Antibiotics Inthe Treatment of Periodontal Disease

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CLINICAL AND RESEARCH REPORTS

INTRODUCTION

Perforation of teeth through the continuous epithe-lial lining of the oral cavity is a singular anatomi-cal situation. The dental surface consists of hardtissues that lack the potential to renew themselvesand to shed their superficial layer. The microeco-logic system of the oral cavity is colonised bymore than 400 different bacterial species (Mooreand Moore, 1994). Approximately 150 or moredifferent species may be detected and cultivatedfrom the oral cavity of a single individual. Somebacteria are capable of adhering to and colonisingdental surfaces, thereby preparing the ground forthe colonisation by other microorganisms. The layerthat is generated in this manner is calleddentalplaque, bacterial plaque, orbiofilm. Biofilm is thename of organised aggregations on solid surfaces(e.g. on teeth but also ship bodies, artificial heartvalves, water pipes etc.) that consist of microorgan-isms, extracellular bacterial macromolecules, and

products originating from the surrounding medi(e.g. saliva or sulcus fluid). Bacterial plaque is thparticular oral form of biofilm. The structure biofilm not only hinders diffusion of growth facinto bacterial plaque but also forms an effective barier against host defence (e.g. antibodies,lysozyme, lactoferrine) and antimicrobial sustances (e.g. mouth rinses, antibiotics).In contrast to the epithelial surfaces of the bodteeth are not capable of shedding their superficialayers with the adhering microorganisms. Hencgingivitis and periodontitis are characterised by iflammatory and immune response to the oral mcroflora, particularly that part that adheres to thtooth surface or has been established subgingivaly. The primary etiologic factor of most inflammtory periodontal diseases (plaque-induced gingivtis, chronic and aggressive periodontitis) is bactrial plaque. The removal of supra- and subgingivbiofilm that is required for therapy of periodondiseases is accomplished mechanically by profe

Antibiotics in Periodontal Therapy

Peter Eickholz, Bettina Dannewitz, Ti-Sun Kim

The majority of inflammatory periodontal diseases is caused by bacteria. Mechanical removalof bacterial deposits from the teeth by the patient (individual oral hygiene) and mechanical de-bridement by the dentist (professional tooth cleaning, antiinfective periodontal therapy, peri-odontal surgery) are effective in treatment of most cases of plaque-induced gingivitis and peri-odontitis. However, in particular risk patients (e.g. under elevated risk for bacterial endocardi-tis) periodontal procedures that cause transitory bacteremia require systemic antibioticprophylaxis. Further, in severe cases of necrotising ulcerative gingivitis and periodontitis localtherapy has to be supported by systemic antibiotics. In cases of aggressive and generalised se-vere chronic periodontitis that show subgingival infection with particular periodontal pathogens,especially by Actinobacillus actinomycetemcomitans,successful therapy requires systemic an-tibiotics adjunctively to mechanical antiinfective therapy. Therapy of persisting pockets duringsupportive periodontal therapy may additionally benefit from application of locally delivered an-tibiotic devices.

Key words: adjunctive systemic and local antibiotic therapy, periodontitis therapy, prophylaxterial endocarditis, necrotising ulcerative gingivitis/periodontitis


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sional tooth cleaning and subgingival instrumenta-tion of root surfaces in the course of antiinfectivetherapy in most cases.In some particular cases, however, additional ad-junctive use of systemic (Table 1) or local antibi-otics is reasonable and required.Historically the termantibiotic referred to antimi-crobial agents that were produced by living mi-croorganisms (bacteria, fungi). Penicillin that wasderived from the funguspenicillium notatumis anexample for this. Synthetical antimicrobial agentsoriginally are called antimicrobial chemothera-peutics (e.g. metronidazole). However, todaymost natural antibiotics are chemically modified(semisynthetic) to improve their pharmacokineticsor to widen their range of effect. Thus, usually to-day and in this article the term antibiotic is usedfor both groups of substances - natural antibioticsand antimicrobial chemotherapeutics (vanWinkelhoff and Vandenbrouke-Grauls, 2001).

ANTIBIOTIC PROPHYLAXIS

Prophylaxis of Bacterial EndocarditisBacterial endocarditis fortunately is a rare (inci-dence of 2060 cases per ONE million) but dan-gerous disease. Untreated bacterial endocarditisis lethal in 100% of cases. However, even prop-erly treated, depending on the microbial floralethality ranges from 576% (Jeserich and Just,2001). Endocarditis develops if bacteria thathave got access to blood circulation (bacteremia)colonise the internal surface of the heart andcause symptoms of infection (sepsis, septicemia).Sepsis in general and infection of the endocard in

particular are facilitated by primary or secondarydeficiency of host defence. General or local de-fective host defence is generally found in immune-suppressed patients after organ transplantation,leukaemia and cardiac defects (e.g. heart andvalvular defects or heart valve prostheses) (Tables2 and 3).In 25% of patients who develop bacterial endo-carditis medical history reports recent dental treat-ment or orofacial infection. A risk for endocarditisexists with all dental procedures that cause bac-teremia, i.e. gingival, pulpal, and periapical bleed-ing. Periodontal procedures that are likely to elicitbacteremia are pocket probing, scaling and rootplaning, supportive periodontal therapy, periodon-tal surgery, subgingival application of antibioticslow and controlled release devices as well as pro-phylactic cleaning of teeth and implants if gingivalbleeding is to be expected (Table 4). Thus, theseprocedures require antibiotic prophylaxis (Table 4)in patients with moderate and high endocarditis risk (Table 2). In many cases patients at elevated risk forbacterial endocarditis have a so-called heart pass-port that gives information about the required an-tibiotic prophylaxis. Table 5 shows a prophylacticregime that is applicable under normal conditions;in uncertain cases it is advisable to contact the par-ticular patients physician.

Prophylaxis after Radiation Therapyin the Maxillofacial RegionTherapy of malignant craniomandibular neoplasiasin most cases includes radiotherapy. Salivaryglands, jaws and teeth are located in the field ofradiation. The high radiation doses that normallyare applied result in a severely reduced vitality of

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Eickholz et al Antibiotics in Periodontal Therapy

Table 1 Indications for sys-temic use of antibiotics inperiodontal therapy (Beikleret al, 2003).

antibiotic prophylaxis (e.g. with increased risk of endocarditis)

NUG/NUP (American Academy of Periodontology, 2001)adjunctive antibiotic therapy in presence of specific periodontal pathogensin aggressive periodontitis (American Academy of Periodontology, 2000b) generalised severe chronic periodontitis refractory periodontitis (American Academy of Periodontology, 2001) moderate to severe periodontitis with systemic diseases or immune defi-

ciencies (American Academy of Periodontology, 2000b)periodontal abscess spreading into adjacent tissue loges, with fever and/orsevere lymphadenopathia (American Academy of Periodontology, 2001)


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Diabetes MellitusA patient has diabetes mellitus if glucose concen-tration in blood plasma has been assessed twiceto be 126 mg/dl or higher in sober patients or atleast 200 mg/dl two hours after oral intake of glu-cose (hyperglycemia) (American Diabetes Asso-ciation, 1997). For differentiation between good

and poor glycemic control in diabetics the socalled hemoglobin-A1c value (HbA1c) is used.HbA1c assesses control of blood glucose withinthe past one to two months. In healthy adults it is4.35.8% and in well controlled diabetics 67%.Under poor glycemic control in diabetics HbA1cvalues between 810% are found. For a HbA1c

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Endocarditis prophylaxis recom-mended

Endocarditis prophylaxis not rec-ommended

Dental extractions

Restorative dentistry (operative

and prothodontic) with or withoutretraction cord

Periodontal procedures includ-ing surgery, scaling and rootplanning, probing, and recallmaintenance

Local anesthetic injections (nonin-traligamentary)

Intracanal endodontic treatment;post placement and build up

Placement of rubber dams

Dental implant placement andreimplantation of avulsed teeth

Postoperative suture removal

Taking of oral impressions Endodontic (root canal) instrumen-

tation or surgery only beyond theapex

Placement of removable prostho-dontic or orthodontic appliances

Subgingival placement ofantibiotic fibers or strips

Fluoride treatments

Taking oral radiographs

Initial placement of orthodonticbands but not brackets

Orthodontic appliance adjustment

Shedding of primary teeth

Intraligamentary local anaestheticinjections

Prophylactic cleaning of teeth orimplants where bleeding is an-ticipated

Table 4 Dental therapy andendocarditis prophylaxis(Dajani et al, 1997)

Table 5 Antibiotic endo-carditis prophylaxis for oral

procedures (Dajani et al,1997; Jeserich and Just,2001).

Standard:amoxicillinAdults: 2g orallyChildren: 50mg/kg orally1 hour before procedure

Allergic to penicillin:clindamycinAdults: 600mg orallyChildren: 20mg/kg orally1 hour before procedure


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value of more than 10% there is a high risk foracute diabetic decompensation (Allolio andSchulte, 1996).In almost all well-controlled diabetics conventional

periodontal therapy may be performed. However,some particular aspects should be taken into con-sideration. Diabetics generally are predisposed tobacterial infections, which vice versa may disturbmetabolic control severely. If periodontal surgery isplanned in well-controlled diabetes mellitus antibi-otic prophylaxis should be considered from caseto case (Seymour and Heasman, 1992). How-ever, up to now there are no evidence-based stud-ies that advocate obligate antibiotic medication inwell-controlled diabetics in general (Rees and

Otomo-Corgel, 1992; Rees, 2000).In poorly controlled or uncontrolled diabetes melli-tus elective dental and periodontal proceduresshould not be performed, at least temporarily(Alexander, 1999). If oral or periodontal surgeryis required in cases of emergency due to acuteprocesses, antibiotic prophylaxis is required in anycase to minimise the risk of postsurgical infectionsand complications of wound healing (AmericanDental Association, 1994).

HIV InfectionIn patients with asymptomatic HIV infection anydental therapy may be performed (Little andFalace, 1991). Whether antibiotic prophylaxisshould be applied in asymptomatic HIV patients ornot has to be considered very carefully. It hasbeen demonstrated that particularly HIV patients inmore advanced stages of the disease show aller-gic reactions to prescribed antibiotics in high fre-quency (Glick, 1994).According to the guidelines of the American HeartAssociation (AHA) and of the Council on DentalTherapeutics of the American Dental Association(ADA) (Dajani et al, 1997), antibiotic prophylaxisfor dental treatment is required in patients at risk ofa subacute bacterial endocarditis unrelated to HIVstatus.In AIDS patients with severe immune suppressionand neutropenia as well as thrombocytopenia, den-tal and periodontal treatment should be limited todental emergencies. Elective treatments under theseconditions are contraindicated in general. Emer-gency therapy that cannot postponed from a med-ical point of view should be performed as conserv-atively as possible. Analgetics and antibiotics

should only be used or prescribed after consultatiof the patients physician. If surgical treatment is quired, antibiotic prophylaxis should be considereto avoid hematogenic spread of infections due t

frequent transitory bacteremias. This applies in pticular in cases of severe neutropenia with cecounts below 500/mm3 (Glick, 1994).Periodontal surgery may be performed safely evin HIV-positive patients with low CD4+ cell counts.However, careful medical history taking and cosultation with the patients physician or internspecialist are required. In cases with CD4+ cellcounts below 100/mm3, severe neutropenia withless than 500 neutrophil granulocyts/mm3 has tobe considered and controlled for (Glick, 1994).

In HIV-infected patients some particular aspechave to be considered regarding choice of suitable antibiotics. In cases of severe neutropeniabactericidal antibiotics are required (e.g. penicillin, amoxicillin, cephalosporin), whereas bactriostatic antibiotics (e.g. erythromycin, clindmycin, tetracycline) are not indicated. If bacteristatic antibiotics are used, bacteremia may persiafter prophylaxis has been finished and possiblresult in even increasing bacterial counts. Addtionally, in HIV patients the risk for overgrowthCandida albicans has to be considered after an-tibiotic medication for longer periods. Thus, sytemic use of antibiotics in HIV patients is alwacombined with local application of antimycotidrugs. Further, in HIV patients suffering from sevimmune suppression systemic antifungal prophlaxis is advisable (Ryder, 2000).

SYSTEMIC ANTIBIOTIC THERAPY

Necrotising Ulcerative Gingivitis (NUG)and Periodontitis (NUP)Necrotising ulcerative gingivitis starts interdentat the gingival papillae. Linear erythema is pathgnomic (a fiery red line), which delineates the rgion of yellowish gray fibrin-covered necrosis frhealthy gingival tissue (attempt of demarcatio(Fig 1). Patients complain of intense pain and rport that the process had appeared quite sudden-ly. In many cases halitosis, regional lymphadenopathy, and in some cases symptoms of generadisease (e.g. fever), are reported.Table 6 shows the risk factors that predispose foNUP/NUG (trench disease: widespread disease

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of an exogenic pathogen (Slots and Ting, 2002)and which, in most cases, cannot be eradicated orsuppressed below the detection limit by mechanicaltreatment alone (Christersson et al, 1985; Mller etal, 1993; Mombelli et al, 1994). A. actino-mycetemcomitansis capable of leaving the pocketand invading the tissues or colonising extraperi-

odontal habitats (e.g. tongue, tonsils). In those rtreats the microorganism cannot be reached be mechanical instrumentation of the root surfaces (Fig Treatment with systemic antibiotics alone would einate those bacteria that have invaded the tissuesHowever, the effect on the biofilm at the root surfawould be insufficient (Fig. 3). If A. actinomycetem-

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Table 7 Indications formicrobiological diagnosticsand possibly adjunctive sys-temic use of antibiotics inperiodontal therapy(Flemmig et al, 1998;Beikler et al, 2003).

early onset periodontitis (aggressive periodontitis*)

severe generalised adult periodontitis (> 50% bone loss > 14 teeth(generalized severe chronic periodontitis*)

periodontitis exhibiting progessive attachment loss despite approptherapy (refractory periodontitis)

moderate to severe periodontitis with systemic diseases (particulardysfunctions of neutrophils, diabetes mellitus, HIV infection with < 200/mm3) (periodontitis as symptom of systemic disease*)

* actual classification (Armitage, 1999)

Fig 2a,b Exclusive mechanical therapy ofa periodontal lesion infected byActinobacillus actinomycetemcomitans:a) subgingival deposits inclusiveA. actino- mycetemcomitansare removed from theroot surface. However, the periodontalpathogen persists within soft tissues, b)from where it recolonises the pocketagain.

Fig 3a,b Exclusive systemic antibiotictherapy of a periodontal lesion infectedby Actinobacillus actinomycetemcomitans:a) the antibiotic killsA. actinomycetem- comitanswithin soft tissues. However, itfails to penetrate the biofilm that adheresto the root surface.A. actinomycetem- comitanspersists with the biofilm, b) fromwhere it recolonises the soft tissues again.


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comitansis not eradicated or at least significant-ly reduced, remission will not be obtained andperiodontal destruction will further progress(Christerrsson et al, 1985). Systemic use of tetra-cyclines adjunctively to mechanical therapy resultsin a reduction of A. actinomycetemcomitans, buteradication is not achieved (Mller et al, 1993).After combined use ofamoxicillin and metron-idazole adjunctively to subgingival scaling androot planing the periodontal pathogen could notbe detected in 21 of 22 cases of aggressive andgeneralised severe chronic periodontitis (vanWinkelhoff et al, 1989) (Table 8) (Fig 4).Amoxicillin and metronidazole three times daily forone week parallel to mechanical subgingival in-strumentation are effective againstA. actino- mycetemcomitansin aggressive periodontitis,periodontitis in Papillon-Lefvre syndrom, gener-alised severe chronic and refractory periodontitis(Slots and Ting, 2002). However, this combina-tion is not effective againstPseudomonasand en-terobacteria, which are found in approximately

14% of advanced lesions in the USA. Culturaltests for the detection of subgingival pseudomon-ads and enterobacteria is available commercial-ly. In patients who are allergic to penicillin, amox-icillin may be replaced by the gyrase inhibitorciprofloxacin. Ciprofloxacin and metronidazolealso are effective againstPseudomonasand en-terobacteria (Slots and Ting, 2002). These com-binations of bactericidal antibiotics result in stableclinical and microbiological long-term results.Detection of periodontal pathogens alone aftercombined mechanical and systemic antibiotic ther-apy is no indication for renewed systemic antibi-otic therapy if clinical results are favourable. Notonly occurrence but also counts of e.g. A. actino-mycetemcomitansand P. gingivalisat a single siteare decisive for further attachment loss. An elevat-ed risk of further attachment loss is associated withbacterial counts of at least 3 x 104 for A. actino- mycetemcomitansand of 6 x 105 for P. gingivalis,respectively (Haffajee et al, 1983).To achieve optimal efficacy the intake of systemicantibiotics should start immediately after mechani-cal instrumentation is finished and, thus, the biofilmis disintegrated (Beikler et al, 2003). It should bekept in mind that, after adjunctive systemic antibi-otic therapy, maintenance of effective individualhygiene by the patient and compliance with sup-portive periodontal therapy are required to main-tain a stable periodontal status on long-term.Independently from microbiological detection of pe-riodontal pathogens before therapy systemic intakeof 250 mg tetracycline four times daily parallel tononsurgical instrumentation in patients suffering fromsevere periodontitis for a period of three weeks

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Fig 4a,b Combined mechanical and an-tibiotic therapy of a periodontal lesion in-fected byActinobacillus actinomycetemcomitans: a) subgingival deposits includ-ing A. actinomycetemcomitansareremoved from the root surface. The antibi-otic kills A. actinomycetemcomitans withinthe soft tissues. Mechanical instrumenta-tion destroys the biofilm,b) resolution of infection, remission of in-flammation and establishment of a longepithelial attachment.

Table 8 Adjunctive systemic antibiotic therapy ofActinobacillus actinomycetemcomitans(van Winkelhoff etal, 1989; Beikler et al, 2003).

Standardamoxicillin375500mgmetronidazole250400mg

Allergic to penicillinciprofloxacin250mgmetronidazole250500mg

3x daily for one week parallel to mechanical

therapy (subgingival instrumentation)


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resulted in more favorable clinical results (attach-ment gain) than mechanical therapy alone. Over aperiod of 12 years after therapy attachment losswas observed in both groups. However, the tetra-

cycline group maintained better clinical results forthe whole observation period (Ramberg et al,2001). In contrast to metronidazole, tetracycline isan antibiotic that does not play an important role ingeneral medicine. However, tetracycline maycause systemic adverse effects, e.g. photosensitivi-ty. Hence, for adjunctive application of antibioticsin nonsurgical treatment of severe periodontitis thatis not associated withA. actinomycetemcomitansperhaps topically subgingival application of antibi-otics may be favoured.

Periodontal Abscess with Tendency to SpreadTherapy of choice in localised and generalised pe-riodontal abscesses is subgingival instrumentationof the affected pocket or pockets under local anes-thesia. This type of therapy eliminates the acutecause of the process and provides marginal pusdrainage. After mechanical instrumentation subgin-gival irrigation with 0.1 to 0.2% chlorhexidine so-lution or instillation of 1% chlorhexidine gel are ap-propriate. If the respective site is controlled, remis-sion of complaints is mostly found the following dayand consequent case-related therapy of the causeof abscess (vertical root fracture, subgingival foodimpaction, subgingival infection in deep pockets,furcation involvement, infrabony defects, or margin-al epithelial attachment after superficial instrumenta-tion with persisting subgingival infection) may beinitiated (systematic periodontal therapy, resectivefurcation therapy). However, systemic antibiotictherapy adjunctive to local treatment is required inthose rare cases in which a spreading of the ab-scess into adjacent compartments threatens or feverand/or significant lymphadenopathia is found (an-tibiotic of first choice: amoxicillin with clavulanicacid 500 mg 3 p.d.; in cases of penicillin intoler-ance: clindamycin 300 mg 3 p.d.) (Wagner andShah, 2002).

LOCAL ANTIBIOTIC THERAPY

Theriskof causing allergies and the developmentof resistencies (development of bacteria that areno longer sensitive to a particular antibiotic) be-long to the disadvantages of use of antibiotics in

general and in periodontal therapy. Thus, in perodontics ideally only antibiotics that do not plaan important role in general medicine, and particularly intensive care, should be used (e.g. tetrcyclines). However, systemic use of antibiotics hfurther disadvantages: systemic adverse even(e.g. drug exanthema) (Fig 5) and effects on extraoral bacteria (e.g. enteric flora). These disadvantages have led to the development of local applications of antibiotics which are intended to eclusively affect bacteria within the periodontpocket. Sulcus fluid flow causes an exchange othe volume of a 5 mm deep pocket 40 times anhour (Goodson, 1989). This high rate of ex-change results in a rapid dilution of the concentration of subgingivally applied agents. Henceapplications had to be developed that establish astable subgingival depot from which effective atibiotic concentrations are released continuouslLocal subgingival delivery devices that release aactive agent (antibiotic) for up to 24 hours arecalled sustained release devices. In contrast,controlled release devices set free effective con-centrations for more than 24 hours (AmericaAcademy of Periodontology, 2000a).Local application of antibiotics aims at three tagets: 1) Support of nonsurgical mechanical antiifective therapy (application adjunctive to scalinand root planing to increase the efficacy of therapy), 2) support of reinstrumentation during suportive periodontal therapy (application adjuntive to scaling and root planning to increase thefficacy of therapy), and 3) as alternative to subgingival reinstrumentation during supportive podontal therapy (application instead of scalingand root planing to achieve the same effect)

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Fig 5 Drug induced exanthema (red rush) after systemicintake of amoxicillin.


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A meta-analysis comparing the efficacy of surgicaland nonsurgical periodontal therapy with or with-out topical subgingival application of antibioticsdemonstrated better clinical results after topicalsubgingival antibiotics adjunctive to nonsurgicalmechanical therapy than after mechanical instru-mentation alone (Hung and Douglass, 2002).For adjunctive systemic antibiotic therapy aimed atspecific periodontal pathogens, metronidazole (theantibiotic of first choice in anaerobic infections) andciprofloxacin may be used. These are antibioticsthat have important significance in general medi-cine. However, these antibiotics regularly are usedonly for one therapy cycle. Local antibiotics possi-bly are used again and again within the same pa-tient over years of supportive periodontal therapy.Thus, only those antibiotics should be used for localapplication that have no or only minor significancein general medicine and particularly intensive care(e.g. tetracyclines).One of the first available devices was theActisitefiber (not available any more), a nonresorbablemonolithic ethylene vinyl acetate polymer fibre( 0.5mm, length 35cm) that was loaded with25% tetracycline HCl. After mechanical instrumen-

tation of the lesion the tetracycline fiber was placedsubgingivally using a periodontal probe or a re-traction fibre applicator (Fig 6). Finally the pockethad to be closed using cyanoacrylate to prevent ex-pulsion of the fibre by crevicular fluid flow (Fig 6c).The fibres have to be removed in a second ap-pointment seven to 13 days after application. Thetetracycline fibre had good pharmacokinetic prop-erties: for a period of seven days after applicationa mean tetracycline concentration of more than1300 g/ml was detected (controlled release de-vice) (Tonetti et al, 1990). One Actisite fibre is suf-ficient for the treatment of three to five lesions, de-pending on depths and extension of the respectivepockets. However, application is difficult and time-consuming. Additionally, a second appointment isrequired to remove the device. Thus, slow-releasedevices were sought that on one hand can be eas-ily applied and on the other hand are bioab-sorbable. A bioabsorbable slow-release device isElyzol 25% dental gel (Colgate-PalmoliveCompany, New York, NY, USA). The gel consistsof 250mg metronidazole benzoate in a matrix con-sisting of glyceryl mono-oleat and sesame oil in 1ggel (Norling et al, 1992). The gel comes in cap-sules or disposable applicators (Fig 7). Two appli-cations of the agent with a one-week interval arerecommended. On contact with crevicular fluid thegel is transformed into a highly viscous and adhe-sive substance. While dissolving, the agent contin-uously releases metronidazole. However, concen-tration of metronidazole in crevicular fluid drops ex-ponentially after application of the gel (Stoltze,1992). One applicator provides material for thetreatment of three to five lesions, depending ondepth and extent of periodontal pockets.

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Fig 6ac Actisite fibre: persisting pocket mesiolingual of a second maxillary left molar during supportive periodontal apy: a) probing pocket depth 7 mm, b) subgingival application of actisite fibre, c) closure of pocket using cyanoacryl

Fig 7 Applicator for Elyzol dental gel.


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Minocycline ointment(Dentomycine, Lederle, UK;Periocline, Sunstar, Japan) is a biodegradableagent consisting of 2% minocycline HCl in a matrixof hydroxyethyl-cellulose, aminoalkyl-methacrylate,triacetine and glycerine. The ointment is instilledsubgingivally, using a special applicator. The agentis biodegradable and releases minocycline duringbiodegradation.

Minocycline microspheres(Arestine, OraPharmaInc., Warminster, PA, USA) is a powder of micros-pheres that encapsule minocycline hydrochloride ina bioabsorbable polymer (polyglycolide-co-DHLIlactide). This powder is dispensed subgingivally tothe base of the pocket by means of a disposableplastic cartridge affixed to a stainless-steel handle.Immediately upon contact with moisture, the poly-mer begins to hydrolyse and to release minocycline(Williams et al, 2001).

PerioChip (Dexxon Ltd., Hadera, Israel) is a bio-absorbable slow-release device that is not loadedwith an antibiotic but with an antimicrobial agenThe chip has a square shape with round edges atone of the short sides with 5 mm length, 5 mmwidth and 1 mm thickness (Fig 8a). The bioabsorbable matrix consists of gelatine glutaraldehypolycondensate, glyceryl and purified water. Thvehicle is loaded with 34% chlorhexidine-bis-D-conate. Periochip is applied using dental forcep(Fig 8bd). After contact with fluids the chip bcomes very sticky. Thus, sometimes under applition it must be sheared off the forceps into thpocket with another instrument. One PerioChican be used for the treatment of one lesion.There are two slow-release devices for topical sugingival application using doxycycline as active atibiotic agents.Atridox (Atrix Laboratories, FortCollins, CO, USA) is a bioabsorbable gel contain

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Fig 8ad PerioChip: persistingpocket buccal of a lateralmandibular left incisor during sup-portive periodontal therapy: a)probing pocket depth 6 mm, b)PerioChip, c) subgingival applica-tion of PerioChip using a dentalforceps, d) PerioChip in situ.


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ing 10% by weight doxycycline, 33% by weightpoly (DL-lactide) and 57% by weight N-methyl-2-pyrrolidone. The antibiotic agent comes as powderthat has to be mixed with the polymer immediatelybefore use (Fig 9ac). Having contact with tissue flu-

id the light-flowing gel is applied using a blunt sy-ringe, which transformes it to a highly viscous sub-stance (Fig 9d). The syringe is pushed to the bottemof the pocket and, moving the syringe slowly coro-nally, gel is pressed into the pocket until overflow isvisible at the gingival margin. After this overflow hashardened it can be pushed apically into the pock-et. In some cases the highly viscous gel does not de-grade totally and remnants have to be removed us-ing a curette at another appointment (Fig 10, 11).Another 14% doxycycline gel for topical subgingi-val use, based on a synthetical biodegradable poly-mer vehicle, has been evaluated (Eickholz et al,2002; Kim et al, 2003). Pharmacokinetic profilesof both agents are comparable: five days after sub-gingival application of the 14% doxycycline gelwithout closure of the pocket concentration increvicular fluid was 126.47 38.10 g/ml (Kimet al, 2002). Five days after subgingival applica-tion of Atridox with closure of the periodontal pock-ets using tissue glue or dressing doxycycline con-centration in crevicular fluid was 361.92 92.32g/ml and 533.37 202.19 g/ml, respective-ly (Stoller et al, 1998). Eight days after subgingival

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Fig 9ad Atridox: a) from above to below: application syringe containing the polymer, syringe containing the doxycycline powder, blunt needle, b) syringes with polymer and doxycycline screwed together for mixing, c) application syringe with gel mixed from polymer and doxyxycline powder, d) subgingival application of Atridox gel.

Fig 10 Atridox 14 days after subgingival applicationand gingival recession.


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penicillin

bactericidal, mainly active against gram-positive bacteria;adverse effects: hypersensitivity (0.6% to10%), Herxheimer reaction

amoxicillinbroad spectrum,-lactamase sensitive;adverse effects: gastrointestinal distur-bances, diarrhea, skin reactions (exanthe-ma) in 20% of cases; colitis ulcerosa

amoxicillin & clavulanic acidbroad spectrum,-lactamase stable;adverse effects: as amoxicillin

tetracyclines

bacteriostatic, broad spectrum, collage-nase inhibitory effect, numerous bacterialresistancies;

adverse effects: photosensitivity reactions,gastrointestinal disturbances, oral candidi-asis, allergic reactions are uncommon, athigh doses: hepatotoxicity and nephrotox-icity; permanent discolouration of teeth iftaken during tooth formation; reversiblevertigo (only minocycline)

tetracycline 4 doses a day

minocycline semisynthetical tetracycline derivative;2 doses a day

doxycycline strongest collagenase inhibitory effect ofall tetracyclines; 1 dose a day

metronidazole

bactericidal, active against strict anaero-bic bacteria, synergistic effect with amoxi-cillin againstA. actinomycetemcomitans;adverse effects: metallic taste, vertigo,nausea (12%), disulfiram (antabus) reac-tion, at high doses peripheral neuropathyCave: important antibiotic in generalmedicine

clindamycinbacteriostatic;adverse effects: diarrhea, gastrointestinaldisturbances (thus, intake together withfood recommended); colitis ulcerosa

ciprofloxacin(fluoroquinolone)

bactericidal;adverse effects: gastrointestinal distur-bances, diarrhea, nausea, vomiting, oralcandidiasis, headaches, dizziness,drowsiness, insomnia, allergic reactions,hyperpigmentation, photosensitivity;

Cave: important antibiotic in generalmedicine

Table 9 Antibiotics in peri-odontal therapy (Ciancioand van Winkelhoff, 2001).


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application the respective values were 115.25 37.83 g/ml (14% doxycycline gel) (Kim et al,2002) and 36.32 14.02 as well as 15.72 10.73 g/ml (Atridox) (Stoller et al, 1998). Directcomparison of both agents in a further study con-firmed these results (Kim et al, 2004). Thus, bothagents may be classified as controlled-release de-vices.Efficacy of local antibiotics was mostly studied inchronic periodontitis. Patients with chronic and ag-gressive periodontitis were included only in a fewclinical trials (Eickholz et al, 2002; Kim et al,2003). Topical subgingival application adjunctiveto nonsurgical instrumentation of untreated and re-current pockets resulted in better clinical results thanmechanical therapy alone or after adjunctive topi-cal application of the vehicle gel (placebo): 2%minocycline ointment (van Steenberghe et al,1993; 1999), PerioChip (Soskolne et al, 1997),minocycline microspheres (Williams et al, 2001),25% metronidazole (Stelzel and Flores-de-Jacoby,2000), 14% doxycycline gel (Eickholz et al,2002). Whereas a single application of 14%doxycyline gel was sufficient to achieve these re-sults after six months (Eickholz et al, 2002), up tothree PerioChips had to be applied into singlepockets over the observation period of nine months(Soskolne et al, 1997). Early studies on minocy-cline microspheres showed more favorable probingdepth reduction for minocycline adjunctive to me-chanical therapy than for mechanical debridementalone. However, more attachment gain was obser-ved after exclusivly mechanical therapy than afteradjunctive minocycline (Jones et al, 1994). A recent-ly published systematic review reveals an additionalbenefit of use of subgingivally delivered topical an-

tibiotics regarding probing depth reduction but notregarding attachment gain (Hanes and Purvis,2003).For therapy of persisting or recurrent pockets duringsupportive periodontal therapy (SPT), topical sub-gingival application of antibiotics adjunctive to me-chanical instrumentation resulted in better clinicaloutcomes after use of Actisite (Kinane and Radvar,1999) and minocycline microspheres (Meinberg etal, 2002), wheras adjunctive use of 25% metron-idazole failed to show an additional benefit (Stelzeland Flores-de-Jacoby, 2000). After exclusivly sub-gingival application of slow-release devices fortreatment of persisting or recurrent pockets duringSPT, insignificantly inferior or equally clinical resultswere reported in comparison to scaling and rootplaning: Elyzol (Stelzel and Flores-de-Jacoby,1992), Atridox (Garrett et al, 1999), 14% doxy-cycline gel (Kim et al, 2003).Use of local antibiotics seems to be appropriate,particularly for SPT, in patients who exhibit persist-ing pathological pockets (probing depths 5 mmwith bleeding on probing) after accomplishment ofactive periodontal therapy (root surfaces free ofmineralised deposits). In these patients repeatedsubgingival scaling in the long term may result inhard-tissue loss and often root sensitivity. Use ofsubgingivally applied slow-release devices maybe a possible strategy to avoid this discomfort andto treat persisting pockets with a concept differentfrom the mechanical therapy that had failed to re-solve pockets at those respective sites.Anti-infectious therapy of untreated periodontitis bylocally subgingival application of doxycycline geland mechanical instrumentation of root surfaceshas been proposed recently under the name

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Fig 11a, b Atridox 14 days aftersubgingival application: a) the fas-tened agent in situ, b) after re-moval by a curett.


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Garrett S, Johnson L, Drisko CH et al. Two multi-center studiesevaluating locally delivered doxycycline hyclate, place-bo control, oral hygiene, and scaling and root planingin the treatment of periodontitis. J Periodontol 1999;70:490503.

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Wagner W, Shah PM. Einsatz von Antibiotika in der zah-nrztlichen Praxis. Stellungnahme der Deutschen Gesell-schaft fr Zahn-, Mund- und Kieferheilkunde (DGZMK).Dtsch Zahnrztl Z 2002;57:451454.

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of locally delivered doxycycline in non-surgical treatmentof chronic periodontitis. A comparative multicentre trial of2 treatment approaches. J Clin Periodontol 2001;28:753761.

Williams RC, Paquette DW, Offenbacher S et al. Treatmentof periodontitis by local administration of minocycline mi-crospheres: A controlled trial. J Periodontol 2001;72:15351544.

Reprint requests:Dr Peter EickholzDepartment of PeriodontologyCenter for Dental, Oral, and Maxillofacial

MedicineHospital of Johann Wolfgang Goethe UniversityFrankfurtTheodor-Stern-Kai 7D-60590 FrankfurtGermanyEmail: [email protected]

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Antibiotics Inthe Treatment of Periodontal Disease

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