Local delivery of antimicrobials: evidence of efficiency in the treatment of gingivitis and periodontitis

Introduction

Both gingivitis and periodontitis are the results of the interactions between a pathogenic microflora which accumulates on the tooth surface at the gingival margin and in the periodontal pocket, and the host immunological defense mechanisms ^{(Löe et al., 1965} ; ^{Lindhe et al., 1973} ; ^{Lindhe et al., 1975} ; ^{Socransky and Haffajee, 1992} ; ^{Haffajee and Socransky, 1994)}. Bacteria are essential for the disease to be initiated and for its progression to occur. To a certain extent gingivitis can be considered as the result of the defense mechanisms protecting the host tissues against the bacterial actions and their metabolites. During the transformation of gingivitis into a periodontitis lesion and during the further progression of the periodontal defect, the mere presence of bacteria alone is not sufficient, since the destruction of the periodontal tissues is the result of multiple interactions between a complex microbial population in the subgingival pocket and the specific host defense mechanisms.

As a result of this knowledge, therapy of both gingivitis and periodontitis has mainly been based upon the mechanical debridement of the supra- and subgingivally located root surfaces in order to disrupt and remove the bacterial biofilm. Simultaneously, scaling and root planing and polishing of the supragingival tooth surfaces aimed at obtaining a clean, smooth and biologically compatible tooth surface ^{(Ramfjord, 1977)}. In the treatment of residual deep pockets, surgery aiming at the elimination of these niches favoring the development of an anaerobic flora has been used successfully. Recently, with the advent of regenerative periodontal procedures some of the negative features, accompanying the resective techniques, i.e. gingival recession causing tooth sensitivity and esthetic concerns, have been overcome to some extent. For the maintenance of clinically healthy periodontal conditions daily personal plaque removal is required in order to avoid the bacterial recolonization of the non-shedding tooth surfaces ^{(Löe et al., 1965}, ^{Axelsson and Lindhe, 1978)}.

The use of antimicrobial substances aiming at interfering with new plaque formation or at disrupting existing dental plaque has been one of the goals since the causative nature of the dental plaque in periodontal diseases has been established. During the past decades, the increasingly better understanding of the bacterial interactions within the dental plaque mass and their interactions with the host periodontal tissues has led to a gradual shift from a mainly non-specific approach towards more specifically targeted therapeutic approaches and substances directed at the specific pathogenic bacteria in the complex bacterial biofilm. In this perspective, the basic goals of mechanical plaque removal have been broadened in that sense that one of its most important effects might be the disruption of the bacterial biofilm, thereby making the pathogenic bacteria in it accessible for the antimicrobial agents.

In the prevention of supragingival plaque formation the use of antimicrobial agents incorporated in mouthrinses or toothpastes has demonstrated a variable degree of success. The most important problem encountered in the development of such agents is their relatively rapid clearance from the oral cavity, thereby limiting their efficacy. Products that possess substantivity, i.e. that bind to surfaces in the oral cavity and are subsequently released, have been more efficient in the reduction of plaque formation when used in conjunction with mechanical plaque control or as a replacement of mechanical plaque control measures (e.g. after surgery). Chlorhexidine digluconate is an antimicrobial agent with substantive characteristics ^{(Hugo and Longworth, 1964} ; ^{Russell, 1969} ; ^{Löe and Schiott, 1970} ; ^{Schiott et al., 1970} ; ^{Gjermo et al., 1974} ; ^{Bonesvoll, 1978)}. Some agents without inherent substantivity have been combined with molecules that result in the combination of these molecules becoming substantive. Such an example is the combination of triclosan and a polyvinylmethyl ether maleic acid copolymer, which results in an increased retention by teeth and high levels in dental plaque and saliva ^{(Nabi et al., 1989} ; ^{Afflitto et al., 1989} ; ^{Addy et al., 1989)}. Triclosan is a molecule with antimicrobial and anti-inflammatory effects that has been successfully incorporated in mouthrinse and toothpaste formulations. The effects of antimicrobial agents incorporated in mouthrinses ^{(Rölla et al., 1997} ; ^{Addy and Renton-Harper, 1997)} and in toothpastes ^{(Adriaens and Gjermo, 1997)} are mainly limited to the supragingival environment. These formulations have demonstrated variable effects on plaque formation and on the development of gingival inflammation.

The aim of the present review is to focus on compounds that have been developed and tested during the past decades and that specifically address the problem of bringing antimicrobial agents into the subgingival pocket in an attempt to reduce the deleterious effects of the interactions between the host and parasites.

Problems encountered in subgingival drug delivery

The most important pharmacological criteria that have to be met by a pharmacological agent in order to be effective in vivo when used in a local delivery protocol are : possess proven in vitro efficacy against the target microorganisms, reach the site of action where the targeted microflora causes the pathology, be maintained at an adequate concentration and remain during a sufficient time period for the pharmacological effects to occur ^{(Goodson, 1989)}.

Choice of the antimicrobial agent

Based on the increased knowledge on the composition of the subgingival microflora and its composition in different clinical disease entities, Gram-negative anaerobic bacteria have been identified as the most important pathogenic bacteria. Anaerobic microorganisms significantly associated with adult periodontitis, early onset periodontitis and refractory periodontitis include Porphyromonas gingivalis, Bacteroides forsythus, Prevotella intermedia, Fusobacterium nucleatum and Treponema denticola ^{(Loesche et al., 1985} ; ^{Christersson et al., 1992} ; ^{Loesche et al., 1992b} ; ^{Listgarten et al., 1993} ; ^{Moore and Moore, 1994} ; ^{Grossi et al., 1995} ; ^{Ashimoto et al., 1996} ; ^{Umeda et al., 1996} ; ^{Socransky et al., 1998)}. Some other anaerobic species have been found to be present in elevated proportions, e.g. Eubacterium species, Peptostreptococcus micros. These studies indicate that these species are the most frequently associated with the occurrence of periodontal disease. Moreover, successful therapy results in a significant decrease of the proportions of these microorganisms in the microflora of these sites and mouths. These changes are accompanied with a reduction of the total bacterial mass and a concomitant increase of the facultative anaerobic Gram-positive bacterial component of the bacterial biofilm.

In a smaller proportion of diseased sites in adult periodontitis, in early onset periodontitis and in refractory periodontitis patients, some studies demonstrated the presence of micro-aerophilic bacteria possessing virulence factors that would enable them to play some role in the periodontal pathogenesis. These species include Actinobacillus actinomycetemcomitans ^{(Slots, 1982} ; ^{Mandell et al., 1987} ; ^{Tanner et al., 1979} ; ^{Dzink et al., 1988} ; ^{Slots et al., 1990} ; ^{Haffajee and Socransky, 1994} ; ^{Lowenguth et al., 1995)}, Wolinella (Campylobacter) recta ^{(Papapanou et al., 1997)} and Eikenella corrodens ^{(Papapanou et al., 1997)}. Compared to the anaerobic strains, these microaerophilic bacteria were always present in a minority of the sites and in smaller proportions ^{(Loesche et al., 1992b} ; ^{Listgarten et al., 1993} ; ^{Kamma et al., 1994} ; ^{Lowenguth et al., 1995} ; ^{Ashimoto et al., 1996} ; ^{Umeda et al., 1996)}.

Anaerobic bacteria are sensitive to several systemically administered antibiotics, of which doxycycline ^{(McCulloch et al., 1990} ; ^{Asikainen et al., 1990} ; ^{Loesche et al., 1996)}, tetracycline ^{(Palmer et al., 1996)}, penicillin and penicillin analogues ^{(Walker et al., 1993)}, clindamycin (^{Gordon et al., 1990}) and metronidazole ^{(Lindhe et al., 1983} ; Loesche et al. ; ^{Loesche et al., 1985} ; ^{Loesche et al., 1991} ; ^{Loesche et al., 1992a} ; ^{Loesche et al., 1996}) and its analogues ^{(Mombelli et al., 1989)} have been documented to have a beneficial effect on the clinical outcome of mechanical subgingival debridement of the periodontal lesions.

Site of action to be reached by the antimicrobial agent

Multiple studies on the pathogenesis of different forms of periodontal disease have led to a better understanding of the site where the antimicrobial agent should exert its action. The majority of the bacteria involved in the periodontal destruction are present in the periodontal pocket, with the most pathological organisms mainly being located in the apical part of this site ^{(Newman and Socransky, 1977)}. Moreover, bacteria invading the soft and hard tissue walls of the periodontal pocket may be involved. These include the bacteria invading the junctional epithelium and the deeper infiltrated portions of the soft tissue wall of the pocket ^{(Frank and Vogel, 1978} ; ^{Saglie et al., 1982} ; ^{Saglie, 1991)} and the exposed cementum and radicular dentin (^{fig. 1a} and ^1b) ^{(Adriaens, 1988} ; ^{Adriaens et al., 1988a} ; ^{Adriaens et al., 1988b)}.

The active agents present in mouthrinses or in supragingival irrigation solutions are unable to reach the site of action, i.e. the deepest part of the subgingival domain, once the depth of the pocket is 5 mm or more. Therefore, this approach in the application of antimicrobials has been ineffective in the treatment of periodontitis ^{(Pitcher et al., 1980} ; ^{MacAlpine et al., 1985} ; ^{Braatz et al., 1985} ; ^{Wennström and Lindhe, 1986} ; ^{Eakle et al., 1986)}. In contrast, antimicrobials can successfully be delivered to the deepest part of the subgingival pocket by the use of irrigating devices being placed intracrevicularly ^{(Pitcher et al., 1980)}. However, gaining access to the anatomical boundaries of the periodontal pocket does not necessarily mean that the active antimicrobial agent also effectively reaches the target bacteria ^{(Tonetti, 1998)}. Indeed, recent insights in the complex interactions between antimicrobials and bacteria organized in a biofilm, such as dental plaque, have drawn attention to diffusion barriers within the microbial biofilms. Moreover, interactions between biofilm polysaccharides and the antimicrobial agent may inactivate the antimicrobial agent before the target bacteria in the biofilm have been reached. In studies aiming at pharmacological therapy of periodontal infections it is not until recently that attention has been given to the specific problems caused by the biofilm environment ^{(Gilbert et al., 1997} ; ^{Marsh and Bradshaw, 1997} ; ^{Bradshaw et al., 1998} ; ^{Kleinfelder et al., 1999} ; ^{Costerton et al., 1999)}.

Delivery of the antimicrobial agent at an appropriate concentration

Each drug placed in the subgingival environment is confronted with two problems representing major obstacles in the attempt to reach and maintain an effective concentration at the site of action. Firstly, the space into which the drug can be delivered, is limited. It has been estimated that the volume of a 5 mm deep pocket around a single-rooted tooth is approximately 0.5 µL ^{(Binder et al., 1987} ; ^{Goodson, 1989} ; ^{Tonetti et al., 1990)}. Secondly, the subgingival pocket is filled with the crevicular fluid which is leaving the inflammatory infiltrated component of the pocket wall and undergoes a continuous outward flow, thus clearing continuously the content of the periodontal pocket. The flow rate of the crevicular fluid was estimated to be 20 µL/hour ^{(Binder et al., 1987)} which means that the content of the subgingival pocket with a probing depth of 5 mm around a single-rooted tooth is replaced approximately 40 times per hour ^{(Goodson, 1989} ; ^{Tonetti et al., 1990)}. From these data it has been calculated that the intracrevicular concentration of a subgingivally placed antimicrobial substance decays according to an exponential equation. The half-life of elimination of such a substance was calculated to be approximately 1 minute ^{(Goodson, 1989)}. Therefore, it is apparent that for the localized delivery of antimicrobial agents in the subgingival pocket, both the physical limitations of the subgingival space combined with the high clearance rate are the main obstacles in the quest of reaching and maintaining efficacious concentrations at the site of action.

An estimation of the appropriate in vivo concentrations needed for growth inhibition (MIC : minimum inhibitory concentration) or for bacterial killing (MBC : minimum bactericidal concentration) can be made from in vitro testing of periodontal pathogens against various concentrations of interesting antibacterial compounds. For most periodontopathogens the in vitro concentrations needed for 98 % or more growth inhibition was around 5 μg/mL for penicillin G, tetracycline hydrochloride, clindamycine and minocycline, and around 25 μg/mL for chlorhexidine digluconate ^{(Baker et al., 1985} ; ^{Walker et al., 1985} ; ^{Nakashima et al., 1987} ; ^{Pajukanta et al., 1993)}. However, for some of these pathogenic bacteria the in vitro MIC values were up to ten times higher ^{(Baker et al., 1985} ; ^{Walker et al., 1985)}.

In vitro determination of the MIC and MBC values is performed with cultures growing under planktonic conditions, i.e. bacteria are in suspension in a liquid growth media containing the antimicrobial compound in varying concentrations. In contrast, subgingival bacteria are mostly organized as a bacterial biofilm. Recent research on biofilm bacteria has established that antimicrobial action on biofilm bacteria requires concentrations of the antimicrobial compound that are several orders of magnitude greater than the concentrations required for the same bacteria growing under planktonic conditions ^{(Anwar et al., 1992} ; ^{Cargill et al., 1992} ; ^{Brown and Gilbert, 1993} ; ^{Vorachit et al., 1993)}. Therefore, caution is needed with the use of the available data on MIC and MBC values for periodontopathogenic bacteria, since these data are derived from in vitro testing under planktonic conditions. These values may almost certainly be serious underestimations of the concentrations required to reach in vivo bacterial growth inhibition or bacterial killing.

Maintenance of the appropriate concentration during a sufficient period of time

It is not sufficient that the site of action is reached by an effective concentration of the antimicrobial agent : the concentration at that site must be maintained during a sufficient period of time in order for the pharmacological effects to occur. The time required for the pharmacological effect to be reached is dependent on the mechanism by which the active agent inhibits or kills the bacteria. Agents such as tetracycline and its derivatives that have a bacteriostatic action by an inhibitory effect on the bacterial protein synthesis, require a prolonged exposure time to an efficacious concentration of the antimicrobial agent. On the other hand, for bactericidal agents such as chlorhexidine and metronidazole the full antibacterial effect is already reached after a shorter exposure time.

Drugs can be delivered in the subgingival pocket by several techniques. Subgingival irrigation with the antimicrobial drug is easy to perform. Using a syringe an appropriate solution of the antimicrobial is introduced in the periodontal pocket. Taking into account the small volume and the high clearance rate of the periodontal pocket, the half-life of elimination of this substance was calculated to be approximately 1 minute ^{(Goodson, 1989)}. Therefore, only antimicrobial agents that have substantivity, i.e. having the capacity to bind to the structures in the periodontal pocket and to be released in their active form, may have a chance to persist for a sufficient period of time in order to have some effects on the subgingival plaque. Such substantivity is found for tetracyclines and its derivatives ^{(Baker et al., 1983} ; ^{Björvatn et al., 1984}, ¹⁹⁸⁵ ; ^{Demirel et al., 1991} ; ^{Stabholz et al., 1993a} ; ^{Stabholz et al., 1993b)}. Although chlorhexidine demonstrates documented substantivity in the supragingival environment ^{(Hugo and Longworth, 1964} ; ^{Russell, 1969} ; ^{Löe and Schiott, 1970} ; ^{Schiott et al., 1970} ; ^{Gjermo et al., 1974} ; ^{Bonesvoll, 1978)}, in vitro studies have questioned this characteristic in the subgingival environment ^{(Stabholz et al., 1993a} ; ^{Stabholz et al., 1993b)}. For tetracycline it was determined that a 5 minute subgingival irrigation with a 1 % solution of tetracycline hydrochloride resulted in the antimicrobial activity being maintained for approximately 1 day ^{(Tonetti et al., 1990)}, which is significantly longer than the 15 minutes activity after the subgingival irrigation with a non-binding antimicrobial drug ^{(Goodson, 1989)}. However, from the limited number of studies testing the adjunctive effects of subgingival irrigation with antimicrobials it is apparent that the intracrevicular concentration is maintained for too short a period of time to influence the clinical efficacy of the subgingival instrumentation ^{(MacAlpine et al., 1985} ; ^{Greenstein, 1987} ; ^{Silverstein et al., 1988} ; ^{Nylund and Egelberg, 1990} ; ^{Christersson et al., 1993)}.

In order to overcome the problems encountered with subgingival irrigation, antimicrobial compounds have been incorporated in local delivery devices. The function of local delivery devices is to establish and maintain a drug reservoir in the subgingival area for a prolonged period of time. The rate-limiting element incorporated in the local delivery device controls the rate of drug release in the subgingival environment. The combination of the drug reservoir and the rate-limiting element in a local delivery devices results in an intracrevicular concentration of the antimicrobial agent being maintained for a prolonged period of time, since it allows for the replacement of the antimicrobial agent being constantly washed out by the crevicular fluid flow. According to their design and release characteristics two main categories of local delivery devices exist. Sustained delivery devices are designed to provide drug delivery in effective concentrations for periods up to 24 hours, whereas controlled delivery systems should release the drug in effective concentrations for a period exceeding 1 day ^{(Langer and Peppas, 1981} ; ^{Langer, 1990)}.

Antimicrobials incorporated in local delivery devices for subgingival placement

Several antimicrobials with proven efficacy against periodontopathic bacteria have been incorporated into local delivery devices, including antibiotics such as tetracycline hydrochloride, minocycline hydrochloride, doxycycline hyclate, metronidazole, as well as antiseptics, of which chlorhexidine gluconate is currently the sole example. In the following section an overview will be given of the composition of these local delivery devices, their pharmacologic characteristics and the clinical results of their use in clinical trials.

Tetracycline hydrochloride

In the tetracycline fiber (Actisite^®, Alza Corporation, Palo Alto, CA) 25 % w/w tetracycline hydrochloride is incorporated in a non-resorbable, monolithic, cylindrical ethylene vinyl-acetate fiber. The fiber has a diameter of 0.5 mm ^{(Goodson et al., 1983)}. The fiber displays a steady state in vitro release rate of 2 mg of tetracycline hydrochloride per cm and per hour ^{(Tonetti et al., 1990)}. Following the application of tetracycline fibers, the tetracycline concentrations in the gingival crevicular fluid is above 1300 µg/mL and is maintained at this high level for the entire 10-day period during which the tetracycline fiber is to remain in situ ^{(Tonetti et al., 1990)}. This constant high tetracycline concentration in the gingival crevicular fluid is indicative of a zero-order delivery profile ^{(Tonetti et al., 1990)}. During a period of 9 days, even though a high tetracycline concentration is maintained in the gingival crevicular fluid, only 31 ± 9 % of the total tetracycline present in the fiber is released ^{(Litch et al., 1996)}. None of the fibers retrieved from the 13 patients in which 29 teeth were treated with subgingivally placed tetracycline fibers remaining in situ for 9 days, had less than 50 % of the total tetracycline content remaining in the fiber at removal.

The high intracrevicular tetracycline concentration also results in penetration of the tetracycline hydrochloride in the surrounding tissue compartments. In tissue biopsies obtained during modified Widman flap surgery, an average tetracycline concentration of 43 μg/mL was found in the soft tissue of the pocket wall ^{(Ciancio et al., 1992)}. Since these data were derived from whole tissue biopsies, it is likely that the local concentrations in the pocket wall would be higher in the superficial parts than in the deeper tissue compartments. In the superficial 10 mm of the mineralized structures of the roots adjacent to the tetracycline fibers tetracycline was detectable by means of ultraviolet fluorescence microscopy ^{(Morrison et al., 1992)}. Although the soft tissue of the pocket wall was exposed to high intracrevicular tetracycline concentrations and physical irritation by the placement and presence of the tetracycline fiber in the subgingival area, no soft tissue toxicity reactions could be observed in microscopic examinations of human biopsies ^{(Kazakos et al., 1993)}.

After the simultaneous application of tetracycline fibers in multiple sites in the same patient, salivary tetracycline levels between 8 and 51 µg/mL could be detected ^{(Goodson et al., 1985)}. However, the serum levels remained below detection levels (< 0.1 µg/mL) ^{(Rapley et al., 1992)}. No significant change was observed in the tetracycline susceptibility of Gram-negative periodontal microorganisms after tetracycline fiber therapy ^{(Goodson and Tanner, 1992} ; ^{Encarnacion et al., 1997)}. The development of bacterial resistance is unlikely due to the high tetracycline concentration achieved locally for a short therapeutic period in the subgingival pocket where the fiber is applied in a more or less confined environment.

Since these data indicated that the tetracycline fiber placement resulted in the controlled delivery of tetracycline in the periodontal pocket and simultaneously satisfied the pharmacological principles of site, concentration and duration, numerous clinical studies have been undertaken to test the benefits of this therapeutic approach. The clinical procedures comprise the local subgingival debridement by scaling and root planing and the subsequent application of the tetracycline fiber in successive layers until the periodontal pocket is completely filled with the fiber (^{fig. 2a}). An especially designed cyanoacrylate glue (Octyldent^®, Alza Corporation, Palo Alto, CA) is applied to stabilize the fiber to the cervical tooth surface in order to avoid premature loss of the fiber (^{fig. 2b}). After 8 to 12 days the cyanoacrylate glue and the fiber are removed (^{fig. 2c} and ^2d). The placement of the tetracycline fiber requires approximately 5 to 15 minutes according to the defect size and morphology and requires some training. Although several authors have published helpful hints to facilitate the tetracycline fiber placement ^{(Adriaens, 1995} ; ^{Rethman et al., 1995} ; ^{Anderson, 1996} ; ^{Donley, 1997)}, some clinicians experience tetracycline fiber placement as cumbersome and time-consuming even when they have become familiarized with the procedure ^{(Vandekerckhove et al., 1997} ; ^{Killoy, 1998)}.

Data on probing pocket depth reduction, clinical attachment level changes and changes in the bleeding tendency derived from multiple clinical studies with a controlled, randomized, single blind design indicate that tetracycline fiber therapy result in significant improvements of these parameters. Moreover, these improvements are significantly better than those obtained for the control groups (for review : ^{Drisko, 1997} ; ^{Tonetti, 1997}, ^{Tonetti, 1998)}. In a split-mouth design study comparing scaling and root planing (sc + rp) and scaling and root planing combined with tetracycline fiber therapy (sc + rp + fiber), a significant difference was found between the mean differences in probing pocket depth reduction [sc + rp : 1.1 ± 0.1 mm (mean ± SEM) ; sc + rp + fiber : 1.8 ± 0.1 mm] and clinical attachment level gain (sc + rp : 1.1 ± 0.1 mm ; sc + rp + fiber : 1.6 ± 0.1 mm) ^{(Newman et al., 1994)}. In Class II mandibular furcations with persistent bleeding after probing during subsequent recall sessions, a significantly higher reduction in probing pocket depth was obtained after 6 months for those teeth treated with scaling and root planing and tetracycline fiber placement (1.6 mm reduction) than for the sites treated with scaling and root planing only (0.8 mm reduction) ^{(Tonetti et al., 1998)}. Similar results were obtained for the reduction in bleeding tendency. This confirmed treatment results with scaling and root planing and tetracycline fiber placement in non-responding furcation sites ^{(Adriaens, 1995)}. Although interpretation of long-term studies is somewhat problematic due to the continued supportive periodontal treatment protocol during the follow-up, the clinical results obtained after tetracycline fiber therapy demonstrate long-term stability over observation periods up to 5 years ^{(Corsair, 1994} ; ^{Wilson et al., 1997} ; ^{Adriaens et al., 1997} ; ^{Adriaens et al., 1998)}.

Studies examining the biochemical changes in the gingival crevicular fluid following tetracycline fiber therapy demonstrated improvements in the intracrevicular levels of biochemical markers for inflammation and host tissue destruction ^{(Flemmig et al., 1996} ; ^{Lamster et al., 1996)}. Multiple studies followed the microbiological changes in the subgingival pocket after tetracycline fiber therapy and demonstrated beneficial effects (for review : Drisko, 1997 ; ^{Tonetti, 1997)}. The microbiological changes were less pronounced in distal sites of the second molars, most likely as a consequence of a more difficult access during subgingival debridement and fiber placement ^{(Mombelli et al., 1996)}. It was also shown that reinfection of tetracycline fiber treated sites occurred rapidly when single sites were treated in a still infected dentition ^{(Mombelli et al., 1997)} thus explaining the less than optimal results obtained in some clinical trials ^{(Wong et al., 1998)}. Radiographic evaluation with digital sustraction techniques confirmed superior results in tetracycline fiber treated sites in fully disinfected mouths ^{(Fourmousis et al., 1998)}. Reinfection could be delayed by simultaneous treatment of multiple sites with bleeding after probing and probing pocket depth greater than 4 mm ^{(Tonetti et al., 1994} ; ^{Tonetti et al., 1995} ; ^{Mombelli et al., 1997)} and by the use of chlorhexidine rinses during 3 to 4 weeks after tetracycline fiber placement ^{(Goodson, 1989} ; ^{Holborow et al., 1990} ; ^{Niederman et al., 1990)}.

A comparison between tetracycline fiber therapy in conjunction with scaling and root planing with other local delivery devices (minocycline ointment and metronidazole gel) applied after scaling and root planing applied in persistent periodontal defects, demonstrated that all local delivery devices resulted in significant improvements from baseline ^{(Radvar et al., 1996} ; ^{Kinane and Radvar, 1999)}. The improvements in all clinical parameters in the scaling and root planing group alone were less than the improvements in all three groups with adjunctive subgingival application of an antimicrobial medication. At 6 months the mean probing pocket depth reductions were : scaling and root planing alone : 0.71 mm, scaling and root planing + tetracycline fiber : 1.38 mm, scaling and root planing + minocycline ointment : 1.10 mm, and scaling and root planing + metronidazole gel : 0.93 mm. Compared to the scaling and root planing alone, the scaling and root planing combined with tetracycline fiber treatment was the only treatment modality that resulted in a significantly greater probing pocket reduction during the entire course of the study. At week 6 and at month 3, the tetracycline fiber therapy also gave significantly better results than the metronidazole treatment. At month 6, however, this difference only approached statistical significance. Although a reduction of suppuration was observed for all patients treated with antimicrobials, the most effective reductions were observed for the tetracycline fibers. Smokers did have a poorer prognosis of the treatment outcome after subgingival mechanical debridement with or without the application of a topical antimicrobial in the subgingival pocket ^{(Kinane and Radvar, 1997)}.

In summary, the large body of phase I, II, III and IV studies performed with tetracycline fiber therapy support the following conclusions : (a) tetracycline fiber therapy alone resulted in better clinical outcomes than scaling and root planing alone, (b) additional clinical improvements are observed after the combined treatment with scaling and root planing and tetracycline fiber therapy, (c) microbiological and biochemical improvements are superior after tetracycline fiber therapy, (d) the results obtained after tetracycline fiber therapy demonstrate long-term stability.

Minocycline hydrochloride

In vitro testing demonstrated that a concentration of 1 µgmL minocycline hydrochloride is bacteriostatic for 85 % (^{O'Connor et all., 1990}) to 97 % (^{Nakashima et al., 1987}) of the subgingival bacteria. The minimal bactericidal concentration was at least 4 times greater than the minimal inhibitory concentration that ranged between 0.3 and 32 µg/mL. In addition to its antibacterial activity, minocycline hydrochloride displays an inhibitory effect on collagenase activity of bacterial and mammalian origin (^{Maehara et al., 1988}). Porphyromonas gingivalis collagenase is inhibited for 48 % and 80 % at concentrations of 25 and 250 µg/mL, respectively, of the human polymorphonuclear collagenase activity. Minocycline at a concentration of 500 µg/mL caused an 18 % inhibition of human gingival fibroblast collagenase activity. This implies that high concentrations of minocycline hydrochloride can inhibit the bacterial and human polymorphonuclear leukocytes collagenase, while not interfering with the tissue collagenase activity.

Minocycline hydrochloride has been incorporated in three different vehicles for use as a slow-release device in the periodontal pocket : an ethylcellulose film containing 30 % of minocycline hydrochloride (^{Elkayam et al., 1988}), micro-encapsulated in resorbable poly-(glycolide/lactide) microspheres (^{Braswell et al., 1992} ; ^{Jones et al., 1994}) and a 2 % minocycline hydrochloride ointment. Both the ointment and microsphere formulations are applied subgingivally with a disposable plastic syringe (^{fig. 3}).

The only two studies examining the clinical results in humans after subgingival application of the micro-encapsulated minocycline sphere formulation (Lederle Laboratories, USA) gave conflicting results, with significant improvements in probing pocket depth and clinical attachment levels in one study (^{Braswell et all., 1992}) and opposite findings in the other study (^{Jones et al., 1994}). In a short-term (4 weeks) study in adult Beagle dogs with periodontitis scaling and root planing and subgingival application of microspheres resulted in a significant decrease of probing pocket depth, bleeding on probing and gingival crevicular fluid flow rate in minocycline treated sites as compared with vehicle control treated sites (^{Hayashi et al., 1998}). Although microspheres of various composition may function well as sustained delivery devices, they do not possess a zero-order drug release characteristics which is a requirement for a controlled release device (^{Sendil et al., 1999}).

The subgingival application of the 2 % minocycline ointment (Dentomycin^®, Cyanamid International, NJ, USA) results in a 1 300 µg/mL of minocycline hydrochloride at 1 hour after application, followed by a rapid decrease of the concentration in the gingival crevicular fluid over the next hours. At 7 hours, 3 days, 5 days and 7 days after application the concentration decreases to 90 µg/mL, 3.4 µg/mL, 0.3 µg/mL and 0.1 µg/mL, respectively (^{Satomi et al., 1987}). This release profile is characteristic of a sustained delivery device. Two short-term 3 months studies (^{van Steenberghe et al., 1993} ; ^{Graça et al., 1997}) and one long-terme 18 month study (^{Timmerman et al., 1996}) have evaluated the clinical outcomes of the minocycline ointment therapy in conjunction with scaling and root planing in comparison to scaling and root planing alone. Only for periodontal pockets with a baseline probing depth of 7 mm or more some short-terme additional benefits in the order of a few tenths of a millimeter could be demonstrated for the minocycline treated sites over the sites receiving scaling and root planing alone (^{van Steenberghe et al., 1993} ; ^{Graça et al., 1997}). In the long-term study no significant differences in probing depth reduction and in clinical attachment level changes could be found between the sites receiving scaling and root planing alone or sites receiving scaling and root planing followed by minocycline ointment application (^{Timmerman et al., 1996}). Il all these studies the minocycline ointment was applied on several occasions, with 2-week intervals between the successive applications. Therefore, the results of the two 3-month follow-up studies should in fact be regarded as a 1-month follow-up (^{van Steenberghe et al., 1993}) and a 2-month follow-up (^{Graça et al., 1997}) study, which is the time interval that elapsed after the last subgingival application of the antimicrobial agent. This observation might explain some of the conflicting results between these studies and the 18-month study (^{Timmerman et al., 1996}). Moreover, the 3 to 4 repeated subgingival applications require extra chairtime and may cause inconveniences to the patients.

In summary, although in vitro testing of periodontopathic anaerobic bacteria suggests an excellent antimicrobial activity for minocycline hydrochloride, the clinical results obtained with these three sustained delivery systems containing various concentrations of minocycline hydrochloride do not support its use as an useful adjunctive therapy to subgingival scaling and root planing. The rapidly decreasing concentration in the gingival crevicular fluid with these sustained delivery systems might be the major cause for this observation.

Doxycycline hyclate

Systgemically delivered doxycycline demonstrates a wide spectrum of activity against periodontopathogenic microorganisms, including Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum, spirochetes, Eikenella corrodens and Actinobacillus actinomycetemcomitans (^{Walker et al., 1985} ; ^{Kulkarni et al., 1991}). During systemic administration doxycycline is concentrated in the gingival crevicular fluid (^{Pascale et al., 1986}). A local delivery formulation containing 10 % w/w doxycycline hyclate in a bioresorbable poly (DL-lactide) (Atridox^™, Block Drug Corp., USA) applied subgingivally and covered with an non-eugenol wound dressing or with a 2-octyl cyanoacrylate glue resulted in the following dioxycycline concentrations in the gingival crevicular fluid 2 hours after application : 1 473 µg/mL (wound dressing) and 1 986 µg/mL (cyanoacrylate glue) (^{Stoller et al., 1998}). These crevicular fluid concentrations gradually decreased to 309 µg/mL (wound dressing) and 148 µg/mL (cyanoacrylate glue) at 7 days after the application. Both methods of applying this doxycycline hyclate formulation resulted in low salivary concentrations, with a peak value at 2 hours after application of 4.1 µg/mL when a surgical dressing was applied and 8.8 µg/mL with a cyanoacrylate glue protection. The salivary concentrations were below 2.5 µg/mL at the end of the first 24 hours. The serum concentrations after local application never exceeded concentrations of 0.1 µg/mL. As a comparison, the systemic administration of doxycycline resulted in serum concentrations between 0.9 and 2.3 µg/mL during the 8 days of administration, salivary concentrations less than 0.1 µg/mL and crevicular fluid concentrations of 2.5 µg/mL. The high concentration of doxycycline hyclate available at the treated sites combined with low salivary levels and almost non-existent serum levels suggest that this biodegradable controlled-release delivery system displays a favorable pharmacokinetic profile for the delivery of doxycycline into periodontal pockets (^{Stoller et al., 1998}). The concentration/time curve is not a typical zero-order release curve, probably as a consequence of the gradual loss of the local delivery device which is biodegradable.

The doxycycline hyclate local drug delivery system is supplied in a dual-syringe packaging to be mixed thoroughly immediately before application in order to overcome product stability problems. Applications is performed with a 23-gauge cannula fitted to the syringe. The product is applied subgingival until the pocket is completely filled to the leel of the gingival margin. At the end of the application the material is gently packed into the subgingival pocket with a moistened curette. The application of a non-eugenol periodontal dressing or a cyanoacrylate glue aims at enhancing the retention of the subgingivally applied product. After 7 days, the periodontal dressing or the glue and the residual subgingival material are removed qith a curette.

Three 9-month studies have evaluated the efficacy of subgingival delivery of doxycycline hyclate incorporated in a local delivery device (^{Polson et al., 1997a} ; ^{Polson et al., 1997b} ; ^{Garrett et al., 1999}). In all three studies the subgingival application of doxycycline hyclate was compared to other monotherapies, i.e. sanguinarium chloride in poly(DL-lactyide), poly(DL-lactide) vehicle control, subgingival scaling and root planing or improvement in oral hygiene. The subjects were retreated with the same therapy at month 4 in an attempt to reduce reinfection of the treated sites. The results of these studies demonstrated that the therapeutic effects of the doxycycline therapy is equivalent to those obtained with subgingival scaling and root planing. Both therapeutic approaches were superior to the other treatment modalities (^{Garrett et al., 1999}). The doxycycline therapy of sites with initial probing pocket depth of 5 mm or more resulted in a redution in probing pocket depth of 1.3-1.8 mm and a gain in clinical attachment level of 0.8-1.0 mm (^{Polson et al., 1997b} ; ^{Garrett et al., 1999}). These values are in the same order of magnitude as those obtained from a meta-analysis of 27 clinical studies evaluating the effects of subgingival scaling and root planing on probing pocket depth reduction (1.29-1.26 mm) and on clinical attachment level gain (0.55-1.19 mm) (^{Cobb, 1996}).

In summary, the clinical results obtained with the doxycycline hyclate local delivery device appear promising although this device is not a controlled delivery device in the strict sense, i.e. the release pattern is not a zero-order profile. However, studies evaluating the microbiological effects of this therapeutic approach are lacking, as well as studies evaluating the use of this treatment modality after subgingival scaling and root planing in a attempt to disrupt the subgingival biofilm and enhance the antimicrobial activity on the periodontopathogenic microorganisms.

Metronidazole

Metronidazole was initially used in the treatment of vaginal trichomoniasis (^{Hesseltine and Lefebvre, 1963}). Around that same period it was observed that this drug also had beneficial effects on ANUG (^{Shinn, 1962}). This led to its use in the treatment of infections caused by anaerobic bacteria. The drug is accumulated intra-cellylarly by obligate anaerobic bacteria and has a bactericidal effect by its interference with the nucleic acid synthesis (^{Müller et al., 1977} ; ^{Walker, 1992}). There are indications that during systemic administration of metronidazole its hydroxymetabolite produced in the liver, acts synergistically with metronidazole, resulting in an enhanced bactericidal effect (^{Bergan, 1985} ; ^{Jousimies-Somer et al., 1988} ; Pacivic et al., 1992). The in vitro anti-bacterial activity is highest against obligate anaerobes, e.g. black-pigmenting and non-pigmenting Bacteroides species (MIC₉₀ = 4-16 µg/mL), spirochetes (2-8 µg/mL), Fusobacterium nucleatum (< 1.0 µg/mL), Selenomonas sputigena (< 1.0 µg/mL) (^{Walker et al., 1985}). Some facultative anaerobes are less sensitive to its action, e.g. Eikenella corrodens (>32 µg/mL) and Capnocytophaga species (> 32 µg/mL) (^{Walker et al., 1985}). Nevertheless, the facultatively anaerobic Actinobacillus actinomycetemcomitans has a MIC₉₀ value of 16 µg/mL, which is equivalent to the values for the pack-pigmenting Bacteroide species (^{Walker et al., 1985}).

The clinical efficacy of systemic metronidazole administration in conjunction with mechanical debridement of the subgingival pocket has been demonstrated in patients treated for adult periodontitis (^{Loesche et al., 1987}, ¹⁹⁹¹, ^1992a, ¹⁹⁹⁶), localized juvenile periodontitis (Saxén and Asikainen, 1993) and refractory periodontitis (^{Greenstein, 1993)}.

For local delivery in the subgingival pockets, metronidazole has been incorporated in different formulations of local delivery devices. The use of metronidazole in acrylic strips (^{Addy et al., 1982} ; ^{Addy and Langeroudi, 1984}), dialysis tubes (^{Wan Yusof et al., 1984}), ethylcellulose films (^{Loesche et al., 1987}), polyhydroxybutyric acid strips (^{Deasy et al., 1989}) has been tested during short-term expiriments, i.e. 1 week to 14 weeks. Most studies show important shifts in the subgingival flora, reduced inflammation and reduced probing pocket depth values. These results were more pronounced when the application of the metronidazole containing slow release device was preceeded by a subgingival debridement of the periodontal pocket (^{Khoo and Newman, 1983} ; ^{Yeung et al., 1983} ; ^{Newman et al., 1984} ; ^{Wade et al., 1992}).

More recently, 25 % metronidazole benzoate has been incorporated in a mixture of monoglyceride and triglycerides (Elyzol^® dental gel). The gel is applied with a syringe to the deepest parts of the periodontal pocket and the pocket is completely filled while the syringe is gradually being retracted from the subgingival area. The contact with the gingival crevicular fluid and the body temperature induce a change from gel to a semi-solid material which is thus blocked in the subgingival space (^{Norling et al., 1992}). The metronidazole benzoate gradually disintegrates to form free metronidazole. Simultaneously, the gel is being transformed into oleic acid and glycerol, that are gradually washed out from the periodontal pocket. A high concentration of metronidazole in the gingival crevicular fluid is reached shortly after its application, followed by an almost logarithmic reduction of this concentration over the first 24-48 hours (^{Stoltze and Stellfeld, 1992}).

Most of the clinical studies performed with the 25 % metronidazole dental gel are studies aiming at demonstrating the equivalence between the results after its application in the subgingival pocket and the results after subgingival scaling and root planing (^{Klinge et al., 1992} ; ^{Ainamo et al., 1992} ; ^{Pedrazzoli et al., 1992} ; ^{Stelzel and Flores-de-Jacoby, 1997}). In all these studies, the subgingival application of metronidazole gel was repeated at 2 separate sessions during a two week period. The follow-up was 3 months (^{Klinge et al., 1992}), 6 months (^{Ainamo et al., 1992} ; ^{Pedrazzoli et al., 1992}) and 24 months (^{Stelzel and Flores-de-Jacoby, 1997}). All studies were according to the split-mouth design, which might not preclude for a possible carry-over effect from metronidazole treated sites to sites not receiving the medication but undergoing subgingival scaling and root planning. In the metronidazole treated sites, no differences were observed between the application of a 15 and a 25 % metronidazole gel preparation (^{Klinge et al., 1992}). Sites receiving metronidazole gel application displayed a probing pocket depth reduction of approximately 1 to 1.5 mm, whereas for sites receiving scaling and root planning the probing pocket depth was reduced by approximately 1 to 1.3 mm. No significant differences were found between both treatment modalities for probing pocket depth reduction, gain in probing attachment levels and in the reduction of the bleeding tendency. When scaling and root planing alone was compared to scaling and root planing followed by the subgingival application of the metronidazole gel, the reduction in probing pocket depth was 1.0 and 1.3 mm, respectively (^{Stelzel and Flores-de-Jacoby, 1996a} ; ^{Stelzel and Flores-de-Jacoby, 1996b} ; ^{Awartani and Zulqurnain, 1998}). Although this difference was statiscally significant, it was of the same magnitude as the results obtained in the equivalence studies (^{Klinge et al., 1992} ; ^{Ainamo et al., 1992} ; ^{Pedrazzoli et al., 1992} ; ^{Stelzel and Flores-de-Jacoby, 1997}). The results of these therapies were similar in primary periodontal patients and in patients enrolled in a periodontal supportive care program. Based on clinical and microbiological observations, the combined use of subgingival debridement and subgingival application of metronidazole gel appeared to be equally (^{Lie et al., 1998}) or more effective (^{Noyan et al., 1997}).

When metronidazole gel application was combined with periodontal access flap surgery (^{Hirooka et al., 1993}) or with guided tissue regeneration procedures with barrier membranes (^{Sander et al., 1994}), the clinical outcomes (probing pocket depth in angular bony defects, horizontal probing depth in furcation defects, clinical attachment gain) of the metronidazole group were significantly improved compared to the control treatment.

In summary, the clinical results obtained with the metronidazole dental gel indicate that its appliation at two sessions during a two week period yields similar clinical results as a single session of subgingival scaling and root planing. There are indications, however, that improved results are obtained when both treatments are applied in conjunction. Although this metronidazole gel is not a controlled release device, i.e. lacking zero-order release characteristics, the short contact time between the medication and the subgingival flora might be sufficient for its effect to occur. It is unclear whether the absence of the production of the hydroxymetronidazole during this method of metronidazole application is influencing the antimicrobial effect.

Chlorhexidine gluconate

Chlorhexidine digluconate is an effective antimicrobial agent and, as such, it has been used as a topical antiseptic since the early sixties ^{(Hugo and Longworth, 1964} ; ^{Hugo and Longworth, 1965} ; ^{Russell, 1969)}. In the form of an 0.2 % solution used as a mouthwash twice daily, it effectively inhibits dental plaque formation and gingivitis development ^{(Löe and Schiott, 1970} ; ^{Hennessey, 1973} ; ^{Löe et al., 1976} ; ^{Schiott et al., 1976a} ; ^{Schiott et al., 1976b} ; ^{Banting et al., 1989)}. Even when used for prolonged periods of time (up to 2 years) it maintained its efficacy and no bacterial resistance was developed.

Chlorhexidine solutions applied as a mouthrinse or by subgingival irrigation appeared ineffective in the treatment of periodontitis ^{(MacAlpine et al., 1985} ; ^{Braatz et al., 1985} ; ^{Wennström and Lindhe, 1986)}. In contrast, when incorporated into a local delivery device, chlorhexidine thus placed subgingivally has proven to change the subgingival microflora into a microbial community compatible with a healthy periodontium ^{(Stabholz et al., 1986)}. This resulted in a reduction of the probing pocket depth, a gain in clinical attachment level and a reduced bleeding tendency, with all these changes being stable for up to 2 years ^{(Stablholz et al., 1991)}.

In order to improve and facilitate the clinical use of subgingival chlorhexidine delivery, a biodegradable chip was developed ^{(Steinberg et al., 1990)}. The PerioChip^® (Perio Products Ltd, Jerusalem, Israel) has a rectangular shape with one rounded end. It measures 4 mm in width and 5 mm in height with a thickness of 0.35 mm. Its weight is 7.4 mg and it contains 2.5 mg of chlorhexidine digluconate in a gelatin matrix. The use of the chip is indicated for sites with probing pocket depth equal to or exceeding 5 mm. It is inserted with a forceps into the periodontal pocket, with the rounded end towards the bottom of the pocket (^{fig. 4a} and ^4b). The wet subgingival environment causes moistening of the gelatin which thereby sticks to the tooth surface (^{fig. 4c}). No additional retention system is required. The patient should not perform any brushing or flossing in this area during 10 days in order to avoid premature dislodging of the PerioChip^®. The chip is eliminated by biodegradation in 7 to 10 days.

Two hours after installation in the periodontal pocket the chlorhexidine concentration in the gingival crevicular fluid reaches a concentration of approximately 2 000 µg/mL ^{(Soskolne et al., 1998)}. During the next 4 days the concentration fluctuates between 1 300 and 1 900 µg/mL and from the fifth day onwards the concentration gradually decreases to reach a value of 128 µg/mL at day 8. This means that during this entire period of time the concentration in the gingival crevicular fluid remains above the 125 μg/mL required to inhibit the growth of 99 % of the subgingival microflora ^{(Stanley et al., 1989)}. During the first 4 days the release kinetics are indicative of a zero-order delivery system ^{(MacNeil et al., 1999)}. From day 5, the concentration decreases rapidly, most likely due to the biodegradation of the gelatin matrix.

Two multicenter studies have compared the results at 6 months ^{(Soskolne et al., 1997)} and at 9 months ^{(Jeffcoat et al., 1998)} obtained after subgingival scaling and root planing with or without the adjunctive use of the chlorhexidine chip. In one study ^{(Jeffcoat et al., 1998)} a third group was included that received a placebo chip after the subgingival scaling and root planing. Only sites with a probing pocket depth of 5 mm or more that demonstrated bleeding after probing, were included. The results indicated that the use of a chlorhexidine chip resulted in a significantly better reduction in pocket probing depth (1.16 mm for the chlorhexidine group and 0.7 mm for the control group) and gain of clinical attachment level (0.47 mm for the chlorhexidine chip group and 0.31 mm for the control group). The percentage of pockets displaying a reduction in probing pocket depth of 2 mm or more after scaling and root planing and adjunctive subgingival chlorhexidine chip placement was 19 %, which was statistically significantly better than 8 % of the sites receiving mechanical therapy only ^{(Jeffcoat et al., 1998)}. These improvements were most pronounced for periodontal pockets with a probing pocket depth of 7 mm or more at baseline ^{(Soskolne et al., 1997)} where an average pocket probing reduction of 1.77 mm was found for the chlorhexidine group and 1.05 mm for the control group. The gain in clinical attachment level was 0.98 mm for the chlorhexidine group and 0.33 mm for the control group. If sites receiving a chlorhexidine chip at baseline and remaining with a probing pocket depth of 5 mm or more at month 3 and 6, were retreated by an additional chlorhexidine chip at month 3 and 6, further improvements did occur in the reduction of the probing pocket depth and gain of clinical attachment ^{(Jeffcoat et al., 1998)}. Moreover, in both studies the adjunctive use of chlorhexidine chip therapy did result in a significantly more pronounced reduction in bleeding tendency.

In summary, the chlorhexidine containing gelatin chip (PerioChip^®) has a chlorhexidine release profile that is compatible with a zero-order delivery profile during the initial 4 days after insertion in the periodontal pocket. Moreover, the concentration maintained during the initial 4-5 days in the crevicular fluid is at least a ten-fold of the concentration required for in vitro growth inhibition of 99 % of the subgingival flora, which gives it the potential to be of some benefit in combatting bacteria organized in a biofilm. The few data available suggest that the adjunctive use of scaling and root planing and chlorhexidine chip insertion improves the clinical outcomes. Moreover, repeated applications of the chlorhexidine chip in residual deep pockets appears to have additional beneficial effects. However, more clinical data supporting these findings would be useful.

Discussion

Local delivery devices have proven to be beneficial for the clinical outcomes of periodontal therapy, as evidenced by reduction of bleeding after probing, reduction of probing pocket depth and gain in clinical attachment level. Improvements in bone level were not present in any of the studies ^{(Palcanis et al., 1997} ; ^{Fourmousis et al., 1998)}, indicating that the benefits of this treatment modality are limited to the supracrestal compartment of the periodontium.

Comparison of the results obtained with the different local delivery systems, shows that most systems give some clinical improvements in the short term. Apart from a few exceptions studying the long-term effect after tetracycline fiber therapy ^{(Corsair, 1994} ; ^{Wilson et al., 1997} ; ^{Adriaens et al., 1998)} and after minocycline ointment application ^{(Timmerman et al., 1996)}, long-term studies, i.e. for observation periods exceeding 12 month, are lacking. A comparison between the results obtained after the application of the different local delivery devices is complicated by the fact that different therapeutic protocols have been applied. Several studies have been based on a split-mouth approach, which would not preclude for a possible carry-over effect of the active medication towards the control site in the same mouth. Not all studies included scaling and root planing in conjunction with the subgingival application of the local delivery device. Some of the studies are considerably more short-term studies than presented in their title or material and method section. In the 3-month multicenter study of the efficacy of subgingivally placed minocycline ointment ^{(van Steenberghe et al., 1993)}, the last ointment application was at week 8 in the study, thereby effectively reducing the follow-up period to 1 month and not 3 months as stated by the authors. Similarly, in a large multicenter study running over a 9-month period of time ^{(Jeffcoat et al., 1998)} and in another 6-month multicenter study ^{(Soskolne et al., 1997)}, the last application of the chlorhexidine containing gelatin chip was performed at the 6-month and the 3-month follow-up visit, respectively, thereby reducing the real follow-up to a 3-month time period. Moreover, the comparison of studies might be complicated since parameters that usually are not accounted for might negatively influence the clinical outcomes, e.g. smoking ^{(Kinane and Radvar, 1997)}, inefficient supragingival plaque control ^{(Kornman, 1993} ; ^{Kornman et al., 1994)}, differences in the quality of the subgingival scaling and root planing as evidenced from a minimal per protocol time allotted for this treatment ^{(van Steenberghe et al., 1993)}, accessibility of the sites to be treated ^{(Mombelli et al., 1996} ; ^{Mombelli et al., 1997)}, recolonization from other untreated sites ^{(Tonetti et al., 1995} ; ^{Mombelli et al., 1997} ; ^{Fourmousis et al., 1998)}.

At present, a comparison of the efficacy of three locally delivery systems as adjunctive treatment to subgingival scaling and root planing was performed in a clinical trial with a 3-month follow-up period ^{(Radvar et al., 1996)} and with a 6-month follow-up period ^{(Kinane and Radvar, 1999)}. These studies demonstrated that all three local delivery devices resulted in improved clinical outcomes as compared to the results of subgingival scaling and root planing alone. Of the three local delivery systems the tetracycline fiber therapy yielded better results than those obtained after treatment with minocycline ointment or with metronidazole dental gel. In view of these findings, the frequently raised comment that the installation of a tetracycline fiber is a cumbersome and time-consuming procedure even when a practitioner has become familiarized with the procedure ^{(Vandekerckhove et al., 1997} ; ^{Killoy, 1998)}, should be put in the proper perspective. This procedure is indeed technically far less demanding for the practitioner and causes far less postoperative morbidity and discomfort for the patient when compared to the traditional surgical approach.

Although in many of the clinical trials testing the efficacy of the local drug delivery devices for use in the periodontal pockets, the results of the adjunctive use of these devices with scaling and root planing resulted in statistically significantly better results than those obtained after scaling and root planing alone, the frequently asked question is whether these small improvements are also clinically significant. A sensible answer to this question was suggested on the basis of the goals of periodontal therapy ^{(Killoy, 1998} ; ^{Killoy, 1999)}, i.e. (1) arresting the progression of active periodontitis, (2) regenerating lost periodontium, if this is improving the long-term survival of the tooth, and (3) maintain the control gained over the periodontal disease. By eliminating the bacterial infection in the subgingival environment, local delivery devices contribute to the improved clinical outcomes during the initial periodontal treatment and during recurrence of disease activity during the follow-up period. As evidenced from the studies with the presently available local delivery devices, no regeneration of periodontal tissues can be expected from this treatment modality. Based on the current knowledge, the application of a local delivery device in the subgingival pocket might be indicated in (1) the initial anti-infective treatment, (2) at reevaluation for non-responding sites and (3) during the periodontal supportive treatment. Most studies have primarily focused on the first indication, i.e. during the anti-infective therapy where it was combined with subgingival scaling and root planing. However, tetracycline fibers in conjunction with scaling and root planing were successful in improving the clinical outcome variables in non-responding sites as identified during the periodontal reevaluation ^{(Adriaens, 1995} ; ^{Adriaens et a.l., 1996} ; ^{Vandekerckhove et al., 1997)}. These improvements were maintained for up to 2 years without retreatment of the subgingival pocket ^{(Adriaens et al., 1997} ; ^{Adriaens et al., 1998)}.

Although some of these devices, i.e. the doxycycline polymer and the metronidazole dental gel, have been presented as alternatives for the subgingival debridement, the use of these devices without preliminary subgingival scaling and root planing should not be recommended as good clinical practice, primarily because of the beneficial effects of the disruption of the bacterial biofilm before antimicrobials are applied. Since all sites in the oral cavity are to some extent available for recolonization by plaque bacteria, it is unlikely that a single treatment with a subgingivally placed local delivery device would safeguard that site from recurrence of periodontal disease activity for its entire remaining lifetime. Therefore, retreatment of a site comprising application of the local delivery device, might be indicated when new signs of disease activity, e.g. bleeding after probing and/or clinical attachment loss, appear.

In the choice of a local delivery device preference should be given to product corresponding to the criteria for controlled drug delivery at a concentration that is sufficiently high to have an adequate effect on bacteria organized in a bacterial biofilm. Moreover, the treatment protocol should be designed in such a way as to minimize the chances for reinfection of the treated site. This should include the previous full-mouth supra- and subgingival debridement by scaling and root planing, the improvement of supragingival plaque control measures and the use of antimicrobial mouthrinses during the period in which the device remains in situ and during the subsequent healing period.

Concluding remarks

The long-term results of local antimicrobial therapy depend on several parameters. The local delivery device should comply with the basic pharmacological principles : deliver an active agent to the site of action at an adequate concentration and during a time period which is sufficiently long to permit the pharmacological effect to occur. The local delivery device should preferably have a release characteristic which complies with a zero-order release pattern in order to maintain the concentration during a sufficient time period. At present, only the Actisite^® fiber and the PerioChip^® deliver their active agents according to a zero-order release profile.

The use of this therapeutic approach should be restricted to localized lesions displaying residual disease activity following the initial therapy and to localized sites with recurrence of disease activity during periodontal supportive treatment programs. The disruption of the subgingival microbial biofilm by scaling and root planing in order to render the subgingival bacteria more accessible to the action of the antimicrobial agent should be an essential part of this treatment. A maximum of precautions should be taken in order to reduce the chances of recolonization of the treated sites. This includes the absence of multiple sites in the dentition displaying disease activity and the use of therapeutic measures accompanying the local therapy in order to reduce the number of bacteria in the oral cavity. The latter might be accomplished by the use of antimicrobial mouthrinses. An adequate oral hygiene program should be performed by the patient in order to reduce chances of recolonization of the subgingival area. Finally, the prevention of the recolonization of the subgingival area should also be the aim of the supportive periodontal treatment program.

Demande de tirés à part

Patrick A. ADRIENS, International Center for Periodontology and Oral Implants Verlaatstraat 47, B-1000 BRUSSELS - BELGIUM. E-mail : PatrickAdriaens@compuserve.com

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