Treating patients with aggressive periodontitis is challenging. The disease responds less predictably to conventional mechanical periodontal therapy than chronic periodontitis [11, 90], the disease progression is rapid and severe and patients are generally of a younger age. Hence, scientists and clinicians have been exploring adjunctive treatments to enhance the outcome, stability and predictability of conventional mechanical therapy. In view of the specific microbiological nature of both types of aggressive periodontitis, the use of chemotherapeutics and, more specifically, of systemic antibiotics, could play an important role in the treatment of these diseases.
Although it is currently well established that antibiotics should not be administered without prior disruption of the bacterial biofilm , at least two studies have evaluated the effect of systemic antibiotics as the sole form of therapy in patients with localized aggressive periodontitis [17, 69, 70]. These studies show that tetracycline, systemically administered over a period of at least 6 weeks, in combination with supragingival plaque control, decreased the probing pocket depths and resulted in gains in clinical attachment for up to at least 24 months. In addition, this regimen may lead to some repair of the alveolar bone defects. These data were largely confirmed by Slots & Rosling  who administered 1 g of tetracycline for 2 weeks after completion of an initial phase of scaling and root planing. The scaling and root planing reduced the total subgingival bacterial counts and the proportions of certain gram-negative bacteria, but no periodontal pocket became free of A. actinomycetemcomitans, and the study reported small clinical changes after debridement. However, the administration of tetracycline, 6 weeks following scaling and root planing, and in the absence of a new phase of instrumentation, resulted in a gain in clinical attachment level of 0.27 ± 0.45 mm and suppression of A. actinomycetemcomitans, Capnocytophaga and spirochetes to low or undetectable levels in all test periodontal pockets. Although these were important observations in relation to our understanding of aggressive periodontitis, and although they were recently confirmed in patients with chronic periodontitis using metronidazole and amoxicillin , newer data do not validate the treatment approach that was used in the latter study. There is currently a clear consensus that mechanical instrumentation must always precede antimicrobial therapy. One should first mechanically reduce the subgingival bacterial load, which might otherwise inhibit or degrade the antimicrobial agent. Furthermore, one should mechanically disrupt the structured bacterial aggregates that can protect the bacteria from the agent . Insufficient concentrations of the active agent may favor the emergence of resistant bacterial strains.
Surprisingly, little investigation has been carried out into the adjunctive effect of systemic antibiotics on the outcome of mechanical instrumentation in patients with localized aggressive periodontitis. The first reports can be traced back to the end of the 1970s ; however, few studies have focused specifically on localized aggressive periodontitis. It is obvious that this hampers our current understanding of the use of systemic antibiotics in the treatment of this patient group. Furthermore, the approach, in terms of the set-up of the studies, the combination of different treatments used and the way of reporting data, was markedly different in these older papers from what is now considered to be the standard. Even more importantly, the development and the exponential increase of antibiotic resistance over the past two decades should increase our awareness that the antibiotic regimens used then might no longer be as effective. It must be considered that the absence of clinical trials addressing the issue of adjunctive systemic antibiotics in the treatment of localized aggressive periodontitis does not reflect a lack of interest in this disease. However, the low prevalence of localized aggressive periodontitis makes it hard to find sufficient numbers of patients, which might be a reason for this lack of new studies. On the other hand, this lack might reflect a publication bias owing to the absence of any significant adjunctive effect of systemic antibiotics. There is therefore an urgent need for new clinical trials addressing this issue.
Although the adjunctive effect of tetracycline on scaling and root planing was observed by Slots et al. in 1979 , the limited number of patients in the study does not allow a definitive conclusion to be reached. Kornman & Robertson  reported on the administration of systemic tetracycline (1 g/day for 28 days) as an adjunct to scaling and root planing, starting on the first day of scaling and root planing. It is assumed from their article that scaling and root planing was completed within the 28-day period in which the patients were taking the systemic antibiotics. Although this study was not placebo controlled, the eight patients included served as their own controls because they received scaling and root planing without tetracycline 2 months before receiving scaling and root planing supplemented with systemic tetracycline. The authors concluded that scaling and root planing alone had essentially no effect on either clinical or microbiological parameters. The mean probing pocket depth was reduced from 8.0 ± 1.1 mm to 7.9 ± 1.1 mm in this study. However, when scaling and root planing was repeated in conjunction with systemic tetracycline, an additional mean reduction in probing pocket depth to 6.4 ± 1.3 mm was recorded.
Despite several reports on the adjunctive use of systemic antibiotics during periodontal treatment (including surgery) of localized aggressive periodontitis [45, 56, 84], none of these studies actually evaluated the effect of antibiotics relative to scaling and root planing alone. The first actual randomized placebo-controlled study was published by Asikainen et al. in 1990 . Sixteen patients were randomized into a placebo group and a group that received systemic doxycycline at a loading dose of 200 mg and doses of 100 mg daily for 14 days thereafter. All patients received scaling and root planing as part of their treatment. Scaling and root planing was performed over an 8-week period, although the systemic antibiotic or placebo was only used during the first 2 weeks of the scaling and root planing. No significant differences were found between groups in probing pocket depth and bleeding on probing, during and at the end of the study.
These results encouraged the researchers to explore the effect of other systemic antibiotics. Saxén & Asikainen  randomized 27 patients into a placebo group, a tetracycline group (1 g/day for 12 days) and a metronidazole group (600 mg/day for 10 days). Scaling and root planing was performed at baseline and was repeated at 3 months. At 6 months postoperatively, the periodontal condition had improved in all groups. However, in the metronidazole group the percentage of pockets deeper than 4 mm was reduced more than in the other groups. Additionally, only one patient was still positive for A. actinomycetemcomitans, whereas in the tetracycline and control groups, four and six patients, respectively, were still positive for the bacterium. Whilst no statistical analysis was performed, the authors concluded that there was a higher predictability of the treatment results of scaling and root planing when the treatment was performed with adjunctive use of metronidazole than with tetracycline.
In contrast to these results, Palmer et al.  evaluated the effect of adjunctive tetracycline (1 g/day for 14 days) in 38 patients. Scaling and root planing was performed within 7 days, and the antibiotics were administered starting from the last scaling and root planing session. Three months after baseline the improvements in probing pocket depth, clinical attachment level and bleeding on probing were significantly better in the tetracycline group. These results, in relation to the whole study, which also included a surgical phase, led the authors to conclude that systemically administered tetracycline is a useful adjunct in the nonsurgical treatment phase of localized aggressive periodontitis. However, administering the antibiotic at the surgical phase did not provide any further, statistically significant, advantage.
Tinoco et al.  evaluated the effect of metronidazole (750 mg/day for 8 days) combined with amoxicillin (1500 mg/day for 8 days) as an adjunct to scaling and root planing in a randomized, placebo-controlled study involving 20 patients with localized aggressive periodontitis. Although 1 year after treatment, both groups showed significant clinical benefits, patients who had received systemic antibiotics adjunctively showed better results regarding probing pocket depth, clinical attachment level, gingival bleeding index and radiological bone fill.
As it seems, from the above-mentioned studies, that adjunctive systemic antibiotics improve the clinical outcome in patients with localized aggressive periodontitis, the question arises of whether the type of antibiotic is of importance. This aspect was addressed by Akincibay et al. , who compared the clinical outcome of systemic doxycycline vs. systemic metronidazole combined with amoxicillin during scaling and root planing. They randomly divided 30 patients into two treatment groups. The first group received 100 mg of doxycycline for 10 days and the second group received 375 mg of amoxicillin and 250 mg of metronidazole three times a day for 10 days. They found that both groups showed significant improvements in plaque index, gingivitis index, periodontal probing depth and clinical attachment level values. The metronidazole plus amoxicillin group showed significantly more improvement in plaque index and gingivitis index. Although the authors reported no statistically significant differences in probing pocket depths and attachment levels between both groups at the end of the study, there was at least a clear tendency for more improvement in the metronidazole plus amoxicillin group.
In contrast to localized aggressive periodontitis, the effect of systemic antibiotics as an adjunct to scaling and root planing in generalized aggressive periodontitis has been subjected to many more randomized, placebo-controlled studies. Among a variety of antibiotics that can be used and have been tested as adjuncts in generalized aggressive periodontitis, the combination of amoxicillin and metronidazole is becoming advocated to an increasing extent. The rationale behind combining both antibiotics has found its origin in the observation that A. actinomycetemcomitans was resistant to tetracycline, the antibiotic of choice in the 1990s [83, 105]. The failure of tetracycline to suppress A. actinomycetemcomitans, together with in-vitro data showing the synergistic effect of metronidazole and amoxicillin on A. actinomycetemcomitans  instigated van Winkelhoff et al.  to study the efficacy of this antibiotic combination to eliminate A. actinomycetemcomitans from subgingival sites. The combination of 250 mg of metronidazole and 375 mg of amoxicillin, three times a day for 7 days, as an adjunct to scaling and root planing, was found to be very effective in suppressing subgingival A. actinomycetemcomitans . Both microbiological and clinical effectiveness of this combination therapy has been shown for patients with chronic periodontitis . Recently, Sgolastra et al.  performed a meta-analysis of the effectiveness of the adjunctive use of amoxicillin and metronidazole in patients with generalized aggressive periodontitis and included six randomized, placebo-controlled clinical trials [7, 34, 62, 103, 106, 107] published up to September 2011. The study results clearly showed an adjunctive effect of the amoxicillin–metronidazole combination in patients with generalized aggressive periodontitis. Despite the fact that the majority of the included studies individually failed to show a statistically significant effect, significant mean differences in clinical attachment gain of 0.42 mm, pocket-depth reduction of 0.58 mm, bleeding on probing changes of 14.95% and gingival bleeding changes of 21.44% were calculated in favor of the antibiotics. It is interesting to note that the mean differences for clinical attachment gain, probing pocket-depth reduction and bleeding on probing in patients with aggressive periodontitis were higher than the mean differences reported in another meta-analysis by the same authors, which investigated the adjunctive effect of the amoxicillin–metronidazole combination in patients with chronic periodontitis . This may suggest that patients with generalized aggressive periodontitis benefit more from an adjunctive combination therapy than do patients with chronic periodontitis. Since September 2011, two additional randomized, placebo-controlled clinical trials have largely confirmed the outcome of the meta-analysis of Sgolastra et al. [1, 12]. It should be noted that in these studies, a variety of dosages for both antibiotics were used (between 750 mg and 1500 mg/day), as were a variety of administration regimens in terms of duration (between 7 and 14 days) and how scaling and root planing was performed (see Table 1). As no comparative data are available, it is currently impossible to define a clear protocol. However, data are available on the optimal timing of the use of amoxicillin and metronidazole in relation to nonsurgical therapy. It has been suggested that patients with aggressive periodontitis should initially be treated with scaling and root planing alone and then be clinically monitored, and only in refractory cases should systemic antimicrobial therapy be used as an adjunct to re-instrumentation . Thus, antimicrobials are more likely to be used at the retreatment visit rather than as part of the initial therapy . Although this is a reasonable approach, it can only hold if patients who receive antibiotics at the retreatment show at least the same benefits compared with those who receive the same regimen at the initial therapy. Recently, in a retrospective study  as well as in a prospective study , it has been shown that there is a clear clinical benefit of using antibiotics at the initial therapy compared with using them at retreatment.
Despite the fact that the combination of metronidazole and amoxicillin has shown additional clinical benefits beyond those of scaling and root planing alone in patients with generalized aggressive periodontitis, it is still not clear whether this combination is more effective than other antibiotics because few comparative studies have been performed. Sigusch et al.  compared the effects of metronidazole, clindamycin and doxycycline with a control group treated without antibiotics. It should be noted that the antibiotics were used at retreatment as an initial scaling and root planing procedure had been performed 3 weeks before re-instrumentation and antibiotic administration. The authors reported that the use of metronidazole or clindamycin was more effective in reducing probing pocket depth and gaining attachment compared with the control or the use of doxycycline, indicating the superiority of these two antibiotics. Similarly, also using a retreatment approach, 6 weeks after initial therapy, Xajigeorgiou et al.  assessed the effect of adjunctive use of metronidazole plus amoxicillin, metronidazole alone or doxycycline alone, compared with a control group. Presumably owing to the small number of patients in each group, no statistically significant differences could be shown. However, it is interesting to note that for probing pocket-depth reduction and clinical attachment gain, the largest additional benefit after retreatment was seen for the metronidazole alone and metronidazole plus amoxicillin groups. A smaller benefit was noted for the doxycycline group, and no benefit of retreatment was seen for the control group . Similar results, albeit reaching statistical significance, were recently obtained by Baltacioglu et al.  when the antibiotics were administered at initial therapy. In a study comparing the effectiveness of the adjunctive use of metronidazole plus amoxicillin, doxycycline, or scaling and root planing alone, the authors found that the combination of metronidazole plus amoxicillin resulted in a significantly greater probing pocket-depth reduction and gain in clinical attachment compared with the use of doxycycline or with the control treatment. However, doxycycline also showed a statistically significant additional probing pocket-depth reduction and clinical attachment gain vs. the control. In contrast to these studies, Machtei & Younis  could not find differences in clinical outcome between patients receiving either metronidazole combined with amoxicillin or doxycycline as adjuncts to first-phase therapy. In their study, 24 patients with generalized aggressive periodontitis and five patients with localized aggressive periodontitis were divided over the two test groups. Patients received a quadrant-wise scaling and root planing at weekly intervals and were given oral-hygiene instructions. They were placed into one of two treatment groups: 1500 mg/day of amoxicillin and 750 mg/day of metronidazole for 14 days; or a 200-mg loading dose of doxycycline followed by 100 mg of doxycycline, daily, for 30 days. During the 3-month follow-up period, patients were recalled biweekly for oral-hygiene reinforcement and motivation. The authors found that under these conditions, both regimes provided clinical improvements and that the differences in the results between both groups were not significant. However, it should be borne in mind that the duration of the doxycycline therapy was much longer than for the regimen with other antibiotics.
Taking this limited number of comparative studies together, it appears that the adjunctive use of metronidazole plus amoxicillin, metronidazole alone or clindamycin in patients with generalized aggressive periodontitis results in more pronounced clinical improvements when compared with the use of doxycycline for a similar amount of time or with scaling and root planing alone.
Recently, the effectiveness of azithromycin in the treatment of aggressive periodontitis was also tested. Compared with other antibiotics, azithromycin has the advantage of having a long half-life. As azithromycin only needs to be administered once a day for 3 days, one could assume that patient compliance would be better compared with other antibiotic regimens. Compliance to an adjunctive antibiotic regimen seems to be an important aspect for the clinical outcome in aggressive periodontitis. In a retrospective analysis, Guerrero et al.  demonstrated that incomplete adherence to a metronidazole plus amoxicillin regimen resulted in significantly less probing pocket-depth reduction and less gain in clinical attachment. Therefore, Haas et al.  compared the clinical effect of the adjunctive use of azithromycin with scaling and root planing in aggressive periodontitis. One year after treatment, a significant additional 1 mm reduction in probing pocket depth and 0.7 mm gain in attachment was evident, which shows the potential of azithromycin in the treatment of aggressive periodontitis. In this study, localized and generalized periodontitis patients were pooled.
Although there is a clear rationale for the use of local antimicrobials, which is based on the emerging antibiotic resistance, the possibility to achieve maximum antibacterial concentrations and the reduction of systemic side effects, the effectiveness of local antimicrobials in aggressive periodontitis has barely been investigated. However, especially for localized aggressive periodontitis, the localized character and limited number of diseased sites would in theory favor their use. Surprisingly, hardly any study has investigated, in a controlled manner, the possible adjunctive effect of local antimicrobials in localized aggressive periodontitis. To the best of our knowledge, only Ünsal et al.  have performed a comparative study. In this study, 26 patients with localized aggressive periodontitis were randomized, after scaling and root planing, into a control group, a group receiving 1% chlorhexidine gel (subgingivally administered) and a group receiving a 40% tetracycline gel (subgingivally administered). The local subgingival administration of either of the two antimicrobial agents did not result in a significant additional improvement of the clinical parameters in these patients after the 12-week observation period. The use of local antimicrobial agents has also been tested in generalized aggressive periodontitis. However, only one study actually compared the adjunctive use of a local antimicrobial vs. scaling and root planing alone . In this study, the effect of tetracycline fibers was investigated, in a split-mouth design, over a 6-month follow-up period in 10 patients with generalized aggressive periodontitis. The adjunctive use of tetracycline fibers resulted in statistically significant additional probing pocket-depth reductions of 0.6 mm and in gains of clinical attachment of 0.7 mm, up to 6 months after therapy. On the other hand, the effect of local antimicrobials has been compared with the effect of systemic antibiotics in patients with generalized aggressive periodontitis. Purucker et al.  compared the effect of tetracycline fibers with systemically administered amoxicillin/clavulanic acid over a 52-week period in 28 patients. Both adjuvants were applied 15 weeks after initial therapy (8 weeks after the completion of initial therapy) without additional scaling and root planing. Under these conditions, no statistically significant differences between either treatment modalities were recorded in probing pocket depth and clinical attachment level. A significant difference in bleeding on probing was recorded at week 54 in favor of the systemic antibiotic. The study authors stated that, because of the relatively small number of patients included, the claim that both antibiotic treatment modalities are equivalent cannot be made. Moreover, based on the data described above, the timing of usage of both antibiotic modalities might not have been optimal. Additionally, although the data were not statistically analyzed in this way, when the event of antibiotic application (week 15, 8 weeks after completion of initial therapy) is used as the baseline, there seems to be at least a numerical tendency that the systemic antibiotic provided a better clinical adjunctive effect for probing pocket depth, clinical attachment level and bleeding on probing compared with the local antibiotic modality. Similarly, Kaner et al.  recently compared the effect of a chlorhexidine chip with systemically administered amoxicillin (1500 mg/day) plus metronidazole (750 mg/day), both applied 1 week after the completion of scaling and root planing. Over the 6-month observation period, the results show that scaling and root planing plus adjunctive chlorhexidine chips provided clinical improvements, but these were not maintained in full over the entire observation period. In the chlorhexidine chip group, probing pocket depth significantly increased again between 3 and 6 months. Scaling and root planing plus systemic amoxicillin/metronidazole was more effective with regard to reduction of pocket depth and gain in clinical attachment.
In conclusion, in patients with aggressive periodontitis, the adjunctive effects of local antimicrobials, which have been reported in the literature, do not seem to improve on the adjunctive effect of systemic antibiotics. Only for generalized aggressive periodontitis has an adjunctive clinical effect for tetracycline fibers compared with scaling and root planing alone been shown. How local antimicrobials compare with systemic amoxicillin plus metronidazole with regard to both cost–benefit and effectiveness is currently unknown. Therefore, it seems plausible that the decision to use this type of treatment modality should be made on an individual basis rather than be evidence-based.