Evidence-Based Considerations for the Clinical Use of Locally Delivered, Controlled-Release Antimicrobials in Periodontal Therapy

Richard D. Finkelman, DDS, PhD; Alan M. Polson, DMD, MS

December 2013 Course - Expires December 31st, 2016

American Dental Hygienists' Association

Abstract

Locally delivered, controlled-release antimicrobials have long been available in dentistry. Their utilization in routine clinical practice, however, has been slow, perhaps because of concerns about clinical benefits or costs or possibly due to a lack of understanding of their efficacy or proper use. In this paper the evidence regarding locally delivered, controlled-released antimicrobials is considered, and some of the controversies surrounding these agents are discussed. Evidence-based considerations regarding their use are also summarized. Scaling and root planing (SRP) procedures are the backbone of non-surgical periodontal therapy. Since a number of well designed clinical trials have demonstrated that adjunctive, locally delivered, controlled-release antimicrobials make SRP significantly more effective to reduce clinical signs of chronic periodontitis with a known safety profile, and since SRP procedures have previously been considered the standard of care for non-surgical periodontal therapy, a case is made that SRP in combination with adjunctive therapy, administered in a manner consistent with the approved full prescribing information, could be considered a new standard.

You must be signed in to read the rest of this article.

Login Sign Up

Registration on CDEWorld is free. You may also login to CDEWorld with your DentalAegis.com account.

The technologies for the clinical use in dentistry of locally delivered, controlled-release antimicrobials, both antibiotic and antiseptic formulations, have been available for more than a decade, but their routine incorporation in clinical practice for patient treatment has been slow despite the recognition of the bacterial initiation of periodontal disease, that the efficacy of scaling and root planing (SRP) or other mechanical therapy generally is a consequence of either a reduction of the bacterial load or an alteration of the composition of the bacterial flora at the gingival or periodontal site, and that the antibacterial effect of mechanical treatment alone is less than complete. It would therefore seem intuitive that the clinician should desire to augment chemically the antibacterial effect of mechanical therapy.

Four locally delivered, controlled-release antimicrobial products have been developed for use in dentistry in the U.S. based on 4 different antimicrobials: tetracycline (TET) fiber, chlorhexidine (CHX) chip, doxycycline (DOX) gel, and minocycline (MIN) microspheres.1-4 The TET fiber was the first product introduced to the U.S. market and was the prototypic system. Although the TET fiber is no longer available in the U.S., it is included in this discussion because the data generated from studies of the TET fiber are pertinent for a discussion of the general effects of locally delivered, controlled-release antimicrobials. The effects of locally delivered, controlled-release antimicrobials are considered as a drug class rather than individually. Since appropriate comparative trials have not been performed, there are insufficient data on which to base any comparison of agents or to consider differential indications for use. The indications for use for each product can only be based on the indications as noted in the respective full prescribing information.

The appropriate clinical use of locally delivered, controlled-release antimicrobials has been the subject of some controversy, perhaps at least partly fostered by comments and recommendations in position papers that were published shortly after the introduction of these agents into the U.S. market, recommendations published even though a number of them seemed to be based on clinical opinions and not well supported by research data.5,6 The positions were subsequently supported by other reports,7-9 although concerns regarding these positions have also been published.10,11

It has been well accepted that optimal patient care should be evidence-based.12,13 Thus, it is appropriate in this review to revisit the clinical evidence regarding locally delivered, controlled-release antimicrobials. A discussion of perceived controversies and previously published concerns is also needed. This review has been limited mainly to studies with Phase III designs, since these represent the strongest clinical evidence available for the purpose of clinical decision making and are typically the studies on which regulatory decisions are based. Other studies (e.g., Phase I, Phase II) are usually more exploratory in nature to give initial information regarding drug compounds, including preliminary safety or efficacy or to explore doses, but are not sufficiently adequate or well-controlled to provide conclusive data regarding either efficacy or safety. Other studies, although perhaps of high quality to give preliminary information, cannot provide data on which to base clinical decisions. The U.S. Food and Drug Administration (FDA) website notes the common characteristics of study designs that are considered adequate and well-controlled (Table I).14 Comments regarding less robust studies are included as appropriate, although this discussion was not intended to be a systematic review of the literature. The purpose of this paper is to consider existing clinical evidence for the use of these agents and follow with an evidence-based consideration of the appropriate use of locally delivered, controlled-release antimicrobials for patient treatment. Included is a discussion of treatment outcomes, clinical significance and the value of these agents versus other available local therapies, including irrigation.

Previously Published Positions

The position papers5,6 and review7 cited above suggested that the best place to use locally delivered, controlled-release antimicrobials may be at the periodontal site that has not responded to other treatment, essentially recommending that these agents need not be used until other therapy has failed. Supportive evidence for this view is lacking, however, since adequate comparative data from responding versus non-responding sites are not available. Thus, the recommendation seems to be based on opinion rather than evidence, a conclusion also reached at a symposium sponsored by the Oral Health Research Group, co-sponsored by the Periodontal Research Group, at the 2001 Annual Meeting of the American Association for Dental Research (AADR) to consider the clinical significance of non-surgical periodontal therapy.15 Other reports, however, do support the efficacy of locally delivered, controlled-release antimicrobials in persistent pockets or in non-responding sites as an alternative to further SRP or perhaps to surgical treatment, although a lack of additional benefit in non-responding sites has also been reported.16-18

The Research, Science and Therapy Committee of the American Academy of Periodontology has published that they “strongly feel that mechanical instrumentation can usually achieve the same result as local delivery when administered as a monotherapy or when it is used as an adjunct to treatment.”19 However, no supportive data were referenced, especially regarding the adjunctive use of local delivery. The literature suggests otherwise, that locally delivered, controlled-release antimicrobials significantly augment the efficacy of SRP. Multiple clinical trials have consistently shown, in at least 6 multi-centered, randomized, Phase III-style trials, that SRP plus adjunctive treatment resulted in significantly greater efficacy, as measured by probing depth reduction, compared with SRP alone.2,4,20-22 Probing depth is thought to be a clinically meaningful endpoint for periodontitis trials, an appropriate outcome measure of inflammation and predictive of further disease progression, although the progression of periodontitis may be most meaningfully measured by loss of attachment or alveolar bone.23-31

The efficacy of local adjuncts was subsequently supported in 2003 by an international workshop, which also concluded that the clinical result obtained following SRP that includes the adjunctive use of a locally delivered, controlled-release antimicrobial is significantly enhanced in comparison with that following SRP alone.32 The conclusion was based on data derived from multiple randomized clinical trials, long recognized as the strongest and most compelling evidence on which to base clinical treatment.12,13,33

Clinical Significance

The mean differences in clinical trials between the probing depth reduction from baseline between treated groups (SRP plus adjunctive agent) and control (SRP plus placebo or SRP alone) were reported in terms of tenths of a millimeter (approximately 0.2 to 0.7 mm).2,4,20-22 The changes numerically seem small and of little clinical significance, but they need to be viewed from a number of perspectives. For example, it is commonly believed that only a low percentage of periodontal sites are “active,” i.e., actively evidencing tissue breakdown, and that most sites are relatively stable and “inactive.”27,34-36 Since most sites may be stable at most times, it might be anticipated that, in a clinical trial of all patients and all periodontal sites, unless it is a trial which is specifically enriched for “active” sites, there may not be much difference between treated and control in most patients. In other words, many of the data points used to define a mean difference may be small or near zero (i.e., no difference versus the control group, SRP alone). In addition, clinical trials for FDA registration are typically performed using an intent-to-treat analysis. All entered patients are included in the analysis whether they finish the trial or not, therefore, the expected small mean changes may be even further diluted by data recorded prior to the planned endpoint. The trials that have been cited included data from subjects who did not complete the trials per protocol and for whom treatment was incomplete. It would have thus been expected that the outcome as mean changes would be small, further highlighting the importance of the statistical analyses of the changes. Adjunctive locally delivered, controlled-release antimicrobials have consistently shown this statistical benefit in multiple, well designed clinical trials, for example, improving mean probing depth reduction across all tested sites entered, including those patients with incomplete treatment, in a number of trials approximately from 22% to 68% compared with control (Table II), a change that certainly seems clinically significant. A significant mean percentage change versus control implies that the response curve is significantly shifted toward increased benefit for the population under study.

Perhaps the most compelling evidence to support clinical significance comes from the consideration of large changes. A probing depth reduction of 2 mm or greater from baseline is commonly considered evidence of clinical significance.2,4,37 The adjunctive use of locally delivered, controlled-release antimicrobials resulted in a significantly greater proportion of patients or sites with a probing depth reduction from baseline of 2 mm or more in comparison with SRP alone (Table II). This level of reduction may ultimately translate into a clinical outcome of fewer lost teeth, but this hypothesis remains to be tested in clinical trials with tooth mortality as the primary objective rather than surrogate endpoints.38 Thus, the data support that adjunctive therapy is not only statistically significant but clinically significant as well. The clinical significance of the adjunctive benefit was also acknowledged at a symposium to consider locally delivered chemotherapeutic agents in periodontal therapy sponsored by the Periodontal Research Group at the 1998 Annual Meeting of the AADR.39

To consider the results from another perspective, surgery is a common treatment for patients with periodontal pockets, but the mean differences in probing depth reduction between sites treated surgically versus sites treated with SRP alone is also in the neighborhood of several tenths of a millimeter.40,41 If a mean change of tenths of a millimeter is not clinically significant, then it could be questioned whether any patient prospectively ever really needs any periodontal treatment beyond SRP. This conclusion has been supported by the published suggestion that continued non-surgical therapy usually provides a mean probing depth reduction of 2 mm or greater.19 With respect to periodontal surgery, the 1996 World Workshop in Periodontics concluded that “[o]utcomes [following both surgical and non-surgical therapy] after several years are generally similar.”42

Further, with respect to a potential comparison with surgical outcomes, it has been suggested verbally, starting as early as 1993 (Killoy WJ, personal communication, 2002), and in print in 1998, that adjunctive locally delivered, controlled-release antimicrobials may improve outcomes following regenerative periodontal surgery.43,44 In a pilot clinical trial, the adjunctive use of CHX chip with regenerative surgery resulted in more than a 100% greater mean improvement from baseline in bone height and mass 9 months after surgical treatment compared with SRP alone and surgery.45 Interestingly, both groups had also received prophylactic systemic antimicrobial treatment as well prior to surgery (mostly cephalexin).

Other reports support the lack of efficacy of systemic antimicrobials and the benefit of locally delivered antimicrobials as adjunctive treatments in the regenerative setting.46,47 If confirmed by subsequent trials, the collective data could support the use of this intervention to enhance outcomes of regenerative periodontal procedures. Additionally, Aichelmann-Reidy and coworkers have suggested that regenerative surgical procedures should include an adjunctive locally delivered, controlled-release antimicrobial agent in order to provide a more consistent clinical benefit (e.g., improved regeneration).48 However, this hypothesis remains to be tested in prospective trials.

Potentially even more important for a greater number of patients, in a subset of patients from the CHX chip clinical trials, some patients treated with SRP alone lost bone over 9 months as measured by subtraction radiography, but no patient treated adjunctively showed any radiographic evidence of bone loss.49 Adequate and well-controlled clinical trials are needed to test the hypothesis that adjunctive, locally delivered controlled-release antimicrobials may reduce radiographic bone loss.

Adjunctive Therapy and Cigarette Smoking

Smoking has long been identified as a strong risk factor for the development or progression of periodontitis and may limit the effectiveness of periodontal therapy.50-53 The adjunctive use of a locally delivered, controlled-release antimicrobial may enhance the efficacy of SRP in smokers. In a 3 month trial SRP plus adjunctive DOX gel resulted in significantly greater probing depth reduction and clinical attachment gain versus SRP alone approximately equally in both smokers and non-smokers.54 This result was consistent with subset analyses of current smokers, former smokers and non-smokers from 2 multi-center trials (DOX gel)55 and smokers versus non-smokers (MIN microspheres).4 These findings were replicated and extended by a later clinical trial (MIN microspheres).56 Additional periodontal microbiological alterations suggested as beneficial changes in adjunctively treated sites compared with SRP alone have also been reported (DOX gel and MIN microspheres).56-58 A 2 year trial with a small number of patients provided further supportive evidence of clinical efficacy (DOX gel).59 Thus, adjunctive therapy may lessen the adverse impact of smoking on the periodontium and improve treatment outcomes in patients who smoke. A recent systematic review regarding DOX gel and MIN microspheres has suggested that the available evidence for an additional clinical benefit of adjunctive therapy is insufficient to support any definitive conclusions regarding smokers, noting that new randomized clinical trials are necessary to assess outcomes.60

Magnitude of Mean Probing Depth Reduction

The 1996 World Workshop reported that the mean probing depth reduction to be expected following SRP in sites with initial probing depth of 4 to 6 mm is 1.29 mm.61 However, the data from randomized, multi-centered, blinded (mostly double-blinded) clinical trials that have been performed largely for FDA registration have consistently shown a mean reduction of about 1 mm in sites that were either 4 to 6 mm or 5 mm or greater (largely 5 to 6 mm) at baseline.2-4,20-22,37,62,63 Whether the SRP procedures were performed within a pre-specified time limit or performed to the clinical endpoint of smooth roots with no time limit did not impact the extent of the result. The observed mean probing depth reduction has consistently been about 1 mm in at least 11 randomized trials, even when SRP procedures were performed with no time limitation.2-4,20-22,37,62,63 In reported trials there was a variety of SRP methods used, along with a range of the number of included teeth with probing depth greater than 4 or 5 mm (generally 2 to 4 teeth).2-4,20-22,37,62,63 One cannot assess the number of teeth that actually required SRP or the amount of time actually necessary to complete the instrumentation. Thus, comparisons of these reported trials with other reports in the literature are not appropriate, and the concerns do not detract from the findings of statistically significant changes within these internally controlled trials. Indeed, the largest numerical difference between treated and control arms was observed in a trial in which no time limitation for SRP procedures was noted, although this trial was conducted in a private practice setting.20

Trial Design

The randomized clinical trials that confirmed the efficacy of locally delivered, controlled-release antimicrobials and supported FDA registration were well designed to give unequivocal outcomes. Concerns may always be raised regarding trial designs, but multi-centered clinical trials are enormously expensive and are difficult to perform. Trials must be designed appropriately to address the hypotheses of interest. The efficacy of locally delivered, controlled-release antimicrobials for the indication of periodontal disease to reduce probing depth or improve attachment level has been established in multiple trials, otherwise treated groups would not have separated from control (or would not have been equivalent to control).1-4,20-22 These results have included trial designs both of adjunctive use with SRP or of monotherapy (Table II).

It has been speculated that trial results might have been different had control groups also received repeated treatment (i.e., repeated SRP).19 However, if the control group had received repeated SRP, the adjunctively treated group also would have had to receive repeated instrumentation to maintain design balance. Results for both groups may have been different, not just control. Additionally, locally delivered, controlled-release antimicrobials may be effective in the presence of calculus or with reduced amounts of instrumentation.64,65 Additional instrumentation also would have made data interpretation more difficult; multiple treatments at multiple times make it more difficult to separate treatment effects meaningfully. Further, in support of the lack of an impact of additional instrumentation on the outcome, a similarly significant difference was reported when both treatment arms received SRP at baseline and a supragingival prophylaxis at 3 months.21

In summary, in the registration trials of local adjunctive therapy for 2 products (MIN microspheres, CHX chip),2,4 all sites received SRP at baseline ± adjunctive drug as per the randomization. At 3 and 6 months, sites randomized to drug received additional drug only if probing depth remained ≥5 mm (i.e., only a fraction of those sites). If the adjunctive therapy had no effect, probing depth at these sites would have trended back toward baseline as in the SRP alone sites; the observation that probing depth remained reduced clearly demonstrated that the drug was efficacious. The FDA agreed that the designs were adequate and well-controlled. An alternative design might have been to have all sites treated with mechanical instrumentation at 3 and 6 months with drug added per the randomization in sites with probing depth ≥5 mm. With this design, in order to have demonstrated significant changes, most likely a much greater number of patients would have had to have been studied for a greater length of time, a design n that may not have practically been feasible.

Clinical trials need to be conducted in a reasonable time frame and with a reasonable number of subjects. Current designs are generally limited to the evaluation of surrogate endpoints (e.g., probing depth) rather than direct endpoints, such as tooth survival. Surrogate variables, however, are considered reasonable endpoints in periodontal clinical trials and relevant to tooth retention, although the inherent weaknesses of surrogate outcome variables have been noted.38,66,67

Clinical Use and Costs

It has been noted that locally delivered, controlled-release antimicrobials are associated with greater acquisition costs in comparison with readily available antiseptics such as povidone (PVP)-iodine or sodium hypochlorite.68 These agents are discussed in more depth later in this paper. However, since these agents have not been adequately tested in clinical trials, and neither their safety nor their effectiveness have been established, these antiseptics must be considered investigational for the treatment of periodontitis and therefore not appropriate for inclusion in cost-effectiveness analyses.

In a clinical trial of more than 450 patients to study costs associated with the CHX chip, adjunctive therapy increased total treatment costs by approximately 50%, but reduced the likelihood for surgical treatment during the length of the trial by about 50% in comparison with patients treated conventionally.69 Other dental treatment was sufficiently reduced to offset about half of the acquisition costs of the adjunctive antimicrobial. This result was consistent with a previously published modeled assessment regarding the CHX chip.70 After 12 months, the examining periodontists recommended similar further amounts of surgery for both groups.69 No information was available, however, regarding any further disease progression or tooth mortality or whether patients received any further surgical care. Additionally, no information was available for these patients regarding any differential outcomes with either follow-up surgical care or continued non-surgical maintenance with SRP and adjunctive therapy. Heasman et al have recently reviewed the cost-effectiveness of adjunctive antimicrobials in the treatment of periodontitis, and noted the continued need for long-term studies to assess effects on tooth mortality or other patient-reported outcomes.71

It has been suggested that the adjunctive benefits of locally delivered, controlled-release antimicrobials may only be short-term (i.e., clinical trials extended for only 6 or 9 months, however, these products can routinely be re-administered as needed.2,4,9,20-22 A number of clinical trials, including studies of MIN microspheres, DOX gel and CHX chip, have provided evidence for the safety and efficacy of locally delivered, controlled-release antimicrobials for periodontal maintenance.17,72-80 The same could be suggested regarding SRP, that the benefits of SRP may only be short-term. The clinical benefits of SRP seem to result from continued maintenance treatment for life. Similarly, the true benefits of locally delivered, controlled-release antimicrobials most likely will result from their routine use as adjuncts with SRP as well as in a periodontal maintenance program as indicated.

Finally, it has been suggested that other therapies (e.g., systemic antimicrobials) should be considered when there are multiple pockets.5,8,9 It seems likely that locally delivered, controlled-release antimicrobials are effective because of the high concentration of active drug achieved and maintained in the gingival crevicular fluid (GCF),81-83 perhaps especially needed because of the protective biofilm structure in the periodontal ecosystem84,85 (for reviews, see Palmer86 or Kuboniwa and Lamont87). Drug concentrations within the GCF with systemic antimicrobials are orders of magnitude less than those achievable with local agents and cannot provide an equivalent, alternative therapy.83,88 Bacterial biofilms may be highly resistant to penetration by fluids,89 providing further evidence for the critical need for high GCF concentrations of active antimicrobial, concentrations only achievable with suitable locally delivered controlled-release agents and not possible via systemic routes. Additionally, Drisko has suggested that the high concentrations of antimicrobial in the GCF as a result of local delivery may help to reach infected sites within the root or the pocket.90 Other potential benefits include decreased systemic, off-target effects or a decreased risk for promoting microbial resistance.

Informed Consent and Legal Considerations

Clinicians must treat all patients under the principles of informed consent, and all patients must provide their consent for all treatment. The FDA (adapted from 21CFR 50.25(a)91) describes 8 elements of informed consent that include:
1. A description of the planned treatment
2. A description of reasonably foreseeable risks or discomforts
3. A description of any reasonably expected benefits
4. Disclosure of appropriate alternative treatment
5. A description of procedures to maintain confidentiality
6. Disclosure of associated costs
7. Answering all questions
8. Disclosure that all treatment is voluntary

Appropriate treatment that satisfies the principles of informed consent includes treatment that is evidence-based, i.e., supported by appropriate research data. Since locally delivered, controlled-release antimicrobials as adjuncts have been consistently shown in clinical trials to enhance the efficacy of SRP within the timeframe of treatment, performing SRP, but not at least offering an adjunctive agent, seems to violate the principles of informed consent. Clinicians have a responsibility to offer all appropriate treatment options, including adjunctive therapy.

With respect to the issue of malpractice, undiagnosed or under-treated periodontitis are major sources of dental malpractice litigation.92 Since SRP procedures are commonly considered the standard of care for non-surgical periodontal therapy, and available data support that adjunctive locally delivered, controlled-release antimicrobials enhance the efficacy of SRP, at least over the time frame of the clinical trials, then SRP plus adjunctive therapy could potentially be considered a new standard.7,9,32 Other authors have noted the clinical relevance of locally delivered, controlled-release antimicrobials.15,17,39,43,44,73,90,93-109 Would it be plausible to consider a possible defense in a malpractice litigation of alleged improperly managed periodontitis if it were claimed that the patient had not been offered maximally effective therapy (i.e., SRP with an adjunctive agent)?

Combination Adjunctive Therapy

Locally delivered, controlled-release antimicrobials have been clearly shown to enhance the clinical efficacy of SRP. Adjunctive systemic therapy with low-dose (20 mg) doxycycline, given orally twice daily as a host-modulating agent (subsequently reported as a once daily, modified release formulation110), has also been shown to enhance the clinical efficacy of SRP.37,62,63 For a review of matrix metalloproteinase modulation as a treatment strategy for periodontitis, see Reddy et al111 or Ryan and Golub.112 An obvious question is whether a combination of antimicrobial and host modulating adjunctive therapies will result in a greater clinical benefit compared with either adjunctive agent used alone.

In a 6 month clinical trial, combination adjunctive therapies resulted in significantly greater improvements in probing depth and clinical attachment as compared with SRP alone.113 More sites showed a probing depth reduction ≥2 mm, and fewer sites had residual probing depth ≥5 mm.113 Since the appropriate control groups (SRP plus single adjunctive therapy) were not included in the trial, definitive conclusions regarding any increased benefit from combination versus single adjunctive therapy cannot be made. The potential for combined adjunctive therapy to enhance clinical benefit is promising and warrants additional research.

Locally Delivered Antimicrobials or Other Chemotherapeutics, not Controlled-Release

Many chemotherapeutic agents have been studied subgingivally as adjuncts to SRP as well, mainly via irrigation. None of these studies, however, satisfied the requirements necessary to make treatment recommendations (i.e., level 3 evidence based on adequate and well-controlled trials). A brief commentary regarding some of the most well published of these agents is in order, although a complete review of all tested adjunctive agents is out of scope for this paper.

Povidone-iodine: PVP-iodine is a broad spectrum antimicrobial reported to be effective against a broad range of periodontal pathogens and suggested as a beneficial adjunct to SRP as a subgingival irrigant.68,114-116 Its use has recently been reviewed by Sahrmann et al.117 The authors concluded that the adjunctive use of PVP-iodine with SRP may result in an additional clinical benefit but also noted that most of the reviewed studies were small and of low quality, with discordant results - 7 studies were ultimately considered, of which 3 supported a benefit for adjunctive PVP-iodine, but the other four concluded that there was no evidence to support any additional adjunctive benefit.115,118-123 The above studies and review considered a range of PVP-iodine administrations including, for example, irrigation, rinsing and single visit instrumentation. These were included in order to consider available data regarding PVP-iodine and periodontal treatment. Since the authors are not aware of any adequate and well-controlled trials comparing SRP plus adjunctive therapy with subgingivally irrigated PVP-iodine with SRP alone, no further comments can be made regarding the adjunctive efficacy of PVP-iodine.

Chlorhexidine: Chlorhexidine is a broad spectrum antimicrobial with a long history in dentistry, primarily as a supragingival mouth rinse.124 The use of chlorhexidine as an adjunct to SRP administered via subgingival irrigation has been studied by many investigators. Although some trials suggest a clinical benefit,125-128 the current consensus is that there is little evidence that subgingivally irrigated chlorhexidine, as an adjunct to SRP, offers any clinical benefit in comparison with SRP alone, that no additional probing depth reduction can be achieved with adjunctive irrigation.129-136

Bleach/Peroxide: Dilute bleach solutions or peroxides, alone or in combination, have been suggested to provide an additional clinical benefit as an adjunct to SRP. For example, activity has been reported against periodontal pathogens in vitro and against Actinobacillus (now Aggregatibacter) actinomycetemcomitans clinically.137-139 Sodium hypochlorite has also been suggested as an adjunct to curettage.140 Other investigators, however, have reported no additional clinical benefit of salt and/or peroxide as an adjunct to SRP.136,141 Minimal microbiological differences were noted as well.135,142 Since appropriately designed randomized clinical trials have not been performed, there are insufficient data to support any conclusions regarding the use of these agents in periodontal therapy.

Antibiotics and Other Agents: Various antibiotics or other chemotherapeutics in non-controlled release formulations have been studied as subgingivally administered adjuncts to SRP. Topically delivered antimicrobial adjuncts may be useful for periodontitis, but definitive evidence is lacking.68,116,143-145 For example, long term non-surgical periodontal therapy (15 months) that included SRP and subgingival minocycline ointment was reported as clinically and microbiologically superior to SRP alone.146 Others have also reported additional clinical or microbiological benefit with adjunctive subgingival antibiotics (metronidazole or tetracycline),125,147 but the absence of any further benefit has also been reported (tetracycline, minocycline).133,148,149

Substantial data from adequate and well-controlled, randomized clinical trials exist to support a clinical recommendation for the routine, adjunctive use of locally delivered, controlled-release antimicrobials in the treatment of periodontitis. With regard to locally delivered antimicrobials not in controlled-release formulations, there are some preliminary data that support the need for additional research of these agents for adjunctive clinical use. Until adequate and well-controlled clinical trials are conducted to establish safety and efficacy that could support regulatory registration, however, these agents should still be considered investigational in the U.S. as subgingivally administered adjuncts to SRP for the indication of periodontitis.

Conclusion

There is strong evidence that locally delivered, controlled-release antimicrobials make SRP significantly more effective when used adjunctively, therefore, SRP without adjunctive treatment in appropriately eligible sites (i.e., probing depth ≥5 mm) may be less than maximally effective. As was stated at a symposium to consider the clinical significance of locally delivered antimicrobials at the 2001 AADR Meeting, “[t]he case is stronger for local delivery than for surgery.”15

It is no longer appropriate to determine therapy based solely on clinical judgment. The best an individual practitioner can do is to evaluate the evidence and suggest a treatment that the current data predict has the greatest probability for success. All available treatment options should be presented to the patient. Spielman and Wolff have commented on the unfortunate tendency for many dentists to base treatment on personal experience and not on reported evidence; they highlight that optimal care is evidence-based.150 As an example of the sub-optimal care that can result from the lack of incorporation of the best available evidence into clinical practice, O’Donnell and colleagues recently reported on the underutilization of pit-and-fissure sealants in the dental office despite published ADA recommendations.151,152

There is strong evidence to support the routine, adjunctive use of locally delivered, controlled-release antimicrobials, and that these agents provide a significant additional clinical benefit. Many adjuncts are available for clinical use with SRP, including devices for subgingival cleaning and plaque removal and antiseptics or antibiotics for subgingival irrigation. The most robust data available, however, to support an adjunctive benefit to enhance the efficacy of SRP to reduce probing depth may be the data from clinical trials of locally delivered, controlled-release antimicrobials.

The appropriate clinical use of locally delivered, controlled-release antimicrobials therefore seems clear. SRP have previously been considered the non-surgical standard of care.7,9 The evidence supports that adjunctive locally delivered, controlled-release antimicrobials make SRP more effective32 with a known safety profile. In conclusion, based on the currently available data, when these agents are used routinely as adjuncts to SRP when indicated either as part of initial periodontal treatment or maintenance therapy, clinicians can expect an enhanced result as measured by a significantly greater mean reduction in probing depth as a result of treatment in comparison with SRP alone. Thus, SRP plus adjunctive therapy, used in a manner that is consistent with the approved label, could potentially be considered a new standard for non-surgical periodontal therapy.

Richard D. Finkelman, DDS, PhD, Senior Medical Director, Oncology/New Opportunities, at AstraZeneca LP, Wilmington, DE. Alan M. Polson, DMD, MS is Professor of Periodontics and D. Walter Cohen Chair at the Department of Periodontics, School of Dental Medicine at the University of Pennsylvania, Philadelphia, PA.

Disclosure

Dr. Finkelman is a full time employee of AstraZeneca LP and owns stock in AstraZeneca. Dr. Polson reports no conflicts of interest.

References

1. Goodson JM, Cugini MA, Kent RL, et al. Multicenter evaluation of tetracycline fiber therapy: II. clinical response. J Periodont Res. 1991;26(4):371-379.

2. Jeffcoat MK, Bray KS, Ciancio SG, et al. Adjunctive use of a subgingival controlled-release chlorhexidine chip reduces probing depth and improves attachment level compared with scaling and root planing alone. J Periodontol. 1998;69(9):989-997.

3. Garrett S, Johnson L, Drisko CH, et al. Two multi-center studies evaluating locally delivered doxycycline hyclate, placebo control, oral hygiene, and scaling and root planing in the treatment of periodontitis. J Periodontol. 1999;70(5):490-503.

4. Williams RC, Paquette DW, Offenbacher S, et al. Treatment of periodontitis by local administration of minocycline microspheres: a controlled trial. J Periodontol. 2001;72(11):1535-1544.

5. Greenstein G, Tonetti M. The role of controlled drug delivery for periodontitis. The Research, Science and Therapy Committee of the American Academy of Periodontology. J Periodontol. 2000;71(1):125-140.

6. Research, Science and Therapy Committee of the American Academy of Periodontology. Treatment of plaque-induced gingivitis, chronic periodontitis, and other clinical conditions. J Periodontol. 2001;72(12):1790-1800. Erratum in: J Periodontol. 2003 Oct;74(10):1568.

7. Bonito AJ, Lux L, Lohr KN. Impact of local adjuncts to scaling and root planing in periodontal disease therapy: a systematic review. J Periodontol. 2005;76(8):1227-1236. Erratum in: J Periodontol. 2006 Feb;77(2):326.

8. Greenstein G. Local drug delivery in the treatment of periodontal diseases: assessing the clinical significance of the results. J Periodontol. 2006;77(4):565-578.

9. American Academy of Periodontology statement on local delivery of sustained or controlled release antimicrobials as adjunctive therapy in the treatment of periodontitis. J Periodontol. 2006;77(8):1458.

10. Finkelman RD. Letter to the Editor. J Periodontol. 2000;71(12):1929-1932.

11. Soskolne WA. Letter to the Editor. J Periodontol. 2006;77(2):323.

12. Newman MG. Improved clinical decision making using the evidence-based approach. Ann Periodontol. 1996;1(1):i-ix.

13. Pihlstrom BL, Barnett ML. Design, operation, and interpretation of clinical trials. J Dent Res. 2010;89(8):759-772.

14. Hung JHM. Clinical Trial Designs. U.S. Food and Drug Administration. 2011.

15. Killoy WJ. The clinical significance of local chemotherapies. J Clin Periodontol. 2002;29(Suppl 2):22-29.

16. Kinane DF, Radvar M. A six-month comparison of three periodontal local antimicrobial therapies in persistent periodontal pockets. J Periodontol. 1999;70(1):1-7.

17. Rodrigues IF, Machion L, Casati MZ, et al. Clinical evaluation of the use of locally delivered chlorhexidine in periodontal maintenance therapy. J Periodontol. 2007;78(4):624-628.

18. Tomasi C, Koutouzis T, Wennström JL. Locally delivered doxycycline as an adjunct to mechanical debridement at retreatment of periodontal pockets. J Periodontol. 2008;79(3):431-439.

19. Research, Science and Therapy Committee [of the American Academy of Periodontology]. Letter to the Editor. J Periodontol. 2000;71(12):1932-1933.

20. Newman MG, Kornman KS, Doherty FM. A 6-month multi-center evaluation of adjunctive tetracycline fiber therapy used in conjunction with scaling and root planing in maintenance patients: clinical results. J Periodontol. 1994;65(7):685-691.

21. Paolantonio M, D’Angelo M, Grassi RF, et al. Clinical and microbiologic effects of subgingival controlled-release delivery of chlorhexidine chip in the treatment of periodontitis: a multicenter study. J Periodontol. 2008;79(2):271-282.

22. Soskolne WA, Heasman PA, Stabholz A, et al. Sustained local delivery of chlorhexidine in the treatment of periodontitis: a multi-center study. J Periodontol. 1997;68(1):32-38.

23. Pihlstrom B. Issues in the evaluation of clinical trials of periodontitis: a clinical perspective. J Periodont Res. 1992;27(Spec Iss):433-441.

24. Paquette DW. Pocket depth reduction as an outcome measure of inflammation and soft tissue changes in periodontitis trials. J Int Acad Periodontol. 2005;7(4 Suppl):147-156.

25. Khan S, Cabanilla LL. Periodontal probing depth measurement: A review. Compend Contin Educ Dent. 2009;30(1):12-14,16,18-21.

26. Renvert S, Persson GR. A systematic review on the use of residual probing depth, bleeding on probing and furcation status following initial periodontal therapy to predict further attachment and tooth loss. J Clin Periodontol. 2002;29(Suppl 3):82-89.

27. Page RC, DeRouen TA. Design issues specific to studies of periodontitis. J Periodont Res. 1992;27(4 Pt 2):395-404.

28. Acceptance Program Guidelines. Chemotherapeutic agents to slow or arrest periodontitis. Council on Scientific Affairs. American Dental Association. J Periodontol. 1998;69(9):1076-1080.

29. DeRouen TA, Hujoel PP, Mancl LA. Statistical issues in periodontal research. J Dent Res. 1995;74(11):1731-1737.

30. Reddy MS. Radiographic alveolar bone change as an outcome measure for therapies that inhibit bone loss or foster bone gain. J Int Acad Periodontol. 2005;7(4 Suppl):175-188.

31. Ryan ME. Clinical attachment level change as an outcome measure for therapies that slow the progression of periodontal disease. J Int Acad Periodontol. 2005;7(4 Suppl):162-171.

32. Hanes PJ, Purvis JP. Local anti-infective therapy: pharmacological agents. A systematic review. Ann Periodontol. 2003;8(1):79-98.

33. Newman MG, Caton JG, Gunsolley JC. The use of the evidence-based approach in a periodontal therapy contemporary science workshop. Ann Periodontol. 2003;8(1):1-11.

34. Goodson JM, Tanner ACR, Haffajee AD, Sornberger GC, Socransky SS. Patterns of progression and regression of advanced destructive periodontal disease. J Clin Periodontol. 1982;9(6):472-481.

35. Haffajee AD, Socransky SS, Goodson JM. Periodontal disease activity. J Periodont Res. 1982;17(5):521-522.

36. Socransky SS, Haffajee AD, Goodson JM, Lindhe J. New concepts of destructive periodontal disease. J Clin Periodontol. 1984;11(1):21-32.

37. Preshaw PM, Hefti AF, Novak MJ, et al. Subantimicrobial dose doxycycline enhances the efficacy of scaling and root planing in chronic periodontitis: a multicenter trial. J Periodontol. 2004;75(8):1068-1076.

38. Hujoel PP. Endpoints in periodontal trials: the need for an evidence-based research approach. Periodontol 2000. 2004;36:196-204.

39. Killoy WJ. The use of locally-delivered chlorhexidine in the treatment of periodontitis. Clinical results. J Clin Periodontol. 1998;25(11 Pt 2):953-958..

40. Palcanis KG. Surgical pocket therapy. Ann Periodontol. 1996;1(1):589-617.

41. Heitz-Mayfield LJA, Trombelli L, Heitz F, Needleman I, Moles D. A systematic review of the effect of surgical debridement vs. non-surgical debridement for the treatment of chronic periodontitis. J Clin Periodontol. 2002;29(Suppl 3):92-102.

42. Consensus report. Surgical pocket therapy. Ann Periodontol. 1996;1(1):618-620.

43. Killoy WJ. Chemical treatment of periodontitis: local delivery of antimicrobials. Int Dent J. 1998;48(3 Suppl 1):305-315.

44. Killoy WJ, Polson AM. Controlled local delivery of antimicrobials in the treatment of periodontitis. Dent Clin North Amer. 1998;42(2):263-283.

45. Reddy MS, Jeffcoat MK, Geurs NC, et al. Efficacy of controlled-release subgingival chlorhexidine to enhance periodontal regeneration. J Periodontol. 2003;74(4):411-419.

46. Minabe M, Kodama T, Kogou T, et al. Clinical significance of antibiotic therapy in guided tissue regeneration with a resorbable membrane. Periodontal Clin Investig. 2001;23(1):20-30.

47. Yoshinari N, Tohya T, Kawase H, et al. Effect of repeated local minocycline administration on periodontal healing following guided tissue regeneration. J Periodontol. 2001;72(3):284-295.

48. Aichelmann-Reidy ME, Reynolds MA. Predictability of clinical outcomes following regenerative therapy in intrabony defects. J Periodontol. 2008;79(3):387-393.

49. Jeffcoat MK, Palcanis KG, Weatherford TW, Reese M, Geurs NC, Flashner M. Use of a biodegradable chlorhexidine chip in the treatment of adult periodontitis: clinical and radiographic findings. J Periodontol. 2000;71(2):256-262.

50. Bergstrom J. Cigarette smoking as risk factor in chronic periodontal disease. Community Dent Oral Epidemiol. 1989;17(5):245-247.

51. Jansson LE, Hagstrom KE. Relationship between compliance and periodontal treatment outcome in smokers. J Periodontol. 2002;73(6):602-607.

52. Kaldahl WB, Johnson GK, Patil KD, Kalkwarf KL. Levels of cigarette consumption and response to periodontal therapy. J Periodontol. 1996;67(7):675-681.

53. Preber H, Linder L, Bergstrom J. Periodontal healing and periopathogenic microflora in smokers and non-smokers. J Clin Periodontol. 1995;22(12):946-952.

54. Tomasi C, Wennström JL. Locally delivered doxycycline improves the healing following non-surgical periodontal therapy in smokers. J Clin Periodontol. 2004;31(8):589-595.

55. Ryder MI, Pons B, Adams D, et al. Effects of smoking on local delivery of controlled-release doxycycline as compared to scaling and root planing. J Clin Periodontol. 1999;26(10):683-691.

56. Grossi SG, Goodson JM, Gunsolley JC, et al. Mechanical therapy with adjunctive minocycline microspheres reduces red-complex bacteria in smokers. J Periodontol. 2007;78(9):1741-1750.

57. Machion L, Andia DC, Saito D, et al. Microbiological changes with the use of locally delivered doxycycline in the periodontal treatment of smokers. J Periodontol. 2004;75(12):1600-1604.

58. M Shaddox L, Andia DC, Casati MZ, et al. Microbiologic changes following administration of locally delivered doxycycline in smokers: a 15-month follow-up. J Periodontol. 2007;78(11):2143-2149.

59. Machion L, Andia DC, Lecio G, 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. 2006;77(4):606-613.

60. Angaji M, Gelsky S, Nogueira-Filho G, Brothwell D. A systematic review of clinical efficacy of adjunctive antibiotics in the treatment of smokers with periodontitis. J Periodontol. 2010;81(11):1518-1528.

61. Cobb CM. Non-surgical pocket therapy: mechanical. Ann Periodontol. 1996;1(1):443-490.

62. Ciancio S, Ashley R. Safety and efficacy of sub-antimicrobial-dose doxycycline therapy in patients with adult periodontitis. Adv Dent Res. 1998;12(2):27-31.

63. Caton JG, Ciancio SG, Blieden TM, et al. Treatment with subantimicrobial dose doxycycline improves the efficacy of scaling and root planing in patients with adult periodontitis. J Periodontol. 2000;71(4):521-532.

64. Johnson LR, Stoller NH, Polson A, Harrold CQ, Ryder M, Garrett S. The effects of subgingival calculus on the clinical outcomes of locally-delivered controlled-release doxycycline compared to scaling and root planing. J Clin Periodontol. 2002;29(2):87-91.

65. Wennström JL, Newman HN, MacNeill SR, et al. Utilisation of locally delivered doxycycline in non-surgical treatment of chronic periodontitis. A comparative multi-centre trial of 2 treatment approaches. J Clin Periodontol. 2001;28(2):753-761.

66. Greenstein G. The use of surrogate variables to reflect long-term tooth survivability. J Periodontol. 2005;76(8):1398-1402.

67. Hujoel PP, Löe H, Anerud A, Boysen H, Leroux BG. The informativeness of attachment loss on tooth mortality. J Periodontol. 1999;70(1):44-48.

68. Jorgensen MG, Aalam A, Slots J. Periodontal antimicrobials--finding the right solutions. Int Dent J. 2005;55(1):3-12.

69. Henke CJ, Villa KF, Aichelmann-Reidy ME, et al. An economic evaluation of a chlorhexidine chip for treating chronic periodontitis: the CHIP (CHlorhexidine In Periodontitis) study. J Am Dent Assoc. 2001;132(11):1557-1569. Erratum in: J Am Dent Assoc. 2001 Dec;132(12):1658.

70. De Lissovoy G, Rentz AM, Dukes EM, et al. The cost-effectiveness of a new chlorhexidine delivery system in the treatment of adult periodontitis. J Am Dent Assoc. 1999;130(6):855-862.

71. Heasman PA, Vernazza CR, Gaunt FL, Pennington MWL. Cost-effectiveness of adjunctive antimicrobials in the treatment of periodontitis. Periodontol 2000. 2011;55(1):217-230.

72. Cortelli JR, Querido SMR, Aquino DR, Ricardo LH, Pallos D. Longitudinal clinical evaluation of adjunct minocycline in the treatment of chronic periodontitis. J Periodontol. 2006;77(2):161-166.

73. Dean JW, Branch-Mays GL, Hart TC, et al. Topically applied minocycline microspheres: why it works. Compend Contin Educ Dent. 2003;24(4):247-250, 252-257.

74. Heasman PA, Heasman L, Stacey F, McCracken GI. Local delivery of chlorhexidine gluconate (PerioChip) in periodontal maintenance patients. J Clin Periodontol. 2001;28(1):90-95.

75. Martorelli de Lima AF, Cury CC, Palioto DB, Duro AM, da Silva RC, Wolff LF. Therapy with adjunctive doxycycline local delivery in patients with type 1 diabetes mellitus and periodontitis. J Clin Periodontol. 2004;31(8):648-653.

76. Meinberg TA, Barnes CM, Dunning DG, Reinhardt RA. Comparison of conventional periodontal maintenance versus scaling and root planing with subgingival minocycline. J Periodontol. 2002;73(2):167-172.

77. Salvi GE, Mombelli A, Mayfield L, et al. Local antimicrobial therapy after initial periodontal treatment. J Clin Periodontol. 2002;29(6):540-550.

78. Soskolne WA, Proskin HM, Stabholz A. Probing depth changes following 2 years of periodontal maintenance therapy including adjunctive controlled release of chlorhexidine. J Periodontol. 2003;74(4):420-427.

79. Stabholz A, Shapira L, Mahler D, et al. Using the PerioChip in treating adult periodontitis: an interim report. Compend Contin Educ Dent. 2000;21(4):325-328, 330, 332.

80. Stabholz A, Soskolne WA, Friedman M, Sela MN. The use of sustained release delivery of chlorhexidine for the maintenance of periodontal pockets: 2-year clinical trial. J Periodontol. 1991;62(7):429-433.

81. Kim TS, Klimpel H, Fiehn W, Eickholz P. Comparison of the pharmacokinetic profiles of two locally administered doxycycline gels in crevicular fluid and saliva. J Clin Periodontol. 2004;31(4):286-292. Erratum in: J Clin Periodontol. 2004 May;31(5):412.

82. Soskolne WA, Chajek T, Flashner M, et al. An in vivo study of the chlorhexidine release profile of the PerioChip in the gingival crevicular fluid, plasma and urine. J Clin Periodontol. 1998;25(12):1017-1021.

83. Stoller NH, Johnson LR, Trapnell S, Harrold CQ, Garrett S. The pharmacokinetic profile of a biodegradable controlled-release delivery system containing doxycycline compared to systemically delivered doxycycline in gingival crevicular fluid, saliva, and serum. J Periodontol. 1998;69(10):1085-1091. Erratum in: J Periodontol. 1999;70(2):238.

84. Costerton W, Veeh R, Shirtliff M, Pasmore M, Post C, Ehrlich G. The application of biofilm science to the study and control of chronic bacterial infections. J Clin Invest. 2003;112(10):1466-1477. Erratum in: J Clin Invest. 2007;117(1):278.

85. Soukos NS, Mulholland SE, Socransky SS, Doukas AG. Photodestruction of human dental plaque bacteria: enhancement of the photodynamic effect by photomechanical waves in an oral biofilm model. Lasers Surg Med. 2003;33(3):161-168.

86. Palmer RJ Jr. Supragingival and subgingival plaque: paradigm of biofilms. Compend Contin Educ Dent. 2010;31(2):104-106, 108, 110

87. Kuboniwa M, Lamont RJ. Subgingival biofilm formation. Periodontol 2000. 2010;52(1):38-52.

88. Sakellari D, Goodson JM, Kolokotronis A, Konstantinidis A. Concentration of 3 tetracyclines in plasma, gingival crevice fluid and saliva. J Clin Periodontol. 2000;27(1):53-60.

89. Epstein AK, Pokroy B, Seminara A, Aizenberg J. Bacterial biofilm shows persistent resistance to liquid wetting and gas penetration. Proc Natl Acad Sci U S A. 2011;108(3):995-1000.

90. Drisko CH. The use of locally-delivered doxycycline in the treatment of periodontitis. Clinical results. J Clin Periodontol. 1998;25(11 Pt 2):947-952.

91. U.S. Food and Drug Administration. A Guide to Informed Consent - Information Sheet. U.S. Department of Health & Human Services. 2011.

92. Zinman E. Dental and legal considerations in periodontal therapy. Periodontol 2000. 2001;25:114-130.

93. Paquette DW. Locally administered antimicrobials for the management of periodontal infections. Dent Today. 2009;28(2):97-98, 100-101.

94. Krayer JW, Leite RS, Kirkwood KL. Non-surgical chemotherapeutic treatment strategies for the management of periodontal disease. Dent Clin North Am. 2010;54(1):13-33.

95. Hussein I, Ranka M, Gilbert A, Davey K. Locally delivered antimicrobials in the management of periodontitis: a critical review of the evidence for their use in practice. Dent Update. 2007;34(8):494-506.

96. Ryan ME. Nonsurgical approaches for the treatment of periodontal diseases. Dent Clin North Am. 2005;49(3):611-636.

97. Ciancio SG. Site specific delivery of antimicrobial agents for periodontal disease. Gen Dent. 1999;47(2):172-178, 181.

98. Johnson LR, Stoller NH. Rationale for the use of Atridox therapy for managing periodontal patients. Compend Contin Educ Dent. 1999;20(4 Suppl):19-25.

99. Killoy WJ. Assessing the effectiveness of locally delivered chlorhexidine in the treatment of periodontitis. J Am Dent Assoc. 1999;130(4):567-570.

100. Killoy WJ. Local delivery of antimicrobials: a new era in the treatment of adult periodontitis. Compend Contin Educ Dent. 1999;20(4 Suppl):13-18.

101. Magnusson I. Local delivery of antimicrobial agents for the treatment of periodontitis. Compend Contin Educ Dent. 1998;19:953-956, 958, 960.

102. Page RC. The microbiological case for adjunctive therapy for periodontitis. J Int Acad Periodontol. 2004;6(4 Suppl):143-149.

103. Paquette DW. Minocycline microspheres: a complementary medical-mechanical model for the treatment of chronic periodontitis. Compend Contin Educ Dent. 2002;23(5 Suppl):15-21.

104. Paquette DW, Hanlon A, Lessem J, Williams RC. Clinical relevance of adjunctive minocycline microspheres in patients with chronic periodontitis: secondary analysis of a phase 3 trial. J Periodontol. 2004;75(4):531-536.

105. Pavia M, Nobile CGA, Angelillo IF. Meta-analysis of local tetracycline in treating chronic periodontitis. J Periodontol. 2003;74(6):916-932.

106. Soskolne WA. Subgingival delivery of therapeutic agents in the treatment of periodontal diseases. Crit Rev Oral Biol Med. 1997;8(2):164-174.

107. Tonetti MS. Local delivery of tetracycline: from concept to clinical application. J Clin Periodontol. 1998;25(11 Pt 2):969-977.

108. Van Dyke TE. The clinical significance of new therapies for the management of periodontal disease. J Int Acad Periodontol. 2005;7(4 Suppl):191-196.

109. Van Dyke TE, Offenbacher S, Braswell L, Lessem J. Enhancing the value of scaling and root-planing: Arestin clinical trial results. J Int Acad Periodontol. 2002;4(3):72-76.

110. Preshaw PM, Novak MJ, Mellonig J, et al. Modified-release subantimicrobial dose doxycycline enhances scaling and root planing in subjects with periodontal disease. J Periodontol. 2008;79(3):440-452.

111. Reddy MS, Geurs NC, Gunsolley JC. Periodontal host modulation with antiproteinase, anti-inflammatory, and bone-sparing agents. A systematic review. Ann Periodontol. 2003;8(1):12-37.

112. Ryan ME, Golub LM. Modulation of matrix metalloproteinase activities in periodontitis as a treatment strategy. Periodontol 2000. 2000;24:226-238.

113. Novak MJ, Dawson DR 3rd, Magnusson I, et al. Combining host modulation and topical antimicrobial therapy in the management of moderate to severe periodontitis: a randomized multicenter trial. J Periodontol. 2008;79(1):33-41.

114. Nakagawa T, Hosaka Y, Ishihara K, et al. The efficacy of povidone-iodine products against periodontopathic bacteria. Dermatology. 2006;212(suppl 1):109-111.

115. Hoang T, Jorgensen MG, Keim RG, Pattison AM, Slots J. Povidone-iodine as a periodontal pocket disinfectant. J Periodont Res. 2003;38(3):311-317.

116. Slots J. Selection of antimicrobial agents in periodontal therapy. J Periodont Res. 2002;37(5):389-398.

117. Sahrmann P, Puhan MA, Attin T, Schmidlin PR. Systematic review on the effect of rinsing with povidone-iodine during nonsurgical periodontal therapy. J Periodont Res. 2010;45(2):153-164.

118. Forabosco A, Spinato S, Grandi T, Prini M. A comparative study between different techniques in non-surgical periodontal treatment. Minerva Stomatol. 2006;55(5):289-296.

119. Rosling B, Hellström MK, Ramberg P, Socransky SS, Lindhe J. The use of PVP-iodine as an adjunct to non-surgical treatment of chronic periodontitis. J Clin Periodontol. 2001;28(11):1023-1031.

120. Del Peloso Ribeiro E, Bittencourt S, Ambrosano GM, et al. Povidone-iodine used as an adjunct to non-surgical treatment of furcation involvements. J Periodontol. 2006;77(2):211-217.

121. Koshy G, Kawashima Y, Kiji M, et al. Effects of single-visit full-mouth ultrasonic debridement versus quadrant-wise ultrasonic debridement. J Clin Periodontol. 2005;32(7):734-743.

122. Leonhardt A, Bergström C, Krok L, Cardaropoli G. Healing following ultrasonic debridement and PVP-iodine in individuals with severe chronic periodontal disease: a randomized controlled clinical study. Acta Odontol Scand. 2006;64(5):262-266.

123. Zanatta GM, Bittencourt S, Nociti FH Jr, Sallum EA, Sallum AW, Casati MZ. Periodontal debridement with povidone-iodine in periodontal treatment: short-term clinical and biochemical observations. J Periodontol. 2006;77(3):498-505.

124. Löe H, Schiott CR. The effect of mouthrinses and topical application of chlorhexidine on the development of dental plaque and gingivitis in man. J Periodont Res. 1970;5(2):79-83.

125. Khoo JGL, Newman HN. Subgingival plaque control by a simplified oral hygiene regime plus local chlorhexidine or metronidazole. J Periodont Res. 1983;18(6):607-619.

126. Reynolds MA, Lavigne CK, Minah GE, Suzuki JB. Clinical effects of simultaneous ultrasonic scaling and subgingival irrigation with chlorhexidine. Mediating influence of periodontal probing depth. J Clin Periodontol. 1992;19(8):595-600.

127. Southard SR, Drisko CL, Killoy WJ, Cobb CM, Tira DE. The effect of 2% chlorhexidine digluconate irrigation on clinical parameters and the level of Bacteroides gingivalis in periodontal pockets. J Periodontol. 1989;60(6):302-309.

128. Vignarajah S, Newman HN, Bulman J. Pulsated jet subgingival irrigation with 0.1% chlorhexidine, simplified oral hygiene and chronic periodontitis. J Clin Periodontol. 1989;16(6):365-370.

129. Chapple ILC, Walmsley AD, Saxby MS, Moscrop H. Effect of subgingival irrigation with chlorhexidine during ultrasonic scaling. J Periodontol. 1992;63(10):812-816.

130. Cosyn J, Sabzevar MM. A systematic review on the effects of subgingival chlorhexidine gel administration in the treatment of chronic periodontitis. J Periodontol. 2005;76(11):1805-1813.

131. Guarnelli ME, Franceschetti G, Manfrini R, Trombelli L. Adjunctive effect of chlorhexidine in ultrasonic instrumentation of aggressive periodontitis patients: a pilot study. J Clin Periodontol. 2008;35(4):333-341.

132. Krust KS, Drisko CL, Gross K, Overman P, Tira DE. The effects of subgingival irrigation with chlorhexidine and stannous fluoride. A preliminary investigation. J Dent Hyg. 1991;65(6):289-295.

133. MacAlpine R, Magnusson I, Kiger R, Crigger M, Garrett S, Egelberg J. Antimicrobial irrigation of deep pockets to supplement oral hygiene instruction and root debridement. I. Bi-weekly irrigation. J Clin Periodontol. 1985;12(7):568-577.

134. Quirynen M, Mongardini C, De Soete M, et al. The rôle of chlorhexidine in the one-stage full-mouth disinfection treatment of patients with advanced adult periodontitis. Long-term clinical and microbiological observations. J Clin Periodontol. 2000;27(8):578–589.

135. Wennström JL, Dahlén G, Gröndahl K, Heijl . Periodic subgingival antimicrobial irrigation of periodontal pockets II. Microbiological and radiographical observations. J Clin Periodontol. 1987;14(10):573-580.

136. Wennström JL, Heijl L, Dahlén G, Gröndahl K. Periodic subgingival antimicrobial irrigation of periodontal pockets (I). Clinical observations. J Clin Periodontol. 1987;14(9):541-550.

137. Miyasaki KT, Genco RJ, Wilson ME. Antimicrobial properties of hydrogen peroxide and sodium bicarbonate individually and in combination against selected oral, gram-negative, facultative bacteria. J Dent Res. 1986;65(9):1142-1148.

138. Miyasaki KT, Wilson ME, Genco RJ. Killing of Actinobacillus actinomycetemcomitans by the human neutrophil myeloperoxidase-hydrogen peroxide-chloride system. Infect Immun. 1986;53(1):161-165.

139. Wikesjö UME, Reynolds HS, Christersson LA, Zambon JJ, Genco RJ. Effects of subgingival irrigation on A. actinomycetemcomitans. J Clin Periodontol. 1989;16(2):116-119.

140. Kalkwarf KL, Tussing GJ, Davis MJ. Histologic evaluation of gingival curettage facilitated by sodium hypochlorite solution. J Periodontol. 1982;53(2):63-70.

141. Pihlstrom BL, Wolff LF, Bakdash MB, et al. Salt and peroxide compared with conventional oral hygiene. I. Clinical results. J Periodontol. 1987;58(5):291-300.

142. Wolff LF, Pihlstrom BL, Bakdash MB, et al. Salt and peroxide compared with conventional oral hygiene. II. Microbial results. J Periodontol. 1987;58(5):301-307.

143. Flemmig TF, Petersilka G, Völp A, et al. Efficacy and safety of adjunctive local moxifloxacin delivery in the treatment of periodontitis. J Periodontol. 2011;82(1):96-105.

144. Jorgensen MG, Slots J. The ins and outs of periodontal antimicrobial therapy. J Calif Dent Assoc. 2002;30(4):297-305.

145. Rosling BG, Slots J, Christersson LA, Gröndahl HG, Genco RJ. Topical antimicrobial therapy and diagnosis of subgingival bacteria in the management of inflammatory periodontal disease. J Clin Periodontol. 1986;13(10):975-981.

146. van Steenberghe D, Rosling B, Söder PO, et al. A 15-month evaluation of the effects of repeated subgingival minocycline in chronic adult periodontitis. J Periodontol. 1999;70(6):657-667.

147. Stabholz A, Nicholas AA, Zimmerman GJ, Wikesjö UME. Clinical and antimicrobial effects of a single episode of subgingival irrigation with tetracycline HCl or chlorhexidine in deep periodontal pockets. J Clin Periodontol. 1998;25(10):794-800.

148. Timmerman MF, van der Weijden GA, van Steenbergen TJM, Mantel MS, de Graaff J, van der Velden U. Evaluation of the long-term efficacy and safety of locally-applied minocycline in adult periodontitis patients. J Clin Periodontol. 1996;23(8):707-716.

149. Silverstein L, Bissada N, Manouchehr-Pour M, Greenwell H. Clinical and microbiological effects of local tetracycline irrigation on periodontitis. J Periodontol. 1988;59(5):301-305

150. Spielman AI, Wolff MS. Overcoming barriers to implementing evidence-based dentistry. Letter to the editor. J Dent Educ. 2008;72(3):263-264.

151. O’Donnell JA, Modesto A, Oakley M, Polk DE, Vallapil B, Spallek H. Sealants and dental caries. Insights into dentists’ behaviors regarding implementation of clinical practice recommendations. J Am Dent Assoc. 2013;144(4):e24-e30.

152. Beauchamp J, Caufield PW, Crall JJ, et al. Evidence-based clinical recommendations for the use of pit-and-fissure sealants: a report of the American Dental Association Council on Scientific Affairs. J Am Dent Assoc. 2008;139(3):257-268.

Table I

Table II

Take the Accredited CE Quiz:

LOGIN    or    SIGN UP
CREDITS: 0
COST: $0
PROVIDER: American Dental Hygienists' Association
SOURCE: American Dental Hygienists' Association | December 2013

Learning Objectives:

  • Describe the evidence in support of using locally delivered, controlled-release antimicrobials in periodontal therapy
  • Discuss the bases for concerns about the use of antimicrobial agents
  • Understand how scaling and root planning can be used in combination with microbial therapy to reduce clinical signs of chronic periodontitis