Professionally Delivered Local Antimicrobials in the Treatment of Patients with Periodontitis-A Narrative Review

Amar Sholapurkar, Dileep Sharma, Beverley Glass, Catherine Miller, Alan Nimmo, Ernest Jennings, Amar Sholapurkar, Dileep Sharma, Beverley Glass, Catherine Miller, Alan Nimmo, Ernest Jennings

Abstract

This review sheds light on the recent published scientific evidence relating to the use of professionally delivered local antimicrobial agents (LA's). The review also analyses drug delivery systems available to date and provides an update on the latest scientific evidence about the benefits, limitations, and clinical results obtained by use of local drugs in the treatment of periodontal disease. The search strategy revealed randomized controlled trials (RCTs) that compared the efficacy of adjunctive LA's to mechanical therapy alone. Based on the available evidence gathered from this review, we can infer that the use of local antimicrobial agents in conjunction to scaling and root debridement (SRD) delivers significant benefits in periodontal therapy and it is a useful aid, avoiding many of the side effects that systemic antibiotic therapy may involve. Local drug delivery (LDD) is an efficient and effective means of delivering drugs based on the evidence presented in the review. The authors of this review would suggest the use of local antimicrobials in cases of localized periodontitis or individual areas that do not respond to the usual mechanical therapy alone. This review summarizes the current use of local drug delivery in periodontal management ensuring that the general practitioners are able to choose an appropriate local antimicrobial.

Keywords: local antibiotics; local antimicrobials; local drug delivery; periodontal therapy; periodontal treatment; periodontitis; scaling and root debridement; scaling and root planning; topical oral antibiotic.

Conflict of interest statement

The authors declare no conflict of interest.

References

    1. Pradeep A.R., Sagar S.V., Daisy H. Clinical and Microbiologic Effects of Subgingivally Delivered 0.5% Azithromycin in the Treatment of Chronic Periodontitis. J. Periodontol. 2008;79:2125–2135. doi: 10.1902/jop.2008.070589.
    1. Cantore S., Mirgaldi R., Ballini A., Coscia M.F., Scacco S., Papa F., Inchingolo F., DiPalma G., De Vito D. Cytokine Gene Polymorphisms Associate with Microbiogical Agents in Periodontal Disease: Our Experience. Int. J. Med. Sci. 2014;11:674–679. doi: 10.7150/ijms.6962.
    1. Pradeep A.R., Bajaj P., Agarwal E., Rao N.S., Naik S.B., Kalra N., Priyanaka N. Local drug delivery of 0.5% azithromycin in the treatment of chronic periodontitis among smokers. Aust. Dent. J. 2013;58:34–40. doi: 10.1111/adj.12019.
    1. Walker C., Karpinia K. Rationale for Use of Antibiotics in Periodontics. J. Periodontol. 2002;73:1188–1196. doi: 10.1902/jop.2002.73.10.1188.
    1. Steinberg D., Friedman M., Soskolne A., Sela M.N. A New Degradable Controlled Release Device for Treatment of Periodontal Disease: In Vitro Release Study. J. Periodontol. 1990;61:393–398. doi: 10.1902/jop.1990.61.7.393.
    1. Rabbani G.M., Ash M.M., Jr., Caffesse R.G. The Effectiveness of Subgingival Scaling and Root Planing in Calculus Removal. J. Periodontol. 1981;52:119–123. doi: 10.1902/jop.1981.52.3.119.
    1. Eastham J.E., Seymour R.A. Local drug delivery in the management of periodontal diseases part 2: Specific agents. Dent. Update. 2014;41:796–810. doi: 10.12968/denu.2014.41.9.796.
    1. Jorgensen M.G., Slots J. Responsible use of antimicrobials in periodontics. J. Calif. Dent. Assoc. 2000;28:185–193.
    1. Greenstein G., Polson A. The Role of Local Drug Delivery in the Management of Periodontal Diseases: A Comprehensive Review. J. Periodontol. 1998;69:507–520. doi: 10.1902/jop.1998.69.5.507.
    1. Rajeshwari H.R., Dhamecha D., Jagwani S., Rao M., Jadhav K., Shaikh S., Puzhankara L., Jalalpure S. Local drug delivery systems in the management of periodontitis: A scientific review. J. Control. Release. 2019;307:393–409. doi: 10.1016/j.jconrel.2019.06.038.
    1. Daudt F.A., Rösing C.K., Chiapinotto G.A., Oppermann R.V. Effect of the topical application of triclosan in periodontally treated patients. Acta Odontol. Latinoam. 2011;24:205–210.
    1. Vitt A., Gustafsson A., Ramberg P., Slizen V., Kazeko L.A., Buhlin K. Polyhexamethylene guanidine phosphate irrigation as an adjunctive to scaling and root planing in the treatment of chronic periodontitis. Acta Odontol. Scand. 2019;77:290–295. doi: 10.1080/00016357.2018.1541099.
    1. Sindhura H., Harsha R.H., Shilpa R.H. Efficacy of subgingival irrigation with 10% povidone-iodine as an adjunct to scaling and root planing: A clinical and microbiological study. Indian J. Dent. Res. 2017;28:514–518. doi: 10.4103/ijdr.IJDR_497_15.
    1. Denez E.-M., Toma S., Lasserre J.F., Brecx M.C. Evaluation of a unique subgingival irrigation with 10% povidone-iodine after scaling and root planing: A randomized clinical trial. Quintessence Int. 2016;47:549–558.
    1. Sahrmann P., Imfeld T., Ronay V., Attin T., Schmidlin P.R. Povidone-iodine gel and solution as adjunct to ultrasonic debridement in nonsurgical periodontitis treatment: An RCT pilot study. Quintessence Int. 2014;45:281–290.
    1. Sahrmann P., Manz A., Attin T., Zbinden R., Schmidlin P.R. Effect of application of a PVP-iodine solution before and during subgingival ultrasonic instrumentation on post-treatment bacteraemia: A randomized single-centre placebo-controlled clinical trial. J. Clin. Periodontol. 2015;42:632–639. doi: 10.1111/jcpe.12416.
    1. Galván M., Gonzalez S., Cohen C.L., Alonaizan F.A., Chen C.T.-L., Rich S.K., Slots J. Periodontal effects of 0.25% sodium hypochlorite twice-weekly oral rinse. A pilot study. J. Periodontal Res. 2013;49:696–702. doi: 10.1111/jre.12151.
    1. Saglam M., Arslan U., Bozkurt S.B., Hakki S.S. Boric Acid Irrigation as an Adjunct to Mechanical Periodontal Therapy in Patients with Chronic Periodontitis: A Randomized Clinical Trial. J. Periodontol. 2013;84:1297–1308. doi: 10.1902/jop.2012.120467.
    1. Al Habashneh R., Alsalman W., Khader Y. Ozone as an adjunct to conventional nonsurgical therapy in chronic periodontitis: A randomized controlled clinical trial. J. Periodontal Res. 2015;50:37–43. doi: 10.1111/jre.12177.
    1. Soskolne W.A. Subgingival Delivery of Therapeutic Agents in the Treatment of Periodontal Diseases. Crit. Rev. Oral Biol. Med. 1997;8:164–174. doi: 10.1177/10454411970080020501.
    1. Medlicott N.J. Delivery systems for the administration of the drugs to the periodontal pocket. Adv. Drug Deliv. Rev. 1994;13:181–203. doi: 10.1016/0169-409X(94)90033-7.
    1. Vyas S.P., Sihorkar V., Mishra V. Controlled and targeted drug delivery strategies towards intraperiodontal pocket diseases. J. Clin. Pharm. Ther. 2000;25:21–42. doi: 10.1046/j.1365-2710.2000.00261.x.
    1. Agarwal V., Sachdeva S. Evaluation of commercially available biodegradable tetracycline fiber therapy in chronic periodontitis. J. Indian Soc. Periodontol. 2011;15:130–134. doi: 10.4103/0972-124X.84381.
    1. Meharwade V.V., Gayathri G.V., Mehta D.S. Effects of scaling and root planing with or without a local drug delivery system on the gingival crevicular fluid leptin level in chronic periodontitis patients: A clinico-biochemical study. J. Periodontal Implant. Sci. 2014;44:118–125. doi: 10.5051/jpis.2014.44.3.118.
    1. Khan F.Y., Jan S.M., Mushtaq M. Clinical utility of locally-delivered collagen-based biodegradable tetracycline fibers in periodontal therapy: Anin vivostudy. J. Investig. Clin. Dent. 2014;6:307–312. doi: 10.1111/jicd.12111.
    1. Chhina S., Rathore A.S., Juneja S. Alpha-2-Macroglobulin Levels in Gingival Crevicular Fluid Pre- and Post-scaling and Root Planing with Adjunctive Tetracycline Fibers in Chronic Periodontitis: A Randomized Controlled Trial. J. Contemp. Dent. Pract. 2015;16:474–478. doi: 10.5005/jp-journals-10024-1709.
    1. Gill J.S., Bharti V., Gupta H., Gill S. Non-surgical management of chronic periodontitis with two local drug delivery agents-A comparative study. J. Clin. Exp. Dent. 2011;3:424–429. doi: 10.4317/jced.3.e424.
    1. Puri K., Puri N. Local drug delivery agents as adjuncts to endodontic and periodontal therapy. J. Med. Life. 2013;6:414–419.
    1. Konuganti K., Kumar A. Efficacy of subgingivally delivered flurbiprofen and chlorhexidine chip in the treatment of chronic periodontitis—A randomized controlled clinical trial. Int. J. Pharm. Sci. Rev. Res. 2016;40:149–153.
    1. Gonzales J.R., Harnack L., Schmitt-Corsitto G., Boedeker R.H., Chakraborty T., Domann E., Meyle J. A Novel Approach to the Use of Subgingival Controlled-Release Chlorhexidine Delivery in Chronic Periodontitis: A Randomized Clinical Trial. J. Periodontol. 2011;82:1131–1139. doi: 10.1902/jop.2011.100287.
    1. Pattnaik S., Anand N., Chandrasekaran S.C., Chandrashekar L., Mahalakshmi K., Satpathy A. Clinical and antimicrobial efficacy of a controlled-release device containing chlorhexidine in the treatment of chronic periodontitis. Eur. J. Clin. Microbiol. Infect. Dis. 2015;34:2103–2110. doi: 10.1007/s10096-015-2459-x.
    1. Reddy B.V.R., Chava V.K., Kumar A.J. Effect of chlorhexidine chip in the treatment of chronic periodontitis. J. Nat. Sci. Biol. Med. 2014;5:268–272. doi: 10.4103/0976-9668.136159.
    1. Grover V., Kapoor A., Malhotra R., Battu V.S., Bhatia A., Sachdeva S. To assess the effectiveness of a chlorhexidine chip in the treatment of chronic periodontitis: A clinical and radiographic study. J. Indian Soc. Periodontol. 2011;15:139–146. doi: 10.4103/0972-124X.84383.
    1. Carvalho J., Novak M.J., Mota L.F. Evaluation of effect of subgingival placement of chlorhexidine chips as an adjunct to scaling and root planing. J. Periodontol. 2007;78:997–1001. doi: 10.1902/jop.2007.060122.
    1. Lecic J., Cakic S., Pavlovic O.J., Cicmil A., Vukotic O., Petrovic V., Cicmil S. Different methods for subgingival application of chlorhexidine in the treatment of patients with chronic periodontitis. Acta Odontol. Scand. 2016;74:502–507. doi: 10.1080/00016357.2016.1206964.
    1. Jain M., Dave D., Jain P., Manohar B., Yadav B., Shetty N. Efficacy of xanthan based chlorhexidine gel as an adjunct to scaling and root planing in treatment of the chronic periodontitis. J. Indian Soc. Periodontol. 2013;17:439–443. doi: 10.4103/0972-124X.118313.
    1. Matesanz P., Herrera D., Echeverría A., O’Connor A., González I., Sanz M. A randomized clinical trial on the clinical and microbiological efficacy of a xanthan gel with chlorhexidine for subgingival use. Clin. Oral Investig. 2012;17:55–66. doi: 10.1007/s00784-012-0685-5.
    1. Shamami M.S., Faramarzi M., Shirmohmmadi A., Chitsazi M., Ghanitab S. The clinical and metabolic effects of subgingival application of xanthan-based chlorhexidine gel in Type 2 diabetic patients with chronic periodontitis. Dent. Res. J. 2016;14:299–305. doi: 10.4103/1735-3327.215961.
    1. Chandra C., Chandra S. Effect of chlosite (xanthan gel with chlorhexidine) on clinical & microbiological parameters in smokers—A case series. Indian J. Forensic Med. Toxicol. 2010;4:39–41.
    1. Da Rocha H.A.J., Silva C.F., Santiago F.L., Martins L.G., Dias P.C., De Magalhães D. Local Drug Delivery Systems in the Treatment of Periodontitis: A Literature Review. J. Int. Acad. Periodontol. 2015;17:82–90.
    1. Sandhya Y.P., Prabhuji M.L., Chandra R.V. Comparative evaluation of the efficacy of 10% doxycycline hyclate in the periodontal treatment of smokers—A clinical and microbiological study. Oral Health Prev. Dent. 2011;9:59–65.
    1. Jalaluddin, Ahamed S., Khalid I., Moon N., Shafi T.K., Ali F.M. The Use of Controlled Release Locally Delivered 10% Doxycycline Hyclate Gel as an adjunct to Scaling and Root Planing in the Treatment of Chronic Periodontitis: Clinical and Microbiological Results. J. Contemp. Dent. Pract. 2013;14:1080–1086. doi: 10.5005/jp-journals-10024-1455.
    1. Tonetti M., Lang N.P., Cortellini P., Suvan J.E., Eickholz P., Fourmousis I., Topoll H., Vangsted T., Wallkamm B., on behalf of the European Research Group on Periodontology (ErgoPerio) Effects of a single topical doxycycline administration adjunctive to mechanical debridement in patients with persistent/recurrent periodontitis but acceptable oral hygiene during supportive periodontal therapy. J. Clin. Periodontol. 2012;39:475–482. doi: 10.1111/j.1600-051X.2012.01864.x.
    1. Calderini A., Pantaleo G., Rossi A., Gazzolo D., Polizzi E. Adjunctive effect of chlorhexidine antiseptics in mechanical periodontal treatment: First results of a preliminary case series. Int. J. Dent. Hyg. 2013;11:180–185. doi: 10.1111/idh.12009.
    1. Phogat M., Rana T., Prasad N., Baiju C.S. Comparative evaluation of subgingivally delivered xanthan-based chlorhexidine gel and herbal extract gel in the treatment of chronic periodontitis. J. Indian Soc. Periodontol. 2014;18:172–177. doi: 10.4103/0972-124X.131319.
    1. Rusu D., Stratul S.-I., Sarbu C., Roman A., Anghel A., Didilescu A., Jentsch H. Evaluation of a hydrophobic gel adhering to the gingiva in comparison with a standard water-soluble 1% chlorhexidine gel after scaling and root planing in patients with moderate chronic periodontitis. A randomized clinical trial. Int. J. Dent. Hyg. 2015;15:53–64. doi: 10.1111/idh.12155.
    1. Jain R., Mohamed F., Hemalatha M. Minocycline containing local drug delivery system in the management of chronic periodontitis: A randomized controlled trial. J. Indian Soc. Periodontol. 2012;16:179–183. doi: 10.4103/0972-124X.99259.
    1. Agarwal E., Pradeep A.R., Bajaj P., Naik S.B. Efficacy of Local Drug Delivery of 0.5% Clarithromycin Gel as an Adjunct to Non-Surgical Periodontal Therapy in the Treatment of Current Smokers with Chronic Periodontitis: A Randomized Controlled Clinical Trial. J. Periodontol. 2012;83:1155–1163. doi: 10.1902/jop.2012.110600.
    1. Kathariya R., Pradeep A.R., Raghavendra N.M., Gaikwad R. Evaluation of subgingivally delivered 0.5% clarithromycin as an adjunct to nonsurgical mechanotherapy in the management of chronic periodontitis: A short-term double blinded randomized control trial. J. Investig. Clin. Dent. 2012;5:23–31. doi: 10.1111/jicd.12009.
    1. Bajaj P., Pradeep A.R., Agarwal E., Kumari M., Naik S.B. Locally delivered 0.5% clarithromycin, as an adjunct to nonsurgical treatment in chronic periodontitis with well-controlled type 2 diabetes: A randomized controlled clinical trial. J. Investig. Clin. Dent. 2012;3:276–283. doi: 10.1111/j.2041-1626.2012.00168.x.
    1. Agarwal E., Bajaj P., Naik S.B., Pradeep A.R. Locally Delivered 0.5% Azithromycin as an Adjunct to Non-Surgical Treatment in Patients With Chronic Periodontitis With Type 2 Diabetes: A Randomized Controlled Clinical Trial. J. Periodontol. 2017;88:1281–1287. doi: 10.1902/jop.2012.120172.
    1. Vaish S., Dodwad V., Tyagi P. Clinical efficacy of subgingivally delivered 0.5% controlled release azithromycin gel in the management of chronic periodontitis. Indian J. Med. Sci. 2011;65:223–230. doi: 10.4103/0019-5359.107017.
    1. Flemmig T.F., Petersilka G., Völp A., Gravemeier M., Zilly M., Mross D., Prior K., Yamamoto J., Beikler T. Efficacy and Safety of Adjunctive Local Moxifloxacin Delivery in the Treatment of Periodontitis. J. Periodontol. 2011;82:96–105. doi: 10.1902/jop.2010.100124.
    1. Miani P.K., do Nascimento C., Sato S., Filho A.V., da Fonseca M.J., Pedrazzi V. In vivo evaluation of a metronidazole-containing gel for the adjuvant treatment of chronic periodontitis: Preliminary results. Eur. J. Clin. Microbiol. Infect. Dis. 2011;31:1611–1618. doi: 10.1007/s10096-011-1484-7.
    1. Priyanka N., Kalra N., Saquib S., Kudyar N., Malgaonkar N., Jain H., Pradeep A.R. Clinical and microbiological efficacy of 3% satranidazole gel as a local drug delivery system in the treatment of chronic periodontitis: A randomized, controlled clinical trial. Contemp. Clin. Dent. 2015;6:364–370. doi: 10.4103/0976-237X.161891.
    1. Priyanka N., Kalra N., Saquib S., Saquib S., Malgaonkar N., Nikhil M., Tarakji B., Varsha J., Umashree D., Pradeep A.R. Efficacy of Subgingivally Delivered Satranidazole in the Treatment of Type 2 Diabetes Subjects with Chronic Periodontitis: A Randomized Controlled Clinical Trial. J. Int. Acad. Periodontol. 2015;17:42–48.
    1. Moura L.A., Ribeiro F.V., Aiello T.B., Duek E.A.D.R., Sallum E.A., Junior F.H.N., Casati M.Z., Sallum A.W. Characterization of the release profile of doxycycline by PLGA microspheres adjunct to non-surgical periodontal therapy. J. Biomater. Sci. Polym. Ed. 2015;26:573–584. doi: 10.1080/09205063.2015.1045249.
    1. Rao S.K., Setty S., Acharya A.B., Thakur S.L. Efficacy of locally-delivered doxycycline microspheres in chronic localized periodontitis and on Porphyromonas gingivalis. J. Investig. Clin. Dent. 2011;3:128–134. doi: 10.1111/j.2041-1626.2011.00110.x.
    1. Gad H.A., Kamel A.O., Ezzatt O.M., El Dessouky H.F., Sammour O.A. Doxycycline hydrochloride-metronidazole solid lipid microparticles gels for treatment of periodontitis: Development, in-vitro and in-vivo clinical evaluation. Expert Opin. Drug Deliv. 2017;14:1241–1251. doi: 10.1080/17425247.2017.1329297.
    1. Bland P.S., Goodson J.M., Gunsolley J.C., Grossi S.G., Otomo-Corgel J., Doherty F., Comiskey J.L. Association of antimicrobial and clinical efficacy: Periodontitis therapy with minocycline microspheres. J. Int. Acad. Periodontol. 2010;12:11–19.
    1. Chiappe V.B., Gómez M.V., Rodríguez C., Fresolone M., Romanelli H.J. Subgingivally applied minocycline microgranules in subjects with chronic periodontitis: A randomized clinical and microbiological trial. Acta Odontol. Latinoam. 2015;28:122–131.
    1. Srirangarajan S., Mundargi R.C., Ravindra S.B., Setty S., Aminabhavi T.M., Thakur S. Randomized, Controlled, Single-Masked, Clinical Study to Compare and Evaluate the Efficacy of Microspheres and Gel in Periodontal Pocket Therapy. J. Periodontol. 2011;82:114–121. doi: 10.1902/jop.2010.100324.
    1. Tabenski L., Moder D., Cieplik F., Schenke F., Hiller K.-A., Buchalla W., Schmalz G., Christgau M. Antimicrobial photodynamic therapy vs. local minocycline in addition to non-surgical therapy of deep periodontal pockets: A controlled randomized clinical trial. Clin. Oral Investig. 2017;21:2253–2264. doi: 10.1007/s00784-016-2018-6.
    1. Kilicarslan M., Gumustas M., Yildiz S., Baykara T. Preparation and characterization of chitosan-based spray-dried microparticles for the delivery of clindamycin phosphate to periodontal pockets. Curr. Drug Deliv. 2014;11:98–111. doi: 10.2174/15672018113109990055.
    1. Madi M., Pavlic V., Samy W., Alagl A. The anti-inflammatory effect of locally delivered nano-doxycycline gel in therapy of chronic periodontitis. Acta Odontol. Scand. 2017;76:71–76. doi: 10.1080/00016357.2017.1385096.
    1. Joshi D., Garg T., Goyal A.K., Rath G. Advanced drug delivery approaches against periodontitis. Drug Deliv. 2014;23:363–377. doi: 10.3109/10717544.2014.935531.
    1. Garg T., Goyal A.K. Liposomes: Targeted and Controlled Delivery System. Drug Deliv. Lett. 2014;4:62–71. doi: 10.2174/22103031113036660015.
    1. Garg T., Singh S., Goyal A.K. Stimuli-sensitive hydrogels: An excellent carrier for drug and cell delivery. Crit. Rev. Ther. Drug Carr. Syst. 2013;30:369–409. doi: 10.1615/CritRevTherDrugCarrierSyst.2013007259.
    1. Di Turi G., Riggio C., Vittorio O., Marconcini S., Briguglio F., Funel N., Campani D., Barone A., Raffa V., Covani U. Sub-micrometric liposomes as drug delivery systems in the treatment of periodontitis. Int. J. Immunopathol. Pharmacol. 2011;25:657–670. doi: 10.1177/039463201202500312.
    1. Liu D., Yang P. Minocycline hydrochloride nanoliposomes inhibit the production of TNF-a in LPS-stimulated macrophages. Int. J. Nanomed. 2012;7:4769–4775. doi: 10.2147/IJN.S34036.
    1. Vandana K.L., Latif S.A., Thimmashetty J., Dalvi P.J. Azithromycin buccal patch in treatment of chronic periodontitis. Indian J. Pharmacol. 2016;48:208–213. doi: 10.4103/0253-7613.178829.
    1. Venkatesh A., Ramamurthy J. Local drug delivery systems in the treatment of periodontitis—An overview. Int. J. Pharm. Pharm. Sci. 2012;4:30–37.
    1. Tomasi C., Wennström J.L. Locally Delivered Doxycycline as an Adjunct to Mechanical Debridement at Retreatment of Periodontal Pockets: Outcome at Furcation Sites. J. Periodontol. 2011;82:210–218. doi: 10.1902/jop.2010.100308.
    1. Abbas S., Mahendra J., Ari G. Minocycline Ointment as a Local Drug Delivery in the Treatment of Generalized Chronic Periodontitis—A Clinical Study. J. Clin. Diagn. Res. 2016;10:ZC15–ZC19. doi: 10.7860/JCDR/2016/19468.7930.
    1. Bharti P., Katagiri S., Nitta H., Nagasawa T., Kobayashi H., Takeuchi Y., Izumiyama H., Uchimura I., Inoue S., Izumi Y. Periodontal treatment with topical antibiotics improves glycemic control in association with elevated serum adiponectin in patients with type 2 diabetes mellitus. Obes. Res. Clin. Pract. 2013;7:e129–e138. doi: 10.1016/j.orcp.2011.11.005.
    1. Norling T., Lading P., Engström S., Larsson K., Krog N., Nissen S.S. Formulation of a drug delivery system based on a mixture of monoglycerides and triglycerides for use in the treatment of periodontal disease. J. Clin. Periodontol. 1992;19:687–692. doi: 10.1111/j.1600-051X.1992.tb02529.x.
    1. Leiknes T., Leknes K.N., Böe O.E., Skavland R.J., Lie T. Topical Use of a Metronidazole Gel in the Treatment of Sites with Symptoms of Recurring Chronic Inflammation. J. Periodontol. 2007;78:1538–1544. doi: 10.1902/jop.2007.060501.
    1. Bergamaschi C.C., Santamaria M.P., Berto L.A., Cogo-Müller K., Bergamaschi C.D.C., Salum E.A., Nociti F.H., Goodson J.M., Groppo F.C. Full mouth periodontal debridement with or without adjunctive metronidazole gel in smoking patients with chronic periodontitis: A pilot study. J. Periodontal Res. 2015;51:50–59. doi: 10.1111/jre.12278.

Source: PubMed

3
Abonneren