Efficacy of subantimicrobial dosing with doxycycline
Point/counterpoint
GARY GREENSTEIN, D.D.S., M.S. and
IRA LAMSTER, D.D.S., M.M.Sc.
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ABSTRACT
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Background. This article addresses the role of subantimicrobial dosing with doxycycline, or SDD, in the treatment of chronic periodontitis. The authors discuss and debate 10 issues with regard to SDD’s utility as an adjunct to scaling and root planing.
Types of Studies Reviewed. The authors reviewed reports of controlled clinical trials that assessed the efficacy of SDD. The main focus of this article is data from the U.S. Food and Drug Administration’s phase 3 clinical trial that evaluated the efficacy of SDD in terms of alterations of probing depth, clinical attachment levels and disease progression.
Results. The authors compared data from test groups, which underwent root planing plus SDD, with data from control groups, which underwent root planing alone. The mean data suggest that SDD provides a defined but limited improvement of periodontal status when used in conjunction with scaling and root planing. Furthermore, several in vivo studies indicated that a nine-month course of SDD did not cause development of drug-resistant bacterial strains or alteration of the subgingival microbiota.
Clinical Implications. Some patients may benefit from SDD. However, there are several issues that should be clarified before widespread use of SDD is recommended for patients with chronic periodontitis. The evidence indicates that suppression of the bacterial challenge, which reduces the host response, is the most efficient way to control periodontal diseases.
It once was believed that destruction of the periodontium was directly related to the presence of subgingival pathogenic bacteria and factors released from these organisms, which had an adverse effect on the periodontal tissues.1 Now it is recognized that an exuberant inflammatory response to bacteria by the host results in loss of connective tissue attachment and alveolar bone.2 This occurs when the immune and inflammatory responses are unable to contain the bacterial challenge, and bacterial antigens and cellular components cause activation of the host’s polymorphonuclear leukocytes and macrophages. These cells and structural cells, such as fibroblasts and epithelial cells, release a variety of inflammatory mediators: prostaglandins (such as prostaglandin E2, or PGE2), matrix metalloproteinases, or MMPs (such as collagenase and gelatinase); and proinflammatory cytokines (such as interleukin-1ß, or IL-1ß, and tumor necrosis factor 
).2 Resorption of alveolar bone is thought to be induced by IL-1ß and PGE2 acting on osteoclasts; collagen destruction has been related to excess production of MMPs. Thus, while the host response is considered primarily protective, tissue destruction can be associated with a hyperinflammatory response.
Several issues should be clarified before widespread use of subantimicrobial dosing with doxycycline is recommended for patients with chronic periodontitis.
Accordingly, it has been proposed that inhibition of an exuberant inflammatory response could reduce tissue inflammation and consequently impede the initiation and progression of periodontal diseases. In this regard, it was determined that members of the tetracycline class of antibiotics could inhibit the MMPs,3,4 a family of at least 13 proteolytic enzymes that mediate degradation of collagen and bone. MMPs usually are involved in normal tissue turnover; however, some are responsible for a substantial part of the destruction caused by the host response (Table 1
).5,6 Researchers have noted that subantimicrobial dosing with doxycycline, or SDD, at 30 milligrams twice per day could lower collagenase levels in gingival crevicular fluid.7 Furthermore, in a multicenter clinical trial, adjunctive use of low doses of doxycycline enhanced clinical results attained with scaling and root planing.8 In 1998, the U.S. Food and Drug Administration approved the use of SDD (20 mg) as an adjunct to scaling and root planing. (At this time, SDD is available in a single marketed form, called Periostat [Colla-Genex]). This article presents, in a point/counterpoint format, issues relevant to the clinical use of SDD in the treatment of chronic periodontitis.
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DOES DAILY USE OF SUBANTIMICROBIAL DOSING WITH DOXYCYCLINE, OR SDD, ENHANCE THE EFFICACY OF SCALING AND ROOT PLANING?
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Point.
In the phase 3 clinical trial, SDD administered twice per day for nine months after scaling and root planing (combined therapy) resulted in a statistically greater probing depth reduction and gain of clinical attachment than scaling and root planing alone (Table 2).8
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TABLE 2 SCALING AND ROOT PLANING PLUS SDD* VS. SCALING AND ROOT PLANING ALONE: COMPARISON OF PERIODONTAL STATUS IMPROVEMENT.
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Counterpoint.
Mean improvements observed with combined therapy, beyond scaling and root planing, are less than 0.5 millimeters in terms of both probing depth reduction and gain of clinical attachment (Table 2
). This improvement may not be clinically relevant to clinicians if the degree of change induced by treatment is outweighed by the severity of periodontal disease. Furthermore, in another study that compared the effect of scaling and root planing with and without SDD, researchers found no differences between the test and control groups with respect to gain of clinical attachment or probing depth reduction.9
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WHAT IS THE MOST ACCURATE WAY TO EXPRESS THE DEGREE OF IMPROVEMENT IN PROBING DEPTH REDUCTION?
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Point.
In an analysis of the phase 3 clinical trial comparing the efficacy of combined therapy after nine months of SDD with the efficacy of scaling and root planing alone, researchers interpreted data as indicating that at sites with an initial probing depth of 
7 mm, combined therapy resulted in a 40 percent improvement in probing depth reduction (1.68 mm vs. 1.20 mm)10 (Table 2).
Counterpoint.
This type of calculation can be misleading. For instance, if one therapy induces a 0.1-mm probing depth reduction and a second therapy improves the result to 0.2 mm, this would constitute a 100 percent improvement.
Another method of expressing the data could provide the percentage reduction of the initial probing depth. For instance, at sites with an initial mean probing depth of 7 mm, the mean probing depth reduction after combined therapy would be about 1.68, and after scaling and root planing it only would be about 1.20 mm.8 The precise result cannot be calculated because the published data were averaged for all sites 7 mm. Therefore, the residual probing depth at sites initially 7 mm deep would be about 5.32 mm after combined therapy and about 5.8 mm after scaling and root planing. In reality, combined therapy would reduce the initial 7-mm probing depth by about 24 percent, and scaling and root planing would decrease it by about 17 percent. Thus, the difference between therapies with respect to the percentage reduction of pocketing would be about 7 percent of the initial probing depth.
Clinicians need to question if overall mean differences of < .5 millimeter with respect to probing depth reduction or gain of clinical attachment are clinically important.
From another perspective, even though the results of the study by Caton and colleagues8 were presented with regard to specific ranges of initial probing depths (that is, 0–3 mm, 4–6 mm and 7 mm) (Table 2), changes vary with different levels of pre-existing disease. Therefore, publication of frequency distributions regarding how often specific magnitudes of change (1 mm, 2 mm and so on) occurred at different initial probing depths would assist the clinician in estimating the benefit that might be achieved in different clinical situations.
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HOW MUCH CLINICAL ATTACHMENT CAN BE GAINED WITH ADJUNCTIVE USE OF SDD?
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Point.
After combined therapy, at sites with initial probing depths of 4 to 6 mm, subjects in the phase 3 clinical trial experienced a numerically greater gain of clinical attachment (1.03 mm) than of probing depth reduction (0.95 mm) (Table 2).8 In monitored locations initially 7 mm deep, the probing depth reduction was 1.68 mm and the amount of clinical attachment gain was 1.55 mm (Table 2). In addition, at sites with an initial probing depth of 4 mm, a greater gain of clinical attachment of 2 mm was detected at more sites after combined therapy (34.3 percent [1,193 of 3,477 sites]) than after scaling and root planing alone (30.7 percent [1,054 of 3,435 sites]).8
Counterpoint.
After scaling and root planing, probing depth reduction consists of two components: recession and clinical attachment gain. In some studies, the gain of clinical attachment is approximately 50 percent of the probing depth reduction; however, this relationship does vary.11–13 In the phase 3 clinical trial that assessed the efficacy of SDD, it is unclear why patients experienced a larger-than-usual gain of clinical attachment and minimal gingival recession in the test and control groups (Table 2).8 Furthermore, it is unclear how some sites gained more clinical attachment than probing depth reduction. For example, at sites with an initial probing depth of 4 mm, the finding that 34.3 percent (1,193 of 3,477 sites) of the sites treated with combined therapy gained 2 mm of clinical attachment, but only 29.9 percent of the locations (1,040 of 3,477) experienced a 2-mm probing depth reduction. Similarly, the percentage of sites that gained 3 mm of clinical attachment after combined therapy was 12.5 percent (435 of 3,477 sites), whereas only 7.9 percent (275 of 3,477 sites) of the locations demonstrated a probing depth reduction of 3 mm. These findings could be attributed to coronal migration of the gingiva and enhanced clinical attachment gain or to measurement error. Furthermore, the number of sites that gained 2 mm of clinical attachment after nine months’ use of SDD was not dramatically greater than the number of such sites that underwent scaling and root planing alone (34.3 percent vs. 29.9 percent).
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HOW DOES ONE DIFFERENTIATE BETWEEN STATISTICAL AND CLINICAL SIGNIFICANCE OF RESULTS?
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Point.
Hypothesis testing is done as an extension of the scientific method to furnish an objective evaluation of whether there is a difference between therapies. When two treatments are compared with respect to a particular outcome (for instance, clinical attachment gain), the finding that one therapy causes a statistically significantly better result than the other indicates the likelihood that the detected difference occurred by chance is extremely small.14
In the phase 3 clinical trial that assessed the efficacy of SDD, combined therapy usually attained a statistically significantly better improvement (P < .05) than scaling and root planing alone with regard to probing depth reduction and gain of clinical attachment (Table 2).8 Furthermore, at sites with an initial probing depth 4 mm, when combined therapy was compared with scaling and root planing alone, it resulted in more sites’ achieving a 2-mm probing depth reduction than did the scaling and root planing alone (29.9 percent [1,040 of 3,477 sites] vs. 22.0 percent [755 of 3,435 sites]).8 In addition, a greater percentage of sites with an initial probing depth 7 mm experienced a probing depth reduction to < 5 mm with combined therapy than with scaling and root planing alone (37 percent vs. 26 percent).15
Counterpoint.
Statistical significance denotes that a finding usually does not occur by chance; however, the term does not indicate that a large change occurred or that the improvement is clinically meaningful. Clinicians need to question if overall mean differences of < .5 mm with respect to probing depth reduction or gain of clinical attachment are clinically important (Table 2). In this regard, it would be advantageous to know if combined therapy induced these improvements in a small percentage of patients who were highly susceptible to periodontitis or if the 7.9 percent increase in the number of sites experiencing a 2-mm probing depth reduction was generalized across many patients. This question is brought to mind by data presented in another investigation that assessed the utility of SDD as an adjunct to supragingival scaling.10 In that study, the investigators found that periodontal disease had progressed ( 3-mm loss of clinical attachment) in only 18 (nine in the test and nine in the control group) of 437 total patients. Furthermore, when these patients were removed from the study for ethical reasons and retreated with scaling and root planing, the subjects who were administered SDD achieved a greater probing depth reduction and gain of clinical attachment. Thus, the greatest advantage of using a host-modulating agent may be limited to patients who are highly susceptible to periodontal disease.
Finally, there is no precise standard for defining clinical significance. However, it would be beneficial if the discussion of the data with regard to the efficacy of low-dose doxycycline also included information concerning how many sites experienced improvement and what percentage of the patients benefited from the adjunctive treatment. In addition to using reasonable criteria (for example, noninflamed sites with a probing depth of < 5 mm), it would be useful to know what percentage of sites were returned to health and how many still required additional treatment.
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IS DOXYCYCLINE BEING ADMINISTERED AT A SUBANTIMICROBIAL DOSE, AND DOES THIS AVOID DEVELOPMENT OF DRUG-RESISTANT STRAINS OF BACTERIA?
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Point.
In the phase 3 clinical trial, SDD was administered at 20 mg twice per day for nine months.8 When other investigators measured the doxycycline level in the gingival crevicular fluid, or GCF, after twice-per-day administration of SDD, they found it to be 0.6 to 0.8 microgram per milliliter,9 which is considered below the minimum inhibitory concentration, or MIC, for most subgingival bacteria (in vivo, 1 µg/mL is considered an antibacterial level).16 With respect to inducing drug-resistant bacteria, several in vivo studies have indicated that a nine-month course of SDD did not result in development of any drug-resistant bacterial strains, alterations of the subgingival microbiota, development of cross-resistance to other antibiotics or inducement of opportunistic infections.8,9,17
Counterpoint.
In an in vivo study,9 20-mg doses of doxycycline twice per day resulted in a 0.6- to 0.8-µg/mL concentration of doxycycline in the GCF, and in vitro this concentration was bactericidal for some strains of Porphyromonas gingivalis (MIC 0.047 µg/mL)18 and Actinobacillus actinomycetemcomitans (MIC 0.25 to 2.0 µg/mL 19 and 0.40 to 3.1 µg/mL).20 These data imply that the doxycycline level present after SDD is administered may not be sublethal; therefore, there may be potential for drug-resistant bacterial strains to develop (Table 3).21 Furthermore, concerns have been expressed that use of sublethal concentrations of tetracycline may promote drug-resistant bacterial strains by stimulating the transfer of genetically transmissible elements (for example, plasmids).22–29 Several in vivo studies have addressed the potential of SDD to induce drug-resistant bacterial strains and reported that this did not occur8,9,17; however, additional long-term investigations are needed to verify this finding.
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IS ADJUNCTIVE USE OF SDD THE MOST EFFECTIVE WAY TO ENHANCE SCALING AND ROOT PLANING?
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Point.
SDD can be used in conjunction with scaling and root planing, thus preventing the need to use systemic antibiotics (Table 2). Avoiding use of systemically administered antibiotics reduces or eliminates untoward drug side effects (such as gastrointestinal disturbances) and the potential to induce drug-resistant bacterial strains.
Counterpoint.
In several investigations, systemically and locally applied antibiotics administered in conjunction with scaling and root planing at deep probing sites ( 7 mm) consistently achieved a numerically greater result with regard to probing depth reduction than that resulting from the use of SDD plus root planing at lesions of similar size (Table 4).30–35 After systemic or local antibiotic therapy in conjunction with root planing, the mean reduction in probing depth usually was 1.8 mm,30–35 and there was a decrease in the number of sites experiencing disease progression.33,36,37 Therefore, administration of an antibiotic for one week to reduce or eliminate putative pathogens may preclude the need to administer SDD. In this regard, culturing to determine the presence of alleged pathogens and their sensitivity to various antibiotics would be advantageous.
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TABLE 4 PROBING DEPTH REDUCTION AND GAIN OF CLINICAL ATTACHMENT AFTER SCALING AND ROOT PLANING COMBINED WITH ADJUNCTIVE ANTIBIOTIC THERAPY.
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From a different perspective, other researchers who addressed the efficacy of repeated root planing have reported results that were numerically greater in terms of probing depth reduction than those achieved with scaling and root planing plus SDD (Table 5).38–40 Thus, before administering a host-modulating drug for as long as nine months, clinicians need to consider the benefits that could be attained with repeated root planing, systemic or local administration of an antibiotic, or both.
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DOES SDD IN CONJUNCTION WITH SCALING AND ROOT PLANING REDUCE DISEASE PROGRESSION MORE THAN SCALING AND ROOT PLANING ALONE?
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Point.
During a nine-month monitoring period, at sites initially 7 mm in probing depth, combined therapy achieved a 92 percent greater reduction in the number of sites experiencing disease progression (defined as 2-mm loss of clinical attachment) (Table 6) than did scaling and root planing alone.8
Counterpoint.
After scaling and root planing, during the nine-month monitoring period, the absolute rate of disease progression was 3.6 percent of the sites initially 7 mm deep, whereas after combined therapy, disease progression occurred at 0.3 percent of these sites.8 The investigators expressed the results as a relative proportional risk reduction of 92 percent, which was calculated as the difference in these two rates divided by the placebo rate (3.6 percent –0.3 percent/3.6 percent = 92 percent). Results of controlled clinical trials commonly are reported in this manner. However, the relative risk reduction of 92 percent is dramatically different than the absolute risk reduction of 3.3 percent, which is the actual difference between the incidence of disease progression in the test and control groups (3.6 percent vs. 0.3 percent).
With regard to patient care, a calculation of absolute risk provides the clinician with information that can be applied more readily to the management of patients with periodontitis than can calculations that describe relative risk reduction. Thus, it can be concluded that 96.4 percent of the sites treated with scaling and root planing did not experience disease progression, and, therefore, it probably is unnecessary to administer SDD to most patients with chronic periodontitis.
The inverse of absolute risk difference, referred to as the "number needed to treat," or NNT, also has enormous utility in clinical decision making. The NNT identifies the number of patients who need to be treated to avoid an adverse outcome for one patient or one site in a patient.41 In this study, the NNT is 30; 3.6 percent –0.3 percent = 3.3 percent is the difference in the incidence of disease progression, and the inverse of the absolute risk difference is 100/3.3 = 30. Therefore, a clinician would need to treat people with a total of 30 sites at risk (probing depths 7 mm) with low-dose doxycycline for possibly as long as nine months to prevent loss of attachment of 2 mm at one site. From the data, it is unclear how many patients actually would have to be treated to attain this benefit. Ultimately, clinicians must cautiously interpret the data to determine the extent that adjunctive therapy will enhance therapeutic outcomes for their patients.
It probably is unnecessary to administer subantimicrobial dosing with doxycycline to most patients with chronic periodontitis.
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IS IT POSSIBLE TO CLINICALLY MONITOR ENZYMES INHIBITED BY SDD?
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Point.
Use of SDD is intended to inhibit MMPs that are believed to be associated with progressive periodontitis—specifically, MMP-8, MMP-9 and MMP-13.42–46
Counterpoint.
No commercially available test exists to precisely monitor levels of specific MMPs in the periodontal tissues or the GCF. A commercially available enzyme kit (Periocheck, Pro-Dentec) can be used to assess for neutral proteases (for example, cathepsins, collagenases and elastase).47 However, this test is not specific enough to monitor MMPs (for example, MMP-8 and MMP-9 from polymorphonuclear leukocytes) associated with loss of connective tissue. The use of this or other tests to titrate the use of SDD needs to be assessed.
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WHAT ARE THE INDICATIONS FOR USE AND THE PROPER LENGTH OF ADMINISTRATION OF SDD?
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Point.
SDD was approved by the FDA as an adjunct to scaling and root planing in the treatment of chronic periodontitis (formerly called adult periodontitis).48 After SDD administration, collagenase levels in GCF decreased by 54 percent within two weeks of administration.7 However, after two weeks, there was no significant reduction of gingival inflammation or probing depths.7 It is logical to expect biochemical alterations to precede clinical changes by several months. During the phase 3 clinical trial, SDD was administered twice per day for nine months.8
Counterpoint.
There are no specific criteria by which to identify patients who will benefit the most from adjunctive use of SDD. An unlabeled indication of SDD may be the treatment of patients with recurrent periodontitis or patients who have not responded to conventional therapy. However, this concept needs to be verified in controlled clinical trials. Furthermore, before administering SDD to modulate the host response, the clinician would be prudent to focus on controlling the bacterial challenge and, thereby, possibly precluding the need to administer a host-modulating agent.
The duration of SDD therapy that will achieve optimal results is unknown and probably will vary among patients. In the phase 3 trial, it appears that 90 percent of the results were attained after three months.8 Therefore, for any patient selected to receive SDD, it may be reasonable to administer the drug for three months and then reassess his or her periodontal status.
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IS SDD ECONOMICAL, AND WILL PATIENTS COMPLY WITH THE DRUG REGIMEN?
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Point.
The cost of SDD is approximately $1.28 per 20-mg tablet (oral communication, CVS Pharmacy, July 2000). Therefore, the cost of a twice-per-day regimen for nine months would amount to approximately $690. With respect to compliance, patients must take the medication only twice daily, and, if they fail to take the drug as often as recommended, there is no problem with inducing drug resistance.
Counterpoint.
A course of systemic antibiotics (which typically lasts 10 days) would cost between $7 and $70, depending on the choice of drug. Therefore, considering the benefit that usually is attained with systemic antibiotics (Table 4), it is questionable whether treatment with SDD is economical. Furthermore, the expenditure for SDD could be used for additional mechanical therapy. Patient compliance during nine months also needs to be assessed, because investigators previously reported that approximately 44 percent of patients instructed to take antibiotics three times daily for seven days did not fully adhere to their recommended dosing regimen.49
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UPDATE: AN ADDITIONAL CLINICAL TRIAL
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Since this article was accepted for publication, an additional small clinical trial comparing the efficacy of supragingival and subgingival scaling for a total of 30 minutes with and without SDD (respectively, test and control groups) has been published.50 Four test groups recieved varied dosing regimens of SDD and one control group received placebo. The study confirmed that, after 12 weeks, the group that received adjunctive SDD (at a dose of 20 mg twice per day) had a statistically lower level of collagenase than did the control group. It also validated the concept that SDD needed to be administered for 12 weeks to maximize lowered collagenase levels in the GCF (47.3 percent reduction). However, the individual test and control groups demonstrated no statistically significant differences with regard to five clinical parameters:
- – clinical attachment levels;
- – probing depth reduction;
- – bleeding on probing;
- – gingival crevicular flow;
- – clinical signs of inflammation.
The evidence indicates that suppression of the bacterial challenge and subsequent reduction of the host response is the most efficient way to control periodontal diseases.
When three of the test groups, each with about 10 patients per group, were collapsed into one group and compared with the control group, the mean gain of clinical attachment was 0.3 mm for the test group vs. zero for the control group. Subsequently, there was an additional 12 weeks of no adjunctive therapy. Then all groups received an additional scaling and prophylaxis and three of the test groups were administered 12 more weeks of SDD (20 mg, daily). At 36 weeks, it was noted that the test group that received 20 mg twice per day and then 20 mg once per day lost 0.15 mm of clinical attachment, whereas the control group lost 0.8 mm. Other comparisons between the test and control groups showed no differences with respect to the other four clinical parameters mentioned above.
The observation that the control group lost 0.8 mm of clinical attachment after receiving supragingival and subgingival scaling at baseline and after 24 weeks contradicts the usual findings in the periodontal literature.51 All studies that evaluated the efficacy of subgingival mechanical instrumentation reported a gain of clinical attachment.51 Furthermore, the phase 3 clinical trial that assessed the efficacy of SDD clearly demonstrated this for all probing depths8 (Table 2). Therefore, the benefit provided by SDD should be interpreted cautiously.
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CONCLUSIONS
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Despite the finding that SDD provided some benefits beyond that achieved with scaling and root planing alone,8 there are numerous issues that need to be clarified before widespread use of SDD can be recommended for patients with chronic periodontitis. In general, it is important to assess critically many issues associated with the introduction of any new treatment for disease management, to ensure that the most appropriate clinical guidelines for its application are established. The evidence accumulated to date indicates that suppression of the bacterial challenge and subsequent reduction of the host response is the most efficient way to control periodontal diseases.
The data from the phase 3 clinical trial indicated that adjunctive SDD might provide some additional benefit beyond scaling and root planing alone in the treatment of chronic periodontitis.8 However, clinicians need to decide if the improvement provided beyond that attained with scaling and root planing alone is clinically meaningful in the management of specific patients. It is possible that problematic cases that do not respond to conventional therapy and are unsuccessfully managed despite intensive efforts to control the bacterial challenge will benefit most from adjunctive use of SDD. However, this unlabeled use of SDD needs to be verified in controlled clinical trials, and additional studies are needed to help define the most beneficial treatment strategies.
Finally, considering the prevalence of periodontitis, concern must be expressed about the possibility that large numbers of patients may be prescribed low doses of antibiotics over an extended period. This may prove to be of greater import than the benefit. Specifically, the long-term effect of using low-dose doxycycline in terms of induction of drug-resistant bacterial strains warrants additional investigation.
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Dr. Greenstein is a clinical professor, Department of Periodontology, University of Medicine and Dentistry of New Jersey, Newark. He also maintains a private practice in periodontics at 900 W. Main St., Freehold, N.J. 07728. Address reprint requests to Dr. Greenstein.
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Dr. Lamster is an assistant professor, Division of Periodontics, and the vice dean, Columbia University School of Dentistry and Oral Surgery, New York.
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