Aggressive and recurrent forms of periodontitis are associated with infections by A. actinomycetemomitans and P. gingivalis. The ability of these pathogens to invade epithelial cells and phagocytes makes them difficult to eliminate by conventional scaling and root planing alone. However, the use of systemic antibiotics in conjunction with scaling and root planing significantly enhances clinical and microbiological treatment outcomes. While not widely prescribed by periodontists, azithromycin and clarithromycin are potentially useful because they are taken up by host cells and have favorable antimicrobial activity. Both agents can potentially attain higher levels in gingiva than in serum. Preliminary studies suggest that active transport plays an important role in this process. Cultured gingival fibroblasts, epithelial cells and PMN-like HL-60 cells appear to take up clarithromycin by a concentrative and saturable transport mechanism. Clarithromycin uptake by fibroblasts is temperature-dependent and exhibits Michaelis-Menten kinetics, suggesting the involvement of an energy-dependent transport system. We hypothesize that gingival fibroblasts, epithelial cells and PMNs possess active transporters that accumulate macrolides. These transporters play a beneficial role by enhancing macrolide levels in the soft tissue wall of the periodontal pocket, in phagocytes and in gingival crevicular fluid. Since fibroblasts are a relatively large cellular compartment of the gingiva, macrolide transporters could permit these cells to function as drug reservoirs that enhance and sustain macrolide levels in gingival connective tissue and in gingival crevicular fluid. In epithelial cells and PMNs, these transporters could facilitate elimination of invasive pathogens by enhancing intracellular macrolide accumulation. The objective of this proposal is to study mechanisms by which macrolides are transported and concentrated by host cells in the gingiva.
Specific aim 1 is to characterize transport systems by which gingival fibroblasts, epithelial cells and PMNs take up these agents, using radiolabeled macrolides to assay transport activity. [Specific aim 2 is to assess the pharmacological benefits of intracellular macrolide accumulation by host cells (including effects on drug distribution).
Specific Aim 3 is to assess the killing of intracellular A. actinomycetemcomitans and P. gingivalis by macrolides in cultured PMNs and gingival epithelial cells]. The broad goal of this work is to provide a rational basis for selecting the most effective agents for periodontal antimicrobial chemotherapy. Ultimately, this work could contribute to reductions in tooth loss and the cost burden of treating periodontitis.

Public Health Relevance

This proposal will study mechanisms by which macrolide antibiotics are transported and concentrated by cells in human gingiva. Exploiting cellular accumulation of macrolides could enhance the elimination of invasive periodontal pathogens that are difficult to treat with conventional scaling and root planing. By providing a rational basis for selecting an antibiotic for periodontal antimicrobial chemotherapy, this work could ultimately contribute to reductions in tooth loss and the cost burden of treating destructive periodontitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DE018804-02
Application #
7783831
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
2009-04-01
Project End
2013-09-30
Budget Start
2010-04-01
Budget End
2013-09-30
Support Year
2
Fiscal Year
2010
Total Cost
$185,625
Indirect Cost
Name
Ohio State University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Walters, John; Lai, Pin-Chuang (2015) Should Antibiotics Be Prescribed to Treat Chronic Periodontitis? Dent Clin North Am 59:919-33
Lai, Pin-Chuang; Schibler, Mark R; Walters, John D (2015) Azithromycin enhances phagocytic killing of Aggregatibacter actinomycetemcomitans Y4 by human neutrophils. J Periodontol 86:155-61
Lai, Pin-Chuang; Walters, John D (2013) Azithromycin kills invasive Aggregatibacter actinomycetemcomitans in gingival epithelial cells. Antimicrob Agents Chemother 57:1347-51
Jain, Nidhi; Lai, Pin-Chuang; Walters, John D (2012) Effect of gingivitis on azithromycin concentrations in gingival crevicular fluid. J Periodontol 83:1122-8
Lai, Pin-Chuang; Ho, Weiting; Jain, Nidhi et al. (2011) Azithromycin concentrations in blood and gingival crevicular fluid after systemic administration. J Periodontol 82:1582-6
Iskandar, Irma; Walters, John D (2011) Clarithromycin accumulation by phagocytes and its effect on killing of Aggregatibacter actinomycetemcomitans. J Periodontol 82:497-504
Ho, W; Eubank, T; Leblebicioglu, B et al. (2010) Azithromycin decreases crevicular fluid volume and mediator content. J Dent Res 89:831-5