Objective: Azithromycin and other macrolides have been shown to
produce antimicrobial and anti-inflammatory effects when used to treat
chronic inflammatory airway diseases. Azithromycin produces potent
inhibition of Aggregatibacter actinomycetemcomitans, Porphyromonas
gingivalis and Prevotella intermedia, and previous studies suggest
that azithromycin improves non-surgical periodontal therapy outcomes
in patients with chronic and aggressive periodontitis or drug-induced
gingival enlargement. Macrolides distribute to gingiva at concentrations
higher than those found in blood serum. They are taken up and accumulated
by gingival fibroblasts, epithelial cells and phagocytes, which serve as
reservoirs that buffer and sustain their therapeutic concentrations in
the gingiva. It is unclear whether macrolides produce anti-inflammatory
effects in the gingiva, but it is feasible that azithromycin can decrease
the rate of gingival crevicular fluid (GCF) flow by decreasing the level
of inflammatory mediators in GCF.
Methods: Ten healthy volunteers
in good periodontal health were administered an initial 500 mg dose of
azithromycin followed by 250 mg doses 24 and 48 hours later. GCF samples
were collected from twelve maxillary posterior interproximal sites on
day 0 (prior to the first dose of azithromycin) and on days 2, 4, 7,
14 after the first dose. GCF samples were collected with paper strips
for 30 seconds and measured with a gingival fluid meter. The paper
strips were pooled and stored in sealed vials in liquid nitrogen.
At the time for cytokine analysis, GCF samples were eluted from paper
strips in 200 µl of Hanks balanced salts solution. A commercially
available multiplex cytokine immunoassay was used to measure the content
of IL-1β, IL-8, TNF-α, VEGF, IL-6 and IL-10.
Results:
Azithromycin had significant treatment effects on pooled GCF volume as
well as the amount of IL-1β, VEGF, TNF-α and IL-8 measured
in GCF over time (P < 0.005). Significant decreases in pooled GCF
volume were evident on days 2, 4 and 7 (P < 0.05). GCF volume increased
after day 7 and was not significantly different from baseline on day
14. Azithromycin triggered a significant decrease in GCF IL-1β
content relative to baseline on days 2, 4, 7 and 14. In comparison
to baseline levels, VEGF content was significantly lower on days 2,
4 and 7, while TNF-α content was significantly lower on days 4
and 7. IL-8 content decreased from baseline levels on days 2, 4 and 7,
but the difference was statistically significant only on day 4. IL-6 and
IL-10 were not detected in GCF samples obtained from healthy gingiva in
this population. The median Gingival Index and Plaque Index values were
0 throughout the study period.
Conclusions: Azithromycin induces
significant decreases in GCF volume and biological mediator content
at healthy periodontal sites that were essentially free of bacterial
plaque. This suggests it has potent anti-inflammatory effects in addition
to its known antimicrobial effects. The close temporal relationship
between the decreases in GCF volume and GCF pro-inflammatory cytokine
content suggests that azithromycin effects on GCF volume could be mediated
by inhibition of cytokine production.