Locally Delivered Antimicrobials: Clinical Evidence and Relevance David W

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Locally Delivered Antimicrobials: Clinical Evidence and Relevance David W. Paquette, DMD, MPH, DMSc; Maria Emanuel Ryan, DDS, PhD; Rebecca S. Wilder, RDH, BS, MS

Introduction Abstract Periodontal disease is a common, mixed oral infection affecting the sup- Periodontitis is a common oral infection and inflammatory condition. porting structures around the teeth. Following treatment, residual or persistent periodontal inflammation is While 75% of the adult population has at associated with disease progression and tooth loss. Cumulative evi- least mild periodontal disease (gingivi- dence from clinical trials and meta-analyses support a complementary tis), 20%-30% exhibits the severe medical-mechanical model that combines locally delivered antimicrobials destructive form (chronic periodontitis).1 with scaling and root planing for the treatment of chronic periodontitis. Characteristically, the disease is silent Accordingly, greater pocket depth reductions and/or attachment level until the advanced stage when patients gains occur in patients treated with adjunctive locally administered may report symptoms like swelling antimicrobials (eg, tetracycline, chlorhexidine, doxycycline, and minocy- (abscess), discomfort, shifting of the cline). These responses are clinically relevant because they are accom- dentition, or tooth mobility. The clini- panied by a higher probability of patient maintenance or pocket resolu- cal signs of periodontitis emanate from tion. Recent trials also indicate that locally administered antimicrobials inflammatory and destructive changes may enhance the effects of periodontal surgical therapy and may reduce in the gingiva, connective tissues, alve- the signs of peri-implantitis. The consistency of these findings supports olar bone, periodontal ligament, and root the use of locally administered antimicrobials for managing dental cementum. These signs include the for- patients with chronic periodontitis. mation of periodontal pockets, loss of Keywords: periodontitis, antibiotics, antimicrobials, local delivery, peri- clinical attachment, and resorption of implantitis, scaling and root planing alveolar bone.2 Accordingly, periodontitis begins with a pathogenic shift in the bacterial flora around teeth. Gram-negative organisms, such as Porphyromonas gin- Longitudinal population studies indi- Complementary givalis, Tannerella forsythia, Treponema cate that these destructive changes (dis- denticola and Aggregatibacter (formally ease progression) are not continuous Medical-Mechanical Actinobacillus) actinomycetemcomi- over time but appear restricted to “ran- Treatment Model with tans, predominate in the subgingival dom bursts” of activity confined to short Adjunctive space and organize as a biofilm.3 Several intervals (6 months or less).5 Risk fac- Antimicrobials of the gram-negative bacteria in the tors associated with progressive peri- biofilm are particularly important odontitis include smoking, diabetes, Strategies for treating periodontitis because they have been identified as obesity, poor plaque control, and certain principally focus on addressing the etio- red-complex bacteria (T. forsythia, P. genetic polymorphisms.6-10 In addition, logic bacteria or biofilm.13,14 According to gingivalis, and T. denticola) and have residual or persistent deep probing the mechanical model, the bacterial bio- been linked with important parameters depths are associated with periodontitis film is disrupted and removed via scaling of periodontal diagnosis, such as pocket progression.11 Paulander and coworkers and root planing (SRP) procedures. These depth and bleeding on probing.3 This recently demonstrated that periodontitis debridement procedures can be accom- bacterial biofilm is in direct contact with subjects with moderate (4-5 mm) and plished nonsurgically or surgically, and host tissues along an ulcerated epithe- deep (> 6 mm) probing depths were 2 to both approaches result in pocket depth lial interface called a periodontal pocket. 3 times more likely to exhibit alveolar (PD) reductions in patients.15,16 In addi- Locally, bacteria and their products (eg, bone loss over 10 years.12 Similarly for tion, a number of adjunctive chemothera- lipopolysaccharide entotoxin) penetrate tooth loss, the odds ratio for moderate peutic approaches have been developed, host periodontal tissues and stimulate pockets was 2.9 (95% CI, 1.9-4.2), and tested and approved for use in patients host expression of inflammatory medi- the odds for deep pockets was 4.2 (95% with chronic periodontitis (Table 1). These ators like arachidonic acid metabolites CI, 2.4-7.3). These data imply pocket “locally delivered antimicrobials” follow (prostaglandin E2) and cytokines (inter- depth reduction (or resolution) is a clin- a complementary medical-mechanical leukin-1).4 These mediators in turn trig- ically important treatment goal to treatment model since they are used in ger local inflammatory and destructive ensure stability and maintenance in combination with SRP for enhanced effi- changes in the tissues. patients. cacy. These formulations typically cou-

10 The Journal of Dental Hygiene Special supplement Table 1. Summary of FDA-approved locally administered antimicrobials and clinical evidence from pivotal trials.

Locally Pivotal Number Administered Active Trial of Experimental Antimicrobial Agent Polymer Reference Subjects Treatment Controls Results

Periochip® Chlorhexidine Cross-linked 25 447 Periochip® plus Placebo chip Periochip® plus SRP significantly gluconnate hydrolyzed SRP (adjunct) plus SRP reduced PD and increased CAL at (2.5 mg) gelatin SRP alone 9 months compared to SRP alone. Atridox® Doxycycline poly DL- 29 411 Atridox® alone Placebo gel, Treatment with Atridox® alone (10% or lactide (monotherapy) SRP alone, produced improvements in PD and 50 mg) no treatment CAL at 9 months that were equiv- lent to SRP alone. Arestin® Minocycline Polyglycolide- 33 748 Arestin® plus Placebo Subjects treated with Arestin® plus (1 mg) co-dl-lactide SRP (adjunct) microspheres SRP exhibited significantly greater plus SRP, PD reductions at 1, 3, 6, and 9 SRP alone months versus SRP alone. ple an antimicrobial or antibiotic with a introduced to second generation locally Chlorhexidine gluconate chip has a doc- drug polymer that extends drug release delivered antimicrobials that are easier umented safety profile, and unlike within the periodontal pocket (controlled- to utilize and produce greater clinically chlorhexidine mouthrinse, does not release delivery).17 significant results. Following is a dis- cause any visible staining of teeth. A recent systematic review and meta- cussion about the 3 products currently analysis conducted by Hanes and available in the United States. coworkers demonstrated that adjunctive Doxycycline locally administered antimicrobials Bioresorbable Gel improved PD over SRP alone in chronic Chlorhexidine periodontitis patients.18 This group of Gluconate Chip Atridox® (Atrix Laboratories, Fort investigators searched electronic data- Collins, Colo, USA) is a 10% formula- bases and relevant dental journals and The PerioChip® (Dexcel Technolo- tion of doxycycline (50 mg) in a biore- identified 32 clinical studies fitting selec- gies Limited, Jerusalem, Israel) is a sorbable gel system (poly DL-lactide and tion criteria. The studies (28 randomized biodegradable gelatin-based polymer N-methyl-2-pyrrolidone mixture). The controlled clinical trials, 2 cohort, and 2 system containing the active antimicro- system is supplied as 2 pre-filled syringes case-control studies) represented a vari- bial, chlorhexidine gluconate (2.5 mg). that are mixed chair-side and applied sub- ety of locally administered antimicro- Each chlorhexidine (CHX)-gelatin gingivally to the base periodontal pock- bials (eg, minocycline, doxycycline, wafer or chip is placed subgingivally ets using a syringe. The “flowable” poly- tetracycline, metronidazole, and chlor- with cotton pliers. While pharmacoki- mer gel fills and conforms to pocket hexidine formulations). The resulting netic studies indicate that chlorhexidine morphology, then solidifies to a wax-like meta-analysis indicated an overall sig- is released from the system for 7-10 consistency upon contact with gingival nificant reduction in PD with adjunctive days in periodontal pockets, microbial crevicular fluid. Doxycycline is released local antimicrobials versus SRP alone. studies have shown suppression of the at effective concentrations over 7 days, These findings strongly support the use pocket flora for up to 11 weeks follow- and significant reductions (60%) in of locally administered antimicrobials in ing CHX chip treatment.20,21 In the phase anaerobic pathogens are sustained for up combination with SRP in patients with 3 clinical trials, CHX chip treatment to 6 months posttreatment.24,25 In subjects chronic periodontitis, especially those at plus SRP significantly reduced PD and with chronic periodontitis, the applica- risk for disease progression. maintained CAL at 9 months compared tion of doxycycline gel (at baseline and 4 The first local delivery system with SRP controls.22 Importantly, SRP months later) reduced PD (1.3 mm) and approved for use by the US Food and was limited in these trials to one hour of improved CAL (0.8 mm) comparable to Drug Administration (FDA) was called ultrasonic scaling. In addition, retreat- SRP alone at 9 months following treat- Actisite® (ALZA Corporation, Palo Alto, ment with CHX chip occurred at 3 and ment.26While current and former smokers Calif, USA) and was developed by Dr. 6 months at sites with residual pockets within the trials did not respond as well to Max Goodson in 1983.19 This product (> 5 mm). Nevertheless, after 9 months SRP alone, smoking status did not dimin- consisted of a nonresorbable polymer of adjunctive CHX chip treatment, no ish the clinical improvements observed fiber of ethyl vinyl acetate containing sites exhibited bone loss, and 25% of with doxycycline gel.27 While these stud- tetracycline hydrochloride (25% or 12.7 the sites exhibited bone gain as meas- ies demonstrated equivalency of doxy- mg). Each fiber (23 cm) was placed sub- ured with subtraction radiography.23 In cycline gel (monotherapy) with SRP and gingivally similar to retraction cord. contrast, 15% of periodontal sites treated supported regulatory approval, this sys- Since that time, clinicians have been with SRP alone exhibited bone loss. tem like other locally delivered antimi-

Special supplement The Journal of Dental Hygiene 11 crobials is conventionally used as an adjunct to SRP in clinical practice. One phase 4 or postmarketing trial investigated the use of doxycycline gel as an adjunct to SRP and demonstrated incremental benefits when the system was used in combination with SRP.28 Accordingly, one arm of the adjunctive use trial involved initiating treatment with ultrasonic scaling plus doxycycline gel at baseline, and then isolated SRP at 3 months for those sites with residual pocketing (PD > 5 mm). The second arm of the study involved SRP alone at baseline, and then isolated ultrasonic scaling and doxycycline gel at those sites with residual pocketing. While both treatment strategies were equally effective at improving probing depths and clinical attachment levels over 6 months, responses were Figure 2. Mean probing-depth reductions over nine greater on average for the adjunctive doxycycline gel months for periodontitis subjects treated with adjunctive treatment at 3 months compared to SRP alone. minocycline microspheres, adjunctive vehicle, or SRP alone. Adapted from Williams et al.30 Minocycline Microspheres

Arestin® (OraPharma, Inc., Warminster, Pa, USA) is an approved local delivery system featuring 1mg of minocycline hydrochloride microencapsu- lated in resorbable polymer microspheres (polyglycolide- Figure 1. Syringe co-dl-lactide). The delivery sys- handle and pre- tem (cartridge and syringe) is measured car- designed for quick and easy tridges for dispens- administration of one unit dose ing minocycline of Arestin subgingivally in microspheres. periodontal pockets measuring > 5 mm with bleeding on probing (BOP) (Figure 1). With this system, minocycline hydrochloride is maintained within pockets for 21 days at concentrations effective against periodontal pathogens. The agent may also Figure 3. Mean probing-depth reductions over nine block collagenases that are implicated in host tissue months for periodontitis subjects who smoke and were 29 breakdown. treated with minocycline, adjunctive vehicle, or SRP The pivotal clinical trials of minocycline microspheres alone. Adapted from Paquette et al.31 involved approximately 750 subjects with generalized moderate to advanced chronic periodontitis recruited at 18 centers.30 Periodontitis subjects meeting inclusion criteria at baseline were randomized to 1 of 3 treatments: 1) scaling and root planing (SRP) alone (positive control); 2) SRP plus polymer vehicle (placebo control); or 3) SRP plus minocycline microspheres. Full mouth probing exams were performed at baseline (prior to treatment) and at 1, 3, 6, and 9 months. Figure 2 graphs mean probing depth reductions observed in the 9-month trial for all subjects (intent-to-treat population) in the primary analysis. Analyses of covariance adjusting for centers indicated significant-inter-group differences in probing depth reductions at all time points (p < 0.001). In particular, subjects treated with adjunctive minocycline microspheres exhibited significantly greater probing depth reductions as compared to control subjects treated with SRP alone. When Figure 4. Mean probing-depth reductions over nine smokers (Figure 3) or those with advanced periodontitis months for advanced periodontitis subjects (mean base- (mean baseline PD > 6 mm) (Figure 4), were considered line probing depth > 6 mm) treated with minocycline, in secondary analyses, again ANCOVA indicated signif- adjunctive vehicle, or SRP alone. Adapted from Williams icant probing depth reductions with adjunctive minocy- et al.30

12 The Journal of Dental Hygiene Special supplement cline microspheres over control treat- was conducted to evaluate the use of pheres therapy (baseline and weeks 2, ments.31 Indeed, inter-group differences minocycline microspheres in private 3, and 5) or surgery alone.35 At week 25, in PD reduction were greater among practices throughout the United States.34 the mean PD reduction from baseline advanced periodontitis subjects versus Accordingly, 1095 patients received 2 was 2.51 mm in the surgery plus the overall population. applications of minocycline micros- minocycline microspheres (test) group A priori, a shift in subject mean prob- pheres (at baseline and 3 months) per versus 2.18 mm in the control group. ing depth < 5 mm with treatment was protocol, and 1710 patients received Smokers in the test group had a signifi- considered a clinically relevant and only one minocycline microsphere cantly greater probing depth reduction “maintainable” response. When regres- application (at baseline). Mean 6-month (2.30 mm) as compared to smokers in sion analyses were performed compar- pocket depth reductions were 1.82 and the control group (2.05 mm). In addi- ing response odds with adjunctive 1.94 mm for the patients receiving one tion, the number of sites with probing minocycline microspheres treatment and 2 minocycline microspheres treat- depth reductions of 2 mm or more was versus SRP alone, the odds ratios for ments, respectively. Similar results were significantly higher in the test group subjects who smoked or who had obtained in smokers, diabetic patients, than in the control group. Hence, advanced periodontitis were 2.06 (95% and cardiovascular disease patients. minocycline microspheres may be CI 1.10, 3.85) and 2.86 (95% CI 1.45, After one minocycline microspheres adjuncts to both nonsurgical and surgi- 5.66), respectively.32 These data indicate treatment, 62% of sites had decreased cal therapies for patients with moderate that patients with advanced periodonti- to less than 5 mm, and after 2 treatments to severe, chronic periodontitis. tis or smokers are 2 to 3 times more the corresponding proportion increased These efficacy findings for minocy- likely to respond, and that this increase to 67%. This large private practice study cline microspheres have been extended in odds is clinically relevant. Site analy- demonstrated that minocycline micros- to peri-implantitis, an inflammatory ses on pocket resolution (posttreatment pheres plus SRP is effective in reducing process around one or more osseointe- PD < 5 mm) were also designated as pocket depth and that efficacy increased grated implants in function, resulting in a meaningful. Again, a significantly and with retreatment (dose-response). loss of supporting bone and associated consistently higher percent of pockets One recently published trial indicates with a similar pathogenic flora. Renvert were “resolved” with adjunctive that the effects of flap surgery may be and coworkers conducted a clinical trial in minocycline microspheres versus SRP enhanced with adjunctive minocycline which 32 subjects with peri-implantitis alone for all subjects and smokers, microspheres treatment. Hellström and (one implant with PD > 4 mm, bleeding respectively (Table 2).33 coworkers recruited 60 periodontitis and/or exudate on probing and the pres- A large, phase 4 (postmarketing) trial patients and randomized them to either ence of putative pathogens) randomly involving 2805 patients and 895 dentists flap surgery plus minocycline micros- received debridement plus minocycline Table 2. Percentage of periodontal pockets resolving with adjunctive minocycline microspheres versus SRP. Adapted from Paquette et al.33

Baseline PD 5mm 6mm 7mm >8mm

Treatment Mino SRP Mino SRP Mino SRP Mino SRP All Subjects Micro Alone Micro Alone Micro Alone Micro Alone

76 69 47 39 22 20 10 8 Month 1 p<0.0001 p<0.001 p=0.31 p=0.24

78 71 52 48 28 23 19 14 Month 3 p<0.0001 p=0.01 p=0.01 p=0.02

75 66 54 49 34 27 22 16 Month 9 p<0.0001 p=0.0005 p=0.001 p=0.01

Treatment Mino SRP Mino SRP Mino SRP Mino SRP Smokers Micro Alone Micro Alone Micro Alone Micro Alone

73 66 40 34 17 15 6 3 Month 1 p<0.0001 p=0.003 p=0.53 p=0.09

74 66 44 41 22 15 16 5 Month 3 p<0.001 p=0.17 p=0.04 p=0.003

70 61 45 39 27 20 20 12 Month 9 p<0.0001 p=0.006 p=0.04 p=0.04

Special supplement The Journal of Dental Hygiene 13 microspheres or debridement plus moderate to advanced chronic peri- because they are accompanied by a chlorhexidine gel (0.2%) at baseline, 1 odontitis. Subjects were randomly greater likelihood for patient mainte- month, and 3 months.36 While both treat- assigned to either SRP alone or minocy- nance or pocket resolution. Recent trials ments reduced putative pathogens, cline microspheres and SRP. All patients also indicate that locally administered adjunctive minocycline microsphere treat- received full-mouth SRP at baseline, fol- antimicrobials may enhance the effects ment resulted in significant improvements lowed by treatment with minocycline of periodontal surgical therapy and may in PD compared to chlorhexidine gel at 1 microspheres if assigned to the SRP and reduce the signs of peri-implantitis. The month, 3 months, and 6 months. Signifi- minocycline microspheres group. The consistency of these findings supports cant reductions in bleeding on probing examiner was blinded to the patient’s the use of locally administered antimi- were also noted for up to 12 months. This treatment. Clinical assessments were crobials for managing dental patients investigative group published the results made and plaque samples were collected with chronic periodontitis. from a second trial with 30 peri-implanti- at baseline and at Day 30. The results tis subjects. Again, adjunctive minocy- demonstrated that adjunctive minocycline microspheres improved PD and cline microspheres significantly reduced Clinical Implications bleeding scores, whereas the adjunctive red-complex periodontal pathogens as use of chlorhexidine gel had limited compared to SRP alone by one month.40 • Recent clinical trials indicate that effects on bleeding scores.37 Another Another investigation conducted by locally administered antimicrobials investigative team, Salvi and coworkers, Oringer et al41 investigated the effect of may enhance the effects of periodon- also noted consistent efficacy with minocycline microspheres on gingival tal surgical therapy and may reduce minocycline microspheres for treating crevicular fluid (GCF) levels pyridino- the signs of peri-implantitis. peri-implantitis.38 Here, the investigators line cross-linked carboxy-terminal • Patients with periodontitis exhibiting applied minocycline microspheres to telopeptide of type I collagen (ICTP) moderate (4-5mm) and deep (> 6 implant sites exhibiting bone loss and PD and interleukin 1-beta (IL-1). ICTP is a mm) probing depths were 2 to 3 times > 5 mm following a 3-week debridement bone-specific degradation product and more likely to exhibit alveolar bone and hygiene interval. While 6 of 31 IL-1 is a potent bone-resorptive cyto- loss over 10 years. implants were either rescued or exited kine. Forty eight periodontitis patients • A systematic review and meta-analy- from the trial because of persistent peri- were randomized to receive SRP fol- sis demonstrated that adjunctive implantitis, all other implants (80.6%) lowed by minocycline microspheres or locally administered antimicrobials showed significant reduction in both PD vehicle. Eight healthy individuals served improved PD over SRP alone in and BOP over 12 months with minocy- as a control group. Results found a chronic periodontitis patients. cline microspheres therapy. The investi- potent short term reduction of ICTP and • Patients with advanced periodontitis gators also examined peri-implant IL-1 in the SRP plus minocycline or smokers are 2 to 3 times more likely microflora using DNA-DNA checker- microspheres group. to respond to SRP + minocycline board hybridization techniques and microspheres than to SRP alone. observed significant reductions in A. • Use of minocycline microspheres has actinomycetemcomitans at 12 months and Summary and been shown to be advantageous when reductions in “red complex” bacteria (T. Conclusions used as an adjunctive therapy to both forsythia, P. gingivalis, and T. denticola) nonsurgical and surgical therapies in for 6 months.39 Binary regression analysis Residual or persistent periodontal patients with moderate to severe, showed that the clinical parameters and inflammation is associated with insta- chronic periodontitis. smoking history could not discriminate bility of dental tissues (periodontal dis- • Adjunctive use of minocycline between successfully treated and res- ease progression and tooth loss). Cumu- microspheres has shown a reduction cued/exited implants at any observation lative data from clinical trials and in red-complex periodontal pathogens time point. In addition, failures in treat- meta-analyses support a complementary as compared to SRP alone. ment could not be associated with the medical-mechanical model using locally presence of specific pathogens or by the delivered antimicrobials for treating total bacterial load at baseline. Collec- chronic periodontitis. Overall, the clini- Disclosure tively, these new data indicate improve- cal evidence accrued to date consistently ments in the clinical signs of peri-implan- shows that when locally administered Dr. Paquette has served as a scien- titis over 12 months with adjunctive antimicrobials are used adjunctively, sig- tific consultant and investigator for locally administered minocycline. nificantly greater PD reductions and/or OraPharma, Inc. Dr. Ryan and Ms. Goodson and coworkers conducted a attachment level gains occur in patients. Wilder are scientific consultants for clinical trial utilizing 124 subjects with These responses are clinically relevant Orapharma, Inc.

References 3. Socransky SS, Haffajee AD. Periodontal microbial ecol- ogy. Periodontol 2000 2005;38:135-187. 1. Albandar J, Brunelle JA, Kingman A. Destructive peri- 4. Offenbacher S. Periodontal diseases: pathogenesis. Ann odontal disease in adults 30 years of age and older in the Periodontol 1996;1:821-878. United States, 1988-1994. J Periodontol 1999;70:13-29. 5. Socransky SS, Haffajee AD, Goodson JM, Lindhe J. New 2. Flemmig TF. Periodontitis. Ann Periodontol 1999;4:32-38. concepts of destructive periodontal disease. J Clin Peri-

14 The Journal of Dental Hygiene Special supplement odontol 1984; 11:21-32. the anaerobic flora and antibiotic-resistant patterns in sub- 6. American Academy of Periodontology Research, Science gingival plaque and saliva. J Periodontol 2000;71:768-774. and Therapy Committee. Tobacco use and the periodon- 26. Garrett S, Johnson L, Drisko CH, Adams DF, Bandt C, tal patient. J Periodontol 1999;70: 1419-1427. Beiswanger B et al. Two multi-center studies evaluating 7. Grossi SG, Genco RJ. Periodontal disease and diabetes locally delivered doxycycline hyclate, placebo control, oral mellitus: a two-way relationship. Ann Periodontol hygiene, and scaling and root planing in the treatment of 1998;3:51-61. periodontitis. J Periodontol 1999;70:490-503. 8. Saito T, Shimazaki Y, Sakamoto M. Obesity and peri- 27. Ryder MI, Pons B, Adams D, Beiswanger B, Blanco V, odontitis. N Eng J Med. 1998;482-483. Bogle G et al. Effects of smoking on local delivery of con- 9. Ramfjord SP, Morrison EC, Burgett FG, Nissle RR, Shick trolled-release doxycycline as compared to scaling and RA, Zann GJ, Knowles JW. Oral hygiene and maintenance root planing. J Clin Periodontol 1999;26:683-691. of periodontal support. J Periodontol 1982;53:26-30. 28. Wennstrom JL, Newman HN, MacNeill SR, Killoy WJ, Grif- 10. Kornman KS, Crane A, Wang HY, di Giovine FS, Newman fiths GS, Gillam DG et al. Utilisation of locally delivered MG, Pirk FW, Wilson TG Jr et al. The interleukin-1 geno- doxycycline in non-surgical treatment of chronic peri- type as a severity factor in adult periodontal disease. J odontitis. A comparative multi-centre trial of 2 treatment Clin Periodontol 1997;24:72-77. approaches. J Clin Periodontol 2001;28:753-761. 11. Halazonetis TD, Haffajee AD, Socransky SS. Relationship 29. Oringer RJ, Al-Shammari KF, Aldredge WA, Iacono VJ, of clinical parameters to attachment loss in subsets of sub- Eber RM, Wang HL, Berwald B et al. Effects of locally jects with destructive periodontal diseases. J Clin Peri- delivered minocycline microspheres on markers of bone odontol 1989;16:563-568. resorption. J Periodontol 2002;73:835-842. 12. Paulander J, Axelsson P, Lindhe J, Wennstrom J. Intra-oral 30. Williams R, Paquette D, Offenbacher S, Adams D, pattern of tooth and periodontal bone loss between the Armitage G, Bray K et al, Treatment of periodontitis by age of 50 and 60 years. A longitudinal prospective study. local administration of minocycline microspheres: a con- Acta Odontol Scand 2004;62:214-222. trolled trial. J Periodontol 2001;72:1535-1544. 13. American Academy of Periodontology. Parameter on 31. Paquette DW, Oringer R, Lessem J, Offenbacher S, Genco chronic periodontitis with slight to moderate loss of peri- R, Persson GR, Williams R. Locally delivered minocycline odontal support. J Periodontol 2000;71:853-855. microspheres for the treatment of periodontitis in smokers. 14. American Academy of Periodontology. Parameter on J Clin Periodontol 2003;30:787-794. chronic periodontitis with advanced loss of periodontal 32. Paquette DW. Pocket depth reduction as an outcome measure support. J Periodontol 2000;71:856-858. of inflammation and soft tissue changes in Periodontitis trials. 15. Cobb CM. Non-surgical pocket therapy: Mechanical. Ann J Int Acad Periodontol 2005;7/4 (Supplement):147-156. Periodontol 1996;1:450-490. 33. Paquette DW, Williams RC, Hanlon A, Lessem J. Clinical 16. Palcanis KG. Surgical pocket therapy. Ann Periodontol relevance of adjunctive minocycline microspheres in 1996;1:589-606. patients with chronic periodontitis: secondary analysis of a 17. Drisko CH. Nonsurgical pocket therapy: Pharmacothera- phase 3 trial. J Periodontol 2004;75:531-536. peutics. Ann Periodontol 1996;1:491-566. 34. Lessem J, Hanlon A. A post-marketing study of 2805 18. Hanes PJ, Purvis JP, Gunsolley JC. Local anti-infective patients treated for periodontal disease with Arestin. J Int therapy: pharmacological agents. A systematic review. Ann Acad Periodontol 2004;6:150-153. Periodontol 2003;8:79-98. 35. Hellström MK, McClain PK, Schallhorn RG, Bellis L, Han- 19. Goodson JM, Holborow D, Dunn RL, Hogan P, Dunham S. lon AL, Ramberg P. Local minocycline as an adjunct to Monolithic tetracycline-containing fibers for controlled deliv- surgical therapy in moderate to severe, chronic periodon- ery to periodontal pockets. J Periodontol 1983; 54:575-579. titis. J Clin Periodontol 2008;35:525-31. 20. Soskolne WA, Chajek T, Flashner M, Landau I, Stabholtz 36. Renvert S, Lessem J, Dahlén G, Lindahl C, Svensson M. A, Kolatch B, Lerner EI. An in vivo study of the chlorhexi- Topical minocycline microspheres versus topical chlorhex- dine release profile of the PerioChip in the gingival crevic- idine gel as an adjunct to mechanical debridement of incip- ular fluid, plasma and urine. J Clin Periodontol ient peri-implant infections: a randomized clinical trial. J 1998;25:1017-1021. Clin Periodontol 2006;33:362-9. 21. Stabholz A, Sela MN, Friedman M, Golomb G, Soskolne 37. Renvert S, Lessem J, Dahlén G, Renvert H, Lindahl C. A. Clinical and microbiological effects of sustained release Mechanical and repeated antimicrobial therapy using a local chlorhexidine in periodontal pockets. J Clin Periodontol drug delivery system in the treatment of peri-implantitis: a 1986;13:783-788. randomized clinical trial. J Periodontol 2008;79:836-44. 22. Jeffcoat MK, Bray KS, Ciancio SG, Dentino AR, Fine DH, 38. Salvi GE, Persson GR, Heitz-Mayfield LJ, Frei M, Lang NP. Gordon JM et al. Adjunctive use of a subgingival con- Adjunctive local antibiotic therapy in the treatment of peri- trolled-release chlorhexidine chip reduces probing depth implantitis II: clinical and radiographic outcomes. Clin Oral and improves attachment level compared with scaling and Implants Res 2007;18:281-5. root planing alone. J Periodontol 1998;69:989-997. 39. Persson GR, Salvi GE, Heitz-Mayfield LJ, Lang NP. Antimi- 23. Jeffcoat MK, Palcanis KG, Weatherford TW, Reese M, crobial therapy using a local drug delivery system (Arestin) Geurs NC, Flashner M. Use of a biodegradable chlorhex- in the treatment of peri-implantitis. I: Microbiological out- idine chip in the treatment of adult periodontitis: clinical comes. Clin Oral Implants Res 2006;17:386-93. and radiographic findings. J Periodontol 2000;71:256-262. 40. Goodson JM, Gunsolley JC, Grossi SG, Bland PS, Otomo- 24. Stoller NH, Johnson LR, Trapnell S, Harrold CQ, Garrett S. Corgel J, Doherty F, Comiskey J. Minocycline HCl micros- The pharmacokinetic profile of a biodegradable controlled- pheres reduce red-complex bacteria in periodontal dis- release delivery system containing doxycycline compared ease therapy.J Periodontol. 2007;78:1568-79. to systemically delivered doxycycline in gingival crevicular 41. Oringer RJ, Al-Shammari KF, Aldredge WA, Iacono VJ, fluid, saliva, and serum. J Periodontol 1998;69:1085-91. Eber RM, Wang HL et al. Effects of locally delivered 25. Walker CB, Godowski KC, Borden L, Lennon J, Nango S, minocycline microspheres on markers of bone resorption. Stone C et al. The effects of sustained release doxycycline on J Periodontol. 2002; 73:835-842.

Special supplement The Journal of Dental Hygiene 15