Periodontal infections and therapeutic implications

Introduction

Periodontal infections are the result of an imbalance between the host's defence system and the oral microflora. Periodontitis occurs in individuals that have the inability to control the subgingival microflora. Bacteria are essential for the disease to develop, they need however a susceptible host to initiate the disease. In gingivitis the inflammation is restricted to the gingiva whereas in periodontitis destruction of connective tissue attachment and alveolar bone is involved.

Gingivitis occurs in virtually all humans and it is a reversible condition, i.e. dental plaque removal results in resolution of the inflammation. In contrast, periodontitis occurs in only a proportion of the population with a prevalence of 30-35 % in most parts of the world. Periodontal infections are mostly chronic but acute infections can occur, especially in individuals with an impaired host resistance.

Mechanisms that convert gingivitis into periodontitis are largely unknown but it has been speculated that the absence of antagonists of the pro-inflammatory cytokines interleukin-1 and tumor necrosis factor alpha may be critical ^{(Assuma et al., 1998} ; ^{Graves et al., 1998)}. Periodontitis has gained special interest from the medical field since this disease has been linked to pre-term delivery and low birth weight infants ^{(Offenbacher et al., 1996)} and coronary heart diseases ^{(Beck et al., 1996)}. These observations may stimulate the periodontal community to put even more emphasis on the research on the pathogenesis and treatment of periodontitis. It may also have a great impact for researchers that are involved in improvement of clinical treatment protocols and on dental professionals who are daily occupied with the treatment of periodontal infections.

Risk factors

Not all individuals are equally susceptible to develop destructive periodontal disease. Several risk factors for the disease to develop have been proposed. These risk factors may not be identical in different clinical forms of periodontitis. ^{Tableau I} summarizes some risk factors that have been documented in the scientific literature. Some of these factors, especially those associated with prepubertal and early onset periodontitis, are directly related to the host immune system and may explain the inability to sufficiently control the subgingival microbial challenge. Other risk factors are involved in a hampered defence against microbial overgrowth of the commensal microbiota, which is observed frequently in chronic adult periodontitis.

Identification of putative risk factors may be essential for a proper diagnosis of the disease and they can identify susceptible individuals. They may also become part of treatment strategies in different patient categories. However, most of these factors cannot be manipulated which implies that the essential part of periodontal treatment remains control of the periodontal microflora. Knowledge of the bacterial component in periodontitis is therefore of importance for effective and predictable treatment outcome. Also, it is worthwhile to make the patient aware of its risk factors to enforce motivation for compliance of the treatment. Smoking and chronic stress are examples of so called co-factors that may be changed by the patient's behaviour.

Microbiology of periodontitis

An impressive and significant increase of our knowledge and understanding of the bacterial component of periodontal infections has been achieved in the past decade. New species have been discovered and described, clinical studies have clearly identified key pathogens that seem responsible for progression of periodontitis and improved treatment protocols, based on microbiological information, have become available ^{(Haffajee and Socransky, 1994)}. Important findings include the following :

- the subgingival plaque in periodontal lesions can differ significantly between lesions in one individual as well as between subjects ;

- pathogens which have been linked with progressive periodontitis have been identified ^{(Haffajee and Socransky, 1994)} (^{table II}) ;

- periodontal pathogens occur in certain clusters ^{(Socransky et al., 1988a} ; ^{Socransky et al., 1988b)} ;

- certain clusters of periodontal bacterial species are associated with active periodontitis breakdown whereas other clusters are more frequently found in individuals with stable periodontal sites ^{(Socransky et al., 1988a)} ;

- clusters are composed of Gram negative and Gram positive bacteria which are predominantly strict anaerobics ;

- Actinobacillus actinomycetemcomitans can occur in all clinical forms of periodontitis but it is found more frequently in young patients with periodontitis ^{(Rodenburg et al., 1990)} ;

- the frequency of detection of Porphyromonas gingivalis increases with age and is rarely isolated in patients under the age of 25 ^{(Rodenburg et al., 1990)} ;

- the distribution of A. actinomycetemcomitans and P. gingivalis in healthy persons is very low, whereas the presence of these species is highly associated with periodontal disease, suggesting that these bacterial species are primary pathogens ^{(Van Winkelhoff et al., 1994} ; ^{Griffen et al., 1998)} ;

- smoking affects the composition of the subgingival plaque in periodontitis patients ^{(Kamma et al., 1999)}.

Microbial risk factors

Researchers at the Forsyth Dental Center have conducted a number of studies in which they have investigated the microbial component as a risk factor for future periodontal attachment loss (for review, see ^{Haffajee and Socransky, 1994}). Subjects were monitored at baseline for probing pocket depth and attachment level at 6 sites per tooth for all teeth, excluding third molars. These clinical data were taken at baseline and 2 months later without any periodontal treatment in between visits,≥ 2 mm of attachment loss was considered as active disease in this study. With this protocol they were able to link the presence and proportions of microbial species with future attachment loss. ^{Table III} shows the relationship between active and inactive periodontal sites and the presence of 3 periodontal bacterial species. Active sites were found more often positive for A. actinomycetemcomitans, P. gingivalis and Streptococcus intermedius than inactive sites. ^{Table IV} summarizes the relative risks for further attachment loss of 3 periodontal bacterial species. The data show that the odds ratios for further attachment loss are related not only to the presence but also to the total mean counts of the pathogens. The calculated relative risks were highest for A. actinomycetemcomitans and P. gingivalis when they exceeded 10⁶ cells.

Although infections with A. actinomycetemcomitans and P. gingivalis are regarded now as true infections, the commensal subgingival microbiota is of significant importance in the interpretation of the disease and the chosen therapy. As mentioned before, there are several risk factors that may influence the composition of the subgingival microflora. However, it is not well understood which host and environmental factors determine the composition of the subgingival microflora and how they are interrelated. Pocket depth, natural acquisition, supragingival plaque level, hormone levels, transmission at adult age are probably some of the factors that are important. For example, it has been found that presence and proportions of periodontal bacteria are different in periodontitis patients that smoke in comparison to non-smoking patients ^{(Kamma et al., 1999)}.

Effects of treatment on the subgingival microflora

One aim of periodontal therapy is to arrest further loss of periodontal attachment and to ensure an aesthetic outcome. Treatment procedures include removal of tooth-borne bacterial plaques and calculus, often in conjunction with periodontal surgery, instruction in oral hygiene procedures and elimination of plaque retention factors. A microbiological approach to periodontal therapy aims primarily at reducing the total bacterial load and at suppressing specific pathogenic bacteria and permitting a subsequent recolonization of a microflora compatible with health. Supragingival plaque control in the supportive periodontal therapy phase helps to prevent recolonization by periodontal pathogens.

Selective elimination

Treatment studies on the effects of mechanical periodontal treatment have revealed that not all bacteria in deepened periodontal pockets are equally susceptible to scaling and root planing. ^Christersson showed, in patients with localized juvenile periodontitis, that scaling alone has very little effect on presence and levels of subgingival A. actinomycetemcomitans. Also, soft tissue curettage and periodontal surgery resulted in high post-treatment detection of this species. They were able to correlate post-treatment detection of A. actinomycetemcomitans with treatment outcome with clinical attachment gain as a variable. Soft tissue invasion of A. actinomycetemcomitans was suggested to be one major factor for the inability to suppress this pathogen in juvenile periodontitis ^{(Christersson et al., 1985)}. ^Renvert studied the clinical and microbiological effects of initial periodontal treatment in adult periodontitis and focused on A. actinomycetemcomitans and P. gingivalis. They found that post-treatment detection of one of these pathogens was related to minimal pocket depth reduction and reduced clinical attachment gain (^{fig. 1}). They also showed that scaling and root planing had very little effect on the subgingival presence of A. actinomycetemcomitans and that the mean proportion of this species increased after treatment, which was in contrast to all other bacteria monitored. They concluded that A. actinomycetemcomitans is much more difficult to eliminate from periodontal pockets than P. gingivalis, showing the phenomenon of selective elimination of bacteria in the subgingival plaque of periodontitis lesions in adult patients.

There is little information in literature on residual periodontal pathogens and the likelihood for recurrent periodontal attachment loss. ^Wennström investigated 44 pocket in 30 refractory cases of adult periodontitis patients on the presence of A. actinomycetemcomitans, Porphyromonas intermedia and P. gingivalis and monitored these sites for 12 months for clinical attachment loss of ≥ 2 mm. They found that in 5 of 25 pockets, harboring 1 or more of the 3 pathogens, a significant loss of clinical attachment had occurred. In contrast, none of the 19 pockets without detectable pathogens showed periodontal attachment loss, showing that suppression of these periodontal bacteria is a rational treatment goal. In a five-year follow up study, ^Dahlén observed recurrence of A. actinomycetemcomitans or P. gingivalis in 9 out of 13 patients and this event was associated with further periodontal attachment loss in 6 of these 9 (67 %) patients. Interestingly, 4 patients without subgingival recurrence of A. actinomycetemcomitans, P. intermedia or P. gingivalis did not show detectable loss of attachment during the 5 years of clinical monitoring. From these studies one can conclude that suppression of certain periodontal bacteria below detection level contributes to the predictability of periodontal treatment outcome and that microbiological monitoring can be one useful end-point of active periodontal treatment.

Adjunctive therapy with local delivered disinfectants to reduce the bacterial plaque mass has been investigated in numerous studies, both in vitro and in clinical studies. ^{Rams and Slots (1996)} have reviewed this topic extensively. Their conclusions are however reserved. The results of most clinical studies dealing with adjunctive local antimicrobial or disinfectant therapy are as effective as conventional mechanical cleansing. There are however very few reports discussing a rationale for using adjunctive local antimicrobial therapy in relation to the patient's subgingival microbiota. Nevertheless, the use of chlorhexidine as an adjunctive to conventional periodontal therapy may be considered ^{(Addy et al., 1994} ; ^{Addy and Moran, 1997)}. But, as concluded by ^{Rams and Slots (1996)}, controlled clinical studies are warranted to determine the efficacy and safety of such adjunctive therapy in periodontal disease. The role of uncontrolled shifts in the subgingival microbiota should, however, not be underestimated.

Systemic antimicrobial therapy in periodontics

Adult periodontitis patients with ongoing disease activity despite thorough supra- and subgingival debridement may be prime candidates for adjunctive antimicrobial therapy. These patients are often referred to as refractory periodontitis subjects. Also, patients with some form of early onset periodontitis may need additional antimicrobial therapy for a predictable and long-term stable treatment outcome. One prerequisite for an effective periodontal antimicrobial therapy is a thorough knowledge of the periodontal microflora. Periodontal pathogens predominantly belong to the group of Gram negative anaerobic rods, but also Gram positive anaerobic rods and cocci have been implicated. Some Gram negative facultative anaerobic rods are considered pathogens as well (^{table II}).

The concept of antibiotic periodontal therapy revolves around the drug, the pathogenic microorganisms, and the host. Systemic periodontal antimicrobial therapy is based on the premise that specific microorganisms cause destructive periodontal disease ^{(Van Winkelhoff et al., 1994)} and that the antimicrobial agent in the periodontal pocket can exceed concentrations necessary to kill the pathogen(s). Compared to mechanical debridement and topical application of antiseptics, systemic antibiotic therapy has certain advantages. Via serum, systemic antibiotics can reach microorganisms at the base of deep periodontal pockets and furcation areas, and also may affect organisms residing within gingival epithelial and connective tissues. Systemic antibiotics may be capable of eradicating periodontal pathogens colonizing oral mucosa and other extra-dental sites. The possibility of eradicating periodontal pathogens from the entire mouth may reduce the risk for subgingival recolonization of pathogens and for future disease activity. It may also prevent transmission of periodontal pathogens to other humans.

Disadvantages of systemic antibiotic therapy over locally applied antibiotics include adverse drug reactions ^{(Winkel et al., 1998)}, interactions with other drugs and uncertain patient compliance ^{(Van Winkelhoff et al., 1996)}.

Clinical studies using single antibiotic regimes

The number of antibiotics tested for clinical efficacy in periodontics is still rather limited. The most frequently examined drugs involve tetracyclines, metronidazole, amoxicillin, amoxicillin plus clavulanic acid, clindamycin and, later discussed, combinations of antibiotics notably metronidazole and amoxicillin and metronidazole and spiramycin. For a comprehensive review on the clinical and microbiological effects of these drugs, see Van ^Winkelhoff . Some recently published studies on the efficacy of systemic antibiotic therapy will be discussed.

Metronidazole

Systemic metronidazole therapy can augment the clinical effect of mechanical periodontal treatment in some periodontitis patients. Metronidazole therapy without concomitant scaling and root planing provides very short-lived (up to 1 month) clinical and microbiological benefits ^{(Walsh et al., 1986)}. In a placebo-controlled study, ^Lindhe observed that metronidazole (200 mg QID for 14 days, repeated 2 ¥ after 2 months intervals) in conjunction with scaling and root planing yielded a slight improvement in gingival status and clinical attachment compared to controls. Deep pockets (7 mm) responded equally well in the test and control group, whereas pockets of 5-6 mm depth responded better in the metronidazole group. Other researchers have demonstrated adjunctive metronidazole therapy to be more effective in adults with deep pockets than with less advanced periodontitis ^{(Loesche et al., 1984} ; ^{Söder et al., 1990)}. In conjunction with periodontal surgery, systemic metronidazole has not shown additional clinical effects ^{(Sterry et al., 1985)}.

^Loesche suggested that systemic metronidazole plus mechanical debridement may decrease the number of teeth in need of periodontal surgery or indicated for extraction due to periodontitis. The clinical effect paralleled a slight, but statistically significant decrease of subgingival spirochetes. Later ^Loesche and ¹⁹⁹⁴) administered metronidazole or placebo after completion of the mechanical treatment and used 20 % subgingival spirochetes in at least 2 subgingival samples to trigger treatment. Again, at 4-6 weeks post-treatment, significant fewer teeth in the metronidazole group needed periodontal surgery.

^Gusberti observed statistically significant improvement in mean pocket depth, attachment level and percentage of bleeding sites for up to 9 months after a combined therapy of mechanical debridement and systemic metronidazole (250 mg TID, 10 days). Using ornidazole, ^Mombelli observed essentially the same effects in patients with recurrent periodontal disease.

Recently, ^Winkel tested a regime of 500 mg metronidazole TID for 7 days in patients with refractory adult periodontitis. Patients were selected on the basis of subgingival presence of Bacteroides forsythus with or without P. gingivalis and P. intermedia, and absence of A. actinomycetemcomitans. They found that the reduction in probing pocket depth and the gain of clinical attachment after renewed debridement in conjunction with systemic metronidazole therapy was related to post-treatment detection of the target organisms, notably P. gingivalis and B. forsythus (^{fig. 2}).

In conclusion, systemic metronidazole therapy may results in a marked reduction of anaerobics in the periodontal pocket. However, subgingival anaerobic bacteria tend to reappear after metronidazole therapy ^{(Loesche et al., 1992} ; ^{Loesche and Giordano, 1994)}. The reason may be an incomplete removal of pathogens at the treated sites or a rapid recolonization of treated sites from other oral sites. Successful metronidazole therapy is also related to proper supragingival plaque control ^{(Winkel et al., 1997)}. One other determining factor for incomplete removal of periodontal pathogens may be tobacco use ^{(Grossi et al., 1996)}.

Amoxicillin

The use of amoxicillin or amoxicillin plus clavulanic acid (to protect the drug from bacterial degradation) in the treatment of periodontitis has been described in several studies ^{(Abu-Fanas et al., 1991} ; ^{Magnusson et al., 1989} ; ^{Magnusson et al., 1994)}. Although a large proportion of the subgingival microflora is susceptible to amoxicillin in vitro, the clinical effects of this antibiotic are limited and recurrence of disease activity has been reported. ^Winkel found that reduction of mean probing pocket depths and mean change in clinical attachment were similar in test and placebo groups 3 months after active periodontal treatment including systemic amoxicilline and clavulanic acid (500/125 mg TID, 7 days). Darkfield microscopy revealed no differences in the proportions of spirochetes and motile rods in test and placebo groups. Also, no significant differences were observed in the post-treatment detection of A. actinomycetemcomitans, P. gingivalis, B. forsythus and other periodontal pathogens. The authors concluded that systemic amoxicillin plus clavulanic acid provided no additional clinical and microbiological effects in the treatment of adult periodontitis in patients with undetermined disease activity.

Combination antimicrobial therapy

Since the subgingival microbiota in destructive periodontal disease consists of various putative pathogens that may differ in antimicrobial susceptibility, the use of a combination of two or more antibiotics may represent a valuable approach in periodontal chemotherapy. Combination antibiotic therapy may help :

- to broaden the antimicrobial range of the therapeutic regimen beyond that attained by any single antibiotic ;

- to prevent the emergence of bacterial resistance by using agents with overlapping antimicrobial spectra ;

- to lower the dose of individual antibiotics by exploiting possible synergy between two drugs against targeted organisms.

Metronidazole plus amoxicillin or ciprofloxacin have been used successfully in the treatment of advanced A. actinomycetemcomitans-associated periodontitis ^{(Van Winkelhoff et al., 1996)}. Metronidazole and amoxicillin in vitro exert synergistic activity against A. actinomycetemcomitans ^{(Pavicic et al., 1991)} and these antibiotics markedly suppress or eliminate A. actinomycetemcomitans and other subgingival organisms in periodontitis lesions.

Recently, ^Berglundh investigated the clinical and microbiological effects of metronidazole and amoxicillin in adult patients with periodontitis. They used a split-mouth design in a placebo-controlled study protocol with a follow-up period of 24 months. Clinical and microbiological features improved better at sites that were scaled and root planed in patients that had received systemic metronidazole and amoxicillin than sites that had received only mechanical treatment in the placebo group. Especially the proportion of sites gaining ≥ 2 mm of clinical attachment was significantly higher in the antibiotic patients. This was most obvious in sites with an initial probing pocket depth ≥ 6 mm (^{fig. 3}). Only in the patients that had received metronidazole and amoxicillin A. actinomycetemcomitans and P. gingivalis were under the level of detection after 12 months. These observations confirm and complete earlier observations ^{(Van Winkelhoff et al., 1989} ; ^{Van Winkelhoff et al., 1992} ; ^{Goené et al., 1990} ; ^{Pavicic et al., 1994} ; ^{Winkel et al., 1998)}.

Metronidazole/ciprofloxacin can be useful with mixed periodontal infections involving anaerobic bacteria, A. actinomycetemcomitans, enteric rods and Pseudomonas ^{(Slots and Van Winkelhoff, 1993)}. Since metronidazole/ciprofloxacin does not affect most Gram positive facultative bacteria, this combination of antimicrobials may facilitate recolonization of the pocket by health-associated facultative streptococci of low periodontopathic potential.

The combination of metronidazole plus spiramycin is frequently used in some European countries. The long-term clinical and microbiological effects of this therapy have not been documented satisfactory and this drug combination needs more investigation.

Treatment protocol

Antibiotics should be considered one of the possible tools available in periodontal therapy. Use of systemic antimicrobial agents in periodontics without proper diagnosis and mechanical debridement should be regarded as improper. Also, overuse of antibiotics leads to development of microbial resistance not only in the periodontal pockets and other body sites ^{(Van Winkelhoff et al., 2000)}.

Many adult periodontitis lesions are associated with indigenous microorganisms. The general strategy for controlling this type of periodontal infection relies on reduction of the supra- and subgingival microbial load. Many adult periodontitis patients can be treated effectively by conventional non-surgical or surgical debridement and adequate oral hygiene measures in the maintenance phase. Patients with high levels of exogenous periodontal pathogens often are recalcitrant to conventional periodontal treatment and are candidates for adjunctive antibiotic therapy. For exogenous periodontal infections a realistic treatment goal is the complete removal of the pathogen(s) ^{(Van Winkelhoff et al., 1996)}.

Microbiological testing is a useful tool to select patients that may benefit from an adjunctive antibiotic therapy. Administration of systemic antibiotics without microbiological diagnosis may provide a suboptimal therapy with a poor predictability. Subjects that are eligible for microbiological testing include :

- patient with a poor therapy response after conventional periodontal treatment despite good oral hygiene measure ;

- patients with recurrence of disease activity in the maintenance phase ;

- patients with an early onset form of periodontitis ;

- family members in families with early onset forms of periodontitis ;

- partially edentulous patients scheduled for dental implants.

A clinical healthy outcome is the ultimate goal of periodontal therapy. One end-point of active periodontal therapy is absence of certain putative exogenous bacteria, i.e. A. actinomycetemcomitans and P. gingivalis, and levels of commensal periodontopathic bacteria should be under certain threshold values ^{(Rams et al., 1996)}.

CONCLUDING REMARKS

This article discusses the current insights in the microbiological part of periodontal disease management and the impact of the subgingival microbiota in the individual patient. In summary, five concluding statements can be propound :

- periodontitis is an infection in which more than one bacterial species is involved ;

- host factors and/or environmental risk factors play a crucial role in the onset and development of periodontitis ;

- treatment of periodontitis is primarily based on reduction of the subgingival bacterial load. This should be combined with elimination or control of alterable riskfactors ;

- elimination of A. actinomycetemcomitans and P. gingivalis often needs adjunctive antibiotic therapy. Appropriate antibiotic therapy is based on testing of the composition of the microbial flora and the differentiated counts of the microflora ;

- one end-point of active therapy is determined by the composition of the subgingival microbiota which should be dominated by facultative Gram positive cocci and rods. This will result in stabilization of the disease and a renewed balance between host and microflora ^{(Rams et al., 1996)}.

Demande de tirés à part

A.J. VAN WINKELHOLF, Department of Oral Biology, Section Clinical Oral Microbilogy, Academic Centre for Dentistry Amsterdam, Van der Boechorststraat 7, 1081 B1 AMSTERDAM - THE NETHERLANDS.

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