Time-released xylitol

The objective is to control bacteria causing peri-implant disease

by Jeff Burgess, DDS, MSD

Periodontal disease associated with implants (peri-implant mucositis and peri-implantitis) is now understood to be primarily the result of microbial growth dynamics as well as host cellular and molecular mechanisms that may be coupled with other exposures such as disease (diabetes, for example), female sex hormones, xerostomia, bruxism, smoking, and poor oral hygiene.1

Disk releases xylitol over a longer period ot time.

Gingivitis and implant mucositis, characterized by inflammation of the gums surrounding the teeth or implant, has been associated with the development of dental plaque, which is a form of biofilm that is localized to the tooth-gingival interface. This superficial biofilm harbors primarily aerobic bacteria that cause tissue irritation and inflammation.2 With gingivitis and implant mucositis, the gums appear red and slightly swollen.

In contrast, periodontitis and peri-implantitis are thought to be caused by anaerobic bacteria living within the biofilm localized to the subgingival region. Recent investigations of bacterial species associated with periodontitis suggest that the disease is caused by a number of different bacteria and that many novel species may be involved in its etiology3 (see Table 1).

The microbial growth dynamics that occur within biofilm are complex. Animal and human studies involving measurement of bacterial colonization indicate that it occurs in several stages:

• Saturation of enamel pellicular binding sites
• Accumulation to critical density
• Density-dependent growth2

According to Liljemark, the bacteria within the biofilm initiate growth and it is the actual density of these organisms that modulates this activity.

Biofilm development also appears to be associated with interdependence among bacterial species. For example, it has been shown that P. gingivalis enhances biofilm formation by F. nucleatum through release of signal molecules.5 Biofilm growth is also impacted by differential colonization (for example, aggressive periodontal disease appears to be linked to changes in colonization of S. sanguinis6), host factors (the antibody response of the affected individual), the overall community of bacterial species, as well as the availability of growth media (carbohydrates).

In addition, there is evidence that biofilms that have numerous bacteria may exhibit differences in susceptibility to antimicrobials based on the relationship of the associated bacterial species. For example, S. mutans demonstrates increased survival after exposure to various antimicrobials when Veillonella parvula (a nonpathogenic bacteria) is also present.7 All of these factors suggest that a disturbance in the "living arrangement" of the bacteria within plaque biofilm might be capable of altering the course of periodontal and peri-implant disease. This idea is further supported by multiple studies assessing the positive therapeutic effect of a variety of topical, systemic, and subgingival antibacterial preparations designed to reduce bacteria associated with periodontal and peri-implant disease.8,9,10,11,12,13,14,15,16,17,18

Currently, the standards for management of periodontal and peri-implant disease include the initial reduction of periopathogens via mechanical debridement and the use of a variety of antimicrobials. Lang has recommended what is termed CIST (cumulative interceptive supportive therapy) for peri-implantitis that includes mechanical debridement, antiseptic treatment, antibiotic treatment, and regenerative or access/resective surgery.19 Roos-Jansaker reviews a number of suggested strategies for the treatment of peri-implant mucositis and peri-implantitis.20 All of the therapeutic recommendations include use of topical antimicrobials coupled with initial oral hygiene measures and debridement.21,22,23,24,25 The elimination of perio-pathogens makes eminent sense since it has been shown that there is a direct relationship between disease severity and increased numbers of various pathogenic bacteria within the biofilm in patients with periodontitis (C. rectus, P. gingivalis, for example).26 Failed implant therapy also appears to be associated with colonization of the same pathologic bacteria associated with periodontal disease 19, 27 although a number of studies suggest that for implantitis there may be subtle differences in the proportion and type of involved causitive organisms. For example there may be bacteria normally found in the intestine such as Escherichia coli, Enterobacter spp, and Klebsiella spp.28 The literature also suggests that some of these apparent opportunistic colonizers can be more difficult to treat with standard oral systemic antimicrobials.

Table 1

At the present time the primary species considered important in the etiology of periodontitis include:4

• Tannerella forsythensis (Bacteroides forsythus)
• Porphyromonas gingivalis
• Aggregatibacter (Actinobacillus)
• Campylobacter rectus
• Prevotella intermedia

Bacterial pathogens associated with peri-implantitis (PI) include, in addition to the above:4

• Actinobacillus actinomycetemco-mitans
• S. aureaus
• Porphyromonas intermedia/P. nigrescens
• Staphylococcus aureus
• Fusobacterium nucleatum
• Veillonella sp.
• Capnocytophaga
• Campylobacter rectus (PI)
• Eikenella corrodens (PI)
• Bacteroides forsythus (PI)
• Treponema denticola (PI)
• Peptostreptococcus micros (PI)
• Capnocytophaga spp. (PI)
• Prevotella intermedia

Azithromycin is also used to treat periodontal disease. Unfortunately, reported studies touting efficacy of these antibiotic formulations only include case reports or case series and randomized controlled trials appear lacking.31 One study assessed the long-term effect of azithromycin compared to metronidazole and a sub-antimicrobial dose of doxycycline (Periostat) coupled with scaling and root planing. All of the therapies resulted in significant reduction in the anaerobes T. forsythia, P. gingivalis, and T. denticola at two weeks with reduction in numbers of these "red" bacteria maintained to 12 months.30 Of potential significance, the authors note that in subjects using the subantimicrobial doxycycline treatment, several bacterial species approached or exceeded baseline values at 12 months. Further, in subjects using azithromycin and doxycycline, antibiotic resistance increased to significant proportions at the six-month point and continued to the 12-month point for doxycycline subjects.

It has been suggested that structural characteristics of supra- and subgingival biofilm may reduce the diffusion and sensitivity of some of the recommended antibiotics.30,32,33 Providing further support for this concept, an experimental study by Norrington et al. indicates that model biofilms formed on dentin are resistant to many antimicrobial drugs.34

Regardless of the efficacy of systemic antibiotics, these antimicrobials are not currently recommended for long-term use in patients with periodontal or peri-implant disease, primarily because there is a significant potential for the development of resistance. One group of anaerobic pathogens involved in periodontitis and peri-implantitis that have already demonstrated significant resistance to azithromycin are the Fusobacterium strains.35 The relationship between topical antimicrobials and bacterial resistance is unclear, but it is reasonable to conclude that with prolonged use of these products, resistance might also develop.

Unfortunately, the problem of bacterial resistance to topical antimicrobials has not been well studied and is in need of further investigation. Regardless, the efficacy of systemic antibiotics depends on bacterial susceptibility. Unless sensitivity testing is pursued by the clinician treating periodontal or peri-implant disease prior to initiation of antibiotic therapy, successful intervention may be problematic.36

Given what is currently known about bacterial resistance, antibiotic susceptibility, and the complexity of biofilm development – including its dependence on bacterial growth and known species interdependence – it is conceivable that an alteration of bacterial metabolism resulting in reduced numbers of some (if not all) of the pathogens within the supra- or subgingival biofilm could contribute to improvement in periodontal and peri-implant health and a reduction in disease.

One candidate preparation that is capable of altering the metabolic functioning of a number of pathogenic bacteria is xylitol. Xyitol, a naturally occurring pentatol carbohydrate, has been shown to reduce the levels of mutans streptococci in plaque and saliva37, 38,39 and other Streptococcus bacteria such as S. sobrinus, S. salivarius, and S. sanguis,40 as well as Lactobacillus rhamnosus, Actinomyces viscosus, Porphyromonas gingivalis, and Fusobacterium nucleatum that have been experimentally incorporated into model biofilms.41 It has also been shown to be effective in reducing counts of P aeruginosa in maxillary sinus specimens 42 and in altering the viability of Strep pheumococci responsible for acute otitis media.43

Recent evidence further suggests that xylitol may also indirectly affect the inflammatory process. For example, cytokine expression induced by Porphyromonas gingivalis appears to be altered in the presence of xylitol,44 and xylitol appears to be capable of inhibiting LPS-induced secretion of two other inflammatory cytokines: TNF-alpha and IL-1beta by monocytic THP-1 cells.45 Finally, varying xylitol concentrations, tested on models of oral biofilm containing both aerobic and anaerobic bacteria, suggest that xylitol has a generalized inhibitory effect on bacterial growth localized within multispecies biofilm.46 These and other studies underscore the potential use of xylitol in the adjunctive management of periodontal and peri-implant disease.

Current xylitol research suggests that when pathogenic bacteria absorb xylitol, their reproduction capacity is reduced, thus potentially allowing other beneficial or less harmful bacteria to reproduce in their place.

Bacterial carbohydrate absorption mechanisms favor certain carbohydrates over others. Xylitol appears to be favored over all kinds of carbohydrates except fructose.47 That is, when xylitol is present as well as carbohydrates other than fructose, the bacteria preferentially absorb the xylitol, which they cannot metabolize, and this results in their starvation. When fructose is present as well as xylitol, the fructose is selected and absorbed by the bacteria in place of the xylitol. For this reason, xylitol is most effective in reducing bacterial counts if the concurrent consumption of fructose is avoided.

Historically in caries studies, xylitol has been delivered via chewing gum.48,49 However, even though delivery of xylitol via gum appears to be effective in reducing this specific disease,50 the delivery is inefficient as the xylitol is quickly released and swallowed, lasting no more than 15 minutes.

A novel device now available OTC incorporates one-half gram of xylitol in a slowly dissolving substrate that can be applied as an adhering disk to gingiva in the buccal vestibule (XyliMelts, OraHealth Corp.). The disk dissolves over one hour on average when used during the day and up to six hours when used while sleeping, when saliva flow is lowest, to maximize the effectiveness of the xylitol per gram. Xylitol delivered in this manner may be more tolerated by patients unwilling or unable to chew gum (for example, the partially edentulous, those with TMD, disabilities, etc.), and may be more effective.

Studies suggest that a dose of xylitol delivered in chewing gum in the range of 6.44g/day and 10.32g/day is sufficient to reduce streptococci levels.51 While providing this dosage in gum can be "cumbersome" as one of the above authors has suggested (Milgrom, 2006), delivery in a slowly dissolving adhering disk is easily accomplished, especially when used while sleeping, appearing to make the process considerably more palatable and effective. The current recommendation is that the xylitol adhering disk be applied to gingiva above a molar and touching the cheek wall immediately after each meal and just before going to sleep to control bacteria associated with gingivitis and peri-implant mucositis. Use while sleeping is most effective because saliva flow is low and xylitol concentrations are high for a long period.

While the dosage needed to control anaerobic bacteria associated with periodontitis and peri-implantitis has not been established, it is reasonable to assume that a dose equivalent to the amount necessary to reduce the aerobic bacterial load will be equally effective in suppressing anaerobic counts.

Xylitol use in gum has not been associated with significant side effects or adverse reactions. Gut discomfort and diarrhea has been reported with ingestion of more than 10 grams of xylitol, but this is not likely to occur with use of the XyliMelts products which, when used heavily at 10 disks per day, release only 5 grams of xylitol per day.

Considering the research done to date, xylitol delivered via the use of an adhering and time-release disk or via chewing gum should be considered in the adjunctive management of periodontal and peri-implant disease for the following reasons:

• To prevent recolonization of tissue sites following standard short-term antibiotic therapy
• To reduce any reservoir of bacteria not eliminated by antibiotic management or the wrong choice of antibiotic (when the choice is not or cannot be based on species identification and sensitivity testing)
• When bacterial management is felt to be necessary over a prolonged period of time because of confounding contributing factors such as smoking, bruxism, or concurrent systemic disease (diabetes)
• When antibacterial resistance is detected or there is concern for the development of resistance
• When there is concern for the development of an adverse reaction with the use of antimicrobials (tooth or restoration staining)
• When there is need for decontamination of the oral environment during the four to eight weeks that has been suggested to allow for soft tissue healing following tooth extraction that precedes implant placement
• When an implant is placed in the presence of adjacent periodontal disease and there is concern regarding opportunistic colonization of the implant site
• When there is concern regarding a patient’s ability to follow through with suggested periodontal treatment or there may be a significant time lag between the diagnosis and appropriate treatment
• When a patient may not be able to proceed with immediate treatment because of cost concern/issues or insurance delay in covering the cost of treatment

Xylitol, a nonfermentable natural carbohydrate, has been shown to alter the metabolism of several aerobic and anaerobic bacteria and has proven effective in suppressing disease (caries) associated with the presence of bacterial plaque. Published studies have also shown that xylitol has a generalized inhibitory effect on bacterial growth localized within multispecies biofilm and on the metabolism of anaerobic bacteria. However, prospective studies specifically assessing the clinical efficacy of xylitol in reducing or controlling periodontal and peri-implant disease are lacking and need to be pursued.

Jeff Burgess, DDS, MSD, is boarded in oral medicine and is the director of Oral Care Research Associates.

References

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