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Azithromycin, first synthesized in 1980, is a macrolide antibiotic related to erythromycin. It is widely used by the medical profession as a broad-spectrum antibiotic in the treatment of pneumonia, urinary tract infections and tonsillitis. In addition to its antibiotic properties, azithromycin has immune-modulating effects and is used for this reason in the management of cystic fibrosis and chronic obstructive pulmonary diseases. The drug is taken up by neutrophils, macrophages and fibroblasts, and is slowly released by these cells. Three diverse case reports are presented in which a single course of azithromycin (consisting of one 500 mg tablet being taken a day for three days) was prescribed before any periodontal intervention occurred. Azithromycin was the principal mode of treatment of severe chronic and aggressive periodontitis in Cases 1 and 2. Azithromycin, together with monthly subgingival debridement, was the treatment in Case 3 (severe chronic periodontitis in a poorly controlled diabetic complicated by gingival overgrowth related to medication with a calcium channel blocker). Favourable resolution of inflammation, reduction in pocket depths and evidence of bone regeneration were evident, even when no periodontal treatment had occurred. In Case 3, resolution of gingival overgrowth occurred over eight months. The potential implications for periodontal management, understanding of the pathogenesis of periodontal diseases and periodontal research are briefly discussed.
Antibiotics have been used as adjunctive agents in the management of periodontal diseases for many years and their role has recently been reviewed.1 The evidence for their efficacy in the management of various types of periodontitis is conflicting and there is little consensus as to the optimum type, dosage, duration of treatment, and mix of antibiotic when combined therapy is used. However, it is recommended that antibiotics be used adjunctively to periodontal treatment and then as soon as possible after debridement has been completed.2 Antibiotics used in the treatment of periodontitis in Australia have included tetracycline, metronidazole and a combination of metronidazole and amoxicillin. The latter combination, while effective against putative periodontopathogens, causes unpleasant gastro-intestinal side effects that result in reduced patient compliance.
Azithromycin is a macrolide antibiotic related to erythromycin. It was first formulated in 1980 and is a widely prescribed antibiotic in the treatment of tonsillitis, pneumonia, middle ear infections, urinary tract infections, malaria and trachoma.3–5 It has potent antibiotic activity against Gram-negative bacteria relative to erythromycin,6 is able to penetrate dental biofilm,7 has a long half-life as an antibiotic of 3.2 days,8 and good periodontal tissue penetration.6,9 When administered systemically, azithromycin is concentrated in the periodontal tissues where it is retained for at least 14 days.6 Its side effects are mostly mild but it can potentiate the effects of warfarin.10 In addition to its antibiotic activity, azithromycin has important immune-modulating properties that have underpinned its use in the management of cystic fibrosis and chronic obstructive pulmonary diseases.11 It is readily taken up by neutrophils, macrophages and fibroblasts in inflamed tissues12,13 and is retained even after serum levels decline.14 Azithromycin is concentrated at sites of inflammation15 and decreases the expression of pro-inflammatory cytokines by macrophages in vitro.16,17
A significant periodontal effect of azithromycin, first reported in 1995, is its ability to reverse gingival overgrowth related to cyclosporine therapy.18–20 The antibiotic properties of azithromycin in periodontal treatment have only been investigated recently.21–27 However, its immune-modulating properties have received scant attention in the periodontal literature.
A 65-year-old female non-smoker with no contributory medical conditions presented with severe localized chronic periodontitis affecting the 37, 32, 41 and 42. Severe gingival inflammation was present through the gingival tissues in the lower anterior region (Fig 1a). Pocketing exuding pus extended to 12 mm on the 42 and 32 distal surfaces; peri-apical radiographs showed extensive localized bone loss (Fig 2a, c). The 32 and 42 had Class III mobility. Non-specialist treatment provided elsewhere in the previous six months had included repeated “cleaning” and a course of metronidazole but this had not improved the condition according to the patient. A single course of azithromycin 500 mg (one tablet daily for three days) was prescribed and a follow-up appointment was made for further treatment planning and management. However, the patient did not attend again until seven months following her initial consultation. At this time, the patient reported that her periodontal symptoms had improved noticeably soon after taking azithromycin, she no longer had a bad taste in her mouth and her once loose teeth were “stronger”. After seven months, the previously intense gingival inflammation through the attached gingiva around the affected lower anterior teeth had resolved, pocket depths and tooth mobility had decreased markedly even though significant deposits of supra and subgingival calculus and plaque were present (Fig 1b). Periapical radiographs indicated likely bone formation at the bases of the defects on the 32 and 42 (Fig 2b, d). The root surfaces were debrided conventionally and a further visit was arranged in three months.
A 43-year-old female presented with advanced generalized aggressive periodontitis and associated severe gingival inflammation with suppuration in the molar segments (Fig 3a, b). An OPG shows the advanced and aggressive nature of the bone loss (Fig 4a). Pockets extended to 15 mm on the 25 and ranged between 7 to 10 mm on most tooth surfaces around all the premolars and molars and lower anterior teeth. Furcation involvement and mobility ranged from Grade II to III. Plaque formation was extensive but supra and subgingival calculus deposits were light. The patient reported being highly stressed, had hypertension controlled by perindopril, was a non-smoker and had a strong family history of periodontal problems. Subsequent medical investigations showed her to have pre-diabetes. A single course of azithromycin 500 mg was prescribed as in Case 1 and arrangements were made for further treatment planning and management. The patient reported that improvement in her periodontal symptoms started approximately three days after finishing the course of azithromycin. After three weeks, a large amount of gingival recession had occurred around the molar teeth (Fig 3c, d). All teeth were debrided subgingivally with a sonic scaler only. Further gingival recession and resolution of gingival inflammation occurred in the following five weeks when additional subgingival debridement with a sonic scaler was carried out. The patient did not return for more periodontal care until six months after her initial visit. The only conventional periodontal treatment provided after her initial consultation was subgingival debridement of all teeth with a sonic scaler after three weeks and two months. There had been continuing improvement in all periodontal parameters with resolution of inflammation, pocket depth reduction and remodelling of gingival tissues (Figs 3e, f). An OPG taken six months after the initial radiograph shows dramatic improvement in bone levels and fill of bony defects around many teeth (Fig 4b).
A 62-year-old male attended for consultation with severe localized and generalized chronic periodontitis and buccal gingival overgrowth, particularly in the 47–43 region (Fig 5a, e). On first presentation, the 12, 22, 24, 35 and 34 had been extracted by the referring dentist. All teeth had significant periodontal pocketing, ranging from 5 to 12 mm. All molars had Class II furcation involvement and ranged in mobility from Grade II to III. There was profuse bleeding on probing and severe chronic gingivitis throughout. His oral hygiene was very poor and deposits of supra and subgingival calculus were heavy. He was a poorly controlled insulin-dependent Type 2 diabetic (his HbA1c was 8.7%) and had quit smoking some 35 years ago. He was taking diltiazem (a calcium channel blocker), quinapril and irbesartan to control hypertension. A single course of azithromycin 500 mg was prescribed before commencement of periodontal treatment. He was given a chlorhexidine gel (0.2% PDS chlorofluor) to apply with his toothbrush instead of toothpaste and was appointed for further treatment planning and management. Treatment consisted of monthly visits of supra and subgingival debridement of all teeth with a sonic scaler and oral hygiene instruction. Two weeks after taking azithromycin and before periodontal debridement had commenced, the patient reported considerable improvement in his periodontal symptoms. Over the following months, there was clinically evident remodelling of the gingival tissues, with resolution of the gingival overgrowth in the 47–43 buccal region after eight months (Fig 5b–d). There was no change to the patient’s antihypertensive medication in this time and no surgical intervention in the area. Exploratory surgery around the 33 revealed that the tooth was cracked mesio-distally, giving an unfavourable prognosis in the longer term. Minor open flap debridement was undertaken in the 13–14 area to treat a persisting pocket. Overall pocket depths decreased to the extent that six months after azithromycin was taken, approximately 80% of pockets were reduced to <3 mm by a combination of gingival recession and healing. Over this time, the patient’s diabetes continued to be poorly controlled and his oral hygiene remained disappointingly poor. An OPG taken nine months after the initial consultation (Fig 5f) shows stabilization and some consolidation of alveolar bone.
It is important to keep in mind that the cases do not represent the results of a clinical study and that no definitive conclusions or recommendations about the use of azithromycin should be drawn from them.
Although it is recommended that antibiotics should be used as an adjunct to the treatment of aggressive and severe chronic forms of periodontitis only after subgingival debridement has occurred,2 the responses in the cases presented suggest otherwise. Indeed, the response to antibiotic treatment only (metronidazole plus amoxicillin) in terms of clinical and microbiological parameters were similar to scaling and root planing.28 An interesting editorial analysing the pros and cons of treatment of chronic periodontitis with systemic antibiotics only was published in 2006.29 There were no side effects reported to azithromycin and all patients noticed improvement in their periodontal symptoms (bleeding on brushing, pus exudate, tooth mobility) before or shortly after finishing the course. Patient compliance with antibiotic regimens is generally a problem. However, due to the small number of tablets in the course and lack of side effects, it is likely that compliance is not an issue for people prescribed azithromycin.1
Pocket depth reduction occurred as a combination of recession, resolution of inflammation, remodelling and healing of the gingival tissues over time; there was also evidence of regeneration of bone. This occurred without periodontal intervention in Case 1 and with subgingival debridement with a sonic scaler in Cases 2 and 3. Furthermore, the ongoing resolution of the medication-induced gingival overgrowth in Case 3 (Fig 5b–d) over nine months showed that the periodontal effects of azithromycin persisted over this time. This is consistent with its effects in reducing cyclosporine-induced gingival overgrowth over time.18,20 It remains to be established whether a small amount of azithromycin sufficient to influence cell function persists for lengthy periods in long-lived cells of the periodontium such as fibroblasts. In Case 3, the patient had continued taking the medication (diltiazem) and no resective gingival surgery had been carried out. This is the first report of the effect of azithromycin in resolving calcium channel blocker induced gingival overgrowth. Another interesting feature of Case 3 was that continuing improvement in the periodontal condition occurred over time even though the patient’s diabetes was very poorly controlled throughout the eight months of his treatment and his oral hygiene remained abysmal.
The apparent regeneration of alveolar bone (Fig 2b, d and Fig 4b) needs to be interpreted with caution as the sequential radiographs were not taken under standardized conditions. However, the improved radiographic appearance is consistent with the clinical picture (reduced gingival inflammation, pocket depths, furcation involvements and markedly reduced tooth mobility). The radiographs were taken during the course of an everyday specialist practice and as such are representative of the evidence that is usually relied upon by clinicians to assess the reaction of bone to periodontal treatment. Alveolar bone regeneration after azithromycin treatment without concomitant periodontal therapy has not previously been documented, although bone regeneration after the treatment of periodontitis with tetracycline only (1g/day for three weeks) has been reported.30
It is interesting to speculate on the mode of action of azithromycin after observing the positive periodontal responses to it. As a potent, broad-spectrum antibiotic, azithromycin could be active against bacteria in the dental biofilm,7 perhaps accounting for its relatively early effects in reducing the gingival inflammatory response. Antibiotic activity could be anticipated to last up to two weeks depending on concentrations achieved in the gingival tissues. However, even after a single course, azithromycin’s immune-modulating properties may persist over a much longer period due to the high concentrations reached in key cells regulating periodontal function. The immune-modulating effects may require lower drug concentrations than are needed for antimicrobial activity, as is the case with the host-modulating effects of sub-antimicrobial doses of doxycycline which is effective as an adjunct to periodontal therapy.31 However, this drug requires daily administration for up to nine months and is not available in Australia. The high concentrations of azithromycin that are reached in neutrophils, macrophages and fibroblasts (the latter being long-lasting cells in the periodontal tissues),12,13,32 point to the possibility that azithromycin down-regulates hyper-responsive macrophages which are thought to orchestrate periodontal destruction through production of pro-inflammatory cytokines. Azithromycin may also positively influence fibroblast function in the periodontal tissues, accounting for the remodelling of the gingival tissues and the resolution of gingival overgrowth observed. A recent in vitro study showed that azithromycin blocked fibroblast proliferation and collagen synthesis (initiated by cyclosporine) and activated fibroblast MMP-2.33 The apparent bone regeneration also raises the intriguing possibility that azithromycin encourages bone formation once tissue inflammation has subsided.
The need for laboratory and clinical research into the periodontal effects of azithromycin is clear. Clinical work needs to establish whether conventional periodontal debridement gives additional benefit when azithromycin is prescribed. The research may well shed fresh light on the relative role of biofilm and host cells and tissues in the pathogenesis of periodontitis and on new clinical periodontal management strategies. While dentists generally view antibiotics in the context of their role in controlling infections, azithromycin has much broader properties which potentially account for the improvement in periodontal health reported here. It is more than an antibiotic.