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Pin-Chuang Lai Dissertation FINAL.pdf (4.18 MB)

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Azithromycin in periodontal therapy: pharmacokinetic and mechanistic investigations

Lai, Pin-Chuang
http://rave.ohiolink.edu/etdc/view?acc_num=osu1448876943

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Oral Biology.
Bacterial plaque is a primary etiological factor of periodontitis, and a specific group of pathogens is strongly associated with this destructive inflammatory entity. Although conventional periodontal scaling and root planing usually halts the disease process, the loss of periodontal attachment continues in some patients. Aggressive and recurrent forms of periodontitis are associated with persistent infection by Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis. These pathogens can invade gingival epithelium and fibroblasts, allowing them to evade the host immune system and re-colonize pockets after debridement. Although the use of adjunctive systemic antibiotics to treat invasive infection by these pathogens is recommended, an agreement on the most effective regimen has not been reached. Azithromycin is not commonly used in periodontal therapy. Its favorable properties include inhibition of a broad spectrum of periodontal pathogens, a high volume of distribution, a long half-life, and relatively low incidence of side effects. Studies have indicated that human cells take up azithromycin through active transport. In this project, we hypothesize that gingival epithelial cells, fibroblasts, and neutrophils possess active transporters that accumulate azithromycin. These transporters may enhance and sustain levels of azithromycin in cellular compartments of gingiva and in gingival crevicular fluid. The accumulated azithromycin may facilitate elimination of intracellular periodontal pathogens. The chapters of this dissertation are 1) to study the mechanism by which azithromycin is transported by cells in the gingiva, and 2) to evaluate the benefits of this transport system with regards to pharmacokinetics and antimicrobial activity against intracellular A. actinomycetemcomitans and P. gingivalis. The characterization of azithromycin transport was conducted with radiolabeled azithromycin. To study the mechanism of transport, agents with similar molecular features were added to test their effects on azithromycin transport. To study the pharmacological benefits of azithromycin transport, human subjects with clinically healthy periodontal tissues were recruited. Following systemic administration of azithromycin, serum and gingival crevicular fluid were sampled and the content of azithromycin was determined by agar diffusion bioassays. The intracellular antimicrobial activity of azithromycin was evaluated in gingival epithelial cells, fibroblasts, and neutrophils. Periodontal pathogens were first internalized in these cells, and the surviving colony-forming units after antibiotic treatment were measured by growing the cellular lysates on appropriate agar plates. Our data suggest that gingival epithelial cells, fibroblasts, and neutrophils possess saturable, concentrative active transport systems for azithromycin that are shared with organic cations. The transport systems lead to high degrees of intracellular accumulation in gingival epithelial cells, fibroblasts, and neutrophils, with cellular/extracellular concentration ratios of ~20, ~11, and ~5, respectively. Azithromycin concentration in gingival crevicular fluid is significantly higher and more sustained than that in serum over 2 weeks. Accumulation of azithromycin in these cells enhances the elimination of invasive A. actinomycetemcomitans and P. gingivalis. Compared to antibiotics that are not concentrated by host cells, azithromycin exhibits either equivalent or more potent antimicrobial activities. Competitive inhibitors of azithromycin transport significantly reduce the intracellular content of azithromycin and attenuate its antimicrobial effects. Overall, this project provides a rational basis for adjunctive use of azithromycin in periodontal therapy.
John Walters (Advisor)
Sudha Agarwal (Committee Member)
Eugene Leys (Committee Member)
Dimitris Tatakis (Committee Member)
167 p.
Dentistry; Pharmacology
antimicrobial agents; macrolide; periodontitis; pharmacokinetics; invasive microorganisms; neutrophil; gingival fibroblast; gingival epithelium

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Citations

  • Lai, P.-C. (2015). Azithromycin in periodontal therapy: pharmacokinetic and mechanistic investigations [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1448876943

    APA Style (7th edition)

  • Lai, Pin-Chuang. Azithromycin in periodontal therapy: pharmacokinetic and mechanistic investigations. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1448876943.

    MLA Style (8th edition)

  • Lai, Pin-Chuang. "Azithromycin in periodontal therapy: pharmacokinetic and mechanistic investigations." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1448876943

    Chicago Manual of Style (17th edition)

osu1448876943
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This open access ETD is published by The Ohio State University and OhioLINK.