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Veterinary Therapeutics Winter 2002 (Vol 3, No 4)

Treatment of Periodontal Pockets With Doxycycline in Beagles

by Karl Zetner, DrMedVet, DEVDC, Gabriele Rothmueller, DVM

    Abstract

    Following pretreatment with clindamycin, cleaning, scaling, polishing, and curettage, six beagles that were patients at the Dental Department of the Clinic for Surgery and Ophthalmology of the University of Veterinary Medicine of Vienna received a doxycycline polymer filling (Doxirobe, Pharmacia Animal Health) in periodontal pockets of teeth 204, 208, 304, and 309. Gingivitis index, gingival crevicular fluid, probing depth, and attachment loss were determined before and 6 and 12 weeks after treatment. Teeth 104, 108, 404, and 409 did not receive antibiotic therapy but were pretreated in the same manner as the doxycycline-treated teeth. Pocket depth for teeth treated with doxycycline was significantly reduced (improved) by 39% after 6 weeks (P = .001) and by 35% after 12 weeks (P = .001). Pockets around control teeth were improved after cleaning and curettage but were still significantly deeper than around teeth treated with doxycycline. Compared with control teeth, teeth treated with doxycycline had significantly less gingival crevicular fluid after treatment (P = .001). Teeth treated with doxycycline gained significant attachment after 6 (42%) and 12 (38%) weeks. Significantly fewer bacteria were harvested from doxycycline-treated teeth than from control teeth. The gingival index was significantly lower in the doxycycline-treated teeth than in the control teeth 6 (P = .002) and 12 (P = .007) weeks after treatment. Local application of doxycycline complements traditional subgingival curettage therapy in a reasonable and effective way and can significantly improve treatment success, especially with regard to pocket depth reduction and attachment gain.

    Introduction

    The value of tetracyclines for treatment of human periodontal disease has been tested for many years. One study, for example, demonstrated that the broad-spectrum bacteriostatic activity of tetracycline could turn dangerous gram-negative subgingival flora in periodontal pockets into a more gram-positive ecosystem.1 The primary bacteriostatic effect of tetracyclines on many gram-positive and numerous gram-negative bacteria stems from inhibition of the microbial protein synthesis.

    The mechanism of tetracycline sequestration is not yet known. It is assumed that tetracyclines are bound to the root surface and from there are released gradually or remain in the gingival crevicular fluid for some time because of chelation with calcium ions. Apart from their antibacterial effect, tetracyclines also have, based on the suppression of neutrophil functions, an antiinflammatory effect on the periodontal tissue.2 Studies indicate that tetracyclines block or reduce collagenase activity and the loss of alveolar bone substance and promote adhesion of fibroblasts and connective tissue to the root surface.3,4 Ever since Saari and colleagues5 demonstrated that oxygen radicals can activate latent collagenases and that tetracyclines have an inhibitory effect on oxygen radicals, tetracyclines have been considered to have a tissue-protective property.

    Tetracyclines are of particular importance for regeneration of the periodontium because they not only promote the adhesion of fibroblasts to a tetracycline-conditioned root surface but they also have an influence on colonization of fibroblasts.4 Furthermore, it has already been demonstrated that tetracyclines are bound to dentin and may be released from there.4

    Doxycycline is a broad-spectrum antibiotic synthetically derived from oxytetracycline. For periodontal disease in dogs, doxycycline is available as a flowable polymer that quickly solidifies with exposure to water and remains in the periodontal pocket for up to several weeks. Doxycycline is released over this period at levels that greatly exceed the minimum inhibitory concentration (MIC) levels of many periodontal pathogens. The gel formulation of doxycycline (Doxirobe, Pharmacia Animal Health) is packaged with one syringe containing a polymer for delivery of the material into the periodontal pocket and a second syringe containing the active material. The materials are blended and injected directly into infected pockets.

    It has been demonstrated in vitro that doxycycline in a biologically active form has long-lasting antibacterial activity after short local contact with the cement or dentin surface.4,6 After parenteral administration at 100 mg/day, doxycycline has been shown to be present in high concentrations (3 to 10 µg) in gingival crevicular fluid, similar to minocycline.7-9 Doxycycline is significantly bound to proteins and has a longer half-life than tetracycline hydrochloride.

    Of all tetracyclines, doxycycline has the highest anticollagenase activity.10 This is of particular importance because collagenases (me­talloproteinases) formed by fibroblasts, epithelial cells, neutrophils, and macrophages damage the periodontal tissue. Doxycycline is broken down via the liver and excreted via the gastrointestinal tract. As a fat-soluble substance, doxycycline penetrates the cell interior via the lipid layer of the microbial cell wall, binds to the 30S ribosomes, and inhibits bacterial DNA replication.

    Many studies have been conducted to combine substances, including hollow, vinyl acetate copolymer, and ethyl cellulose fibers; collagen preparations; acrylic strips; and polymeth-acrylic acid-hydroxypropylcellulose, with antimicrobials that cause the antimicrobial to be released gradually and in a prolonged manner after a single application in the periodontal pocket.11-15 Depending on the duration of the antibiotic release in the pocket, the literature differentiates between sustained release (high initial concentration with rapid decline after 24 hours) and controlled release (a high initial concentration released slowly over a longer period).16 Whereas tetracycline fibers must be removed from the pocket, chlorhexidine chips, metronidazole gel, minocycline gel, and doxycycline polymer are absorbed. Sustained-release doxycycline has been evaluated and used for periodontal disease in dogs since 1997.17"21 The present study was conducted to evaluate the efficacy of sustained-release doxycycline gel for treatment and control of periodontal disease in dogs.

    Materials and Methods

    Animals

    Six periodontal patients (beagles) were selected from the Dental Department of the Clinic for Surgery and Ophthalmology, University of Veterinary Medicine of Vienna for evaluation in the study. Dogs were 3.1 ± 0.3 years of age, with a mean body weight of 3.75 ± 2.83 kg.

    Treatment

    The modified Triadan system was used for identification of teeth treated and evaluated in the study.22 Teeth 204, 208, 304, and 308 were selected to be treated with doxycycline, and teeth 104, 108, 404, and 409 served as controls. Each dog was pretreated orally with clindamycin daily for 5 days as a treatment of any existing bacterial (Staphylococcus aureus, Bacteroides fragilis, Prevotella melaninogenicus, Fusobacterium necrophorum, and Clostridium perfringens) dental infections. On Day 6, a professional tooth cleaning was performed by ultrasonic removal of plaque and tooth scale; polishing of tooth surfaces; and thorough curettage of periodontal pockets. After an additional 5 days of oral treatment with clindamycin, the gingivitis index (scored from 0 to 4, with 0 representing the absence of the condition and 4 indicating the most severe condition), the amount of gingival crevicular fluid, and the probing depth were assessed by an electronic periodontal probe (FP32 System, Florida Probe) (Figure 1). This periodontal probe operates electronically by its own computer, has a reading accuracy of 0.2 mm and a defined probing pressure of 15 g, and provides for determination of attachment loss and pocket depth. The severity of disease among teeth of the same group as well as between groups of teeth within a single subject were determined to be relatively similar.

    Following these pretreatments and measurements, the dogs were anesthetized with medetomidine and ketamine, and periodontal pockets of teeth 204, 208, 304, and 309 were filled with doxycycline. The gel and carrier were mixed from two syringes according to the label instructions, and the polymer was injected into the pockets with a special injection needle (Figure 2). To avoid the possibility of inflicting any minor injuries to the pocket base surface, the tip of the injection needle was rounded off and polished with rotating sandpaper disks.

    Application of the doxycycline polymer was started at the pocket base, continuing up with a winding motion until surplus material became visible at the gingival margin. After 30 to 60 seconds to allow the material to harden, the visible material was carefully sprayed with water for approximately 3 seconds. The rubber-like, partially hardened material was then pressed back into the periodontal pocket with a Teflon (E.I. du Pont de Nemours)-coated spatula until the polymer protuberance was no longer visible at the tooth surface (Figure 3). No treatment was administered to the control teeth following pretreatment with clindamycin, cleaning, and curettage.

    Evaluations

    Six and 12 weeks after application of doxycycline polymer, supragingival dental plaque and tooth scale were carefully removed with a scaler, and the subgingival plaque of teeth 104, 108, 404, 409 (controls), 204, 208, 304, and 309 (treated) was removed carefully with a sterile curette. The plaque adhering to the flat inner side of the curette was then applied to a sterile pad, put into a tube with specific culture medium suitable for anaerobes, and shipped to the Institute of Bacteriology, Mycology, and Hygiene of the Vienna University of Veterinary Medicine. At the laboratory, gingival crevicular fluid, gingivitis index, pocket depth, and the extent of the attachment were assessed. The time for these individual assessments was chosen in such a way that a direct influence of subgingival plaque removal on the amount of gingival crevicular fluid was avoided. During this 12-week period, no additional treatments were given to the dogs.

    Statistical Evaluations

    Statistical evaluation of quantitative variables was performed by nonparametric analyses (Kolmogorov-Smirnov and Wilcoxon rank sum test) using programs in SPSS for Windows. Pretreatment values for quantitative measurements between treated and control teeth verified that conditions were relatively (statistically) similar at the start of the study.

    Bacteriologic Methodology

    Each sample tube was vortexed for at least 1 minute to separate bacteria from plaque. Then, four serial dilutions were prepared from each sample by transferring 100 µl of the initial material by pipette to a 1.5-ml Eppendorf reaction vial filled with 900 µl sterile Trypticase soy broth, and the material was mixed by vortexing. A new pipette tip was used for each step.

    A 100-µl aliquot was collected from the initial material and from each of the four dilutions, transferred by pipette onto duplicate sets of blood agar plates, and distributed on the agar with a sterile spatula. One set of agar plates was incubated aerobically and another set was incubated anaerobically (95% nitrogen and 5% carbon dioxide) at 37°C for identification of aerobic and anaerobic microorganisms.

    An additional 100-µl aliquot from the initial sample was transferred onto MacConkey agar in the same manner and incubated aerobically at 37°C for identification of Enterobacteriaceae and other aerobic gram-negative bacteria that grow only on this agar. In addition, 10 µl of the initial bacteria suspension was smeared onto Schaedler blood agar plates (5% sheep blood) with a sterile loop and incubated anaerobically.

    Evaluation of Cultures

    Aerobic cultures were evaluated after 48 hours of incubation. Colonies with similar appearances were counted and assigned to specific groups of bacteria by observation of morphology and pigmentation of the colonies, staining behavior, and morphology in Gram's stain, catalase production with a 3% hydrogen peroxide solution, oxidase production, glucose fermentation, and indole production. The growth on MacConkey agar also was evaluated after 48 hours. Differentiation of bacteria was based on lactose fermentation and oxidase production. All anaerobic cultures were evaluated after a minimum of 72 hours. Colonies of possible anaerobic and microaerophilic organisms with similar colony morphology were counted and designated to specific groups of bacteria by performing the following steps for differentiation (facultative anaerobic gram-negative, oxidase-positive bacteria were not included): One aerobic and one anaerobic subculture were prepared on Schaedler blood agar, and colistin, kanamycin, and vancomycin test plates were added to each subculture. In addition, these samples were evaluated by a Gram's-stained smear.

    Attention was paid to whether growth had taken place anaerobically only or both aerobically and anaerobically. Detailed identification of bacteria in the subcultures was determined using similar techniques as for aerobic cultures on blood agar plates described above. Some isolated organisms (aerobic gram-negative, non-Enterobacteriaceae, and anaerobes) were biochemically identified by commercial test kits (API System, bioMerieux).

    Results

    Clinical Results

    Eight days after treatment, probing of the periodontal pockets that had been filled with doxycycline revealed the presence of hard polymer material in approximately 50% of the pockets. In a few cases, the material was visible and could be probed as a thin, hard plaque adjoining the gingival margin and adhering to the tooth surface. One dog exhibited a prominent remnant of the doxycycline polymer adjoining the gingival margin and adhering to the tooth surface. During the 12 weeks following treatment, no changes in food intake were observed and the general health of the animals appeared normal.

    Periodontal Parameters

    No significant differences were found between treated and control teeth for any periodontal parameters before treatment. For teeth treated with doxycycline, the amount of gingival crevicular fluid was reduced by 32% from baseline (P = .003) after 6 weeks and by 37% (P = .001) after 12 weeks (Table 1). Conversely, the amount of gingival crevicular fluid in control dogs increased by 135% after 6 weeks (P = .001) and by 144% after 12 weeks (P = .001). Teeth treated with doxycycline had significantly (P = .001) less gingival crevicular fluid than did control teeth at both evaluations after treatment (Table 1).

    The gingivitis index declined by 84% by 6 weeks after treatment with doxycycline (P = .007) and by 49% 12 weeks after treatment. For controls, the gingivitis index increased by 36% after 6 weeks and increased further (72%) by 12 weeks; however, these increases were not significant relative to baseline. The gingival index was significantly lower in the doxycycline-treated teeth than in the control teeth 6 (P = .002) and 12 (P = .007) weeks after treatment.

    Pocket Depth

    Pocket depth for teeth treated with doxycycline, as measured with the electronic periodontal probe, was significantly reduced (improved) by 39% after 6 weeks (P = .001) and by 35% after 12 weeks (P = .001) (Table 1). Pocket depth also was significantly (P < .005) improved for controls at 6 weeks (14%) and 12 weeks (21%). Despite significant improvement for control teeth, pockets around these teeth were still significantly deeper than for teeth treated with doxycycline at evaluations conducted 6 (P = .001) and 12 (P = .005) weeks after treatment.

    The success of treatment for periodontal pockets of different depths was determined to evaluate if there would be variable efficacy for more severe cases of periodontal disease. Small periodontal pockets (<2 mm) were significantly reduced (74%) within 6 weeks after filling of the pockets with doxycycline (P = .001) and were reduced by 13% after 12 weeks (P = .04) (Figure 4). Medium-depth periodontal pockets (2 to 4 mm) were significantly (P = .001) reduced by 64% within 6 weeks and were reduced by 32% after 12 weeks. Deep periodontal pockets (>4 mm) were reduced by 51% and 53%, respectively, 6 and 12 weeks after treatment with doxycycline (P = .001).

    Attachment

    Teeth treated with doxycycline gained 1.35 + 1.19 mm (P = .001) of attachment after 6 weeks (42%) and 1.22 + 1.20 mm (P = .001) after 12 weeks (38%) compared with 0.50 + 1.35 mm at 6 weeks (P = .003) and 0.70 mm + 1.42 mm at 12 weeks (P = .001) for control teeth (Table 1). The difference between treated and control teeth was significant (P < .007) at both posttreatment evaluations.

    Bacterial Isolations

    Treated teeth had significantly fewer aerobic (P < .009), anaerobic (P < .003), and total (P = .001) bacteria in the periodontal pockets 6 and 12 weeks after treatments than did control teeth (Table 1).

    Aerobic Bacteria

    For treated teeth, the spectrum of aerobic bacteria identified 6 weeks after treatment consisted of 30% Pasteurella; 49.3% Pseudomonas and other gram-negative, oxidase-positive, nonfermenting bacteria; and 20.7% a-hemolytic streptococci. After 12 weeks, the aerobic microbial spectrum for treated teeth consisted of 36% Pasteurella; 58% Pseudomonas and other gram-negative, oxidase-positive, nonfermenting bacteria; and 6% a-hemolytic streptococci.

    The spectrum of aerobic bacteria after 6 weeks for control teeth consisted of 67.7% Pasteurella; 11.2% Pseudomonas and other gram-negative, oxidase-positive nonfermenting bacteria; and 21.1% a-hemolytic streptococci. After 12 weeks the aerobic microbial spectrum for control teeth consisted of 48% Pasteurella; 35% Pseudomonas and other gram-negative, oxidase-positive nonfermenting bacteria; and 17% a-hemolytic streptococci.

    Anaerobic and Microaerophilic Bacteria

    Six weeks after treatment, anaerobic and microaerophilic flora for teeth treated with doxycycline consisted of 70.8% microaerophilic, gram-positive rods (e.g., actinomycetes, corynebacteria, lactobacilli) and 29.2% microaerophilic and anaerobic, gram-negative bacteria (e.g., Prevotella, Porphyromonas, Fusobacterium spp, Capnocytophaga, Campylobacter, or Eikenella).

    Twelve weeks after treatment with doxycycline, the anaerobic and microaerophilic flora consisted of 86% microaerophilic, gram-positive rods and 14% microaerophilic and anaerobic, gram-negative bacteria, similar to those found at 6 weeks.

    For control teeth, anaerobic and microaerophilic flora at 6 weeks consisted of 78.8% microaerophilic gram-positive rods, (e.g., actinomycetes, corynebacteria, or lactobacilli) and 21.2% microaerophilic and anaerobic, gram-negative bacteria (Prevotella, Porphyromonas, Fusobacterium spp, Capno­cytophaga, Campylobacter, or Eikenella). At 12 weeks, the flora for control teeth consisted of 71% microaerophilic, gram-positive rods and 29% microaerophilic and anaerobic, gram-negative bacteria, similar to those found at 6 weeks.

    Discussion

    Inspection of the application cannula supplied with the doxycycline product revealed that edges were not rounded off at the end of the tube. To avoid possible trauma from sharp edges, the ends of the instrument were rounded off and the application cannula was polished with a rotating sandpaper disk using the finest grit before the material was applied to the selected teeth. Following this modification, doxycycline gel was applied to all patients without any complications, and no adverse effects were noted for any dog with regard to food intake or general health parameters.

    Six weeks after treatment with doxycycline, the gingivitis index and gingival crevicular fluid were reduced by 84% and 32%, respectively. In contrast, the gingivitis index and gingival crevicular fluid in control pockets without doxycycline actually increased by 36% and 135%, respectively. Twelve weeks after treatment, measurements of inflammation indicated that the gingivitis index was improved by 49% relative to the value before treatment, and the volume of gingival crevicular fluid was reduced by 37% compared with the initial value. The reason for the relative increase in the gingivitis index for treated teeth from Week 6 to Week 12, despite a further decrease in the volume of gingival crevicular fluid, cannot be explained at this time; however, the gingivitis index and volume of gingival crevicular fluid continued to increase (worsen) for control pockets from Weeks 6 to 12.

    At the 6-week evaluation, the mean depth of pockets treated with doxycycline was reduced by 39% and attachment loss was reduced by 42% (representing an average gain of 1.35 mm in attachment). The depth of pockets for control teeth was reduced by 14%, and the attachment loss was reduced by 16% (average attachment gain of 0.5 mm). From these results, it was concluded that the initial cleaning and curettage for control teeth provided some improvement in terms of decreasing pocket depth and preventing further attachment loss, but treatment with doxycycline provided significantly better results. The reduction in pocket depth and gain in attachment 12 weeks after treatment with doxycycline were relatively similar to those observed at 6 weeks, whereas these measurements for control teeth improved slightly between Weeks 6 and 12.

    Efficacy of doxycycline for gaining attachment surface was similar between the present study and that reported by Polson and coworkers.23 In the present study, attachment was increased by 42% (53% for pockets >4 mm) after 6 weeks and 38% (53% for pockets >4 mm) after 12 weeks compared with 39% at 6 weeks (interpolated from 12- and 16-week data) and 49% after 12 and 16 weeks in the earlier study. According to Polson and coworkers,24 the reduction of pocket depth is mainly attributable to gain in attachment whereby the pocket base relocates toward the cement-enamel juncture. In the opinion of these researchers, the efficacy of doxycycline in the periodontal pocket is based not only on its antimicrobial activity but also on the adsorption to the crown and root surface and on the local inhibition of the collagenase activity.

    When the severity of periodontal disease was examined in terms of differentiating results of treatment for shallow (<2 mm), medium (2 to 4 mm), and deep (>4 mm) periodontal pockets, the depth of pockets was reduced in a linear fashion at the 6-week evaluation, with shallow pockets improving by the greatest margin (74%). After 12 weeks, however, shallow and medium pockets were slightly deeper than at Week 6, whereas the depth for deep pockets treated with doxycycline continued to improve (reduction of 53%) between Weeks 6 and 12. The relative increase in the depth of the pockets treated with doxycycline between Weeks 6 and 12 may be explained by the continued presence of the polymer in some pockets, which could be perceived as pocket depth by the electronic periodontal probe.

    Results of one large-scale, multicenter study24 in humans demonstrated that a doxycycline polymer applied to periodontal pockets produced a significant reduction in pocket depth and a significant gain of attachment within 9 months compared with results obtained by application of a placebo. This success was particularly obvious in deep pockets (>7 mm). These findings are in agreement with results in the present study in which the most significant improvement in pocket depth occurred after 12 weeks in pockets deeper than 4 mm.

    After 6 weeks, pocket depths in the present study were reduced by 39% following treatment with doxycycline, similar to the 41% reported by Polson and coworkers.24 Although the study reported by Polson and coworkers provided a mean reduction of 46% for pocket depth at 12 weeks, compared with 35% in the present study, it is speculated that the better rate in that earlier study could be related to dogs having much deeper pockets initially (6.1 mm compared with 3.0 mm in the present study). Considering only pockets with an initial depth greater than 4 mm, as in the present study, the reduction in pocket depth was 51% after 6 weeks and 53% after 12 weeks. These studies indicate that the rate of improvement for pocket depth was better for pockets 6 to 9 mm deep; however, it was also noted in one study that local treatment with doxycycline did not provide significant improvement for pockets with a depth of 10 mm or more.18

    The success of treatment with doxycycline was also demonstrated by a significant reduction in the presence of aerobic, microaerophilic, and anaerobic bacteria in pockets treated with doxycycline compared with the presence of organisms in pockets treated with curettage only. Both aerobic bacteria and anaerobic microorganisms have previously demonstrated high sensitivity to tetracyclines.25,26 The sensitivity of various bacteria to doxycycline has been reported (Campylobacter: 1 µg/ml; Porphyromonas and Fusobacterium: 4 µg/ml; and Prevotella: 0.5 µg/ml).20

    The increase of Pseudomonas in pockets treated with doxycycline between 6 and 12 weeks (from 49.3% of all bacteria present in Week 6 to 58% in Week 12) could be related to increasing resistance of Pseudomonas to doxycycline.25,26 A similar explanation may apply to the increase of microaerophilic gram-positive rods. These bacteria are known to show different sensitivities toward tetracyclines.26

    An increase in the number of aerobic and anaerobic bacteria in the pockets treated with doxycycline over time was not an unexpected finding because the levels of antibiotic at the treatment site would gradually decrease. There was also a decline in anaerobes between 6 and 12 weeks for control teeth treated only by curettage. In spite of the improvement in the environment for unmedicated periodontal pockets, the level of anaerobes in the control pockets 12 weeks after treatment was six times greater than for pockets treated with doxycycline.

    For a better understanding of the mode of action of perioceutics, some dentistry studies that explain in more detail the development of these locally active preparations and their therapeutic potential are mentioned below.

    In one study in beagles,17 subgingival plaque harvested from the deepest pocket in jaws treated with doxycycline at the start of the study had significantly less bacterial growth than plaque from untreated pockets. Significantly less Porphyromonas was present on Day 14, and spirochete levels were significantly lower on Days 14 and 90. No difference was observed in subgingival plaque with regard to aerobic bacteria, however. Fundamentally, these results are in accordance with the present results to the extent that local application of the doxycycline polymer resulted in a significant reduction of microorganisms in the periodontal pockets.

    One study in humans27 demonstrated that applying minocycline ointment as a follow-up to scaling provided a better outcome than did scaling alone as long as 12 months after treatment. One investigator28 demonstrated that locally applied tetracycline fibers left in situ for 10 days significantly reduced pathogenic bacteria counts (Porphyromonas, Fusobacterium, and actinomycetes, in particular) in periodontal pockets after 90 days in patients treated with tetracycline in addition to scaling. In one study in beagles,19 the bacteria population treated with doxycycline was similar to that of the present study (Campylobacter, Fusobacterium, Porphyromonas, and streptococci). Bacteria with an MIC50 of 0.5 µg/ml and an MIC90 of 4 µg/ml were 98.5% sensitive to doxycycline.

    Lindhe and coworkers29 compared three different treatments in human patients: professional tooth cleaning by scaling, local treatment with cellulose acetate fibers containing 450 µg of tetracycline, and no treatment (controls). After 4 weeks, the group treated locally with tetracycline had lower gingivitis indices, reduced pocket depth, and a reduced number of spirochetes and motile rod-shaped bacteria. However, the improvements with regard to peri­odontal health were not as significant as in the scaling group. Similar results were later described by several researchers.15,30-32 Largely, these researchers found that the local application of tetracycline increased gingival attachment and reduced gingivitis, hemorrhagic diathesis, pocket depth, tooth mobility, and populations of motile microorganisms, spirochetes, and Prevotella spp. One early study33 succeeded in demonstrating improvement in attachment with a single application of a concentrated tetracycline solution (100 mg/ml) in conjunction with scaling compared with scaling alone. Three months after treatment, the only residual benefit of tetracycline washing was attachment gain. Inflammation of the periodontium, which had initially been reduced by the local treatment, recurred in treated teeth, demonstrating that the effect of tetracyclines in humans is on periodontitis in the pockets rather than on superficial inflammation.

    A multicenter study34-36 with a design similar to that of the present study was previously conducted in humans. A thorough gingivitis treatment was given before application of a local treatment with tetracycline fibers. The study design provided for evaluation of the treatment success of tetracycline fiber therapy with regard to periodontitis because gingivitis had already been largely cured before tetracycline treatment was administered. The local tetracycline therapy was performed with 25% tetracycline fibers that were left in situ in the periodontal pockets at a depth of 6 to 10 mm for 10 days. Compared with a group that was treated only with a scaling, the periodontal health of pockets treated with tetracycline fibers was improved after 60 days, as measured by reduced hemorrhagic diathesis, reduced pocket depth, and improved attachment. Pathogenic bacterial populations were markedly reduced for both treatments; however, the presence of Porphyromonas gingivalis was significantly reduced in the group treated with tetracycline compared with reductions in the control group.

    These local applications have the advantage of a protracted release of tetracycline and remote potential for development of resistance because an antibiotic concentration of approximately 65 ng/ml can be achieved in the periodontal tissue.37 Despite the large antibiotic concentration in the periodontal pocket, no significant systemic absorption was observed. Plasma levels of 2 to 3 µg/ml were achieved following systemic administration of tetracyclines to humans at 250 mg every 6 hours in one study, but after local application of tetracycline fibers to a periodontal pocket serum levels were less than 0.1 µg/ml.38 If professional cleaning and local application of antimicrobial substances do not successfully treat the periodontal condition, an antibiotic sensitivity test should be conducted to evaluate susceptibility of the bacteria present in the pockets to various antibiotics.16

    In one study in beagles,23 scanning electron microscopy was used to demonstrate that 30 seconds of washing with a tetracycline solution (100 mg/ml) removes the smear layer after root cleaning (smoothing) and opens the dentinal tubules, thus promoting reattachment. Another study in beagles39 with deep periodontal pockets (average depth 6 mm and average attachment loss 5.4 mm) received either nonmedicated polymer or doxycycline polymer in all pockets observed in the oral cavity. The amount of doxycycline in the gingival crevicular fluid was 10 to 20 µg/ml after 3 to 5 days and 250 µg/ml when the polymer was removed after 7 days. Following removal of the medicated polymer, teeth were cleaned three times weekly with a toothbrush and toothpaste. Throughout the 4 months of the study, teeth treated with doxycycline had significantly less inflammation, pocket depth, and attachment loss than the control group. In the treatment group, the probing depth was reduced 41% after 6 weeks and 46% after 12 weeks. These results are in good agreement with findings in the present study.

    Conclusion

    In dentistry, the advantages of local application are the achievement of high local concentrations without producing any remarkable adverse effects and the avoidance of parenteral or oral administration, which could lead to development of resistance in other parts of the body (e.g., intestinal flora). Several studies cited here have produced satisfactory results using locally applied tetracycline products for periodontal treatment in dogs. Results of the present study indicate that local application of doxycycline complements traditional subgingival curettage therapy in a reasonable and effective way and can significantly improve treatment success with regard to pocket depth reduction and attachment loss.

    Funding for this study was provided by Pharmacia & Upjohn Animal Health, Kalamazoo, MI.

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    2. Gabler WL, Creamer HR: Suppression of human neutrophil functions by tetracyclines. J Periodontal Res 26:52-58, 1991.

    3. Seymour RA, Heasman PA: Tetracyclines in the management of periodontal diseases. A review. J Clin Periodontol 22:22-35, 1995.

    4. Terranova VR, Franzetti LC, Hic S, et al: A biochemical approach to periodontal regeneration: Tetracycline treatment of dentin promotes fibroblast adhesion and growth. J Periodontal Res 21:330-333, 1986.

    5. Saari H, Suomalainen K, Lindy O, et al: Activation of latent human neutrophil collagenase by reactive oxygen species and serine proteases. Biochem Biophys Res Commun 171:979-987, 1990.

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    7. Ciancio SG, Mather ML, McMullen JA: An evaluation of minocycline in patients with periodontal disease. J Periodontol 51:530-534, 1980.

    8. Gordon JM, Walker CB, Murphy JC, et al: Tetracycline levels achievable in gingival crevice fluid and in vitro effect on subgingival organisms. Part I. Concentration in crevicular fluid after repeated doses. J Periodontol 52:609-612, 1981.

    9. Pascale D, Gordon J, Lamster I, et al: Concentration of doxycycline in human gingival crevicular fluid. J Clin Periodontol 64:841-844, 1986.

    10. Burns PR, Stack MS, Gray RD, Paterson CA: Inhibition of purified collagenase from alkaline-burned rabbit corneas. Invest Ophthalmol Vis Sci 30:1569, 1989.

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    12. Goodson JM, Holborow D, Dunn RL, et al: Monolithic tetracycline-containing fibers for controlled delivery to periodontal pockets. J Periodontol 5:575-579, 1983.

    13. Friedman M, Golomb G: New sustained release dosage from chlorhexidine for dental use. I. Development and kinetics of release. J Periodontal Res 17:323-328, 1982.

    14. Addy M, Rawle L, Handley R, Coventry JF: The development and in vitro evaluation of acrylic strips and dialysis tubing for local drug delivery. J Periodontol 53:693-699, 1982.

    15. Minabe M, Kematsu A, Nishijima K, et al: Application of a local drug delivery system to periodontal therapy. I. Development of collagen preparations with immobilized tetracycline. J Periodontol 60:113-117, 1989.

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    References »

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