Microbiology

Doxycycline is a broad-spectrum semisynthetic tetracycline.¹ Doxycycline is bacteriostatic, inhibiting bacterial protein synthesis due to disruption of transfer RNA and messenger RNA at ribosomal sites.¹ In vitro testing has shown that Porphyromonas gingivalis, Prevotella intermedia, Campylobacter rectus, and Fusobacterium nucleatum, which are associated with periodontal disease, are susceptible to doxycycline at concentrations ≤ 6.0 μg/mL.² A single-center, single-blind, randomized, clinical study in 45 subjects with periodontal disease demonstrated that a single treatment with ATRIDOX® resulted in the reduction in the numbers of P. gingivalis, P. intermedia, C. rectus, F. nucleatum, Bacteroides forsythus, and E. corrodens in subgingival plaque samples. Levels of aerobic and anaerobic bacteria were also reduced after treatment with ATRIDOX® . The clinical significance of these findings, however, is not known. During these studies, no overgrowth of opportunistic organisms such as Gram-negative bacilli and yeast were observed. However, as with other antibiotic preparations, ATRIDOX® therapy may result in the overgrowth of nonsusceptible organisms including fungi. (See PRECAUTIONS)

Pharmacokinetics

In a clinical pharmacokinetic study, subjects were randomized to receive either ATRIDOX® covered with Coe-Pak™ periodontal dressing (n=13), ATRIDOX® covered with Octyldent® periodontal adhesive (n=13), or oral doxycycline (n=5) (according to package dosing instructions). The doxycycline release characteristics in gingival crevicular fluid (GCF), saliva, and serum were evaluated.

Doxycycline levels in GCF peaked (-1,500 μg/mL and -2000 μg/mL for Coe-Pak™ and Octyldent® groups, respectively) 2 hours following treatment with ATRIDOX® . These levels remained above 1000 μg/mL through 18 hours, at which time the levels began to decline gradually. However, local levels of doxycycline remained well above the minimum inhibitory concentration (MIC90) for periodontal pathogens ( 6.0 μg/mL)² through Day 7. In contrast, subjects receiving oral doxycycline had peak GCF levels of -2.5 μg/mL at 12 hours following the initial oral dosing with levels declining to -0.2 μg/mL by Day 7. High variability was observed for doxycycline levels in GCF for both oral and ATRIDOX® treatment groups.

The ATRIDOX® doxycycline release profile in GCF is illustrated in the figure below.

The maximum concentration of doxycycline in saliva was achieved at 2 hours after both treatments with ATRIDOX® , with means of 4.05 μg/mL and 8.78 μg/mL and decreased to 0.36 μg/mL and 0.23 μg/mL at Day 7 for the Coe-Pak™ group and the Octyldent® group, respectively.

The concentration of doxycycline in serum following treatment of ATRIDOX® never exceeded 0.1 μg/mL.

Clinical Studies

In 2 well-controlled, multicenter, parallel-design, 9-month clinical trials, 831 patients patients (Study 1=411; Study 2=420) with chronic adult periodontitis characterized by a mean probing depth of 5.9 to 6.0 mm were enrolled. Subjects received 1 of 4 treatments: 1) ATRIDOX® , 2) Scaling and Root Planing, 3) Vehicle Control, or 4) Oral Hygiene. Treatment was administered to sites with probing depths 5 mm or greater that bled on probing. Subjects with detectable subgingival calculus on greater than 80% of all tooth surfaces were excluded from enrollment. All subjects received a second administration of the initially randomized treatment 4 months after their Baseline treatment. Changes in the efficacy parameters, attachment level, pocket depth, and bleeding on probing, between Baseline and Month 9 showed that: 1) ATRIDOX® was superior to Vehicle Control and Oral Hygiene, and 2) ATRIDOX® met the decision rule of being at least 75% as good as Scaling and Root Planing (SRP) (the standard of at least 75% as good as SRP is required for any product approved as a stand alone therapy for periodontitis). Clinicians should note that the studies were of 9 months duration. Additional research would be necessary to establish long-term comparability to SRP. The results of Studies #1 and 2 for efficacy parameters of attachment level gain and probing depth reduction are included in the following graphs.

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