Azithromycin: Author’s Reply

Abstract

Thank you for the opportunity to reply to Dr Higgins’ letter. I agree that whenever possible, our treatment choices should be informed by evidence. There are in fact 10 controlled clinical studies of azithromycin in the treatment of periodontitis;1-10 the majority of these show a beneficial effect in improving periodontal disease and microbiologic parameters over and above scaling and root planing (SRP). The latest study showed that ‘the adjunctive use of systemic azithromycin in the treatment of P. gingivalis periodontitis demonstrated significant clinical and microbiological benefits when compared with SRP plus placebo’.10 None of these studies was designed to assess periodontal regeneration so the case reports represent the first published evidence that azithromycin could be involved in this outcome. In addition, there are biologically plausible mechanisms to support the use of azithromycin in the treatment of periodontal diseases: the first is its activity against periodontopathogens such as P. gingivalis, A. actinomycemcomitans and other gram negative bacteria; the second being its inherent immune-modulatory properties which exert anti-inflammatory effects. Reduction of inflammation is a primary goal of periodontal therapy, especially since periodontal inflammation has been linked to systemic diseases in recent years.11 Finally, azithromycin is a low-risk drug in terms of adverse effects. Furthermore, the efficacy of azithromycin in reducing cyclosporine-induced gingival overgrowth has been documented in numerous studies since 1996; these papers have been published in the non-periodontal literature but provide another line of evidence that azithromycin has significant long-term periodontal effects after a single course.12-14 Although this effect is scarcely acknowledged in periodontal circles, this should not preclude the use of azithromycin to help patients in a different way than by conventional periodontal therapy (gingival resection, followed frequently by return of the gingival overgrowth if drug substitution is not possible). Regarding Dr Higgins’ opinion that the use of azithromycin for the treatment of periodontal diseases was off-label, I consider that azithromycin is in the same category as amoxil and metronidazole when these are prescribed either individually or in combination for severe/aggressive periodontitis. The prescription of these drugs in the treatment of periodontitis is not ‘off-label’; according to eMims 2010, azithromycin is to be used ‘for mild-moderate infections due to susceptible organisms’. Azithromycin is prescribed for its antibiotic properties in diverse infections for which it received FDA approval, but is also prescribed for its anti-inflammatory and immune-modulating effects to treat asthma, diffuse panbronchiolitis, chronic obstructive pulmonary diseases, and more recently cystic fibrosis and bronchiectasis. Its use in the treatment of advanced periodontal diseases is an application of both its antibiotic and immune-modulating properties; the latter may be an ‘off-label’ use if the drug was only prescribed for these effects in periodontal treatment. According to Bennett, ‘off-label use of drugs by individual physicians is legal and leads to new therapeutic advances’.15 It was made clear in the case report ‘that no definitive conclusions or recommendations about the use of azithromycin should be drawn from them’ and I agree with Dr Higgins’ concerns about the over-prescription of antibiotics in general. On the other hand, extensive clinical observations of the periodontal effects of azithromycin in aggressive periodontitis and in patients who had responded poorly to conventional periodontal treatment (including surgery) show that a single course of the drug improves the clinical outcome for these patients in the long term. Colleagues report similar effects in patients who had previously been ‘written off’ periodontally. Azithromycin’s short treatment regimen (one 500 mg tablet a day for three days) could well minimize the development of bacterial resistance. We do need further evidence from randomized controlled clinical trials and laboratory studies, but in the meantime, it is reasonable to prescribe azithromycin on a case-by-case basis adjunctive to periodontal treatment in patients with severe inflammatory periodontal diseases. It is also timely that azithromycin be included in the Therapeutic Guidelines Oral and Dental.