Chapter 6

Systemic and Local Drug Delivery of Antimicrobials

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 above-mentioned 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, several compounds are available for clinicians and a number of 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

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? 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), 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.

As mentioned above, although numerous studies have tested the role of systematic administration of antimicrobials in patients with chronic, aggressive, and refractory periodontitis, several discrepancies among them preclude the comparison and classification of their results and the extrapolation of guidelines. Although as many as 1,300 reports in the literature refer to systemic antibiotics in periodontology, fewer than 30 fulfilled the scientifically sound criteria set by Herrera et al. (2002) for the Fourth European Workshop and Haffajee et al. (2003) for the World Workshop to be included in meta-analysis.

For further comprehensive presentation and comparison of the various studies, the reader is referred to the above mentioned two recent reports, to excellent relevant reviews (Slots and Rams, 1990; van Winkelhoff et al., 1996, Slots and Ting, 2002; Slots 2002a,b, 2004), the previous reports of the American Academy of Periodontology (1996), and previous Workshops of the European Federation of Periodontology (van Winkelhoff et al., 1993).

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.

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 ’90s, both in the U.S. and Scandinavia, it has been shown that in LJP patients, systemic administration of antibiotics (the tetracyclines and metronidazole) can improve clinical parameters and decrease the pathogenic subgingival microflora, especially Aggregatibacter (Actinobacillus) actinomycetemcomitans (Slots and Rosling, 1983; Saxen et al., 1990; Saxen and Asikainen, 1993). 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.

For chronic periodontitis patients, who make up the majority in clinical practice, practitioners should currently comply with the most recent reports and meta-analyses, which generally and under confinements suggest benefits from the systematic administration of antimicrobials in chronic periodontitis, using as clinical evaluation the index probing attachment level (PAL). The Herrera et al. (2002) and Haffajee et al. (2003) reports concluded that the administration of antibiotics improves the mean attachment level in patients with chronic periodontitis when used as adjuncts to scaling and root planing. In both reports, at that time, it was stated that existing data precluded their ability to configure guidelines for clinicians concerning the most efficient antibiotic regimen and the appropriate time for administration (before, during, or after the initial treatment phase).

Current data concerning the impact of the quality of debridement and the sequence of antibiotic usage on clinical parameters were also analyzed in the recent report of the Sixth European Workshop on Periodontology (Herrera et al., 2008). After combining evidence in the literature, the authors suggest that if antibiotics are to be used as adjuncts, there is indirect evidence that they should be administered on the day of completion of debridement, which preferably should be performed in a short time and be of adequate quality to optimize clinical benefits for patients. Therefore, according to existing evidence, when treating chronic periodontitis patients, a meticulous debridement by a highly skilled operator should be performed in less than a week, preferably, and antibiotics—if administered—should be prescribed immediately afterward. Both strategies aim at avoiding the reorganization of the disrupted biofilm and achieving a shift in the sub-gingival microflora compatible with periodontal health. The results of this combined treatment include a reduction of prevalence, levels, and proportions of pathogenic species such as Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola; members of the “red complex” and gram-negative anaerobic species; and members of the “orange complex” described by Socransky et al. (1998), as well as an increase of Streptococcus and Actinomyces spp.

The report by Haffajee et al. (2006) describes the effect of various periodontal therapies (including antibiotic use) on the subgingival microflora. Data from more than 400 periodontal patients who participated in longitudinal studies conducted over a decade by the Department of Periodontology at the Forsyth Institute were combined to evaluate clinical and microbiological effects of therapies adjunctive to scaling and root planing for up to 24 months. The analysis of more than 10,000 subgingival samples for 40 bacterial species by “ checkerboard “ DNA-DNA hybridization developed by Socransky and coworkers (1994) in the same department provides very significant insight into the changes of the sub-gingival habitat induced by various treatments, including periodontal surgery and antibiotic administration. Data from this important report have shown, among others, that the addition of various systemic antibiotics enhanced clinical and microbiological effects of mechanical treatment for up to 24 months. These benefits have been attributed by the authors to several factors, including the reduction of the total bacterial load in the oral cavity and thus the possibility of reinfection, as well as the reduction of specific periodontal pathogens in the pocket environment. Although the main microbiological outcome in this report appears to be the reduction of levels, proportions, and percentages of sites colonized by important periodontal pathogens, they are seldom eliminated and can regrow over time, especially without maintenance care.

After reviewing the literature, the evidence referring to antibiotic effects on patients diagnosed with early-onset or rapidly progressive periodontitis (earlier studies) or aggressive periodontitis (newer studies) is more solid. These patients generally seem to gain further clinical and/or microbiological benefits by the systematic administration of several antimicrobials (metronidazole, tetracyclines, clindamycin, a combination of metronidazole and amoxicillin). These conclusions have been shown in both the Herrera et al. (2002) and the Haffajee et al. (2003) reports after meta-analysis of well-designed studies and in newer RCTs (Guerrero et al., 2005; Xajigeorgiou et al., 2006).

Combining the above findings, it appears that in patients with a diagnosis of aggressive periodontitis, where the genetic background and immunity factors predispose for severe periodontal destruction, optimum control of the bacterial load and periodontal pathogens is extremely important, and from this point of view administration of antimicrobials is indicated for patients in this category.

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 post-surgical 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; Konstantinidis, 2007).

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 peri/>

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