Azithromycin in Periodontal Therapy: Beyond the Antibiotics

Periodontitis is a multifactorial disease, in which microorganisms in plaque biofilm play a major role. Scaling and root planing is the primary mode of non-surgical treatment for periodontal disease. Adjunctive use of an antimicrobial is advocated in certain periodontal disease conditions. Azithromycin might be considered a promising adjunctive drug in the treatment for periodontal disease because of its distinguished characteristic of immunomodulation, anti-inflammatory and antibiotic property along with the accumulation in higher concentration into the acute reactant cells and sustained release at the site of infection. This antibiotic is popular for its very simple dosage regime and limited side effects. The objective of this literature review to highlight the mechanism and potential favourable role in the management of various form of the periodontal disease.


INTRODUCTION
The complete elimination of tissue invasive microorganism is not possible with mere mechanical debridement in certain disease conditions. The systemic antimicrobials as an adjunctive mechanical therapy have been shown to enhance clinical benefits in these patients. 1 Azithromycin (AZM) first synthesised in 1980, is a subclass of macrolides called azalides. 2  AZM well plays a triple role in the treatment of moderate to advanced periodontitis. Its effectiveness against gram-(500 mg on the first day, followed by 250 mg daily for next five days) and in Europe (500 mg daily for three days) are different. 8 Shorter regimens are required because of long half-life, and this makes good patient compliance compared to other antibiotics. 9 The single course of AZM rarely demonstrates any adverse reactions. Nausea, abdominal pain and diarrhoea are the most frequent adverse reactions (in approximately 5%).
Rare, serious, allergic reactions, including angioedema and anaphylaxis (rarely fatal), have been reported in patients on AZM therapy. AZM is only contraindicated in combination with antacid, warfarin and cyclosporin. AZM interacts with the antacids and may potentiate the effect of warfarin.
AZM should be avoided to prescribe in patients with known hypersensitivity to erythromycin. 10,11 Antibiotic Spectrum AZM is a broad spectrum antibiotic acting against both gram-positive and gram-negative bacteria and has bacteriostatic effects, 3

Effect on Biofilm
In vivo, bacteria within the biofilm are thought to be protected from antibiotics. 19    a substantial amount of macrolide antibiotics may be taken up from interstitial fluid and concentrated inside macrolide reservoirs (fibroblasts, epithelial, inflammatory, and immune cells). 13,25 They are thought to enhance macrolide distribution to gingiva and account for the large concentration difference between blood serum and gingival crevicular fluid 26 (Table 1)

Surgical Periodontal Treatment
The only available RCT 46 using the AZM adjunct to surgical periodontal therapy in heavy smokers showed rapid wound healing, short-term gingival inflammation and less plaque formation in AZM group, but failed to demonstrate any difference in PPD or clinical attachment with placebo. (Table 1, 2)

Bone Regeneration
In addition to the resolution of inflammation, remodelling and significant periodontal healing of the gingival tissues over time, regeneration of bone has been reported in few case reports 47,48 in patients with severe localised and generalised periodontitis, following a single course of AZM.
Bone formation was noted on periapical radiographs after the patients took two additional courses of AZM in the treatment of periodontal abscesses in conjunction with SRP. 49 The results from these case reports raise the possibilities of bone formation with the use of AZM (Table 1).

Drug Induced Gingival Overgrowth
Clinically, AZM has been reported to be highly effective in treating Cyclosporin-A (CsA) induced gingival overgrowth. 50,51 These results imply that AZM has an inhibitory effect on CsA induced gingival overgrowth 50,52 (Table1). Three possible mechanisms 53 could be inferred, i) the inherent drug effect of AZM on gingival overgrowth might be related to its antibiotic activity, killing of oral bacteria, reducing local inflammation, and suppressing protein synthesis in fibroblasts; 51 ii) AZM inhibits the inherent effects of CsA, The interaction between AZM and CsA is controversial, but no studies has been found to support this second mechanism; iii) AZM is associated with the inhibition of phagocytosis induced by CsA.
Phagocytosis was thought to be the principal pathway of collagen degradation in CsA induced gingival overgrowth.
Moreover, treatment with AZM appears to restore part of the phagocytosis mechanism.