Periodontal diseases are initiated by subgingival periodontal pathogens in susceptible periodontal sites. The host immune response toward periodontal pathogens helps to sustain periodontal disease and eventual alveolar bone loss. Numerous adjunctive therapeutic strategies have evolved to manage periodontal diseases. Systemic and local antibiotics, antiseptics, and past and future host immune modulatory agents are reviewed and discussed to facilitate the dental practitioner’s appreciation of this ever-growing field in clinical periodontics.
Periodontal disease is a chronic infection of the periodontium affecting soft and mineralized tissues surrounding the teeth. Periodontal disease progression is associated with subgingival bacterial colonization and biofilm formation that provokes chronic inflammation of soft tissues, degradation of collagen fibers supporting the tooth to the gingiva and alveolar bone, and resorption of the alveolar bone itself. The fundamental role of microorganisms as the cause of periodontal disease was systematically demonstrated some 40 years ago, and research efforts have long focused on identifying the pathogenic microorganisms and their virulence factors. The search for these putative microorganisms was driven, in part, by knowledge indicating that colonization of the oral cavity by commensal bacteria and the presence of dental biofilm is normally associated with health, similar to the colonization of the colon. In contrast, the microflora associated with periodontal disease was found to differ, with the biofilm dominated by anaerobic bacteria and spirochetes. To treat periodontal diseases as an infectious disease, numerous therapeutic strategies aimed at eradication of periodontal pathogens have been studied for many years, including local and systemic delivery of antimicrobial and antibiotic agents. This review provides an update on the chemotherapeutic agents used adjunctively to treat and manage periodontal diseases.
In the current paradigm of periodontal disease, specific periodontal pathogens are necessary for disease initiation; however, the extent and severity of tissue destruction are largely dependent on the nature of the host-microbial interactions. These interactions are dynamic, because both the microbial composition of the dental biofilm and the competency of host immune responses can vary, in the same individual, with time. This concept was developed in parallel to the advances on the understanding of the immune response, and research on periodontal disease has focused on the mechanisms of host-microbial interactions to understand the disease process and for the development of novel therapeutic strategies. For the past 2 decades, the host response to the bacterial challenge originating from the dental biofilm has been considered to play a major role on initiation of the disease and on the tissue destruction associated with its progress. The importance of host-microbial interactions is reinforced by epidemiologic data indicating different susceptibilities to periodontal disease among individuals, despite the long-term presence of oral biofilm. Other studies showing increased susceptibility and greater severity of periodontal disease in individuals with impaired immune response caused by systemic conditions also indicate the significance of the host response to the bacterial challenge. Past and future directions of host-modulatory agents are addressed here to provide the dental practitioner with a broader prospective on the use of chemotherapeutic agents used to manage periodontal diseases.
Systemic antibiotics
Traditional periodontal therapies have focused on the mechanical debridement of the root surfaces to maintain a healthy sulcus or produce an environment suitable for new attachment. The inability of mechanical treatment to always produce a desirable root surface coupled with the nature and complexity of the subgingival biofilm has fueled the search for adjunctive treatment regimens that increase the likelihood of successfully management of periodontal diseases.
Although more than 700 bacterial species may be present in the gingival sulcus, it is clear that only a subset of bacterial species are consistently found to be associated with diseased sites. These findings make the prospect of targeted antibiotic therapy an attractive goal. A thorough review of the microbiology of periodontal diseases is beyond the scope of this article; the reader is referred to the many reviews on this topic.
Systemic antibiotic therapy has the obvious advantage of generally conventional and acceptable delivery, especially if oral administration is used. Shortcomings to oral administration include issues of patient adherence to dosing recommendations and the variable absorption of the antibiotic from the gastrointestinal tract. Moreover, it is difficult to be certain that the antibiotic chosen will be effective against the periodontal pathogens present in the sulcus unless culture and sensitivity tests have been completed. Culture and sensitivity tests are particularly useful for those cases that do not respond well to conventional mechanical therapy and/or commonly chosen antibiotic regimens. Another factor that is often overlooked is that systemic antibiotics do not penetrate the subgingival biofilm to kill bacteria. Table 1 provides an overview of some orally active systemic antibiotics commonly used in clinical periodontics.
| Antibiotic Class | Agent | Effect | Target Organisms | Limitation |
|---|---|---|---|---|
| Penicillin | Amoxicillin | Bacteriocidal | Gram + and gram − | Penicillinase sensitive |
| Patient hypersensitivity | ||||
| Augmentin | Bacteriocidal | Narrower spectrum than amoxicillin | More expensive than amoxicillin | |
| Tetracycline | Tetracycline | Bacteriostatic | Gram + > gram − | Bacterial resistance |
| Minocycline | Bacteriostatic | Gram + > gram − | ||
| Doxycycline | Bacteriostatic | Gram + > gram − | ||
| Quinolone | Ciprofloxacin | Bacteriocidal | Gram − rods | Nausea, gastrointestinal discomfort |
| Macrolide | Azithromycin | Bacteriostatic OR bacteriocidal depending on concentration | Broad spectrum | |
| Lincomycin | Clindamycin | Bacteriocidal | Anaerobic bacteria | |
| Nitroimidazole | Metronidazole | Bacteriocidal to gram − | Gram −; especially Porphyromonas gingivalis and Prevotella intermedia | Not good choice for A actinomycetemcomitans infections |
Based on the known spectrum of action of an antibiotic and the cumulative research profiling the bacterial species in the sulcus, it is possible to choose an antibiotic that should be an effective pharmacologic agent. However, caution should be used because none of these antibiotics is effective as a monotherapy to treat periodontal diseases. A systemically administered antibiotic will not produce the same effective concentration in the gingival sulcus as it might at another infected body site. Systemic antibiotics reach the periodontal tissues by transudation across serum, then cross the crevicular and junctional epithelia to enter the gingival sulcus. The concentration of the antibiotic in this site may be inadequate for the desired antimicrobial effect without mechanical disruption of the plaque biofilm. In addition to any effect produced in the sulcus, a systemically administered antibiotic will produce antimicrobial effects in other areas of the oral cavity. This additional effect will reduce bacterial counts on the tongue and other mucosal surfaces, thus potentially delaying in re-colonization of subgingival sites by the offending bacteria. However, research indicates that antibiotics are detectable in the gingival sulcus and the range of their concentrations in the gingival cervicular fluid is known to be in the therapeutic range for treatment efficacy. Table 2 provides information to facilitate the clinician’s decision to the most reasonable choice of antibiotic, dose, and duration of administration.
| Antibiotic Agent | Regimen | Dosage and Duration |
|---|---|---|
| Single agent | ||
| Amoxicillin | 500 mg | Three times per day for 8 d |
| Azithromycin | 500 mg | Once daily for 4–7 d |
| Ciprofloxacin | 500 mg | Twice daily for 8 d |
| Clindamycin | 300 mg | Three times daily for 10 d |
| Doxycycline or minocycline | 100–200 mg | Once daily for 21 d |
| Metronidazole | 500 mg | Three times daily for 8 d |
| Combination therapy | ||
| Metronidazole + amoxicillin | 250 mg of each | Three times daily for 8 d |
| Metronidazole + ciprofloxacin | 500 mg of each | Twice daily for 8 d |
Many studies have described the effect of systemic antibiotic therapy on periodontal disease. Several different treatment regimens have been used successfully to manage periodontal diseases. It is not the intent of this discussion to review all the published studies in this area. The interested reader is referred to one of the many excellent, exhaustive reviews. From many studies, it can be stated generally that systemic antibiotic therapy has little effect on supragingival plaque accumulation with a possible exception in one study where doxycycline significantly decreased plaque accumulation at a 12-week evaluation compared with placebo.
Except for the combination of metronidazole with amoxicillin, systemic antibiotic treatment produces no clinically significant effects on periodontal pocket depth reduction compared with controls. The combination of metronidazole and amoxicillin has been found to produce more pocket depth reduction than control medication. A 7-day regimen of systemic metronidazole significantly reduced the percentage of sites with bleeding compared with controls. Others have reported a 12-month reduction in bleeding after treatment with a metronidazole-amoxicillin combination compared with a placebo treatment. With respect to clinical attachment levels, systemic metronidazole and combinations of metronidazole with other antibiotics have shown improvement in several studies. Several investigators found significant improvement of attachment levels at sites initially 4 to 6 mm in depth with a 7-day treatment with metronidazole. Winkel and colleagues showed that the combination of metronidazole and amoxicillin for 7 to 14 days produced a significant increase in the percentage of sites showing improved attachment levels compared with control sites. A combination of metronidazole and clindamycin for 3 weeks also produced improved attachment levels.
Some data to date support a clinical benefit from the use of azithromycin as a systemic approach in combination with mechanical routines. In 1 limited study, 17 subjects receiving azithromycin (500 mg), 3 days before full-mouth scaling and root planing (SRP) produced greater clinical improvement than in 17 subjects treated with full-mouth SRP only. Dastoor and colleagues studied 30 patients who reported smoking more than 1 pack per day and presented with periodontitis. A comparison was made between the response to treatment with periodontal surgery and 500 mg azithromycin per day for 3 days and treatment with periodontal surgery only. The addition of azithromycin did not enhance improvement seen in both groups for attachment gain, depth reduction, and reduction of bleeding on probing. However, the adjunctive use of azithromycin was associated with a lower gingival index at 2 weeks and what the investigators saw as more rapid wound healing. The addition of azithromycin also produced reductions of red-complex bacteria that were maintained for up to 3 months.
The combination of amoxicillin (375 mg)/metronidazole (500 mg), each taken 3 times per day for 7 days in conjunction with full-mouth periodontal debridement performed within a 48-hour period, produced more favorable clinical effects than the same full-mouth debridement routine alone. In the subjects treated with the antibiotics, probing depths showed a greater reduction with fewer bleeding sites on probing and a smaller number of sites requiring additional therapy at 6 months following initial therapy.
A reasonable choice of a systemic antibiotic routine, particularly in the absence of culture and sensitivity testing, may be the combination metronidazole and amoxicillin, 250 to 500 mg of each, taken 3 times per day for 8 days. Another reasonable choice may be the combination of metronidazole and ciprofloxacin, 500 mg of each, taken twice daily for 8 days. This combination adds the benefit of treatment of infections with Aggregatibacter actinomycetemcomitans .
Concerns are frequently raised regarding bacterial resistance with systemic antibiotic therapy. This has the potential to eliminate a possibly important or critical drug from the possible treatment options for diseases with more life-threatening potential than the risk of ongoing periodontal disease. It is important to remember that systemic antibiotic therapy is not intended as a monotherapy but is always best as an adjunctive therapy combined with mechanical therapy and plaque control. Management of severe types of periodontitis should not rely only on systemic antibiotics used in conjunction with mechanical debridement but may require the subgingival administration of antiseptics and/or local antibiotics and periodontal surgery.
Local antibiotic therapy
After considering the risk to benefit ratio of systemic antibiotic administration as a treatment of periodontal diseases, interest in local delivery of antibiotics developed ( Table 3 ). Historically, the first such local antibiotic therapy for periodontal disease was the Actisite (no longer commercially available) fiber system. Actisite was supplied as hollow, nonabsorbable fibers filled with tetracycline (12.7 mg in 23 cm (9 in) fiber). The fiber was inserted into the pocket, wrapped repeatedly circumferentially around the tooth keeping the fiber in the pocket. Often a periodontal dressing was placed to help keep the fiber in the pocket. The fiber was retained for 10 days until removed by the operator. During this 10-day period drug concentrations of more than 1300 μg/ml of tetracycline were achieved and maintained. When the fiber was removed the soft tissue was often distended allowing temporary improved access and visibility of the root surfaces for any additional root planing or calculus removal. Following removal of the fiber the soft tissues generally showed shrinkage, reduction of depth, and a reduction of the clinical signs of inflammation. The Actisite system, although very effective, was tedious to use and required a second visit for removal of the fiber. These issues fueled the development of absorbable systems for antibiotic delivery.
| Antimicrobial Agent | Delivery Form | Drawback | GCF Concentration | Time to Absorption | Brand Name |
|---|---|---|---|---|---|
| Tetracycline 12.7 mg per 23 cm (9 in) of fiber | Hollow fibers | Must be removed | >1300 μg/mL for 10 d | Not absorbable | Actisite, not commercially available |
| 10% Doxycycline | Fluid; multisite depending on volume of site; in syringe | Often pulls out when removing syringe | 250 μg/mL still noted at 7 d | 21 d | Atridox |
| 25% Metronidazole gel | Fluid; multisite depending on volume of site; in syringe | May require multiple applications for desirable results | More than 120 mg/mL of sulcus fluid in the first few hours | Concentration decreases rapidly after the first few hours | Elyzol |
| 2% Minocycline spheres | Solid; in unit doses applied with syringe | Unit doses may not be sufficient for every site volume | Therapeutic drug levels for 14 d | 14 d | Arestin |
| 0.5% Azithromycin | Gel in syringe | Peak at 2 h at 2041 μg/mL decreased from 324 μg/mL on day 7 to 3 μg/mL on day 28 | Still present at 28 d | Not commercially available |
The first resorbable local antibiotic system was Atridox (Atrix Laboratories, Fort Collins, CO). In this system, longer half-life doxycycline replaced tetracycline supplied at a concentration of 42.5 mg per unit dose of material. This system requires mixing powder and liquid components using 2 linked luer lock syringes. After adequate mixing, a blunt cannula is attached to 1 of the syringes and the material expressed from the syringe into the pocket. Atridox is absorbed after 7 days and reports of antibiotic concentrations of 250 μg/ml in the pocket have been reported. No second visit for removal of the material is necessary. The application of Atridox can be somewhat tedious as the material tends to pull out of the pocket when the syringe is removed. Retaining the material with a periodontal dressing can be helpful but is often unnecessary. Atridox improved the local antibiotic delivery by allowing placement of the material to the depth of most pockets and in a manner that allowed it to conform to the shape of the pocket unlike the solid fibers of Actisite. Depending on the size of the pocket, more than 1 site could be treated with a single unit dose of Atridox.
Further development of absorbable local antibiotic systems led to Arestin (OraPharma), which uses minocycline in a microsphere configuration, each sphere measuring 20 to 60 μm in diameter. Arestin is supplied in single-dose units that are applied into the pocket with a reusable, sterilizable syringe. Each unit dose contains 1 mg of mincocycline. The sphere is a bioabsorable polymer of poly(glycolide-co- dl -lactide), which is hydrolyzed into CO 2 and H 2 O. The antibiotic maintains therapeutic drug levels and remains in the pocket for 14 days. This configuration of material allows placement to the depths of most pockets and although the material cannot conform to the shape of the pocket and the Atridox gel, it is still easier to use than the solid Actisite fibers.
Another material, not now available in the United States, is Elyzol (Colgate), a metronidazole gel system. Elyzol is supplied as 25% metronidazole in a glyceryl mono-oleate and sesame oil base. The concentration of metronidazole in this system is 250 mg/g of material that is applied as a gel using a syringe.
Overall efficacy of local antibiotic therapies has been evaluated using meta-analysis of 50 articles, each reporting studies of at least 6 months follow-up. The meta-analysis considered studies of the addition of local adjuncts and found such additions provide generally favorable but minimal differences compared with SRP alone. Additional statistically significant depth reductions of 0.1 to 0.5 mm may be possible and smaller, less frequently statistically significant improvement in attachment levels were noted. The clinical effects of these various systems have been reported in several publications. Table 4 summarizes several studies of various local adjunctive materials. The overall treatment effect is somewhat variable and, although found to be statistically significant, has not resulted in widespread use of these systems by the clinical community.
| Agent | Subjects | Depth Change with SRP only | Depth Change with SRP + Agent | Sites With at Least 2 mm Attachment Gain with SRP + Agent |
|---|---|---|---|---|
| Tetracycline fibers | 107 | 0.67 | 1.02 (fiber only) | Not reported |
| Doxycycline gel | 411 | 1.08 | 1.30 (drug only) | 38% (drug only) |
| Doxycycline gel | 105 | 1.3 | 1.5 | 52% |
| Doxycycline gel | 48 | 1.5–2.19 | 1.63–2.29 | 34.4% vs 18.1% S/RP only |
| Minocycline spheres | 728 | 1.08 | 1.32 | 42% |
| Minocycline spheres | 127 | 1.01 | 1.38 | Not reported; reports attachment gain of 1.16 with agent, 0.8 S/RP only |
| Metronidazole gel | 206 | 1.3 | 1.5 (drug only) | Not reported |
| Azithromycin gel | 80 | 2.13 | 2.53 | Not reported; reports greater gain at all time points with agent |
Antiseptics
The use of chemical agents with antiplaque or antigingivitis action as adjuncts to oral hygiene seems to be of limited value, because mouth rinses do not penetrate appreciably into the gingival crevice, but they show specific benefits when used as adjuncts to control gingival inflammation, especially in acute situations, postsurgically, and during periods of interrupted hygiene. The American Dental Association (ADA) seal of acceptance is seen as a standard for oral health care products. The ADA Seal Program ensures that professional and consumer dental products meet rigorous ADA criteria for safety and effectiveness. Guidelines have been established for the control of gingivitis and supragingival plaque ( http://www.ada.org/ada/seal/index.asp ). These guidelines describe the clinical, biologic, and laboratory studies necessary to evaluate safety and effectiveness and are subject to revision at any time ( Box 1 ). The guidelines do not describe criteria for evaluating the management of periodontitis or other periodontal diseases. All claims of efficacy, including health benefit claims (eg, gingivitis reduction), and claims that imply a health benefit (eg, plaque reduction) must be documented. There will be two Seal statements to be used with an accepted product, depending on whether or not the product’s mechanism of action is related to plaque reduction.
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Product efficacy must be demonstrated by 2 independent, well-designed, 6-month clinical studies using a placebo control and conducted by independent investigators.
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All published studies assessing the effectiveness of the product must be referenced, including studies that do not show any effect.
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All proprietary studies, including those that do not show any effect, must also be provided.
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Studies should assess the ability of a chemotherapeutic agent to prevent or reduce gingivitis and to inhibit or reduce plaque formation or plaque pathogenicity.
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Masked studies are required; uniquely labeled products must be used and group coding must be avoided.
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At least 1 study shall be conducted on a US population.
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Populations selected for the studies must be representative of individuals for whom the product is intended, which, in most cases, would be individuals with mild to moderate gingivitis.
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Trials must report all treatment groups.
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Statistically significant reductions in both the clinical manifestations of gingivitis and in the inhibition or reduction of plaque or plaque pathogenicity related to gingivitis must be demonstrated.
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Reductions relative to plaque and gingivitis should be demonstrated after 6 months of use in 2 studies and be measured against a placebo control rather than baseline scores.
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The product must show clinical significance in gingivitis reduction compared with placebo controls in at least 2 clinical studies.
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Microbiological sampling should estimate plaque qualitatively to complement indices that measure plaque quantitatively.
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Gingivitis measurements shall demonstrate:
- 1.
that the estimated proportionate reductions (ie, [control−active]/control) be no less than 15% in favor of the active treatment with a confidence interval of ±10%, and statistically significant in each of at least 2 studies;
- 2.
that, in addition, the (arithmetical) mean of the estimated proportionate reductions (ie, [control−active]/control) across the above studies be no less than 20%.
- 1.
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Plaque measurements shall demonstrate that quantitative plaque reductions or reductions in plaque pathogenicity for those products whose antigingivitis action is through plaque reduction or modifications are statistically significant.
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The most likely mechanism(s) of action of the product should be given, with supporting data.
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