mg twice/day	8	Sigusch 2000; Sigusch 2001
iii.	400 mg thrice/day	10	Carvalho 2004
iv.	thrice/day	14	Matarazzo 2008; Silva 2011
3. AZT
i.	500 mg once/day	3	Emingil 2012; Gomi 2007; Haas 2008; Han 2012; Liaw 2019; Martande 2016
ii.	500 mg once/day	5	Sampaio 2011
iii.	250 mg	Double stat first day followed by once/day for next 4 days	Mascarenhas 2005
4. AMOX + CLAV
i.	625 mg thrice/day	10 days	Abu Fanas 1991; Winkel 1999
5. Doxycycline
i.	200 mg/day	8	Sigusch 2000; Sigusch 2001
ii.	200 mg 100 mg/day	On first day 14	Xajigeorgiou 2006
6. Tetracycline
i.	250 mg 4 times/day	14	Abu Fanas 1991; Palmer 1996
ii.	500 mg/day	Not mentioned	Zhang 2006
7. Clarithromycin
i.	500 mg twice/day	3	Pradeep 2011; Rebelatto 2017
ii.	500 mg twice/day	7	Araujo 2019
8. Moxifloxacin
i.	400 mg/day	7	Ardila 2015
9. Levofloxacin
i.	500 mg once/day	10	Pradeep 2014; Pradeep 2015
10. Clindamycin
i.	150 mg 4 times/day	8	Sigusch 2001
11. Cefixime
i.	400 mg once/day	7	Dukic 2016
AMOX = amoxicillin; AZT = azithromycin; CLAV = clavulanate; MTZ = metronidazole.

Table 2. Dosing regimens of antibiotics

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Table 3. Follow‐up periods

Follow‐up period	Studies
Short term (≤ 3 months follow‐up)	Abu Fanas 1991; Akincibay 2008; Araujo 2019; Ardila 2015; Basegmez 2011; Boia 2019; Borges 2017; Carvalho 2004; Casarin 2012; Chin Quee 1988; Cosgarea 2016; D'avila 2005; Dukic 2016; Emingil 2012; Gomi 2007; Guzman 2011; Haas 2008; Han 2012; Li 2015; Liaw 2019; Loesche 1991; Lu 2012; Martande 2016; Mascarenhas 2005; Matarazzo 2008; Moeintaghavi 2007; Mombelli 2013; Palmer 1996; Pradeep 2011; Pradeep 2014; Pradeep 2015; Rebelatto 2017; Ribeiro 2009; Silva 2011; Sigusch 2000; Smith 2002; Taiete 2016; Winkel 1999; Winkel 2001
Intermediate term (> 3 months and < 1 year follow‐up) (varied follow‐up periods falling between short and long term)	Abu Fanas 1991; Araujo 2019; Ardila 2015; Basegmez 2011; Borges 2017; Casarin 2012; Cosgarea 2016; Chin Quee 1988; Emingil 2012; Gomi 2007; Guzman 2011; Haas 2008; Han 2012; Martande 2016; Mascarenhas 2005; Pradeep 2011; Pradeep 2014; Pradeep 2015; Rebelatto 2017; Ribeiro 2009; Sampaio 2011; Sigusch 2000; Smith 2002; Taiete 2016; Winkel 1999; Xajigeorgiou 2006; Yek 2010; Zhang 2006
Long term (≥ 1 year follow‐up)	Borges 2017; Carvalho 2004; Harks 2015; Martande 2016; Sampaio 2011; Sigusch 2000; Sigusch 2001; Winkel 1999; Zhang 2006

Table 3. Follow‐up periods

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Comparison 1. AMOX + MTZ + SRP versus SRP

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Percentage of closed pockets ‐ short‐term (≤ 3 months) improvement Show forest plot	2	73	Mean Difference (IV, Random, 95% CI)	‐10.05 [‐18.78, ‐1.32]

1.2 Percentage of closed pockets ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	44	Mean Difference (IV, Random, 95% CI)	‐13.90 [‐24.16, ‐3.64]

1.3 Percentage of closed pockets ‐ long‐term (≥ 1 year) improvement Show forest plot	1	44	Mean Difference (IV, Random, 95% CI)	‐16.20 [‐25.87, ‐6.53]

1.4 CAL ‐ short‐term (≤ 3 months) improvement Show forest plot	13	501	Mean Difference (IV, Random, 95% CI)	‐0.21 [‐0.41, ‐0.01]

1.4.1 Chronic periodontitis	9	380	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.44, 0.05]
1.4.2 Aggressive periodontitis	4	121	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.62, 0.22]
1.5 CAL ‐ intermediate‐term (> 3 months) improvement Show forest plot	6	215	Mean Difference (IV, Random, 95% CI)	‐0.04 [‐0.35, 0.26]

1.5.1 Chronic periodontitis	3	127	Mean Difference (IV, Random, 95% CI)	‐0.29 [‐0.69, 0.10]
1.5.2 Aggressive periodontitis	3	88	Mean Difference (IV, Random, 95% CI)	0.13 [‐0.27, 0.53]
1.6 CAL ‐ long‐term (≥ 1 year) improvement Show forest plot	2	389	Mean Difference (IV, Random, 95% CI)	‐0.47 [‐0.90, ‐0.05]

1.6.1 Chronic periodontitis	1	44	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.82, 0.62]
1.6.2 Chronic and aggressive periodontitis	1	345	Mean Difference (IV, Random, 95% CI)	‐0.60 [‐0.80, ‐0.40]
1.7 Pocket depth ‐ short‐term (≤ 3 months) improvement Show forest plot	15	562	Mean Difference (IV, Random, 95% CI)	‐0.18 [‐0.33, ‐0.04]

1.7.1 Chronic periodontitis	11	441	Mean Difference (IV, Random, 95% CI)	‐0.21 [‐0.35, ‐0.06]
1.7.2 Aggressive periodontitis	4	121	Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.64, 0.38]
1.8 Pocket depth ‐ intermediate‐term (> 3 months) improvement Show forest plot	6	215	Mean Difference (IV, Random, 95% CI)	‐0.47 [‐0.68, ‐0.25]

1.8.1 Chronic periodontitis	3	127	Mean Difference (IV, Random, 95% CI)	‐0.57 [‐0.79, ‐0.35]
1.8.2 Aggressive periodontitis	3	88	Mean Difference (IV, Random, 95% CI)	‐0.31 [‐0.57, ‐0.05]
1.9 Pocket depth ‐ long‐term (≥ 1 year) improvement Show forest plot	2	389	Mean Difference (IV, Random, 95% CI)	‐0.30 [‐0.42, ‐0.18]

1.9.1 Chronic periodontitis	1	44	Mean Difference (IV, Random, 95% CI)	‐0.30 [‐0.63, 0.03]
1.9.2 Chronic and aggressive periodontitis	1	345	Mean Difference (IV, Random, 95% CI)	‐0.30 [‐0.43, ‐0.17]
1.10 BOP ‐ short‐term (≤ 3 months) improvement Show forest plot	13	460	Mean Difference (IV, Random, 95% CI)	‐2.05 [‐2.98, ‐1.11]

1.10.1 Chronic periodontitis ‐ percentage of BOP	10	354	Mean Difference (IV, Random, 95% CI)	‐8.24 [‐12.00, ‐4.49]
1.10.2 Chronic periodontitis ‐ BOP in Muhlemann score	1	60	Mean Difference (IV, Random, 95% CI)	‐0.44 [‐0.56, ‐0.32]
1.10.3 Aggressive periodontitis ‐ percentage of BOP	1	25	Mean Difference (IV, Random, 95% CI)	‐0.60 [‐3.03, 1.83]
1.10.4 Aggressive periodontitis ‐ BOP score	1	21	Mean Difference (IV, Random, 95% CI)	‐0.11 [‐0.29, 0.07]
1.11 BOP ‐ intermediate‐term (> 3 months) improvement Show forest plot	5	172	Mean Difference (IV, Random, 95% CI)	‐5.32 [‐12.02, 1.37]

1.11.1 Chronic periodontitis	3	127	Mean Difference (IV, Random, 95% CI)	‐9.25 [‐15.48, ‐3.03]
1.11.2 Aggressive periodontitis	1	24	Mean Difference (IV, Random, 95% CI)	‐0.70 [‐2.74, 1.34]
1.11.3 Aggressive periodontitis ‐ BOP score	1	21	Mean Difference (IV, Random, 95% CI)	0.00 [‐0.17, 0.17]
1.12 BOP ‐ long‐term (≥ 1 year) improvement Show forest plot	2	389	Mean Difference (IV, Random, 95% CI)	‐8.06 [‐14.26, ‐1.85]

1.12.1 Chronic periodontitis	1	44	Mean Difference (IV, Random, 95% CI)	‐13.18 [‐22.86, ‐3.50]
1.12.2 Chronic and aggressive periodontitis	1	345	Mean Difference (IV, Random, 95% CI)	‐6.10 [‐8.87, ‐3.33]

Comparison 1. AMOX + MTZ + SRP versus SRP

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Comparison 2. MTZ + SRP versus SRP

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Percentage of closed pockets ‐ short‐term (≤ 3 months) improvement in chronic periodontitis Show forest plot	2	51	Mean Difference (IV, Random, 95% CI)	‐2.56 [‐12.33, 7.22]

2.2 Percentage of closed pockets ‐ intermediate‐term (> 3 months) improvement in chronic periodontitis Show forest plot	1	22	Mean Difference (IV, Random, 95% CI)	‐7.00 [‐23.57, 9.57]

2.3 Percentage of closed pockets ‐ long‐term (≥ 1 year) improvement Show forest plot	1	22	Mean Difference (IV, Random, 95% CI)	‐12.20 [‐29.23, 4.83]

2.4 CAL ‐ short‐term (≤ 3 months) improvement Show forest plot	4	108	Mean Difference (IV, Random, 95% CI)	0.04 [‐0.43, 0.50]

2.4.1 Chronic periodontitis	3	85	Mean Difference (IV, Random, 95% CI)	‐0.19 [‐0.53, 0.15]
2.4.2 Aggressive periodontitis	1	23	Mean Difference (IV, Random, 95% CI)	0.81 [0.07, 1.55]
2.5 CAL ‐ intermediate‐term (> 3 months) improvement Show forest plot	4	94	Mean Difference (IV, Random, 95% CI)	‐0.49 [‐1.29, 0.31]

2.5.1 Chronic periodontitis	2	46	Mean Difference (IV, Random, 95% CI)	‐0.25 [‐1.28, 0.78]
2.5.2 Aggressive periodontitis	2	48	Mean Difference (IV, Random, 95% CI)	‐0.70 [‐2.11, 0.71]
2.6 CAL ‐ long‐term (≥ 1 year) improvement Show forest plot	3	71	Mean Difference (IV, Random, 95% CI)	‐1.12 [‐2.24, ‐0.00]

2.6.1 Chronic periodontitis	2	46	Mean Difference (IV, Random, 95% CI)	‐0.71 [‐2.30, 0.87]
2.6.2 Aggressive periodontitis	1	25	Mean Difference (IV, Random, 95% CI)	‐1.90 [‐2.62, ‐1.18]
2.7 Pocket depth ‐ short‐term (≤ 3 months) improvement Show forest plot	4	108	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.37, 0.16]

2.7.1 Chronic periodontitis	3	85	Mean Difference (IV, Random, 95% CI)	‐0.21 [‐0.44, 0.02]
2.7.2 Aggressive periodontitis	1	23	Mean Difference (IV, Random, 95% CI)	0.28 [‐0.17, 0.73]
2.8 Pocket depth ‐ intermediate‐term (> 3 months) improvement Show forest plot	4	94	Mean Difference (IV, Random, 95% CI)	‐0.59 [‐0.95, ‐0.23]

2.8.1 Chronic periodontitis	2	46	Mean Difference (IV, Random, 95% CI)	‐0.45 [‐1.04, 0.15]
2.8.2 Aggressive periodontitis	2	48	Mean Difference (IV, Random, 95% CI)	‐0.79 [‐1.25, ‐0.34]
2.9 Pocket depth ‐ long‐term (≥ 1 year) improvement Show forest plot	2	47	Mean Difference (IV, Random, 95% CI)	‐1.11 [‐2.84, 0.61]

2.9.1 Chronic periodontitis	1	22	Mean Difference (IV, Random, 95% CI)	‐0.24 [‐0.71, 0.23]
2.9.2 Aggressive periodontitis	1	25	Mean Difference (IV, Random, 95% CI)	‐2.00 [‐2.58, ‐1.42]
2.10 BOP ‐ short‐term (≤ 3 months) improvement Show forest plot	4	108	Mean Difference (IV, Random, 95% CI)	‐9.00 [‐16.59, ‐1.40]

2.10.1 Chronic periodontitis	3	85	Mean Difference (IV, Random, 95% CI)	‐10.33 [‐18.89, ‐1.78]
2.10.2 Aggressive periodontitis	1	23	Mean Difference (IV, Random, 95% CI)	‐4.00 [‐20.53, 12.53]
2.11 BOP ‐ intermediate‐term (> 3 months) improvement Show forest plot	2	45	Mean Difference (IV, Random, 95% CI)	‐4.62 [‐18.83, 9.58]

2.11.1 Chronic periodontitis	1	22	Mean Difference (IV, Random, 95% CI)	‐9.57 [‐23.21, 4.07]
2.11.2 Aggressive periodontitis	1	23	Mean Difference (IV, Random, 95% CI)	6.00 [‐16.93, 28.93]
2.12 BOP ‐ long‐term (≥ 1 year) improvement Show forest plot	1	22	Mean Difference (IV, Random, 95% CI)	‐6.90 [‐22.10, 8.30]

2.12.1 Chronic periodontitis	1	22	Mean Difference (IV, Random, 95% CI)	‐6.90 [‐22.10, 8.30]

Comparison 2. MTZ + SRP versus SRP

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Comparison 3. AZT + SRP versus SRP

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Percentage of closed pockets ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	40	Mean Difference (IV, Random, 95% CI)	‐2.90 [‐13.91, 8.11]

3.2 Percentage of closed pockets ‐ long‐term (≥ 1 year) improvement Show forest plot	1	40	Mean Difference (IV, Random, 95% CI)	2.50 [‐10.19, 15.19]

3.3 CAL ‐ short‐term (≤ 3 months) improvement Show forest plot	6	216	Mean Difference (IV, Random, 95% CI)	‐0.51 [‐0.83, ‐0.19]

3.3.1 Chronic periodontitis	4	114	Mean Difference (IV, Random, 95% CI)	‐0.47 [‐0.97, 0.04]
3.3.2 Agressive periodontitis	2	102	Mean Difference (IV, Random, 95% CI)	‐0.58 [‐1.10, ‐0.06]
3.4 CAL ‐ intermediate‐term (> 3 months) improvement Show forest plot	7	258	Mean Difference (IV, Random, 95% CI)	‐0.43 [‐0.77, ‐0.10]

3.4.1 Chronic periodontitis	4	132	Mean Difference (IV, Random, 95% CI)	‐0.27 [‐0.76, 0.23]
3.4.2 Aggressive periodontitis	3	126	Mean Difference (IV, Random, 95% CI)	‐0.60 [‐0.98, ‐0.22]
3.5 CAL ‐ long‐term (≥ 1 year) improvement Show forest plot	2	110	Mean Difference (IV, Random, 95% CI)	‐0.59 [‐1.27, 0.08]

3.5.1 Chronic periodontitis	1	40	Mean Difference (IV, Random, 95% CI)	‐0.25 [‐0.77, 0.27]
3.5.2 Aggressive periodontitis	1	70	Mean Difference (IV, Random, 95% CI)	‐0.94 [‐1.47, ‐0.41]
3.6 Pocket depth ‐ short‐term (≤ 3 months) improvement Show forest plot	6	216	Mean Difference (IV, Random, 95% CI)	‐0.57 [‐1.08, ‐0.07]

3.6.1 Chronic periodontitis	4	114	Mean Difference (IV, Random, 95% CI)	‐0.61 [‐1.21, ‐0.01]
3.6.2 Aggressive periodontitis	2	102	Mean Difference (IV, Random, 95% CI)	‐0.54 [‐1.61, 0.53]
3.7 Pocket depth ‐ intermediate‐term (> 3 months) improvement Show forest plot	7	258	Mean Difference (IV, Random, 95% CI)	‐0.60 [‐1.02, ‐0.18]

3.7.1 Chronic periodontitis	4	132	Mean Difference (IV, Random, 95% CI)	‐0.37 [‐0.82, 0.07]
3.7.2 Aggressive periodontitis	3	126	Mean Difference (IV, Random, 95% CI)	‐0.93 [‐2.08, 0.22]
3.8 Pocket depth ‐ long‐term (≥ 1 year) improvement Show forest plot	2	110	Mean Difference (IV, Random, 95% CI)	‐0.77 [‐2.33, 0.79]

3.8.1 Chronic periodontitis	1	40	Mean Difference (IV, Random, 95% CI)	0.02 [‐0.27, 0.31]
3.8.2 Aggressive periodontitis	1	70	Mean Difference (IV, Random, 95% CI)	‐1.57 [‐1.91, ‐1.23]
3.9 BOP ‐ short‐term (≤ 3 months) improvement Show forest plot	6	216	Mean Difference (IV, Random, 95% CI)	‐3.18 [‐7.01, 0.65]

3.9.1 Chronic periodontitis	4	114	Mean Difference (IV, Random, 95% CI)	‐6.65 [‐10.41, ‐2.89]
3.9.2 Aggressive periodontitis	2	102	Mean Difference (IV, Random, 95% CI)	‐1.19 [‐3.63, 1.26]
3.10 BOP ‐ intermediate‐term (> 3 months) improvement Show forest plot	6	228	Mean Difference (IV, Random, 95% CI)	‐3.32 [‐6.23, ‐0.42]

3.10.1 Chronic periodontitis	3	102	Mean Difference (IV, Random, 95% CI)	‐4.14 [‐9.27, 1.00]
3.10.2 Aggressive periodontitis	3	126	Mean Difference (IV, Random, 95% CI)	‐1.79 [‐5.27, 1.69]
3.11 BOP ‐ long‐term (≥ 1 year) improvement Show forest plot	2	110	Mean Difference (IV, Random, 95% CI)	‐1.28 [‐4.32, 1.76]

3.11.1 Chronic periodontitis	1	40	Mean Difference (IV, Random, 95% CI)	0.54 [‐3.62, 4.70]
3.11.2 Aggressive periodontitis	1	70	Mean Difference (IV, Random, 95% CI)	‐2.60 [‐5.95, 0.75]

Comparison 3. AZT + SRP versus SRP

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Comparison 4. AMOX + CLAV + SRP versus SRP in chronic periodontitis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 CAL ‐ short‐term (≤ 3 months) improvement Show forest plot	1	21	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.43, 0.63]

4.2 CAL ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	21	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.45, 0.65]

4.3 CAL ‐ long‐term (≥ 1 year) improvement Show forest plot	1	21	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.51, 0.71]

4.4 Pocket depth ‐ short‐term (≤ 3 months) improvement Show forest plot	1	21	Mean Difference (IV, Random, 95% CI)	0.20 [‐0.02, 0.42]

4.5 Pocket depth ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	21	Mean Difference (IV, Random, 95% CI)	0.00 [‐0.19, 0.19]

4.6 Pocket depth ‐ long‐term (≥ 1 year) improvement Show forest plot	1	21	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.17, 0.37]

4.7 BOP ‐ short‐term (≤ 3 months) improvement Show forest plot	1	21	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.19, ‐0.01]

4.8 BOP ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	21	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.19, ‐0.01]

4.9 BOP ‐ long‐term (≥ 1 year) improvement Show forest plot	1	21	Mean Difference (IV, Random, 95% CI)	0.00 [‐0.09, 0.09]

Comparison 4. AMOX + CLAV + SRP versus SRP in chronic periodontitis

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Comparison 5. Doxycycline + SRP versus SRP in aggressive periodontitis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 CAL ‐ short‐term (≤ 3 months) improvement Show forest plot	2	43	Mean Difference (IV, Random, 95% CI)	0.15 [‐0.53, 0.83]

5.1.1 Aggressive periodontitis	2	43	Mean Difference (IV, Random, 95% CI)	0.15 [‐0.53, 0.83]
5.2 CAL ‐ intermediate‐term (> 3 months) improvement Show forest plot	3	65	Mean Difference (IV, Random, 95% CI)	‐0.61 [‐1.14, ‐0.08]

5.2.1 Aggressive periodontitis	3	65	Mean Difference (IV, Random, 95% CI)	‐0.61 [‐1.14, ‐0.08]
5.3 CAL ‐ long‐term (≥ 1 year) improvement Show forest plot	1	22	Mean Difference (IV, Random, 95% CI)	‐0.80 [‐1.49, ‐0.11]

5.3.1 Aggressive periodontitis	1	22	Mean Difference (IV, Random, 95% CI)	‐0.80 [‐1.49, ‐0.11]
5.4 Pocket depth ‐ short‐term (≤ 3 months) improvement Show forest plot	2	43	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.29, 0.50]

5.4.1 Aggressive periodontitis	2	43	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.29, 0.50]
5.5 Pocket depth ‐ intermediate‐term (> 3 months) improvement Show forest plot	3	65	Mean Difference (IV, Random, 95% CI)	‐0.43 [‐0.88, 0.01]

5.5.1 Aggressive Periodontitis	3	65	Mean Difference (IV, Random, 95% CI)	‐0.43 [‐0.88, 0.01]
5.6 Pocket depth ‐ long‐term (≥ 1 year) improvement Show forest plot	1	22	Mean Difference (IV, Random, 95% CI)	‐1.00 [‐1.78, ‐0.22]

5.6.1 Aggressive periodontitis	1	22	Mean Difference (IV, Random, 95% CI)	‐1.00 [‐1.78, ‐0.22]
5.7 BOP ‐ short‐term (≤ 3 months) improvement Show forest plot	1	21	Mean Difference (IV, Random, 95% CI)	‐0.09 [‐0.29, 0.11]

5.7.1 Aggressive periodontitis	1	21	Mean Difference (IV, Random, 95% CI)	‐0.09 [‐0.29, 0.11]
5.8 BOP ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	21	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.21, 0.19]

5.8.1 Aggressive periodontitis	1	21	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.21, 0.19]

Comparison 5. Doxycycline + SRP versus SRP in aggressive periodontitis

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Comparison 6. Tetracycline + SRP versus SRP in aggressive periodontitis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 CAL ‐ short‐term (≤ 3 months) improvement Show forest plot	2	64	Mean Difference (IV, Random, 95% CI)	‐0.92 [‐2.38, 0.54]

6.2 CAL ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	26	Mean Difference (IV, Random, 95% CI)	‐1.90 [‐2.17, ‐1.63]

6.3 CAL ‐ long‐term (≥ 1 year) improvement Show forest plot	1	26	Mean Difference (IV, Random, 95% CI)	‐2.30 [‐2.50, ‐2.10]

6.4 Pocket depth ‐ short‐term (≤ 3 months) improvement Show forest plot	1	38	Mean Difference (IV, Random, 95% CI)	‐0.53 [‐1.14, 0.08]

6.5 BOP ‐ short‐term (≤ 3 months) improvement Show forest plot	1	38	Mean Difference (IV, Random, 95% CI)	‐14.62 [‐27.21, ‐2.03]

Comparison 6. Tetracycline + SRP versus SRP in aggressive periodontitis

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Comparison 7. Clarithromycin + SRP versus SRP

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 CAL ‐ short‐term (≤ 3 months) improvement Show forest plot	2	77	Mean Difference (IV, Random, 95% CI)	‐0.65 [‐1.20, ‐0.09]

7.1.1 Chronic periodontitis	1	37	Mean Difference (IV, Random, 95% CI)	‐0.92 [‐1.11, ‐0.73]
7.1.2 Aggressive periodontitis	1	40	Mean Difference (IV, Random, 95% CI)	‐0.35 [‐0.64, ‐0.06]
7.2 CAL ‐ intermediate‐term (> 3 months) improvement Show forest plot	2	77	Mean Difference (IV, Random, 95% CI)	‐0.64 [‐1.26, ‐0.03]

7.3 Pocket depth ‐ short‐term (≤ 3 months) improvement Show forest plot	2	77	Mean Difference (IV, Random, 95% CI)	‐0.59 [‐1.17, ‐0.01]

7.4 Pocket depth ‐ intermediate‐term (> 3 months) improvement Show forest plot	2	77	Mean Difference (IV, Random, 95% CI)	‐0.67 [‐1.33, ‐0.01]

7.5 BOP ‐ short‐term (≤ 3 months) improvement Show forest plot	1	40	Mean Difference (IV, Random, 95% CI)	‐3.00 [‐6.69, 0.69]

7.6 BOP ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	40	Mean Difference (IV, Random, 95% CI)	‐4.70 [‐8.42, ‐0.98]

Comparison 7. Clarithromycin + SRP versus SRP

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Comparison 8. Moxifloxacin + SRP versus SRP in aggressive periodontitis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 CAL ‐ short‐term (≤ 3 months) improvement Show forest plot	1	40	Mean Difference (IV, Random, 95% CI)	‐0.67 [‐1.01, ‐0.33]

8.2 CAL ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	40	Mean Difference (IV, Random, 95% CI)	‐0.63 [‐0.95, ‐0.31]

8.3 Pocket depth ‐ short‐term (≤ 3 months) improvement Show forest plot	1	40	Mean Difference (IV, Random, 95% CI)	‐0.55 [‐0.87, ‐0.23]

8.4 Pocket depth ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	40	Mean Difference (IV, Random, 95% CI)	‐0.42 [‐0.74, ‐0.10]

8.5 BOP ‐ short‐term (≤ 3 months) improvement Show forest plot	1	40	Mean Difference (IV, Random, 95% CI)	‐3.40 [‐3.72, ‐3.08]

8.6 BOP ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	40	Mean Difference (IV, Random, 95% CI)	‐0.80 [‐1.12, ‐0.48]

Comparison 8. Moxifloxacin + SRP versus SRP in aggressive periodontitis

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Comparison 9. Levofloxacin + SRP versus SRP in chronic periodontitis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 CAL ‐ short‐term (≤ 3 months) improvement Show forest plot	2	131	Mean Difference (IV, Random, 95% CI)	‐1.02 [‐1.39, ‐0.65]

9.2 CAL ‐ intermediate‐term (> 3 months) improvement Show forest plot	2	131	Mean Difference (IV, Random, 95% CI)	‐1.25 [‐1.51, ‐0.99]

9.3 Pocket depth ‐ short‐term (≤ 3 months) improvement Show forest plot	2	131	Mean Difference (IV, Random, 95% CI)	‐1.09 [‐1.33, ‐0.85]

9.4 Pocket depth ‐ intermediate‐term (> 3 months) improvement Show forest plot	2	131	Mean Difference (IV, Random, 95% CI)	‐1.23 [‐1.46, ‐1.00]

9.5 BOP ‐ short‐term (≤ 3 months) improvement Show forest plot	2	131	Mean Difference (IV, Random, 95% CI)	‐1.38 [‐3.30, 0.54]

9.6 BOP ‐ intermediate‐term (> 3 months) improvement Show forest plot	2	131	Mean Difference (IV, Random, 95% CI)	‐0.93 [‐2.88, 1.02]

Comparison 9. Levofloxacin + SRP versus SRP in chronic periodontitis

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Comparison 10. Clindamycin + SRP versus SRP in aggressive periodontitis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 CAL ‐ short‐term (≤ 3 months) improvement Show forest plot	1	21	Mean Difference (IV, Random, 95% CI)	0.40 [‐0.35, 1.15]

10.2 CAL ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	21	Mean Difference (IV, Random, 95% CI)	‐1.30 [‐2.14, ‐0.46]

10.3 CAL ‐ long‐term (≥ 1 year) improvement Show forest plot	1	21	Mean Difference (IV, Random, 95% CI)	‐1.70 [‐2.40, ‐1.00]

10.4 Pocket depth ‐ short‐term (≤ 3 months) improvement Show forest plot	1	21	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.55, 0.75]

10.5 Pocket depth ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	21	Mean Difference (IV, Random, 95% CI)	‐1.10 [‐1.94, ‐0.26]

10.6 Pocket depth ‐ long‐term (≥ 1 year) improvement Show forest plot	1	21	Mean Difference (IV, Random, 95% CI)	‐1.80 [‐2.47, ‐1.13]

Comparison 10. Clindamycin + SRP versus SRP in aggressive periodontitis

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Comparison 11. Cefixime + SRP versus SRP in chronic periodontitis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
11.1 CAL ‐ short‐term (≤ 3 months) improvement Show forest plot	1	60	Mean Difference (IV, Random, 95% CI)	‐0.19 [‐0.77, 0.39]

11.2 Pocket depth ‐ short‐term (≤ 3 months) improvement Show forest plot	1	60	Mean Difference (IV, Random, 95% CI)	‐0.02 [‐0.11, 0.07]

11.3 BOP ‐ short‐term (≤ 3 months) improvement Show forest plot	1	60	Mean Difference (IV, Random, 95% CI)	‐0.48 [‐0.60, ‐0.37]

Comparison 11. Cefixime + SRP versus SRP in chronic periodontitis

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Comparison 12. MTZ + SRP versus AMOX + MTZ + SRP

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
12.1 CAL ‐ short‐term (≤ 3 months) improvement Show forest plot	3	84	Mean Difference (IV, Random, 95% CI)	‐0.07 [‐0.40, 0.26]

12.1.1 Chronic periodontitis	2	62	Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.49, 0.23]
12.1.2 Agressive periodontitis	1	22	Mean Difference (IV, Random, 95% CI)	0.30 [‐0.56, 1.16]
12.2 CAL ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	22	Mean Difference (IV, Random, 95% CI)	0.06 [‐1.06, 1.18]

12.3 Pocket depth ‐ short‐term (≤ 3 months) improvement Show forest plot	3	84	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.12, 0.32]

12.3.1 Chronic periodontitis	2	62	Mean Difference (IV, Random, 95% CI)	0.12 [‐0.14, 0.39]
12.3.2 Aggressive periodontitis	1	22	Mean Difference (IV, Random, 95% CI)	0.03 [‐0.38, 0.44]
12.4 Pocket depth ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	22	Mean Difference (IV, Random, 95% CI)	‐0.26 [‐0.83, 0.31]

12.5 BOP ‐ short‐term (≤ 3 months) improvement Show forest plot	3	84	Mean Difference (IV, Random, 95% CI)	4.46 [‐23.48, 32.40]

12.5.1 Chronic periodontitis	2	62	Mean Difference (IV, Random, 95% CI)	‐8.11 [‐22.40, 6.17]
12.5.2 Aggressive periodontitis	1	22	Mean Difference (IV, Random, 95% CI)	28.78 [20.29, 37.27]
12.6 BOP ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	22	Mean Difference (IV, Random, 95% CI)	20.85 [3.31, 38.39]

Comparison 12. MTZ + SRP versus AMOX + MTZ + SRP

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Comparison 13. Doxycycline + SRP versus AMOX + MTZ + SRP in aggressive periodontitis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
13.1 CAL ‐ short‐term (≤ 3 months) improvement Show forest plot	2	50	Mean Difference (IV, Random, 95% CI)	0.20 [0.06, 0.33]

13.2 CAL ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	20	Mean Difference (IV, Random, 95% CI)	0.17 [‐1.28, 1.62]

13.3 Pocket depth ‐ short‐term (≤ 3 months) improvement Show forest plot	2	50	Mean Difference (IV, Random, 95% CI)	0.14 [‐0.12, 0.40]

13.4 Pocket depth ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	20	Mean Difference (IV, Random, 95% CI)	0.23 [‐0.41, 0.87]

Comparison 13. Doxycycline + SRP versus AMOX + MTZ + SRP in aggressive periodontitis

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Comparison 14. Doxycycline + SRP versus MTZ + SRP in aggressive periodontitis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
14.1 CAL ‐ short‐term (≤ 3 months) improvement Show forest plot	2	49	Mean Difference (IV, Random, 95% CI)	‐0.12 [‐0.72, 0.49]

14.2 CAL ‐ intermediate‐term (> 3 months) improvement Show forest plot	3	75	Mean Difference (IV, Random, 95% CI)	0.34 [‐0.08, 0.76]

14.3 CAL ‐ long‐term (≥ 1 year) improvement Show forest plot	1	27	Mean Difference (IV, Random, 95% CI)	1.10 [0.36, 1.84]

14.4 Pocket depth ‐ short‐term (≤ 3 months) improvement Show forest plot	2	49	Mean Difference (IV, Random, 95% CI)	‐0.16 [‐0.56, 0.24]

14.5 Pocket depth ‐ intermediate‐term (> 3 months) improvement Show forest plot	3	75	Mean Difference (IV, Random, 95% CI)	0.38 [‐0.00, 0.76]

14.6 Pocket depth ‐ long‐term (≥ 1 year) improvement Show forest plot	1	27	Mean Difference (IV, Random, 95% CI)	1.00 [0.30, 1.70]

14.7 BOP ‐ short‐term (≤ 3 months) improvement Show forest plot	1	22	Mean Difference (IV, Random, 95% CI)	‐0.05 [‐0.22, 0.12]

14.8 BOP ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	22	Mean Difference (IV, Random, 95% CI)	‐0.07 [‐0.29, 0.15]

Comparison 14. Doxycycline + SRP versus MTZ + SRP in aggressive periodontitis

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Comparison 15. Clindamycin + SRP versus MTZ + SRP in aggressive periodontitis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
15.1 CAL ‐ short‐term (≤ 3 months) improvement Show forest plot	1	26	Mean Difference (IV, Random, 95% CI)	0.40 [‐0.22, 1.02]

15.2 CAL ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	26	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.60, 0.80]

15.3 CAL ‐ long‐term (≥ 1 year) improvement Show forest plot	1	26	Mean Difference (IV, Random, 95% CI)	0.20 [‐0.55, 0.95]

15.4 Pocket depth ‐ short‐term (≤ 3 months) improvement Show forest plot	1	26	Mean Difference (IV, Random, 95% CI)	‐0.14 [‐0.82, 0.54]

15.5 Pocket depth ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	26	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.79, 0.59]

15.6 Pocket depth ‐ long‐term (≥ 1 year) improvement Show forest plot	1	26	Mean Difference (IV, Random, 95% CI)	0.20 [‐0.38, 0.78]

Comparison 15. Clindamycin + SRP versus MTZ + SRP in aggressive periodontitis

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Comparison 16. AMOX + CLAV + SRP versus tetracycline + SRP in aggressive periodontitis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
16.1 Pocket depth ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	8	Mean Difference (IV, Random, 95% CI)	‐0.40 [‐1.11, 0.31]

16.2 BOP ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	8	Mean Difference (IV, Random, 95% CI)	‐1.60 [‐14.03, 10.83]

Comparison 16. AMOX + CLAV + SRP versus tetracycline + SRP in aggressive periodontitis

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Comparison 17. Clindamycin + SRP versus doxycycline + SRP in aggressive periodontitis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
17.1 CAL ‐ short‐term (≤ 3 months) improvement Show forest plot	1	23	Mean Difference (IV, Random, 95% CI)	0.50 [‐0.26, 1.26]

17.2 CAL ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	23	Mean Difference (IV, Random, 95% CI)	‐0.40 [‐1.15, 0.35]

17.3 CAL ‐ long‐term (≥ 1 year) improvement Show forest plot	1	23	Mean Difference (IV, Random, 95% CI)	‐0.90 [‐1.62, ‐0.18]

17.4 Pocket depth ‐ short‐term (≤ 3 months) improvement Show forest plot	1	23	Mean Difference (IV, Random, 95% CI)	0.20 [‐0.36, 0.76]

17.5 Pocket depth ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	23	Mean Difference (IV, Random, 95% CI)	‐0.40 [‐1.14, 0.34]

17.6 Pocket depth ‐ long‐term (≥ 1 year) improvement Show forest plot	1	23	Mean Difference (IV, Random, 95% CI)	‐0.80 [‐1.58, ‐0.02]

Comparison 17. Clindamycin + SRP versus doxycycline + SRP in aggressive periodontitis

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Comparison 18. AMOX + MZT versus clarithromycin + SRP

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
18.1 CAL ‐ short‐term (≤ 3 months) improvement Show forest plot	1	46	Mean Difference (IV, Random, 95% CI)	‐0.60 [‐0.86, ‐0.34]

18.2 CAL ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	46	Mean Difference (IV, Random, 95% CI)	0.00 [‐0.26, 0.26]

18.3 Pocket depth ‐ short‐term (≤ 3 months) improvement Show forest plot	1	46	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.35, ‐0.05]

18.4 Pocket depth ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	46	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.26, 0.06]

18.5 BOP ‐ short‐term (≤ 3 months) improvement Show forest plot	1	46	Mean Difference (IV, Random, 95% CI)	5.40 [‐0.12, 10.92]

18.6 BOP ‐ intermediate‐term (> 3 months) improvement Show forest plot	1	46	Mean Difference (IV, Random, 95% CI)	4.00 [‐1.09, 9.09]

Comparison 18. AMOX + MZT versus clarithromycin + SRP

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Adjunctive systemic antimicrobials for the non‐surgical treatment of periodontitis

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