#55194: Localized Therapy with Controlled-Release Antimicrobials

Periodontal disease is one of the world's most prevalent chronic diseases. It is estimated that up to 42% of adult Americans have some sign of the disease [1]. Periodontitis is a multifactorial infection with complex and interconnected mechanisms of pathogenesis [2]. The interplay between bacteria within the sulcus and periodontal pocket and the response they elicit in the host defense mechanisms, which in turn can be modified by genetic and acquired risk factors, produces the prospects of a large number of possible permutations of how the disease might present clinically and how it might progress [3,4]. Bacteria have long been established as the etiologic agents [5]. Nearly 800 species of aerobic and anaerobic bacteria have been identified in the oral cavity [6,7]. Only a few, however, have been associated with the connective tissue dissolution, apical migration of the epithelial attachment, and alveolar bone loss that characterize the disease process [8].

Bacteria and other micro-organisms establish themselves in the environment of the periodontal pocket through a complex, sequential colonization, interacting with each other in a variety of ways [6]. The presence and growth of some species may assist others in colonization. For example, among the first bacteria to populate a site and establish themselves are gram-positive, aerobic streptococci. As they proliferate, more and more oxygen is consumed, eventually producing conditions where anaerobic species can establish themselves. Conversely, some species are directly antagonistic to the colonization of others, often competing for similar nutritional and growth factors. Thus, each of the nearly 800 bacterial species has its own specific environmental and nutritional requirements, some of which may be in competition with other species also attempting to establish colonies, and some of which may assist others in colonization [7,9].

Once established, this complex combination of interacting species, bathed in the contents of the gingival crevicular fluid (GCF) and impacted by the mechanisms of the host's defense, accounts in part for the variability of disease manifestation from tooth to tooth and from site to site on the same tooth. On the same tooth surface within the periodontal pocket, different combinations and relative proportions of bacteria within the plaques can be present. Each combination has the potential to produce a different response from the host in a broad range from slight to significant. These responses may lead to varying magnitudes and degrees of tissue destruction. This may result in localized or generalized destruction, producing either an aggressive and rapid loss or a more chronic problem [4].

In general, chronic adult periodontitis may be defined as a mixed anaerobic infection where the overgrowth of potential pathogens is influenced by local factors within the bacterial community and the impact of host defense mechanisms elaborated within the pocket. Some of the most commonly implicated micro-organisms associated with periodontal destruction are Porphyromonas gingivalis, Bacteroides forsythus, Treponema denticola, and Aggregatibacter (formerly Actinobacillus) actinomycetemcomitans [6,10,11]. This group of micro-organisms has been shown to be strongly associated with the progression of the disease as measured by clinical assessment parameters. It is now apparent that even within a given pathogenic species, only certain subsets or clonal types may be pathogenic. It is postulated that these pathogenic microorganisms produce tissue destruction through the release of virulence factors that induce the elaboration of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1B) and tumor necrosis factor-alpha (TNF-a). These agents bind to fibroblast receptor sites, inducing the secretion of prostaglandins (PGE), culminating in the release of matrix metalloproteinases (MMPs) that degrade connective tissue and cause bone resorption, producing the clinical manifestations of pocket depth, bone loss, and bleeding on probing [11].

The two most common means by which periodontal disease is measured are through the use of radiographs (x-rays) and periodontal probing measurements. X-rays are helpful to reveal the presence of alveolar bone loss but have been shown to greatly underestimate the degree of loss [33]. The presence of an interdental crater, for instance, would not been seen on an x-ray. Given a specific time when the disease is actively destroying alveolar bone, it may often take up to six months for the destruction to become evident radiographically. X-rays also do not show the presence of a periodontal pocket [41].

Periodontal pocket depth measurements are made by carefully placing a periodontal probe into the sulcular area and determining the distance, in millimeters, from the height of the gingiva to where the probe comes to rest at the base of the sulcus or periodontal pocket. Where the probe ends with relation to the tooth surface and to the epithelial attachment is variable. The probe does not, in most instances, stop at the base of the sulcus, even in health, but will penetrate to some extent into the epithelial attachment. What restricts the probe from going further into the epithelial attachment is the health of the supporting, underlying connective tissue. As inflammation increases in the connective tissue, its integrity and ability to support the overlying degenerating epithelium and resist the penetration of the probe lessens and the probe penetrates to reach the connective tissue attachment at the base of the sulcus. When the probe reaches the connective tissue, the clinical sign of bleeding is produced. As there is no blood supply within epithelium, when the clinician produces bleeding upon probing, the connective tissue has been contacted. Depending upon the force used in the placement of the probe and the degree of inflammation present, the probe may penetrate into the underlying connective tissue. Thus, a patient who undergoes a periodontal pocket depth examination when the tissues are inflamed will give a pocket depth reading based on the presence of the periodontal probe within the connective tissue. With reduction in the degree of inflammation in the connective tissue and return to health of the epithelial attachment, the probe, given the same amount of force applied, will not penetrate to the previous depth but will stop somewhere within the newly formed epithelial attachment. The difference between these two levels may be as much as 2 mm. This does not mean that there is a gain of 2 mm in attachment, but rather it is a reflection of the variability of how far the probe penetrates as determined by the relative health of the underlying connective tissue [42].

Although periodontal probing and x-rays have been the main tools for diagnosing periodontitis for several decades, researchers continue to make advances toward technology that will aide in screening, prevention, and early diagnosis of periodontal disease. One such technology is the development of tests that use oral fluid-based diagnostics. Saliva carries the same diagnostic potential as blood; however, the concentrations of micro-organisms are 1,000 to 10,000 times lower, requiring the development of tests with greater sensitivity to detect these low concentrations [45]. Potential benefits of salivary testing include [50,52,53]:

Screening products available include MyPerio-ID, which detects type and concentration of specific bacteria that cause periodontal disease; MyPerioPath, which tests for genetic susceptibility to periodontal disease; and Electronic Taste Chips, which identifies multiple biomarkers for periodontal disease, including CRP [53,54,55]. As of 2022, there are no FDA-approved salivary diagnostic tests for evaluating the risk of periodontal disease, dental caries, or head and neck cancer [12].

There are a number of pharmacokinetic parameters that should be appreciated and understood before using locally applied antimicrobials. There are several targets within the periodontal pocket to which antimicrobial agents are directed. These include micro-organisms residing within the soft tissue walls of the pocket; for example, A. actinomycetemcomitans has been shown to invade the connective tissue, and P. gingivalis may invade the epithelium [56]. Experimental evidence has suggested that many forms of local delivery, such as through the use of an antibacterial agent in an oral rinse and applied through an irrigating device, may not reach the intended targets [6]. Irrigants have been shown to reach a maximum of 4–5 mm into the periodontal pocket [57]. Even when a patient is facile enough to employ a cannula and insert it into the sulcular area, thereby accessing the deeper portions of the pocket, merely gaining access to these boundaries does not necessarily mean that the agent has reached the targeted bacteria [31,58].

Subgingival bacterial plaque behaves as a biofilm. Consisting of bacterial communities that exist in a self-produced, hydrated polymeric matrix, biofilm attaches to both living and nonliving surfaces. The bacteria that are present within the biofilm are organized into a community that is resistant to host defenses and antibiotics and may impair the diffusion of or inactivate pharmacologic agents [6,59]. In order for an agent to have an effective action on the bacteria within the biofilm, it must meet all three pharmacokinetic parameters [60]:

The duration of exposure is dependent upon the mechanisms by which the antimicrobial agent inhibits or destroys the target bacteria in addition to the relative potency of the agent. For example, chlorhexidine gluconate kills micro-organisms by compromising the integrity of the cell membranes and requires a shorter exposure time than bacteriostatic agents, such as the members of the tetracycline family, whose action impedes protein synthesis within the bacterial cell.

Another factor to consider when placing antimicrobial agents within the periodontal pocket is the clearance of the area through the action of the GCF. GCF is an altered serum transudate found in the gingival sulcus and is a result of mechanical irritation or the response to the presence of micro-organisms and their products within the pocket. There is an ongoing flow of GCF when the tissue is mechanically irritated or inflamed. It has been estimated that in a 5-mm periodontal pocket, the contents of that pocket are replaced about 40 times each hour [31]. Thus, any antimicrobial agent placed subgingivally has its concentration rapidly reduced by GCF flow [31]. The estimated half-life of any pharmacologic agent placed in the periodontal pocket is about one minute. This very high rate of clearance represents a significant obstacle in producing and maintaining effective concentrations to effectively impact the bacteria within the biofilm. Because of this high rate of GCF clearance, it became evident that to prolong therapeutic duration, the use of a subgingival drug reservoir needed to be developed that could release the agent over a period of time, counteracting its continuous loss due to GCF flow.

A number of local delivery devices have been developed to provide a reservoir of the antimicrobial agent that would limit the release, providing for application over an extended period of time. The goal is to maintain a sufficient concentration of the agent in the site despite GCF clearance [61]. Local delivery devices may be categorized in two classes according to release and duration [31]:

Sustained release is defined as those formulations within a delivery device that provide for drug delivery in less than a 24-hour period. By contrast, controlled-release delivery systems allow the delivery of the drug for longer than 24 hours [31].

The American Dental Association (ADA) has defined localized therapy with antimicrobials in the Current Dental Terminology (CDT) update. Section D4381 of the CDT procedure code nomenclature pertains to localized therapy. The CDT definition of localized therapy should be used as a starting point for the development of a practical protocol to incorporate the use of localized, antimicrobial therapy into daily clinical practice [62]:

D4381 – localized delivery of antimicrobial agents via a controlled release vehicle into diseased crevicular tissue, per tooth, by report. FDA-approved subgingival delivery devices containing antimicrobial medication(s) are inserted into periodontal pockets to suppress the pathogenic microbiota. These devices slowly release the pharmacologic agents so they can remain at the intended site of action in a therapeutic concentration for a sufficient length of time.

The development of controlled-release antimicrobial agents to be delivered into localized sites was championed by Dr. J. Max Goodson in the late 1970s [63,64]. Dr. Goodson used tetracycline in a vehicle of hollow fibers of cellulose acetate as the delivery system. In this initial delivery system, 95% of the tetracycline was released in the first few hours. Most of the early work on the drug release kinetics dealt with the delivery system used, how the release could be sustained for at least 24 hours, and how to control release beyond that period of time. Various agents, such as 20% chlorhexidine and 5% metronidazole in a gel preparation, and sanguinarine in 2.5%, 5%, and 10% gel preparations, were studied in the early 1980s. Other vehicles, such as dialysis tubing, were used as delivery systems.

As a result of decades of research and development, a number of products have been developed and marketed for use, including Actisite (no longer available in the United States), PerioChip, Atridox, and Arestin [65,66].

Locally delivered antimicrobials allow a concentration many times that of systemic therapy [62]. A number of products designed to be locally delivered to specific sites of periodontal involvement are now available for clinical application. These products have been developed to release an antimicrobial agent within a periodontal pocket in a controlled manner for periods exceeding 24 hours. In 2002, an amendment was approved to the California Dental Practice Act (chapter 3: article 5: section 1088[d] [1]) authorizing registered dental hygienists to place these agents [67].

There are a number of variables to consider when making a choice of which available product to employ when establishing a protocol for the use of locally delivered, controlled-release agents. The first of these is U.S. Food and Drug Administration (FDA) approval. Actisite, Arestin, and PerioChip have been approved by the FDA for use in conjunction with SRP, although, as previously mentioned, Actisite is no longer produced by the manufacturer. Atridox has been approved as a monotherapy and has demonstrated improvements in probing depth and attachment loss at nine months that were equivalent to SRP alone [11]. Many studies have additionally shown that the adjunctive use of Atridox in combination with SRP shows significant clinical improvement in pocket depth reduction, clinical attachment gains, and bleeding upon probing [84]. For all of the antimicrobials discussed, adjunctive therapy is recommended over monotherapy for patients with chronic periodontitis [11,47,48,51,52,85].

An overview of the pharmacokinetics concludes that all of the products available provide concentration of the active antimicrobial agent at levels in excess of the MICs for periodontal pathogens. Their efficacy in the clinical studies also is very similar in terms of pocket depth reduction. Some studies have not addressed gain of clinical attachment [82]. Others have indicated that the gains are small and statistically insignificant [49]. When microbiologic data is present, it reveals that even with high concentrations of agents maintained over a period of time, the agents are not completely capable of eliminating all pathogens from treated sites.

Another consideration is the agent's handling characteristics. The methodology in the application of Arestin makes this product superior to the others. The simplicity of placement of the cannula and a short and swift injecting movement, placing the product into the pocket area, is superior to the less efficient and labor-intensive placement of PerioChip or Atridox.

There are other factors that may impact a clinician's decision as to which product to use that are more in the line of practice management and cost considerations. These factors will be discussed in the Practice Management section of this course.

Many clinicians developing a rationale and strategy for the use of these agents look at the treatment of multiple sites as being an essential requirement. Their intent is not only to treat sites exhibiting advancing disease but also to reduce and eliminate possible reservoirs of pathogens that may be present in other areas in the mouth. Some clinicians speculate that there is an advantage in disrupting the biofilm through SRP to permit penetration of the active agent to the micro-organisms. Other clinical considerations may include the time and duration of therapy, ease of use, cost, side effects, and patient acceptability [43].

All of the agents described in this course have demonstrated through clinical studies a statistically significant difference when used in conjunction with SRP or, in the case of Atridox, equivalency to SRP when used as monotherapy. However, the use of a given agent may result in a statistically significant result that may or may not have significant clinical impact. Statistical significance only validates a difference between the tested groups to a certain level of probability. It does not indicate the magnitude of clinical change or the importance of the difference in resolving clinical problems [43,44].

Making a choice first centers on the clinician's desire to possibly use the agent as a monotherapy or to only use it in conjunction with SRP. The second consideration is the agent's handling characteristics and whether the agent is to be applied to multiple sites at one time. In developing the protocol, the recommendation is to select those sites that are resistant to conventional therapy after initial therapy has been accomplished or for those sites that the clinician can anticipate will be less likely to respond to conventional therapy [40,47].

Though SRP continues to be the standard nonsurgical approach to periodontal therapy, the AAP has recommended that clinicians consider the adjunctive use of locally delivered antimicrobials in cases of chronic periodontitis [6,85]. Additionally, two separate trials indicated that the application of minocycline microspheres enhanced the effects of surgery in patients for whom surgery was indicated [15,26].

The first subject to consider before structuring treatment protocols is the necessity for a basic change in practice philosophy. That is, the perspective for treatment of any given patient should be altered from restorative to periodontal. Typically, in a practice providing general dentistry, the perspective is for short-term benefit. General dentistry provides restorative solutions that are lasting and require follow-up that is not as critical as that required for periodontal therapy. If the practice is to institute a program of periodontal therapy, incorporating the utilization of site-specific agents, then the entire practice's attitude toward treatment should shift to the long-term [34]. This requires informing patients of the necessity for more frequent visits and the requirement for monitoring and maintenance of gains achieved through initial therapy. After patients are diagnosed with periodontal disease, the recurrence of the disease process and its multifactorial complexity requires that the patient understands that [16,38,40]:

The last consideration before a protocol can be put together is that of cost:

The cost of the agents also enters into this consideration. The unit dose packaging of both PerioChip and Arestin is far less expensive than that of Atridox and appears to be the differentiator in the selection of PerioChip or Arestin over Atridox. However, consider that for the smaller cost of Arestin, the clinician will receive 1 mg of antibiotic, and for the larger cost of Atridox, the clinician will receive 42.5 mg of antibiotic. The cost per mg of antibiotic utilized is less for Atridox than for Arestin. If multiple sites are to be treated at one time, or if monotherapy is to be used, then Atridox is the product of choice. Using Atridox also permits the clinician to treat multiple sites with the same syringe, stabilizing the unit cost and regulating the fee based on the unit cost of the material. In contrast, multiple uses of Arestin or PerioChip would necessitate establishing a fixed fee for each site where the agent is applied. Many practices employ a fee schedule for Atridox, based upon a set fee for three or four sites, and then increase that fee by small increments per each additional site until the entire syringe contents have been used. Clinical use of Atridox has shown that the agent may be applied in more than 10 sites per syringe of Atridox.

The bottom line is to consult with the manufacturer's representatives, conclude whether monotherapy is to be part of the clinical protocol, establish a fee based on single or multiple applications, and conclude what the cost basis would be in the treatment versus single or multiple sites. When multiple sites are present, the clinician should also consider the cost of these agents versus systemic utilization of an antibiotic. If the patient is allergic to the tetracycline family, the choice becomes obvious. Practitioners in California should select an agent that is biodegradable.

When establishing or revising a clinical protocol for nonsurgical periodontal therapy, practitioners should start with diagnosis (Table 4 and Table 5) [37,38,39]. As stated, diagnosis should incorporate the supplemental information provided by the 2018 staging and grading system.

Stage I periodontitis requires nonsurgical treatment. No post-treatment tooth loss is expected and a good prognosis is indicated going into maintenance. Stage II periodontitis requires both nonsurgical and surgical treatment. No post-treatment tooth loss is expected, and the prognosis is good going into maintenance. Stage III requires surgical and possibly regenerative treatments. A loss of up to four teeth may occur. The complexity of implant and/or restorative treatment is increased, and the patient may require multispecialty treatment. The overall prognosis is fair. Stage IV may require advanced surgical treatment and/or regenerative therapy, including augmentation treatment to facilitate implant therapy. Very complex implant and/or restorative treatment may be needed. The patient often requires multispecialty treatment. The overall prognosis for stage IV is questionable going into maintenance [39].

It is important to develop a second protocol with regard to how to deal with individual isolated sites presenting either at initial treatment or at subsequent maintenance times. Before concluding initial treatment of an isolated site of involvement, the clinician should determine the cause of the isolated defect. Isolated defects are not only attributable to periodontal disease but also to endodontic lesions that manifest themselves through the sulcular area, fractured teeth, and developmental defects on teeth such as distal lingual grooves commonly associated with maxillary lateral incisors.

There are many individual circumstances that may require ongoing consideration for controlled-release antimicrobials during the course of the maintenance period. These include: inoperable sites distal to the lower second molars, furcation involvement where further surgical or definitive therapy is not possible, maxillary incisors where esthetics is a consideration, and areas showing advancing disease. It is absolutely essential that clinicians are very conscientious about monitoring the disease presence and activity through pocket depth readings and evaluations at each maintenance visit. The patient should be forewarned of the possible necessity for the utilization of localized agents when the need presents itself. It is appropriate to treat the patient immediately rather than delay another three months to see if further progression occurs [17,34]. This means that the patient must be prepared for the fee associated with periodontal maintenance procedures, which should be greater than that for a prophylaxis, and also be prepared for the additional fee of the localized therapy. If this is communicated from the initial exam through the initial therapy and at each maintenance visit, the patient is much more likely to accept and go forward with the recommended treatment.

The AAP has met with several insurance carriers to determine how the new classification will affect reimbursement. All carriers have indicated that the new classification system will not affect reimbursement at this time [39]. Third parties will still determine reimbursement based on the documentation required for the treatment rendered (e.g., probing depths, radiographic evidence of bone loss). The classification will affect diagnosis codes; however, these are currently not required for dental insurance reimbursement [39].