Introduction

The recognition of the importance of bacteria as etiologic agents of periodontal disease and the seminal studies of previous decades which identified key pathogens have led to numerous investigations into the role of antibiotics in periodontal treatment. Unfortunately, due to differences of these studies in design, duration, antibiotic class and dosage, concomitant mechanical treatment, and disease classification, the extrapolation of concise conclusions is not easy, as several authors in the field have noted. In addition, during the last two decades, advances in laboratory technology have provided new insight about the structure and properties of the subgingival biofilm and its resistance to antimicrobials and raised questions about their efficacy. The abovementioned parameters combined with the emerging global threat of antimicrobial resistance and the well-known side effects or adverse reactions during antibiotic administration have developed a trend among clinicians for more cautious prescription of this class of drugs.

Knowledge of the disadvantages of systematic administration of antibiotics and difficulties in patient compliance (especially in long-term regimens) have also prompted researchers to develop several local delivery systems in periodontology, i.e., antimicrobial agents embodied in excipients for direct placement and action in periodontal pockets. Due to advanced material technology, a number of such products are available for clinicians and several studies have evaluated their effects on periodontal conditions.

This chapter focuses on evidence-based systemic and local administration of antibiotics in periodontology and provides guidelines for their indications, according to current evidence and documentation.

Evidence-based Outcomes

Historically, clinical studies regarding the benefits of the systematic administration of antimicrobials in periodontology began in the late 1970s and initially referred to patients with localized juvenile periodontitis (LJP), a disease which partially coincides with localized aggressive periodontitis. In the classical studies of the 1980s and 1990s, both in the US and Scandinavia, it has been shown that in LJP patients, systemic administration of antibiotics such as the tetracyclines can improve clinical parameters and decrease the pathogenic subgingival microflora, especially Aggregatibacter (Actinobacillus) actinomycetemcomitans (Saxen and Asikainen 1993; Saxen et al. 1990; Slots and Rosling 1983). The efficiency of the combined systemic administration of metronidazole and amoxicillin in LJP patients was investigated by Van Winkelhoff et al. (1989), who have shown an improvement of clinical parameters and elimination of A. actinomycetemcomitans for at least nine months and therefore introduced this regimen in other classes of periodontal diseases.

After years of including antimicrobials in clinical practice, current major issues of concern among clinicians include the following: Can antibiotics be considered as a sole therapy for periodontal diseases? Are there adjunctive benefits to conventional mechanical treatment or periodontal surgery? Can antibiotics enhance periodontal regeneration or treat acute periodontal conditions and peri-implantitis? In this section, we review current evidence which should guide clinicians to indications and methods of delivery.

The issue of using antibiotics as monotherapy to treat periodontal disease has been addressed in several studies. Current data regarding biofilm structure and resistance to antimicrobials show that subgingival biofilms can be more effectively controlled when they are mechanically disrupted. When their dense structure has been altered and the huge number of bacteria diminished, the antimicrobials have the potential to better diffuse and eliminate the microbial target (Socransky and Haffajee 2002). In addition, antimicrobial activity has been shown to be more effective in “young” and not well-organized biofilms. In the Sixth European Workshop on Periodontology, in 2008, Herrera and coworkers addressed the question of whether systemic antimicrobials can be efficacious if the biofilm is not disrupted. The authors reviewed the existing literature and concluded, in agreement with previous position papers and systematic reviews (AAP 1996; Haffajee et al. 2003; Herrera et al. 2002), that clinicians should not consider antibiotics as a sole therapy for periodontal diseases and that antibiotics should be combined with mechanical means of disrupting or removing biofilms in gingival sulci and pockets. Therefore, currently, clinicians should act based on good medical practice and administer systemic antibiotics as adjuncts rather than as the main and sole therapy. The cornerstone of effective periodontal therapy should include meticulous mechanical therapy by a highly skilled operator, patient compliance (oral hygiene and smoking cessation), and effective control of systemic diseases such as diabetes.

As mentioned above, although numerous studies have tested the role of systematic administration of antimicrobials in patients with periodontitis, several discrepancies among them preclude the comparison and classification of their results and the extrapolation of guidelines. Today, scientifically sound clinical studies should be designed as randomized clinical trials (RCTs) with the inclusion of controls, a duration of at least six months, and in accordance with strictly defined criteria and statistical analysis as described in the Consolidated Standards for Reporting Trials (CONSORT) statement (Altman et al. 2001). Therefore, clinicians are encouraged to thoroughly examine the design of scientific trials on antibiotics before considering their conclusions. The most recent relevant report of the European Federation of Periodontology (Teughels et al. 2020) has addressed the following question: which is the efficacy of adjunctive systemic antimicrobials, in patients with periodontitis, compared to subgingival debridement plus a placebo, regarding probing pocket depth (PPD) reduction in RCTs with at least 6 months duration? In this report, data from 34 articles which strictly fulfilled criteria for inclusion were pooled and analyzed. According to the most recent classification of periodontal diseases (2018), the clinical entities chronic and aggressive periodontitis are no longer valid. However, a number of previous conducted studies are based on the previous classification. Data referring to aggressive periodontitis cases correspond to Stages III/IV and Grade C periodontitis and have been incorporated to the meta-analysis accordingly.

For PPD, statistically significant benefits (p < 0.001) from adjunctive systemic antibiotics were observed in short-term studies (Weighted Mean Differences = 0.448 mm, 95% Confidence Intervals [0.324; 0.573], Prediction Intervals [−0.10 to 0.99]) and long-term studies (WMD = 0.485 mm, 95% CI [0.322; 0.648], PI [−0.11 to 1.08]). Additionally, statistically significant benefits were also found for clinical attachment level, bleeding on probing, pocket closure, and frequency of residual pockets (Teughels et al. 2020).

In specific, the administration of the combination of amoxicillin plus metronidazole as an adjunct to scaling and root planing (SRP) results in statistically significant greater reduction of PPD, reduction in frequency of pockets of > 4, 5, 6, and 7 mm and bleeding on probing, higher percentage of pocket closure and higher CAL gain. The additional PPD reduction and CAL gain elicited by the combination of metronidazole and amoxicillin and to a lesser extent by metronidazole alone and azithromycin are more pronounced in initially deep than in initially moderately deep pockets and these clinical effects are maintained up to 12 months after their administration. Currently, there is no evidence for the benefits of systemic antimicrobials as adjuncts to SRP, above 2 years of follow-up and no indications that these effects are different between the former aggressive and chronic periodontitis. Metronidazole alone and azithromycin result in clinical benefits but of a smaller magnitude compared to the combination of metronidazole and amoxicillin (Teughels et al. 2020).

It should be noted that although statistically significant clinical benefits were observed in patients who received systemic antimicrobials, adverse events were more frequently reported in these groups, with the group administered the combination of metronidazole and amoxicillin exhibiting the largest frequency of side effects.

During the last years, the tetracyclines are no longer popular as adjuncts of periodontal therapy. One of the main reasons is that bactericidal and not bacteriostatic antimicrobials have been proven to be effective against periodontal pathogens, especially in the biofilm structure and density of microbial populations. In addition, the phenomenon of antimicrobial resistance to this class of antimicrobials is widespread due to overuse or misuse not only for medical purposes in humans, but also in veterinary medicine, agriculture, livestock, and fishing farms.

In fact, the global emergence of specific-drug resistant and multidrug-resistant species (among them periodontal pathogens) and the possible contribution of clinical dentistry to this serious health and socioeconomic problem should be taken into consideration before prescribing systemic antimicrobials for periodontal therapy. It has been noted that populations with higher consumption of antimicrobials in Europe exhibit higher percentages of resistant periodontal pathogens or carriage of antimicrobial resistance genes in the oral cavity (Koukos et al. 2016; Van Winkelhoff et al. 2005). The 2020 report of the EFP highlights the issue of contribution to antimicrobial resistance among the possible adverse effects from excessive prescribing of systemic antimicrobials for periodontal therapy, despite favorable clinical outcomes and encourages clinicians for antibiotic stewardship (Teughels et al. 2020).

The results of clinical studies concerning the systematic administration of antimicrobials in combination with periodontal surgery to eliminate the pockets or to achieve periodontal regeneration are contradictory. It is known that antimicrobials can be useful for preventing postsurgical complications. In this case, antibiotic coverage usually targets bacteria that can cause transfections, although for periodontal surgery there are no studies confirming the necessity of antimicrobial administration. It is suggested that sterile conditions and antiseptic mouthwashes can be efficient in preventing complications (Newman and van Winkelhoff 2001).

Findings concerning the clinical benefits of the combined use of antimicrobials with surgical periodontal treatment are controversial. Based on the limited data in the literature, both the Haffajee et al. (2003) and Herrera et al. (2008) reports suggest marginal or insufficient evidence for additional clinical benefits from periodontal surgery when combined with systemic antimicrobials.

The combination of guided tissue regeneration (GTR) with the administration of several antimicrobial regimens also does not appear to uniformly offer stable beneficial clinical outcomes, neither to efficiently prevent bacterial colonization nor to prevent complications (Demolon et al. 1993; Loos et al. 2002; Vest et al. 1999; Zucchelli et al., 1999). The relevant report of the Sixth European Workshop states that there is no sufficient evidence to support the administration of antibiotics during regenerative procedures.

At this point, it should be emphasized, the microflora of patients with deep periodontal pockets, especially after the repeated administration of antimicrobials, can include nonoral Gram-negative species such as enteric rods and Pseudomonas spp., where the administration of other classes of antimicrobials such as the quinolones are indicated (Rams et al. 1992; Slots et al. 1990). In this group of patients the administration of a combination of metronidazole and ciprofloxacin appears to provide additional clinical improvement.

Antimicrobials also have been administrated for acute inflammatory conditions of the periodontal tissues, such as periodontal abscess, necrotizing gingivitis (NG) or periodontitis (NP), and peri-implantitis.

In the previous century, antiseptics were used for the treatment of NG, while in the 1960s it was confirmed that the systematic administration of penicillin or metronidazole could contribute to the management of the acute phase of inflammation, especially when systemic manifestations such as fever, malaise, and lymphadenitis are present (Collins 1970; Fletcher and Plant 1966). Clinical cases without these symptoms can be adequately managed with no antimicrobials (Holmstrup and Westergaard 2003).

The frequent occurrence of NG in patients who are HIV positive raised the question about the necessity of administration of antimicrobials in this patient category. According to the latest findings there is no need for antimicrobial coverage of this group if generalized symptoms are absent. In addition, the possibility of Candida spp. infection as a side effect of systemic antimicrobial administration suggests that antibiotics should be prescribed with caution and after consulting the physician.

There is insufficient or contradictory evidence in the literature to document the necessity of antimicrobial administration for treatment of acute periodontal abscess. Existing studies are usually case reports and there are no comparative studies that demonstrate adjunctive benefits from systemic antimicrobials. Generally, in the case of acute periodontal abscess, antimicrobials are considered necessary when the abscess is very extended, diffused, and accompanied by intense pain and/or coexisting compromising medical conditions and systemic manifestations. The combination of drainage with systemic administration of penicillin, hydrochloric tetracycline, or metronidazole was found efficient for the management of the acute conditions, while the combination of amoxicillin/clavulanic and the newer macrolide azithromycin resulted in recovery from acute symptoms without the simultaneous initial drainage of the abscess (Genco 1991; Herrera et al. 2000a; Palmer 1984; Smith and Davies 1986). In any event, according to good medical practice, the initial drainage or surgical fission of the periodontal abscess is considered the necessary first step for managing its acute phase (AAP 2000; Herrera et al. 2000b).