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Periodontitis may be viewed as an infectious disease with a number of specific characteristics. Pathogens of the subgingival microbiota can interact with host tissues even without direct tissue penetration. Hence, antimicrobial agents must be available at a sufficiently high concentration not only within the periodontal tissues, but also outside, in the environment of the periodontal pocket. The subgingival microbiota accumulate on the root surface to form an adherent layer of plaque with the characteristics of a biofilm. Several mechanisms, such as diffusion barriers, and selective inactivation of agents lead to an increased resistance of bacteria in biofilms. Mechanical supragingival plaque control is indispensable to prevent the re-emergence of periodontal pathogens and the re-establishment of a biofilm in treated sites. Since specific features have important implications for the use of antimicrobial agents in periodontal therapy, extrapolations from experiences made in the therapy of other infections are only partially valid. The ultimate evidence for the efficacy of systemic or local chemotherapy must be obtained from treatment studies in humans with adequate follow-up.