An Evidence-Based Update on the Impact of Local Antimicrobials as Adjunct to Periodontal Therapy

Nabaz Yahya Hussein; Sadat Abdulla Aziz; Twana Mohammed M. Ways; Omed Amiri; Hisham Al-Obaidi; Dianne Ford

doi:10.24017/science.2023.1.6

Authors

Nabaz Yahya Hussein Department of Periodontics, College of Dentistry, University of Sulaimani, Sulaymaniyah, Iraq | Halabja General Health Directory, Ministry of Health, Halabja Governate, Iraq
Sadat Abdulla Aziz Department of Anesthesia, College of Health Sciences, Cihan University-Sulaimaniya, Sulaimaniyah, Iraq. | Department of Basic Sciences, College of Veterinary Medicine, University of Sulaimani, Sulaymaniyah, Iraq. https://orcid.org/0000-0001-9455-2639
Twana Mohammed M. Ways Department of Pharmaceutics, College of Pharmacy, University of Sulaimani, Sulaymaniyah, Iraq. https://orcid.org/0000-0002-7595-2159
Omed Amiri Cihan University Sulaimaniya Research Center (CUSRC), Cihan University Sulaimaniya, Sulaymaniyah, Iraq
Hisham Al-Obaidi School of Pharmacy, University of Reading, Reading, RG6 6AD, UK https://orcid.org/0000-0001-9735-0303
Dianne Ford Faculty of Health & Life Sciences, Northumbria University, Newcastle upon Tyne, UK https://orcid.org/0000-0001-8121-9319

Abstract

Local antimicrobials as adjunct to mechanical periodontal therapy have been used widely to enhance the outcome of treatment. However, consensus has yet to be achieved regarding what and how these antimicrobials can be used. Therefore, this narrative review highlights the most common antimicrobials examined and provides an updated analysis of the benefits, limitations, and clinical outcomes associated with use of antimicrobials as adjunct to mechanical periodontal therapy. Based on the evidences gathered, it is clear that combining local antimicrobial agents with scaling and root debridement (SRD) offers significant therapeutic advantages in periodontal therapy and minimizing many side effects linked to systemic antibiotic therapy. Amongst the antimicrobials used, chlorhexidine (CHX) showed the most significant clinical improvement, followed by doxycycline (DOX), tetracycline, and metronidazole (MTZ), all of which helped reduce periodontal bacteria load and improve treatment outcome. CHX demonstrated the greatest clinical improvement due to its broad-spectrum antimicrobial activity, strong substantivity, and its application in sustained-release formulations. DOX followed closely in effectiveness, offering a unique advantage through its dual role as both an antimicrobial and a matrix metalloproteinase inhibitor. Tetracycline, though slightly less effective than DOX, still provided considerable clinical benefits, especially when used in sustained-release systems, despite increasing bacterial resistance in some cases. MTZ showed the lowest clinical improvement among the agents reviewed, but it remains valuable due to its targeted action against anaerobic bacteria, which are prominent in periodontal infections. The findings of this study will help the general practitioners select the most suitable local antimicrobial therapy as adjunct to mechanical periodontal therapy.

Keywords:

Periodontal therapy, Adjunc-tive, Local antimicrobials, Effec-tiveness , Treatment outcome

References

T. Dietrich et al., "Periodontal diagnosis in the context of the 2017 classification system of periodontal diseases and conditions–implementation in clinical practice," Br. Dent. J., vol. 226, no. 1, pp. 16-22, 2019. doi: 10.1038/sj.bdj.2019.3. DOI: https://doi.org/10.1038/sj.bdj.2019.3

Z. Zhang, D. Liu, S. Liu, S. Zhang, and Y. Pan, "The role of Porphyromonas gingivalis outer membrane vesicles in periodontal disease and related systemic diseases," Front. Cell. Infect. Microbiol., vol. 10, p. 585917, 2021. doi: 10.3389/fcimb.2020.585917. DOI: https://doi.org/10.3389/fcimb.2020.585917

W. Pan, Q. Wang, and Q. Chen, "The cytokine network involved in the host immune response to periodontitis," Int. J. Oral Sci., vol. 11, no. 3, p. 30, 2019. doi: 10.1038/s41368-019-0064-z. DOI: https://doi.org/10.1038/s41368-019-0064-z

S. S. B. Qasim, D. Al-Otaibi, R. Al-Jasser, S. S. Gul, and M. S. Zafar, "An evidence-based update on the molecular mechanisms underlying periodontal diseases," Int. T. Mol. Sci., vol. 21, no. 11, p. 3829, 2020. doi: 10.3390/ijms21113829. DOI: https://doi.org/10.3390/ijms21113829

G. Hajishengallis and R. J. Lamont, "Beyond the red complex and into more complexity: the polymicrobial synergy and dysbiosis (PSD) model of periodontal disease etiology," Mol. Oral Microbiol., vol. 27, no. 6, pp. 409-419, 2012. doi: 10.1111/j.2041-1014.2012.00663.x. DOI: https://doi.org/10.1111/j.2041-1014.2012.00663.x

G. Hajishengallis, "Periodontitis: from microbial immune subversion to systemic inflammation," Nat. Rev. Immunol., vol. 15, no. 1, pp. 30-44, 2015. doi: 10.1038/nri3785. DOI: https://doi.org/10.1038/nri3785

M. S. Tonetti et al., "Principles in prevention of periodontal diseases: consensus report of group 1 of the 11th Europe-an Workshop on Periodontology on effective prevention of periodontal and peri‐implant diseases," J. Clin. Periodon-tol., vol. 42, pp. S5-S11, 2015. doi: 10.1111/jcpe.12368. DOI: https://doi.org/10.1111/jcpe.12368

J. Tanwar, S. A. Hungund, and K. Dodani, "Nonsurgical periodontal therapy: A review," J. Oral Res. Rev., vol. 8, no. 1, pp. 39-44, 2016. doi:10.3390/biomedicines10112752. DOI: https://doi.org/10.4103/2249-4987.182490

J. Slots, "Selection of antimicrobial agents in periodontal therapy," J. Periodontal Res., vol. 37, no. 5, pp. 389-398, 2002. doi: 10.1034/j.1600-0765.2002.00004.x. DOI: https://doi.org/10.1034/j.1600-0765.2002.00004.x

M. Feres et al., "The ideal time of systemic metronidazole and amoxicillin administration in the treatment of severe periodontitis: study protocol for a randomized controlled trial," Trials, vol. 19, pp. 1-7, 2018. doi: 10.1186/s13063-018-2540-8. DOI: https://doi.org/10.1186/s13063-018-2540-8

[11] W. Teughels, M. Feres, V. Oud, C. Martín, P. Matesanz, and D. Herrera, "Adjunctive effect of systemic an-timicrobials in periodontitis therapy: A systematic review and meta‐analysis," J. Clin. Periodontol., vol. 47, pp. 257-281, 2020. doi: 10.1111/jcpe.13264. DOI: https://doi.org/10.1111/jcpe.13264

H. Rajeshwari et al., "Local drug delivery systems in the management of periodontitis: A scientific review," J. Control. Release, vol. 307, pp. 393-409, 2019. doi: 10.1016/j.jconrel.2019.06.038. DOI: https://doi.org/10.1016/j.jconrel.2019.06.038

S. C. Nair and K. Anoop, "Intraperiodontal pocket: An ideal route for local antimicrobial drug delivery," J. Adv. Pharm. Technol. Res., vol. 3, no. 1, pp. 9-15, 2012. doi: 10.4103/2231-4040.93558 DOI: https://doi.org/10.4103/2231-4040.93558

A. Sholapurkar, D. Sharma, B. Glass, C. Miller, A. Nimmo, and E. Jennings, "Professionally delivered local antimi-crobials in the treatment of patients with periodontitis—A narrative review," Dent. J., vol. 9, no. 1, p. 2, 2020. doi: 10.1016/j.jconrel.2019.06.038. DOI: https://doi.org/10.3390/dj9010002

B. L. Pihlstrom, B. S. Michalowicz, and N. W. Johnson, "Periodontal diseases Lancet 366: 1809–1820. doi: 10.1016," S0140-6736 (05), pp. 67728-67728, 2005. doi: 10.1016/S0140-6736(05)67728-8. DOI: https://doi.org/10.1016/S0140-6736(05)67728-8

T. DeRouen, P. Hujoel, and L. Mancl, "Concise review: statistical issues in periodontal research," J. Dent. Res., vol. 74, no. 11, pp. 1731-1737, 1995. doi: 10.1177/00220345950740110301. DOI: https://doi.org/10.1177/00220345950740110301

B. G. Loos and I. Needleman, "Endpoints of active periodontal therapy," J. Clin. Periodontol., vol. 47, pp. 61-71, 2020. doi: 10.1111/jcpe.13253. DOI: https://doi.org/10.1111/jcpe.13253

F. Van Der Weijden and D. E. Slot, "Oral hygiene in the prevention of periodontal diseases: the evidence," Periodontol. 2000, vol. 55, no. 1, 2011. doi: 10.1111/j.1600-0757.2009.00337.x. DOI: https://doi.org/10.1111/j.1600-0757.2009.00337.x

[19] M. Sanz et al., "Treatment of stage I–III periodontitis—The EFP S3 level clinical practice guideline," J. Clin. Periodontol., vol. 47, pp. 4-60, 2020. doi: 10.1111/jcpe.13290. DOI: https://doi.org/10.1111/jcpe.13290

S. S. Gul, G. S. Griffiths, G. P. Stafford, M. I. Al‐Zubidi, A. Rawlinson, and C. W. Douglas, "Investigation of a novel predictive biomarker profile for the outcome of periodontal treatment," J. Periodontol., vol. 88, no. 11, pp. 1135-1144, 2017. doi: 10.1902/jop.2017.170187. DOI: https://doi.org/10.1902/jop.2017.170187

C. M. Cobb, "Clinical significance of non‐surgical periodontal therapy: an evidence‐based perspective of scaling and root planing," J. Clin. Periodontol., vol. 29, pp. 22-32, 2002. doi: 10.1034/j.1600-051X.29.s2.4.x. DOI: https://doi.org/10.1034/j.1600-051X.29.s2.4.x

S. S. Gul, C. W. Douglas, G. S. Griffiths, and A. Rawlinson, "A pilot study of active enzyme levels in gingival crevicu-lar fluid of patients with chronic periodontal disease," J. Clin. Periodontol., vol. 43, no. 8, pp. 629-636, 2016. doi: 10.1111/jcpe.12568. DOI: https://doi.org/10.1111/jcpe.12568

M. S. Tonetti, H. Greenwell, and K. S. Kornman, "Staging and grading of periodontitis: Framework and proposal of a new classification and case definition," J. Periodontol., vol. 89, pp. S159-S172, 2018. doi: 10.1002/JPER.18-0006. DOI: https://doi.org/10.1002/JPER.18-0006

J. Waerhaug, "Healing of the dento‐epithelial junction following subgingival plaque control: ii: as observed on ex-tracted teeth," J. Periodontol., vol. 49, no. 3, pp. 119-134, 1978. doi: 10.1902/jop.1978.49.3.119. DOI: https://doi.org/10.1902/jop.1978.49.3.119

T. Kwon, I. B. Lamster, and L. Levin, "Current concepts in the management of periodontitis," Int. Dent. J., vol. 71, no. 6, pp. 462-476, 2021. doi: 10.1111/idj.12630. DOI: https://doi.org/10.1111/idj.12630

G. J. Petersilka, B. Ehmke, and T. F. Flemming, "Antimicrobial effects of mechanical debridement," Periodontol. 2000, vol. 28, no. 1, 2002. doi: 10.1034/j.1600-0757.2002.280103.x. DOI: https://doi.org/10.1034/j.1600-0757.2002.280103.x

R. Cosgarea et al., "One year results of a randomized controlled clinical study evaluating the effects of non-surgical periodontal therapy of chronic periodontitis in conjunction with three or seven days systemic administration of amoxicillin/metronidazole," PLoS One, vol. 12, no. 6, p. e0179592, 2017. doi: 10.1371/journal.pone.0179592. DOI: https://doi.org/10.1371/journal.pone.0179592

S. Eick, J. Nydegger, W. Bürgin, G. E. Salvi, A. Sculean, and C. Ramseier, "Microbiological analysis and the outcomes of periodontal treatment with or without adjunctive systemic antibiotics—a retrospective study," Clin. Oral Investig., vol. 22, pp. 3031-3041, 2018. doi: 10.1007/s00784-018-2392-3. DOI: https://doi.org/10.1007/s00784-018-2392-3

L. Machion et al., "Locally delivered doxycycline as an adjunctive therapy to scaling and root planing in the treatment of smokers: A 2‐year follow‐up," J. Periodontol., vol. 77, no. 4, pp. 606-613, 2006. doi: 10.1902/jop.2006.050087. DOI: https://doi.org/10.1902/jop.2006.050087

A. Pradeep, S. V. Sagar, and H. Daisy, "Clinical and microbiologic effects of subgingivally delivered 0.5% azithromy-cin in the treatment of chronic periodontitis," J. Periodontol., vol. 79, no. 11, pp. 2125-2135, 2008. doi: 10.1902/jop.2008.070589. DOI: https://doi.org/10.1902/jop.2008.070589

V. Goswami, R. K. Yeltiwar, S. Kujur, P. Agrawal, S. Bodhi, and S. Bhatnagar, "Evaluation of efficacy of subgingival administration of 1% chlorhexidine gel as an adjunct to scaling and root planing in the treatment of chronic periodon-titis-A clinical and microbiological study," Indian J. Dent. Res., vol. 33, no. 2, pp. 174-179, 2022. doi: 10.4103/ijdr.ijdr_936_21. DOI: https://doi.org/10.4103/ijdr.ijdr_936_21

K. Jepsen and S. Jepsen, "Antibiotics/antimicrobials: systemic and local administration in the therapy of mild to moderately advanced periodontitis," Periodontol. 2000, vol. 71, no. 1, pp. 82-112, 2016. doi: 10.1111/prd.12121. DOI: https://doi.org/10.1111/prd.12121

Z. A. Al Marah, A. A. Abdulkareem, S. S. Gul, and M. L. Alshami, "A Survey of Systemic Antibiotic Prescription Patterns Amongst Iraqi Dentists," Int. Dent. J., vol. 72, no. 3, pp. 338-345, 2022. doi:10.1016/j.identj.2021.06.002. DOI: https://doi.org/10.1016/j.identj.2021.06.002

P. N. Papapanou et al., "Periodontitis: Consensus report of workgroup 2 of the 2017 World Workshop on the Classi-fication of Periodontal and Peri‐Implant Diseases and Conditions," J. Periodontol., vol. 89, pp. S173-S182, 2018. doi: 10.1002/JPER.17-0721. DOI: https://doi.org/10.1002/JPER.17-0721

B. Pretzl et al., "Administration of systemic antibiotics during non-surgical periodontal therapy—A consensus re-port," Clin. Oral Investig., vol. 23, pp. 3073-3085, 2019. doi: 10.1007/s00784-018-2727-0. DOI: https://doi.org/10.1007/s00784-018-2727-0

H. Ahmadi, A. Ebrahimi, and F. Ahmadi, "Antibiotic therapy in dentistry," Int. J. Dent., vol. 2021, no. 1, p. 6667624, 2021. doi: 10.1155/2021/6667624. DOI: https://doi.org/10.1155/2021/6667624

E. Ramanauskaite and V. Machiulskiene, "Antiseptics as adjuncts to scaling and root planing in the treatment of periodontitis: a systematic literature review," BMC Oral Health, vol. 20, pp. 1-19, 2020. doi: 10.1186/s12903-020-01127-1. DOI: https://doi.org/10.1186/s12903-020-01127-1

H. Alassy, J. A. Pizarek, I. Kormas, A. Pedercini, and L. F. Wolff, "Antimicrobial adjuncts in the management of periodontal and peri-implant diseases and conditions: a narrative review," Front. Oral Maxillofac. Med., vol. 3, no. 16, pp. 1-10, 2021. doi: 10.21037/fomm-20-84. DOI: https://doi.org/10.21037/fomm-20-84

A. Herrera et al., "Cementless hydroxyapatite coated hip prostheses," BioMed Res. Int., vol. 2015, no. 1, p. 386461, 2015. doi: 10.1155/2015/386461. DOI: https://doi.org/10.1155/2015/386461

[P. Heasman, L. Heasman, F. Stacey, and G. McCracken, "Local delivery of chlorhexidine gluconate (PerioChipTM) in periodontal maintenance patients,", J. Clin. Periodontol., vol. 28, no. 1, pp. 90-95, 2001. doi: 10.1034/j.1600-051x.2001.280114.x. DOI: https://doi.org/10.1034/j.1600-051x.2001.280114.x

E. Unsal, M. Akkaya, and T. Walsh, "Influence of a single application of subgingival chlorhexidine gel or tetracycline paste on the clinical parameters of adult periodontitis patients," J. Clin. Periodontol., vol. 21, no. 5, pp. 351-355, 1994. doi: 10.1111/j.1600-051x.1994.tb00725.x. DOI: https://doi.org/10.1111/j.1600-051X.1994.tb00725.x

R. Gupta, N. Pandit, S. Aggarwal, and A. Verma, "Comparative evaluation of subgingivally delivered 10% doxycy-cline hyclate and xanthan-based chlorhexidine gels in the treatment of chronic periodontitis," J. Contemp. Dent. Pract., vol. 9, no. 7, pp. 25-32, 2008. doi: 10.5005/jcdp-9-7-25. DOI: https://doi.org/10.5005/jcdp-9-7-25

A. Verma, S. Sanghi, D. Grover, S. Aggarwal, R. Gupta, and N. Pandit, "Effect of insertion of xanthan-based chlor-hexidine gel in the maintenance phase following the treatment of chronic periodontitis," J. Indian Soc. Periodontol., vol. 16, no. 3, pp. 381-385, 2012. doi: 10.4103/0972-124X.100916. DOI: https://doi.org/10.4103/0972-124X.100916

P. Matesanz, D. Herrera, A. Echeverría, A. O’Connor, I. González, and M. Sanz, "A randomized clinical trial on the clinical and microbiological efficacy of a xanthan gel with chlorhexidine for subgingival use," Clin. Oral Investig., vol. 17, pp. 55-66, 2013. doi: 10.1007/s00784-012-0685-5. DOI: https://doi.org/10.1007/s00784-012-0685-5

A. S. Chauhan, V. K. Bains, V. Gupta, G. Singh, and S. S. Patil, "Comparative analysis of hyaluronan gel and xan-than-based chlorhexidine gel, as adjunct to scaling and root planing with scaling and root planing alone in the treat-ment of chronic periodontitis: A preliminary study," Contemp. Clin. Dent., vol. 4, no. 1, pp. 54-61, 2013. doi: 10.4103/0976-237X.111619. DOI: https://doi.org/10.4103/0976-237X.111619

M. T. Chitsazi, A. Kashefimehr, R. Pourabbas, A. Shirmohammadi, V. G. Barghi, and B. D. Azar, "Efficacy of sub-gingival application of xanthan-based chlorhexidine gel adjunctive to full-mouth root planing assessed by Real-time PCR: A microbiologic and clinical study," J. Dent. Res. Dent Clin. Dent. Prosp., vol. 7, no. 2, p. 95, 2013. doi: 10.5681/joddd.2013.017.

M. Jain, D. Dave, P. Jain, B. Manohar, B. Yadav, and N. Shetty, "Efficacy of xanthan based chlorhexidine gel as an adjunct to scaling and root planing in treatment of the chronic periodontitis," J. Indian Soc. Periodontol., vol. 17, no. 4, pp. 439-443, 2013. doi: 10.4103/0972-124X.118313. DOI: https://doi.org/10.4103/0972-124X.118313

M. Phogat, T. Rana, N. Prasad, and C. Baiju, "Comparative evaluation of subgingivally delivered xanthan-based chlorhexidine gel and herbal extract gel in the treatment of chronic periodontitis," J. Indian Soc. Periodontol., vol. 18, no. 2, pp. 172-177, 2014. doi: 10.4103/0972-124X.131319. DOI: https://doi.org/10.4103/0972-124X.131319

J. Lecic et al., "Different methods for subgingival application of chlorhexidine in the treatment of patients with chronic periodontitis," Acta Odontol. Scand., vol. 74, no. 6, pp. 502-507, 2016. doi: 10.1080/00016357.2016.1206964. DOI: https://doi.org/10.1080/00016357.2016.1206964

M. Faramarzi, A. Shirmohammadi, M. Chitsazi, M. S. Shamami, and S. Ghanitab, "The clinical and metabolic effects of subgingival application of xanthan-based chlorhexidine gel in Type 2 diabetic patients with chronic periodontitis," Dent.Res. J., vol. 14, no. 5, p. 299, 2017. doi: 10.4103/1735-3327.215961. DOI: https://doi.org/10.4103/1735-3327.215961

M. Quirynen et al., "Benefit of 'one‐stage full‐mouth disinfection' is explained by disinfection and root planing within 24 hours: a randomized controlled trial," J. Clin. Periodontol., vol. 33, no. 9, pp. 639-647, 2006. doi: 10.1111/j.1600-051X.2006.00959.x. DOI: https://doi.org/10.1111/j.1600-051X.2006.00959.x

K. Swierkot, C. I. Nonnenmacher, R. Mutters, L. Flores‐de‐Jacoby, and R. Mengel, "One‐stage full‐mouth disinfection versus quadrant and full‐mouth root planing," J. Clin. Periodontol.y, vol. 36, no. 3, pp. 240-249, 2009. doi: 10.1111/j.1600-051X.2008.01368.x. DOI: https://doi.org/10.1111/j.1600-051X.2008.01368.x

V. R. Santos et al., "Full‐mouth disinfection as a therapeutic protocol for type‐2 diabetic subjects with chronic perio-dontitis: Twelve‐month clinical outcomes. A randomized controlled clinical trial," J. Clin. Periodontol., vol. 40, no. 2, pp. 155-162, 2013. doi: : 10.1111/jcpe.12040. DOI: https://doi.org/10.1111/jcpe.12040

D. C. Fonseca et al., "Clinical and microbiologic evaluation of scaling and root planing per quadrant and one‐stage full‐mouth disinfection associated with azithromycin or chlorhexidine: a clinical randomized controlled trial," J. Peri-odontol., vol. 86, no. 12, pp. 1340-1351, 2015. doi: : 10.1902/jop.2015.150227. DOI: https://doi.org/10.1902/jop.2015.150227

C. B. Walker et al., "The effects of sustained release doxycycline on the anaerobic flora and antibiotic‐resistant pat-terns in subgingival plaque and saliva," J. Periodontol., vol. 71, no. 5, pp. 768-774, 2000. doi: 10.1902/jop.2000.71.5.768. DOI: https://doi.org/10.1902/jop.2000.71.5.768

G. V. Kulkarni, W. K. Lee, S. Aitken, P. Birek, and C. A. McCulloch, "A randomized, placebo‐controlled trial of doxycycline: effect on the microflora of recurrent periodontitis lesions in high risk patients," J. Periodontol., vol. 62, no. 3, pp. 197-202, 1991. doi: 10.1902/jop.1991.62.3.197. DOI: https://doi.org/10.1902/jop.1991.62.3.197

A. M. Polson et al., "Multi‐center comparative evaluation of subgingivally delivered sanguinarine and doxycycline in the treatment of periodontitis. I. Study design, procedures, and management," J. Periodontol., vol. 68, no. 2, pp. 110-118, 1997. doi: 10.1902/jop.1997.68.2.110. DOI: https://doi.org/10.1902/jop.1997.68.2.110

M. I. Ryder et al., "Effects of smoking on local delivery of controlled‐release doxycycline as compared to scaling and root planing," J. Clin. Periodontol., vol. 26, no. 10, pp. 683-691, 1999. doi: 10.1034/j.1600-051x.1999.261008.x. DOI: https://doi.org/10.1034/j.1600-051X.1999.261008.x

J. L. Wennström et al., "Utilisation of locally delivered doxycycline in non-surgical treatment of chronic periodontitis," J. Clin. Periodontol., vol. 28, no. 8, pp. 753-761, 2001, doi: 10.1034/j.1600-051X.2001.280806.x. DOI: https://doi.org/10.1034/j.1600-051X.2001.280806.x

L. Machion et al., "Locally Delivered Doxycycline as an Adjunctive Therapy to Scaling and Root Planing in the Treat-ment of Smokers: A Clinical Study," J. Periodontol., vol. 75, no. 3, pp. 464-469, 2004, doi: 10.1902/jop.2004.75.3.464. DOI: https://doi.org/10.1902/jop.2004.75.3.464

C. Tomasi and J. L. Wennström, "Locally delivered doxycycline improves the healing following non‐surgical perio-dontal therapy in smokers," J. Clin. Periodontol., vol. 31, no. 8, pp. 589-595, 2004. doi: 10.1111/j.1600-051X.2004.00524.x. DOI: https://doi.org/10.1111/j.1600-051X.2004.00524.x

A. Bogren, R. P. Teles, G. Torresyap, A. D. Haffajee, S. S. Socransky, and J. L. Wennström, "Locally Delivered Doxycycline During Supportive Periodontal Therapy: A 3-Year Study," J. Periodontol., vol. 79, no. 5, pp. 827-835, 2008, doi: 10.1902/jop.2008.070515. DOI: https://doi.org/10.1902/jop.2008.070515

C. Tomasi, T. Koutouzis, and J. L. Wennström, "Locally Delivered Doxycycline as an Adjunct to Mechanical Deb-ridement at Retreatment of Periodontal Pockets," J. Periodontol., vol. 79, no. 3, pp. 431-439, 2008, doi: 10.1902/jop.2008.070383. DOI: https://doi.org/10.1902/jop.2008.070383

H. Al Hulami, N. Babay, F. Awartani, and S. Anil, "The effect of locally delivered doxycycline as an adjunctive ther-apy to scaling and root planing in smokers," Saudi Dent. J., vol. 23, no. 3, pp. 143-148, 2011. doi: 10.1016/j.sdentj.2011.04.001. DOI: https://doi.org/10.1016/j.sdentj.2011.04.001

Y. Sandhya, M. Prabhuji, and R. V. Chandra, "Comparative evaluation of the efficacy of 10% doxycycline hyclate in the periodontal treatment of smokers—A clinical and microbiological study," Oral Health Prev. Dent., vol. 9, no. 1, pp. 59-65, 2011. doi: 10.3290/j.ohpd.a21286.

C. Tomasi and J. L. Wennström, "Locally Delivered Doxycycline as an Adjunct to Mechanical Debridement at Re-treatment of Periodontal Pockets: Outcome at Furcation Sites," J. Periodontol., vol. 82, no. 2, pp. 210-218, 2011, doi: 10.1902/jop.2010.100308. DOI: https://doi.org/10.1902/jop.2010.100308

S. K. Rao, S. Setty, A. B. Acharya, and S. L. Thakur, "Efficacy of locally-delivered doxycycline microspheres in chron-ic localized periodontitis and on Porphyromonas gingivalis," J. Investig. Clin. Dent., vol. 3, no. 2, pp. 128-134, 2012, doi: 10.1111/j.2041-1626.2011.00110.x. DOI: https://doi.org/10.1111/j.2041-1626.2011.00110.x

M. Madi, V. Pavlic, W. Samy, and A. Alagl, "The anti-inflammatory effect of locally delivered nano-doxycycline gel in therapy of chronic periodontitis," Acta Odontol. Scand., vol. 76, no. 1, pp. 71-76, 2018/01/02 2018, doi: 10.1080/00016357.2017.1385096. DOI: https://doi.org/10.1080/00016357.2017.1385096

N. Jain et al., "Recent approaches for the treatment of periodontitis," Drug Discov. Today, vol. 13, no. 21-22, pp. 932-943, 2008. doi: 10.1016/j.drudis.2008.07.010. DOI: https://doi.org/10.1016/j.drudis.2008.07.010

N. Sadaf, B. Anoop, B. Dakshina, and B. Shweta, "Evaluation of efficacy of tetracycline fibers in conjunction with scaling and root planing in patients with chronic periodontitis," J. Indian Soc. Periodontol., vol. 16, no. 3, pp. 392-397, 2012. doi: 10.4103/0972-124X.100918. DOI: https://doi.org/10.4103/0972-124X.100918

B. S. Michalowicz et al., "Evaluation of periodontal treatments using controlled‐release tetracycline fibers: Mainte-nance response," J. Periodontol., vol. 66, no. 8, pp. 708-715, 1995. doi: 10.1902/jop.1995.66.8.708. DOI: https://doi.org/10.1902/jop.1995.66.8.708

D. Kinane and M. Radvar, "A six‐month comparison of three periodontal local antimicrobial therapies in persistent periodontal pockets," J. Periodontol., vol. 70, no. 1, pp. 1-7, 1999. doi: 10.1902/jop.1999.70.1.1. DOI: https://doi.org/10.1902/jop.1999.70.1.1

S. Singh, S. Roy, and S. Chumber, "Evaluation of two local drug delivery systems as adjuncts to mechanotherapy as compared to mechanotherapy alone in management of chronic periodontitis: A clinical, microbiological, and molecu-lar study," J. Indian Soc. Periodontol., vol. 13, no. 3, pp. 126-132, 2009. doi: 10.4103/0972-124X.60224. DOI: https://doi.org/10.4103/0972-124X.60224

S. Sachdeva and V. Agarwal, "Evaluation of commercially available biodegradable tetracycline fiber therapy in chron-ic periodontitis," J. Indian Soc. Periodontol., vol. 15, no. 2, pp. 130-134, 2011. doi: 10.4103/0972-124X.84381. DOI: https://doi.org/10.4103/0972-124X.84381

F. Y. Khan, S. M. Jan, and M. Mushtaq, "Clinical utility of locally-delivered collagen-based biodegradable tetracycline fibers in periodontal therapy: an in vivo study," J. Investig. Clin. Dent., vol. 6, no. 4, pp. 307-312, 2015, doi: 10.1111/jicd.12111. DOI: https://doi.org/10.1111/jicd.12111

D. Mitchell, "Metronidazole: its use in clinical dentistry," J. Clin. Periodontol., vol. 11, no. 3, pp. 145-158, 1984. doi: 10.1111/j.1600-051x.1984.tb01318.x. DOI: https://doi.org/10.1111/j.1600-051X.1984.tb01318.x

P. K. Miani, "Avaliação de um gel contendo metronidazol para o tratamento adjuvante da periodontite crônica," Universidade de São Paulo, 2010. doi: 10.11606/T.58.2010.tde-06122010-154131. DOI: https://doi.org/10.11606/T.58.2010.tde-06122010-154131

A. D. Haffajee, S. S. Socransky, and J. C. Gunsolley, "Systemic anti‐infective periodontal therapy. A systematic re-view," Ann. Periodontol., vol. 8, no. 1, pp. 115-181, 2003. doi: 10.1902/annals.2003.8.1.115. DOI: https://doi.org/10.1902/annals.2003.8.1.115

. Yeung, H. Newman, and M. Addy, "Subgingival metronidazole in acrylic resin vs. chlorhexidine irrigation in the control of chronic periodontitis," J. Periodontol. vol. 54, no. 11, pp. 651-657, 1983. doi: 10.1902/jop.1983.54.11.651. DOI: https://doi.org/10.1902/jop.1983.54.11.651

W. Wan Yusof, H. Newman, J. Strahan, and J. Coventry, "Subgingival metronidazole in dialysis tubing and subgingi-val chlorhexidine irrigation in the control of chronic inflammatory periodontal disease," J. Clin. Periodontol., vol. 11, no. 3, pp. 166-175, 1984. doi: 10.1111/j.1600-051x.1984.tb01320.x. DOI: https://doi.org/10.1111/j.1600-051X.1984.tb01320.x

I. Aziz‐Gandour and H. Newman, "The effects of a simplified oral hygiene regime plus supragingival irrigation with chlorhexidine or metronidazole on chronic inflammatory periodontal disease," J. Clin. Periodontol., vol. 13, no. 3, pp. 228-236, 1986. doi: 10.1111/j.1600-051x.1986.tb01465.x. DOI: https://doi.org/10.1111/j.1600-051X.1986.tb01465.x

C. Hitzig et al., "Topical metronidazole as an adjunct to subgingival debridement in the treatment of chronic perio-dontitis," J. Clin. Periodontol., vol. 21, no. 2, pp. 146-151, 1994. doi: 10.1111/j.1600-051x.1994.tb00293.x. DOI: https://doi.org/10.1111/j.1600-051X.1994.tb00293.x

M. Stelzel and L. Flores‐de‐Jacoby, "Topical metronidazole application in recall patients," J. Clin. Periodontol., vol. 24, no. 12, pp. 914-919, 1997. doi: 10.1111/j.1600-051x.1997.tb01211.x. DOI: https://doi.org/10.1111/j.1600-051X.1997.tb01211.x

T. Lie, G. Bruun, and O. E. Böe, "Effects of topical metronidazole and tetracycline in treatment of adult periodonti-tis," J. Periodontol., vol. 69, no. 7, pp. 819-827, 1998. doi: 10.1902/jop.1998.69.7.819. DOI: https://doi.org/10.1902/jop.1998.69.7.819

R. Palmer, J. Matthews, and R. Wilson, "Adjunctive systemic and locally delivered metronidazole in the treatment of periodontitis: a controlled clinical study," Br. Dent. J., vol. 184, no. 11, pp. 548-552, 1998. doi: 10.1038/sj.bdj.4809695. DOI: https://doi.org/10.1038/sj.bdj.4809695

M. Stelzel and L. Florès‐de‐Jacoby, "Topical metronidazole application as an adjunct to scaling and root planing," J. Clin. Periodontol., vol. 27, no. 6, pp. 447-452, 2000. doi: 10.1034/j.1600-051x.2000.027006447.x. DOI: https://doi.org/10.1034/j.1600-051x.2000.027006447.x

G. Griffiths, G. Smart, J. Bulman, G. Weiss, J. Shrowder, and H. Newman, "Comparison of clinical outcomes follow-ing treatment of chronic adult periodontitis with subgingival scaling or subgingival scaling plus metronidazole gel," J. Clin. Periodontol., vol. 27, no. 12, pp. 910-917, 2000. doi: 10.1034/j.1600-051x.2000.027012910.x. DOI: https://doi.org/10.1034/j.1600-051x.2000.027012910.x

G. J. Linden and H. N. Newman, "The effects of subgingival irrigation with low dosage metronidazole on periodontal inflammation," J. Clin. Periodontol., vol. 18, no. 3, pp. 177-181, 1991. doi: 10.1111/j.1600-051x.1991.tb01130.x. DOI: https://doi.org/10.1111/j.1600-051X.1991.tb01130.x

H. Akıncıbay, S. Şenel, and Z. Yetkin Ay, "Application of chitosan gel in the treatment of chronic periodontitis," J. Biomed. Mater. Res B Appl. Biomater., vol. 80B, no. 2, pp. 290-296, 2007, doi: 10.1002/jbm.b.30596. DOI: https://doi.org/10.1002/jbm.b.30596

T. Leiknes, K. N. Leknes, O. E. Böe, R. J. Skavland, and T. Lie, "Topical Use of a Metronidazole Gel in the Treatment of Sites With Symptoms of Recurring Chronic Inflammation," J. Periodontol., vol. 78, no. 8, pp. 1538-1544, 2007, doi: 10.1902/jop.2007.060501. DOI: https://doi.org/10.1902/jop.2007.060501

N. Pandit, R. Dahiya, R. Gupta, D. Bali, and A. Kathuria, "Comparative evaluation of locally delivered minocycline and metronidazole in the treatment of periodontitis," Contemp. Clin. Dent., vol. 4, no. 1, pp. 48-53, 2013, doi: 10.4103/0976-237x.111615. DOI: https://doi.org/10.4103/0976-237X.111615

T. P. Paul, R. Emmatty, J. J. Pulikkottil, A. A. Rahman, S. A. Kumar, and N. George, "Comparative Evaluation of Sustained Release Collagen Device Containing 5% Metronidazole (Metrogene) along With and Without Scaling and Root Planing at Regular Intervals with Treatment of Chronic Periodontitis: A Case Control Study," (in eng), J. Int. Oral Health, vol. 7, no. 6, pp. 18-22, 2015. PMID: 26124594.

C. C. Bergamaschi et al., "Full mouth periodontal debridement with or without adjunctive metronidazole gel in smok-ing patients with chronic periodontitis: A pilot study," J. Periodontal Res., vol. 51, no. 1, pp. 50-59, 2016, doi: doi.org/10.1111/jre.12278. DOI: https://doi.org/10.1111/jre.12278