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Periodontology 2000, Vol. 28, 2002, 106–176 Copyright C Munksgaard 2002Printed in Denmark ¡ All rights reserved

PERIODONTOLOGY 2000ISSN 0906-6713

Systemic antibiotics in thetreatment of periodontal diseaseJØRGEN SLOTS & MIRIAM TING

Periodontitis in many patients is a lifelong diseasecharacterized by periods of exacerbation and re-mission. In most patients, mechanical debridementand anti-infective chemotherapy can readily controlthe disease without the need for surgery. A subset ofpatients with more severe periodontitis may requiresurgery, which results in almost complete cure of theinfection, at least temporarily. Properly managed,virtually all periodontitis patients can retain theirdentition for a lifetime.

Current periodontal therapy strongly emphasizessuppressing or eradicating specific periodontalpathogens (116, 119). However, present treatmentmodalities differ in their ability to eliminate peri-odontal pathogens. Nonsurgical scaling and rootplaning may remove subgingival Campylobacter rec-tus (94) but is frequently ineffective against Porphyr-omonas gingivalis, Prevotella intermedia, Bacteroidesforsythus, staphylococci and enteric rods (27, 68, 87,92, 106), and may not significantly reduce Actino-bacillus actinomycetemcomitans (95, 123, 143) orPeptostreptococcus micros (93). Mechanical debride-ment may fail to remove pathogenic organisms be-cause of their location in subepithelial gingival tissue(A. actinomycetemcomitans) (16, 86), crevicular epi-thelial cells (A. actinomycetemcomitans, P. micros, P.intermedia and P. gingivalis) (24, 33, 49, 98), colla-genous substrata (P. gingivalis) (75), altered ce-mentum and radicular dentinal tubuli (2, 37), sub-gingival hard deposits (105) or furcations or otheranatomic features complicating adequate instru-mentation. Moreover, periodontal pathogens fre-quently colonize oral mucosa, tongue dorsum, ton-sils and other oral domains and may translocatefrom non-periodontal sites to periodontal crevices(70, 74, 89, 120).

During the past two decades, dentists and micro-biologists have embraced periodontal antibiotictherapy as the evidence for bacterial specificity inperiodontitis has accumulated and strengthened(108, 110). Antibiotics, defined as naturally occurring

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or synthetic organic substances that, in low concen-trations, inhibit or kill selective microorganisms, areparticularly useful in combating severe periodontalinfections. Systemic antibiotics enter the periodontaltissues and the periodontal pocket via serum andcan affect organisms outside the reach of cleaninginstruments or topical anti-infective chemothera-peutics. Systemic antibiotic therapy can also poten-tially suppress periodontal pathogens residing onthe tongue or other oral surfaces, thereby delayingsubgingival recolonization of pathogens (69). Sys-temic antibiotics may even be required for eradi-cation of periodontal infections by A. actinomyce-temcomitans and other pathogens (71).

Practitioners have traditionally chosen the anti-microbial agents, route of administration and dur-ation of use based more on personal bias and experi-ence than on data from microbiological studies andrigorous clinical trials. However, because the peri-odontopathic microbiota includes a variety of micro-organisms with differing antimicrobial susceptibility,because clinical disease features can only rarely in-criminate the offending bacteria and because inap-propriate antibiotic therapy may adversely affect hu-man microbial ecology and give rise to resistancedevelopment among serious pathogens, microbio-logical analysis and antimicrobial susceptibility test-ing should ideally form the basis for selecting theoptimal antimicrobial therapy (9, 21, 26, 32, 91, 124,126). Antibiotic-resistant bacteria can emerge by ac-quiring new genes via transposons or horizontalgene transfer or by selection of resistant variants ornaturally resistant strains. Microbiological analysis isparticularly advisable in patients who are recalci-trant to conventional periodontal therapy and mayharbor a great variety of periodontal pathogens. Inaddition, the medical status of the patient and po-tential adverse effects of antibiotics are importanttherapeutic considerations.

Single drug therapies with penicillins, tetracyclines,metronidazole or clindamycin have been used fre-

Systemic antibiotics in the treatment of periodontal disease

quently in periodontal practice. However, since peri-odontitis lesions often harbor a mixture of pathogenicbacteria, drug combination therapies have gained in-creased importance (108, 109). Valuable combinationtherapies include metronidazole–amoxicillin for A.actinomycetemcomitans and various anaerobic peri-odontal infections (85, 143) and metronidazole–cip-rofloxacin for mixed anaerobic and enteric rod/Pseudomonas periodontal infections (111).

Knowledge of the efficacy and safety of periodontalantibiotic therapy is growing rapidly, but many im-portant aspects of the choice of medication, mode ofdelivery, dosage and length of therapy remain to bedetermined. This chapter therefore attempts to de-scribe the potential of systemic antibiotic therapy tocontrol the periodontopathic microbiota and de-structive periodontal disease rather than comprisinga comprehensive state-of-the science report thatprobably soon would be outdated anyway.

This chapter evaluates the utility of systemic anti-biotics in the treatment of moderate to severe typesof adult periodontitis and of some special clinicalsituations and makes recommendations for therapy.However, because destructive periodontal diseasehas variable clinical manifestations and often an un-predictable course, which makes evaluation of casereports and studies with small sample sizes or shortduration difficult, and because relatively few anti-biotic studies have been placebo-controlled, the spe-cific recommendations for antibiotic periodontaltherapy will unquestionably be revised along with

Table 1. Selected pharmacological features and common adverse reactions of antibiotics

ApproximatePeak Serum wholesale price

% absorption serum half-life Usual adult (generic) forafter oral level dosage Most common adverse dosage (oral) in one usual adult

Antibiotics administration in mg/ml in hours reactions, % occurrence periodontics dosage

Clindamycin 90 5 2.4 Diarrhea: 7% 300 mg three or $3.25four times daily

Metronidazole 90 20–25 6–14 Nausea/vomiting: 12% 250 three times $0.25daily or500 mg twice daily

Penicillins 75 5–8 1.2 Hypersensitivity (rash): 5% 250–500 mg three $0.25(amoxicillin) Diarrhea: 5% times daily

Tetracyclines 93 2–4 18 Photosensitivity 200 mg once daily $0.10(doxycycline) (sunscreen advised) (doxycycline)

Erythromycins 18–45 0.1–2 2–4 Diarrhea: 8% 250–500 mg three $0.25times daily

Azithromycin 37 0.4 12 Diarrhea: 5% 250–500 mg once $6.50 (250 mg)daily

Clarithromycin 50 2–3 5–7 Diarrhea: 3% 500 mg twice daily $3.50Photosensitivity

Fluoroquinolones 70 1.5 4 Nausea/vomiting: 5% 500 mg twice daily $3.75(ciprofloxacin) Photosensitivity

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the development of even better understanding of thepathogenic periodontal microbiota and the avail-ability of new drugs that are tested in placebo-con-trolled, long-term studies.

General considerations inantibiotic therapy

The pharmacological characteristics of antibioticsare critical in deciding their use, dosage and routesand frequency of administration. Important phar-macological determinants include the degree of ab-sorption, rate of metabolism and duration of effec-tive antimicrobial levels at the site of infection. Aspointed out by van Winkelhoff et al. (134), a suffi-ciently high dosage of metronidazole or other anti-biotics must be prescribed to ensure efficacy in peri-odontal treatment.

To maintain effective antimicrobial levels afteroral administration, penicillins and clindamycinmust be taken three times a day, metronidazole, cip-rofloxacin and erythromycin twice a day, and doxy-cycline and azithromycin suffice once a day (Table1). Tenenbaum et al. (125) showed that effectivelevels of amoxicillin and clavulanic acid in the gingi-val crevicular fluid, well above the minimal inhibi-tory concentrations of some periodontopathic bac-teria (P. intermedia), could be achieved after multipledrug applications. Metronidazole can readily attaineffective antibacterial concentrations in gingival

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Table 2. Adverse drug reactions in relation to patient age

Age Drug Reactions Comments

Pregnancy Clindamycin None known Probably safe– fetal toxicity Metronidazole Perhaps teratogenic Avoid

Penicillins None known Probably safe

Tetracyclines Discoloration and hyperplasia of teeth and Contraindicateddepressed skeletal growth

Erythromycins Chlorithromycin may cause fetal toxicity in primates Avoid

Fluoroquinolones Arthropathy in animals Contraindicated

Children All antibiotics Adjust dosage to avoidexcessive concentrations

Tetracyclines Discoloration and hyperplasia of teeth and Contraindicateddepressed skeletal growth

Fluoroquinolones Cartilage toxicity in young animals Contraindicated

Elderly adults All antibiotics Advanced age may be associated with alteredpharmacokinetics of antibiotics

Clindamycin Increased frequency of pseudomembranous colitis

Penicillins Increased frequency of anaphylaxis due toprior exposure

tissue and crevicular fluid (13, 51, 129). The macro-lide antibiotic roxithromycin (23) and spiramycinand metronidazole, which are combined in Rodo-gylA (97), can also reach effective antimicrobiallevels in gingival tissue and crevicular fluid. Azithro-mycin exhibits excellent ability to penetrate intoboth normal and pathological periodontal tissues(12, 64). Fluoroquinolones also penetrate readily intoperiodontal tissue and gingival crevicular fluid andmay reach even higher concentrations than in serum(10, 20, 43, 84). In contrast to earlier studies, Sakkela-ri et al. (100) found that the average concentrationof systemically administered tetracyclines in gingivalcrevicular fluid was less than in plasma and variedwidely among individuals (between 0 and 8 mg/ml),with approximately 50% of samples not achievinglevels of 1 mg/ml, possibly explaining much of thevariability in clinical response to systemic tetracy-clines observed in practice.

Food does not influence the bioavailability ofmost oral antimicrobial agents, except for tetracy-clines, quinolones and azithromycin. These threegroups of antibiotics should be given 1 hour beforeor 2 hours after food intake.

Systemic antibiotics can give rise to a number ofadverse reactions and should be administered onlyafter proper indication has been determined. Table1 lists the frequency of the most common adversereactions of antibiotics used in periodontal treat-ment. Serious adverse reactions are fortunately rareand are discussed elsewhere (136).

Cost can be a determinant in selecting anti-

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microbial periodontal therapy. Table 1 shows the av-erage wholesale prices in US dollars for antibioticsin the United States in spring 1999. Antibiotics in thelower-cost group include tetracyclines, amoxicillinand metronidazole. Antibiotics in the higher costgroup include azithromycin, clarithromycin, cipro-floxacin, amoxicillin/clavulanic acid and clinda-mycin.

The possibility of unique age-related adverse ef-fects is an important consideration in prescribingantibiotics. Prescribing antibiotics to pregnantwomen is a cause for particular concern. Table 2 listsage-related safety issues of antibiotics commonlyused in periodontal therapy.

Many antibiotics may interact with other drugsand cause clinically significant effects (Table 3). In-teraction occurs when one drug alters the otherdrug’s pharmacokinesis with respect to absorption,distribution, metabolism or excretion. The list ofdrug–drug interactions keeps expanding and is toolong to be memorized. Patients on long-term medi-cation for cardiovascular disease, asthma, seizures ordiabetes are at particularly high risk for drug–druginteractions.

Effectivess of systemic antibiotics inperiodontal therapy

This chapter concentrates on studies that haveevaluated the utility of systemic antibiotic treat-ments commonly employed in periodontics. The


Table 3. Antibiotic drug–drug interactions

ClinicalAntibiotic Interacting drug Effect significance

Clindamycin Anti-diarrheal agents (kaolin) Decreased absorption of clindamycin Probable

Muscle relaxants (diazepam) Increased frequency and duration of respiratory Probableparalysis

Erythromycin Mutual antagonism Probable

Metronidazole Barbiturates and hydantoins Decreased effectiveness of metronidazole Probable

Oral anticoagulants (warfarin) Increased anticoagulant effect Definite

Ethanol Disulfiram-like (AntabuseA) reaction Probable

Disulfiram (AntabuseA) Acute toxic psychosis Probable

Penicillins/ Probenecid Increased levels of penicillins Probableamoxicillin

Tetracyclines/ Antacids, aluminum, bismuth, Decreased absorption of tetracyclines due to Probabledoxycycline iron, Mgππ chelation

Barbiturates and hydantoins Decreased serum half-life of doxycycline Probable

Carbamazepine (TegretolA) Decreased serum half-life of doxycycline Probable

Digoxin Increased serum levels of digoxin Probable

Erythromycins/ Carbamazepine Increased serum levels of carbamazepine: Definiteazithromycin/ nystagmus, nausea, vomiting and ataxiaclarithromycin

Cisapride Increased cisapride concentration, with the risk Definiteof life-threatening arrhythmia

Cyclosporine Increased serum levels of cyclosporine, Probablewith toxic effects

Methylprednisolone Increased steroid concentration Definite

Nonsedating antihistamines Increased antihistamine concentration, Definite(terfenadine, astemizole) with the risk of life-threatening arrhythmia

Theophylline Increased serum levels of theophylline, Definitewith nausea, vomiting, seizures and apnea

Oral anticoagulants (warfarin) Increased anticoagulant effect Probable

Fluoroquinolones Cations (Alπππ, Caππ, Feππ, Decreased absorption of fluoroquinolones Definite(ciprofloxacin) Mgππ, Znππ) in antacids, due to chelation

vitamins and dairy products

Caffeine Increased caffeine concentration Probable

Cimetidine Increased serum levels of fluoroquinolones Probable

Cyclosporine Increased serum levels of cyclosporine Probable

Nonsteroidal Increased risk of central nervous system stimulation Definiteanti-inflammatory drugs

Probenecid Decreased ciprofloxacin clearance Probable

Sucralfate Decreased absorption of fluoroquinolones Definite

Theophylline Increased serum levels of theophylline Definite

Oral anticoagulants (warfarin) Increased anticoagulant effect Probable

studies selected originate from a variety of researchcenters and include patients with chronic as well asaggressive periodontitis. Table 4 presents an over-view of the antibiotic therapies examined, the studydesigns and the clinical and microbiological vari-ables studied.

Effect of systemic antibiotic therapyon clinical variables

Systemic antibiotic therapy does not significantly af-fect supragingival plaque accumulation (Table 5).

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Reduction in dental plaque depends mostly on pa-tients’ oral hygiene efforts. However, Ng & Bissada(76) reported that systemic doxycycline administra-tion for 6 weeks was associated with significantly re-duced plaque accumulation at week 12 posttreat-ment compared with placebo.

Systemic antibiotics might not have a significanteffect on gingival inflammation, with the possibleexception of metronidazole, doxycycline and me-tronidazole–amoxicillin combinations (Table 6).Watts et al. (139) found that 7 days of systemic me-tronidazole therapy significantly reduced the pro-portion of gingival bleeding sites compared with

Slots & Ting

Table 4. Overview of study designs on systemic antibiotic periodontal therapy

Number Systemicof subjects Periodontal antibiotic Periodontal Clinical Microbiological

Study (age) condition regimen treatment variables variables

LincosamidesGordon 20 Adult refractory Clindamycin- Patients with history of Number of active Not done

et al. (38) (31–69 years) periodontitis HCl 150 mg, unsuccessful treatment with sitesfour times daily, scaling, periodontal % active sites per7 days surgery, tetracycline 250 mg, subject

four times daily,% active sites per10–14 days, and at least onesubject per monthother antibiotic, including

penicillin V, ampicillin, % sites probingAugmentinA, 1–3 mmerythromycin, cephalexinand metronidazole

Patients were treated withscaling and clindamycintherapy

Gordon 13 Refractory Clindamycin- History of periodontal Number of active % spirocheteset al. (39) (31–67 years) periodontitis HCl 150 mg, therapy with extensive sites

four times daily, antibiotic therapy including % active sites per7 days tetracycline-HCl, a subject

penicillin compound,% active sites pererythromycin andsubject per monthcephalexin

Patients were treated withscaling and clindamycin

Eight patients participatedin microbial analysis

Side effects: one subjectdevelopedpseudomembranous colitis

MacrolidesAl-Joburi 79 (mean age: Advanced adult Spiramycin Subjects were randomly Plaque Index % spirochetes

et al. (4) 46 years) periodontitis 1,500,000 IU assigned to spiramycin, Number of sitestwice daily, tetracycline and placebo.Tetracycline: 27 bleeding on probing14 days Scaling and root planning

Spiramycin: 28 Probing depth for:started at baselinePlacebo, four Pockets 4–6 mmPlacebo: 24 Only data for placebo andtimes daily, Pockets Ø7 mm

spiramycin presented14 daysAttachment levelfor:Pockets 4–6 mmFor pockets Ø7 mm

Periotron readingsfor gingivalcrevicular fluid

NitroimidazolesAitken Doxycycline π Periodontitis Metronidazole Treatment in the previous % subjects with % sites positive for:

et al. (3) metronidazole: patients 250 mg, three 7 months included disease recurrence % A. actinomycetemcomitans11 previously times daily, bimonthly scaling with within 3 months E. corrodens(mean age: treated with 10 days (11 subjects) or without F. nucleatumGingival50 years) placebo or (12 subjects) 3 weeks of P. intermediaattachment level

doxycycline systemic doxycycline P. gingivalis spirochetesPlacebo π7 months agometronidazole: All patients receivedshowing12 thorough subgingivalcontinued(mean age: scaling, root planning andattachment loss54 years) prophylaxis and oralgreater than hygiene instruction2 mm

Only data from placebo andmetronidazole grouppresented

Clark 23 mentally Destructive Metronidazole Prophylaxis and root Gingival Index % spirocheteset al. (18) retarded periodontal 250 mg, three planning was not done. Attachment level

adolescents disease times daily, Subjects randomly assignedexcluding acute 7 days to antibiotic group ornecrotizing Placebo, three placebo groupulcerative times daily,gingivitis and 7 daysjuvenileperiodontosis

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Table 4. Continued



Gusberti 5 Recurrent Metronidazole History of scaling, root Plaque index % A. naeslundiiet al. (40) periodontal 250 mg, three planning and modified % A. odontolyticusBleeding on probing

disease times daily, Widman flap surgery % Capnocytophaga spp.Probing depth10 days followed by maintenance % E. corrodens

visits every 3–5 months % Fusobacterium spp.Attachment level% P. gingivalisScaling, root planning and% P. intermediaantibiotic treatment% spirochetes

Jenkins 10 (38–55 years) Advanced adult Metronidazole Supragingival and Plaque index % spirocheteset al. (45) periodontitis 200 mg, three subgingival debridement % streptococciProbing depth

times daily, and, 3 months later,Attachment level5 days antibiotic therapy and half-

mouth debridement

The experimental designallowed comparisonsbetween debridement only,metronidazole only anddebridement πmetronidazole

Lindhe 16 (32–48 years) Advanced adult Metronidazole Subjects randomly assigned % sites having: % spirocheteset al. (53) periodontitis 200 mg, four to antibiotic group or Plaque IndexΩ0

times daily for control group. Subjects Gingival IndexΩ0three periods of received a series of scaling Probing dept2 weeks treatments involving only Æ4 mmseparated by two quadrants of the

Attachment levelintervals of 8 dentitionweeks

Loesche 33 Advanced adult Metronidazole Scaling and root planning, Probing depth: % A. actinomycetemcomitanset al. (57) periodontitis 250 mg, three antibiotics or placebo For initial % A. naeslundiiTest: 15

times daily, probingÆ3 mm % A. odontolyticusNeed for periodontalControl: 18 7 days For initial probing % A. viscosussurgery or extraction4–6 mm % Fusobacterium spp.determined 4–6 weeks afterFor initial % P. gingivalisinitial treatmentprobingØ7 mm % P. intermedia

% S. sanguisAttachment level:% S. mutansFor initial% Selenomonas spp.probingÆ3 mm% Treponema spp.For initial probing% Veillonella spp.4–6 mm

For initialprobingØ7 mm

Number of teethrequiring surgery

% teeth requiringsurgery

Loesche Test: 29 Advanced adult Metronidazole Scaling and root planning Number of teeth Not doneet al. (58) (26–77 years) periodontitis 500 mg, twice followed by random requiring surgery

daily, 14 days assignment to control, and extractionPlacebo: 33simultaneously metronidazole or(31–71 years)with placebo, doxycycline grouponce daily, Only data for the first round14 days of metronidazole andPlacebo, twice control are presenteddaily, 14 dayssimultaneouslywith anotherplacebo, oncedaily, 14 days

Loesche Test: 18 Advanced adult Metronidazole Antibiotic therapy, multiple % teeth requiring Anaerobic species:et al. (59) periodontitis 250 mg, three visits for scaling, root surgery % F. nucleatumControl: 21

times daily, planning and oral hygiene % P. gingivalisProbing depths7 days instruction % P. intermedia

Attachment level % Selenomonas spp.Placebo, threetimes daily, Facultative species:7 days % A. actinomycetemcomitans

% A. naeslundii% A. viscosus% S. sanguis% S. mutans

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Table 4. Continued



Loesche 40 Moderate to Metronidazole All three groups received Number of % A. naeslundiiet al. (60) advanced adult 250 mg, three mechanical debridement pocketsØ7 mm per % A. odontolyticusAdvanced

periodontitis times daily, and oral hygiene subjects % A. viscosusdisease test7 days instruction % Capnocytophaga spp.group Number of sitesPlacebo, three % F. nucleatumAdvanced disease test with attachmentModerate times daily, % P. intermediagroup received antibiotics lossØ7 mmdisease test 7 days % P. gingivalis

group Moderate disease test group Pocket depth: % S. mutansand moderate disease For initial probing % S. sanguisModerateplacebo group were 4–6 mm % Veillonella spp.disease placeborandomly assigned in a For initial probinggroupdouble-blind fashion to .6 mmreceive antibiotics or Attachment level:placebo For initial probing

4–6 mmFor initial probing.6 mm

Lundström 4 Advanced adult Metronidazole Oral hygiene instruction, Probing depths % spirocheteset al. (63) periodontitis 200 mg, three subgingival debridementSufficient oral % bleeding sites

times daily, and antibiotic therapyhygiene group: 27 days Only data from patientsPoor oral

randomly chosen forhygiene group: 2metronidazole therapy werepresented

Nieminen 33 Advanced adult Metronidazole After initial nonsurgical Bleeding on probing % subjects, % microflora:et al. (77) periodontitis 250 mg, three therapy, patients were A. actinomycetemcomitansNumber of pockets:Surgery: 15

times daily, randomly assigned to either P. gingivalisProbing depthØ6Metronidazole: 10 days periodontal surgery mm18 (modified Widman flap) or Probing depth

systemic antibiotics Ω4–5 mmPost-treatment % subjects withunresponsive patients attachment lossreceived surgery orsystemic metronidazole,depending on which of theprocedures had alreadybeen given previously

Data for periodontalsurgery only and antibiotictherapy only werepresented

Noyan 10 (35–51 years) Adult Metronidazole Oral hygiene instruction Plaque Index % obligate anaerobeset al. (79) periodontitis 250 mg, threeTest: 5 Patients divided into two Gingival Index

times daily, groups (five patients each)Control: 5 Probing depth7 days consisting of a topicalAttachment lossantibiotic group and a

systemic antibiotic group.In the systemic antibioticgroup, subjects receivedscaling in two quadrantsand no scaling in theremaining two quadrants

Only data for systemicantibiotic group (test), andscaling and root planningonly group (control) werepresented

Palmer Test: 31 Moderate to Metronidazole Oral hygiene instruction, % sites with plaque % spirocheteset al. (82) (mean age: advanced adult 200 mg, three ultrasonic instrumentation, % bleeding sites

45 years) periodontitis times daily, followed by random% sites probing Ø77 days assignment to eitherControl: 27 mmsystemic or topical(mean age:

antibiotics or control group Attachment level51 years)Only data for systemicantibiotic and controlgroups were presented

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Table 4. Continued



Palmer Smoker Moderate to Metronidazole Oral hygiene instruction Proportion of sites % spirochetes at 6 monthset al. (83) treatment advanced adult 200 mg, three and subgingival scaling with plaque

groups: periodontitis times daily, Subjects randomly assigned % sites with plaquetest: 10 7 days to three groups: no further at 6 monthscontrol: 9 treatment group, systemic Proportion of sitesNonsmoker antibiotics group and with bleeding ontreatment topical antibiotics group probinggroups: Only data for systemic % bleeding sites at 6test: 21 antibiotics were presented monthscontrol: 18

Probing depth

Attachment level

Saxen & Asikainen Test: 9 Localized Metronidazole Oral hygiene instruction, % bleeding sites % subjects:(101) (14–25 years) juvenile 200 mg, three scaling and root planning A. actinomycetem-comitans% sites probing

periodontitis times daily, every 3 months, antibioticControl: 9 Ø4 mm10 days therapy, modified Widman(14–25 years) Number of sites:flap surgery performed at 6

with ,25% bonemonthsloss

Control: no medication with 25–48% boneOnly data for lossmetronidazole and controlgroups were presented

Söder et al. (121) Test: 46 Moderate and Metronidazole All patients received oral Mean number of Number of spirochetes per(35–45 years) advanced 400 mg, three hygiene instruction, sites Ø5 mm unit

periodontitis, times daily, professional cleaning andControl: 46 Mean probing Number of P. gingivalis–with more than 7 days deep scaling(35–45 years) depth positive patientsthree teeth with Placebo, three Reported side effects: Plaque Index Number of.5 mm pockets times daily, Test: 15 patients A. actinomycetemcomitans–and radiographic 7 days % subjects havingPlacebo: nine patients positive sitesalveolar bone more than three

Gastric discomfort:loss after scaling teeth with pocketsTest: six patientsand root Ø5 mmPlacebo: seven patientsplanning

Severe diarrhea:Test: one patient,metronidazole treatmentwas discontinued

Objection to the taste:Test: eight patientsPlacebo: one patient

Söder et al. (122) 64 (mean age: Advanced adult Metronidazole Comprehensive % teeth with: % subjects:36 years) periodontitis 400 mg, three professional prophylactic Plaque Index Ω2 A. actinomycetemcomitans

times daily, treatment, including scaling Plaque Index Ω3 P. gingivalisSmokers7 days and root planning, followed P. intermediaTest: 16 % teeth bleeding onPlacebo, three by antibiotics or placebo, % spirochetesPlacebo: 21 probingtimes daily, with or without periodontal

Nonsmokers Subjects surgically7 days surgery, and regularTest: 16 and non-surgicallymaintenance over 5 yearsPlacebo: 11 treated

% teeth withpockets Ø5 mm

Probing depth

Attachment level

% bone height

von Troil-Linden 10 (mean age: Advanced Metronidazole Scaling and root planning, % sites with plaque % patients:et al. (135) 56 years) periodontitis 500 mg, twice soft tissue curettage, A. actinomycetemcomitans% sites with gingival

daily, gingivoplasty when C. rectusbleeding7 days indicated, antibiotic P. gingivalis

% sites probingtherapy, twice daily P. intermedia/P. nigrescensÆ3 mmchlorhexidine rinse and P. micros

chlorhexidine gel in % sites with:interdental areas during and alveolar bone lossan additional week after ,1/3mechanical therapy alveolar bone loss

Ø1/2Spouse data were notpresented

Walsh et al. (138) Test: 6 Adult Metronidazole Test group: antibiotics only Plaque Index % Fusobacterium spp.(28–59 years) periodontitis 2 g single dose % obligate anaerobesScaling group: oral hygiene Bleeding Index

for treatment of % spirochetesScaling: 6 instruction, scaling and root Probing depthTrichomonas(23–53 years) planningvaginalis by Attachment loss

Control: 6 Control: no treatmentmedical staff(25–44 years)

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Table 4. Continued



Watts et al. (139) Test: 13 Adult Metronidazole Scaling and root planning % bleeding sites % spirochetesperiodontitis 200 mg, three followed by randomControl: 7

times daily, assignment to either7 days antibiotic or placebo groupPlacebo, threetimes daily,7 days

Winkel 27 (29–64 years) Refractory Metronidazole Supragingival and Plaque Index % subjects, % microflora:et al. (142) periodontitis, 500 mg, three subgingival debridement, Posttreatment B. forsythus inBleeding on probing

culture-positive times daily, antibiotic therapy. pretreatment B. forsythus–Probing depthfor B. forsythus 7 days Re-examination at positive subjects

and culture- 6 months Attachment level Posttreatment P. gingivalis innegative for pretreatment P. gingivalis–A. actino- positive subjectsmycetemcomitans

Posttreatment P. gingivalis inpretreatment P. gingivalis–negative subjects

Posttreatment P. intermediain pretreatmentP. intermedia–positivesubjects

Posttreatment P. intermediain pretreatmentP. intermedia–negativesubjects

PenicillinsAbu Fanas 4 Rapidly Amoxicillin Oral hygiene instruction, % sites bleeding on % F. nucleatum

et al. (1) progressive 250 mg with supragingival and probingperiodontitis clavulanic acid subgingival scaling and root Mean probing

(125 mg), three planning pocket depthtimes daily, Supragingival plaque14 days control was maintained

throughout theexperimental period, withfurther scaling and oralhygiene instruction ifnecessary

Collins 30 (23–70 years) Refractory Amoxicillin Patients with history of % sites: % subjects:et al. (19) periodontitis 250 mg with periodontal treatment Bleeding on probing A. actinomycetemcomitans

clavulanic acid (including periodontal Probing 0–3 mm E. corrodens(125 mg), four surgery and antibiotic Probing 4–6 mm F. nucleatumtimes daily, therapy) and progressive Probing .6 mm Capnocytophaga spp.14 days attachment loss or repeat C. recta

abscess development P. gingivalis

The refractory treatmentprotocol consisted ofsystemic antibiotic therapy,topical povidone–iodine, 3%hydrogen peroxide rinse toremove coronal staining,and twice-dailychlorhexidine (0.12%) rinse

All patients had alreadyreceived periodontalmaintenance within the last3 months and werecalculus-free at theinitiation of therapy

Haffajee 98 (14–71 years) Mild to Amoxicillin Subgingival scaling, Clinical data % sites:et al. (41) moderate 250 mg with modified Widman flap and presented in graphs, A. actinomycetemcomitans

periodontitis clavulanic acid antibiotics mean values not serotype a(125 mg), three given A. actinomycetemcomitansPatients with evidence oftimes daily, 30 serotype bprior attachment lossdays B. forsythus

Subjects with localized C. ochraceaPlacebo 250 mg juvenile periodontitis or P. gingivalissucrose, three rapidly progressive P. intermediatimes daily, periodontitis were not P. nigrescens30 days included

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Table 4. Continued



Winkel Test: 10 Generalized Amoxicillin Scaling and root planning, Mean Plaque Index% subjects, % microflora:et al. (140) (36–66 years) adult 500 mg with oral hygiene instruction. Bleeding on probing A. actinomycetemcomitansperiodontitis clavulanic acid Repeated oral hygieneControl: B. forsythusGingival Index(125 mg), three instruction, scaling and11 (28–47 years) F. nucleatumtimes daily, root planning and Mean probing P. gingivalis10 days antibiotic therapy at 6 pocket depth P. intermediaweeks after initial therapy

Clinical attachment P. microslevel spirochetes

TetracyclinesAbu Fanas 4 Rapidly Tetracycline-HCl Oral hygiene instruction, % sites bleeding on % F. nucleatum

et al. (1) progressive 250 mg, four supragingival and probingperiodontitis times daily, subgingival scaling and Mean probing

14 days root planning pocket depthSupragingival plaquecontrol was maintainedthroughout theexperimental period withfurther scaling and oralhygiene instruction

Al-Joburi 79 (mean age: Advanced adult Tetracycline Subjects were randomly Plaque Index % spirocheteset al. (4) 46 years) periodontitis 250 mg, four assigned to spiramycin, Number of sites

times daily, tetracycline and placebo.Placebo: 24 bleeding on probing14 days Scaling and root planning

Tetracycline: 27 Probing depth for:initiated at baselinePlacebo, four Pockets 4–6 mmSpiramycin: 28 times daily, Only data for placebo and Pockets Ø7 mm14 days tetracycline presented

Attachment levelfor:Pockets 4–6 mmPockets Ø7 mm

Periotron readingsof crevicular fluids

Atilla et 21 (37–52 years) Moderate to Minocycline-HCl Oral hygiene instruction at Bleeding Index Not doneal. (6) advanced adult 100 mg, once baseline. Patients werePeriodontally Mean probing

periodontitis daily, 14 days divided into two groupshealthy: 5 depthaccording to probing depth(39–55 years) Number of Ø6 mm(4 to 5 mm and 6 mm).

pocketsEach group was furtherdivided, with one group Number ofreceiving scaling and root epithelial cellsplanning only and the other

Salivary proteasegroup receiving scaling andactivityroot planning and

adjunctive antibiotics

Ciancio 19 (22–55 years) Gingivitis and/or Group 1: No information Gingival Index Not doneet al. (17) periodontitis minocycline-Group 1: 9 Plaque Index

HCl 100 mg,Group 2: 10 twice daily,

8 days

Group 2:minocycline-HCl 50 mg in themorning and100 mg in theevening for8 days

Feres et al. (30) 20 (Ø20 years) Adult Doxycycline Full-mouth scaling and root % sites with: Clinical data presented inperiodontitis 200 mg the first planning Plaque graphs, mean values notTest: 10

day and 100 mg Gingival redness givenEarly onset and refractoryControl: 10 each day Bleeding on probingperiodontitis excludedthereafter for Suppuration14 days Mean pocket depth

Mean attachmentlevel

Haffajee 98 (14–71 years) Mild to Tetracycline 250 Subgingival scaling, Clinical data % sites:et al. (41) moderate mg, three times modified Widman flap and presented in graphs, A. actinomycetemcomitans

periodontitis daily, 30 days antibiotics mean values not serotype agiven A. actinomycetemcomitansPlacebo: 250 mg Patients with evidence of

serotype bsucrose, three prior attachment loss wereB. forsythustimes daily, includedC. ochracea30 days Subjects with localized P. gingivalis

juvenile periodontitis or P. intermediarapidly progressive P. nigrescensperiodontitis wereexcluded

115

Slots & Ting

Table 4. Continued



Hellden 12 (27–42 years) Advanced adult Tetracycline 250 Subjects were randomly % sites: Not doneet al. (42) periodontitis mg, four times assigned to a test and Plaque IndexΩ0Test: 6

daily for 2 control group. The test Gingival IndexΩ0Control: 6 periods of 14 group received antibiotic Probing depth

days each. The therapy. Oral hygieneAttachment levelfirst period instruction followed by

extended from scaling and root planning ofday 0 to the end one half of the mouth inof week 2 and each subject. Maintenancethe other period post-antibiotic therapyfrom thebeginning ofweek 7 to theend of week 8

Lindhe 14 (37–52 years) Advanced adult Tetracycline 250 Double-blind, split-mouth % sites: % spirocheteset al. (52) periodontitis mg, four times study. Subjects were Plaque IndexΩ0Test: 7

daily for the first randomly assigned to two Gingival IndexΩ0Control: 7 2 weeks and groups, with one group % sites bleeding on

once daily for receiving long-term probingthe next antibiotics. Oral hygiene

% sites48 weeks instruction, scaling andProbing Æ4 mmroot planning of twoProbing Ø7 mmrandom quadrants of the

mouth Attachment level

Listgarten Test: 6 Advanced adult Tetracycline-HCl Oral hygiene instruction, Plaque Index % spirocheteset al. (56) periodontitis 250 mg, four and scaling and rootControl: 6 Gingival Index

times daily, for planning in half the mouth.Probing depth2 periods of One group received

14 days each antibiotic therapy and oneseparated by a group no therapy4-week interval

Loesche Test: 32 Advanced adult Placebo, twice Scaling and root planning, Number of teeth Not doneet al. (58) (27–72 years) periodontitis daily for 14 days followed by random requiring

simultaneously assignment to control, periodontal surgeryPlacebo: 33with doxycycline systemic metronidazole and and extraction(31–71 years)100 mg, once doxycycline groupsdaily, 14 days Only data for first round ofPlacebo, twice systemic doxycycline anddaily, 14 days control groups weresimultaneously presented.with anotherplacebo, oncedaily, 14 days

Lundström 5 Advanced adult Doxycycline 100 Oral hygiene instruction, Probing depths % spirocheteset al. (63) periodontitis mg, once daily, professional cleaning, % bleeding sites

14 days subgingival debridementand antibiotic therapy

Only data for patientsrandomly chosen fordoxycycline therapy werepresented

Mandell & 8 (13–22 years) Localized Doxycycline 100 No presurgical initial % sites bleeding on % patients, % sites:Socransky (65) juvenile mg, twice daily therapy or home care probing A. actinomycetemcomitans

periodontitis for the first day, instructions were given to Probing depththen 100 mg, the patients. Patients

Attachment levelonce daily for received surgical therapy13 days consisting of inverse bevel,

full-thicknessmucoperiosteal flapwithout osseousrecontouring, and antibioticcoverage. Re-sampling at3 months

Matisko 5 (12–70 years) Refractory Doxycycline 200 Patients were randomly Mean plaque score Mean values not given& Bissada (66) Doxycycline periodontitis: mg for the first assigned to antibiotic or Mean gingival score

only (control A. actino- day and then 100 control groups. Each group% sites:group in study) mycetemcomitans– mg, once daily, was further subdividedBleedingand/or for 10 days using a split-mouthSuppurationP. gingivalis– technique: half of the

associated mouth received one session Mean probingperiodontitis of root planning; the other pocket depth

half received no localMean probingtherapy. Patient’s oralattachment levelhygiene regimen was not

adjusted

Only data for antibiotic orcontrol groups werepresented

116


Table 4. Continued



Müller 33 (16–63 years) Advanced Minocycline-HCl Oral hygiene, weekly Bleeding on probing A. actinomycetemcomitans:et al. (72) A. actino- 200 mg, once prophylaxis, reinforcement % subjectsLocalized Probing depth

mycetemcomitans– daily, 21 days of oral hygiene, systemic % sitesjuvenile Attachment lossassociated antibiotic, subgingival % microfloraperiodontitis,periodontitis scaling and root planning,low plaque: 7

and twice-daily 0.1%(mean age:chlorhexidine digluconate25 years)rinse

LocalizedAt sites with .5 mmperiodontitis,remaining depth andplaque: 10bleeding on probing,(mean age:mucoperiosteal flaps were32 years)elevated and antibiotics

Generalized prescribed for anothersevere 2 weeksperiodontitis,

Patients were recalled forhigh plaque: 9prophylaxis every(mean age:2–3 months35 years)

Generalizedmoderateperiodontitis,low plaque: 6(mean age: 33years)

Ng & 32 (32–72 years) Generalized Doxycycline 200 Split-mouth design for Plaque Index Not doneBissada (76) moderate adult mg the first day scaling and root planning. Gingival Index

periodontitis and then 100 Subjects were randomlyProbing depthmg, once daily, assigned to the different

6 weeks treatment groups Attachment levelIbuprofen 800mg, once daily,6 weeks

Combineddoxycycline (200mg the first dayand 100 mg,once daily,thereafter) andibuprofen (800mg), once daily,6 weeks

Placebo, oncedaily, 6 weeks

Preus et al. (88) 10 (35–63 years) Moderate to Minocycline-HCl Scaling, root planning and Not done % colony-forming units:severe adult 50 mg in the systemic antibiotics Aerobic minocycline-periodontitis morning and resistant strainsOnly data for systemic

100 mg in the antibiotic therapy were Aerobic minocycline-evening for presented resistant strains10 days

Saxen & Test: 9 Localized Tetracycline Oral hygiene instruction, % bleeding sites % subjects:Asikainen (101) (16–24 years) juvenile 250 mg, four scaling and root planning A. actinomycetemcomitans% sites probing

periodontitis times daily, every 3 months, antibioticControl: 9 Ø4 mm12 days therapy, modified Widman(14–25 years) Number of sites:flap procedure performed

with ,25% boneat 6 months after initiallossexaminationwith 25–48% bone

Control: no medication lossOnly data for control andtetracycline were presented

Saxen et al. (102) 14 (14–25 years) Localized Doxycycline Test group: oral hygiene % sites probing % sites:juvenile 200 mg the first instruction, scaling and Ø4 mm A. actinomycetemcomitansTest: 7periodontitis day, then 100 mg, root planning, doxycycline % bleeding sitesPlacebo: 7 once daily for 200 mg on the first day, then

14 days 100 mg for 2 weeks

Placebo Placebo group: oral hygieneinstruction, scaling androot planning and placebo

Periodontal surgeryperformed after 2 monthsin some patients

117

Slots & Ting

Table 4. Continued



Slots & Rosling 6 (13–17 years) Localized Tetracycline-HCl Oral hygiene instruction, Plaque Index A. actinomycetemcomitans:(117) juvenile 250 mg, four scaling, root planning, % patientsGingival Index

periodontitis times daily, topical BetadineA solution % sitesProbing depth14 days (10% povidone-iodine) and Number of infected deep

systemic antibiotics and shallow pockets duringAttachment leveltetracycline therapy

Capnocytophaga spp.:% patients% sitesNumber of infected deepand shallow pockets duringtetracycline therapy

Combination therapy: metronidazole and amoxicillinBerglundh 16 (35–58 years) Advanced Metronidazole Oral hygiene instruction, Plaque Index % A. actinomycetemcomitans

et al. (11) periodontal 250 mg, three supragingival scaling, % P. gingivalisTest: 8 Bleeding on probingdisease times daily π subgingival scaling in only % P. intermedia

Control: 8 Pocket depthamoxicillin 375 one side of the mouth andmg, twice daily, antibiotic or placebo Probing attachment14 days therapy level

Flemmig Test: 18 A. actino- Metronidazole Supragingival and Not reported Number ofet al. (35) (mean age: mycetemcomitans– 250 mg, three subgingival scaling and root A. actinomycetemcomitans–

49 years) and/or times daily π planning, oral hygiene positive subjects:P. gingivalis– amoxicillin 375 instruction, together with or Oral cavityControl: 20positive mg, three times without systemic Subgingival plaque(mean age:periodontitis daily, 8 days antibiotics and daily 0.06% Oral mucous membranes54 years)

chlorhexidine digluconate Tonguerinse Tonsils

Buccal mucosa

Number of P. gingivalis–positive subjects:Oral cavitySubgingival plaqueOral mucous membranesTongueTonsilsBuccal mucosa

Flemmig Test: 18 (mean A. actino- Metronidazole Supragingival and Mean incidence (%) Number of patients:et al. (34) age: 49 years) mycetemcomitans– 250 mg, three subgingival scaling and root of 2 mm or more of A. actinomycetemcomitans

and/or times daily π planning, oral hygiene probing attachment onlyControl: 20P. gingivalis– amoxicillin 375 instruction, together with or level gain for A. actinomycetemcomitans(mean age: 54positive mg, three times without systemic subjects with and P. gingivalisyears)periodontitis daily, 8 days antibiotics and daily 0.06% A. actino- P. gingivalis only

chlorhexidine digluconate mycetemcomitansrinse regardless of

P. gingivalis

Mean incidence (%)of 2 mm or more ofprobing attachmentlevel gain forsubjects withP. gingivalis withoutA. actino-mycetemcomitans

Lopez & Test: 23 Moderate to Metronidazole Subjects were randomly % sites with plaque % sites:Gamonal (61) (mean age: advanced adult 250 mg, three assigned to receive A. actinomycetemcomitans% sites bleeding on

44 years) periodontitis times daily π antibiotics or placebo. No P. gingivalisprobingamoxicillin 375 effort was made to change P. intermediaPlacebo: 21 % active sitesmg, three times the oral hygiene habits of(mean age:daily, 8 days the patients % sites gaining44 years)

attachmentActive sites are sites losingØ2 mm in clinical Probing depthattachment level

Lopez et al. (62) 40 (36–68 years) Moderate to Metronidazole No effort was made to % sites: Not doneadvanced adult 250 mg, three change the oral hygiene with plaqueTest: 20periodontitis times daily π habits of the patients and Bleeding on probing

Placebo: 19 with Ø2 mm amoxicillin 500 no additional therapy was Active sitesattachment loss mg, twice daily, provided Gaining attachmentin Ø2 sites in the 14 days Mean attachmentprevious Placebo, three level2 months times daily, Mean probing

7 days depth

118


Table 4. Continued



Pavicic et al. (85) 48 A. actino- Metronidazole Supragingival and Plaque Index % subjects:mycetemcomitans– 250 mg, three subgingival debridement, A. actinomycetemcomitansBleeding Indexassociated severe times daily π oral hygiene instruction, P. gingivalis

% bleeding sitesperiodontitis amoxicillin 375 and antibiotic therapy P. intermediamg, three times Probing depthdaily, 7 days

% sites:Probing depth,5 mmProbing depth5–8 mmProbing depth.9 mm

Attachment level

van Winkelhoff 22 (14–44 years) A. actino- Metronidazole Subgingival scaling and % sites showing % subjects:et al. (132) mycetemcomitans– 250 mg, three antibiotic therapy bleeding on probing A. actinomycetemcomitansLocalized

associated times daily π P. gingivalisjuvenile Subjects with prior Probing depthperiodontitis amoxicillin 375 P. intermediaperiodontitis: 11 periodontal therapy: 14including mg, three times

Rapidly Subjects with no priorlocalized daily, 7 daysprogressing periodontal therapy: 8juvenileperiodontitis: 11 periodontitis Side effects:

and rapidly Severe diarrhea: 2 subjectsprogressiveperiodontitis

van Winkelhoff Localized A. actino- Metronidazole Supragingival and Pocket depth % subjects, % microflora:et al. (133) juvenile mycetemcomitans– 250 mg, three subgingival debridement, A. actinomycetemcomitansAttachment level

periodontitis: 28 associated times daily π oral hygiene instruction P. gingivalisBleeding index(mean age: periodontitis amoxicillin 375 and antibiotic therapy P. intermedia

27 years) including mg, three timeslocalized daily, 7 daysGeneralizedjuvenileadvanced adultperiodontitis,periodontitis: 50generalized(mean age:advanced adult36 years)periodontitis,

Refractory and refractoryperiodontitis: 50 periodontitis(mean age: 37years)

Winkel 22 (29–54 years) A. actino- Metronidazole Oral hygiene instruction, Plaque Index Number of subjects, meanet al. (143) mycetemcomitans– 250 mg, three supragingival and % microflora:Bleeding Index

positive times daily π subgingival scaling and root A. actinomycetemcomitansSuppuration Indexperiodontitis amoxicillin 375 planning and antibiotic B. forsythus

with either mg, three times therapy F. nucleatumProbing pocketP. gingivalis, daily, 7 days P. gingivalisdepthNumber of patients withB. forsythus or P. intermediaadverse effects: Clinical attachmentP. intermedia P. microsAny adverse effect: 17 levelco-infection Diarrhea: 10

Metallic taste: 4Headache: 4Nausea: 3

Winkel 49 (mean age: Generalized Metronidazole Scaling and root planning Plaque Index Number of subjects, meanet al. (141) 42 years) severe adult 250 mg, three with oral hygiene % microflora:Bleeding Index

periodontitis times daily π instruction. Six weeks later, A. actinomycetemcomitansTest: 23 Suppuration Indexamoxicillin 375 repeat scaling and root B. forsythus(mean age:mg, three times planning, reinforced oral F. nucleatumProbing pocket45 years)daily, 7 days hygiene instruction, and P. gingivalisdepth

Placebo: 26 antibiotic therapy or P. intermediaClinical attachment(mean age: placebo P. microslevel40 years)

Number of placebo grouppatients with adverseeffects:Any adverse effect: 2Rash on the face: 1

Number of test grouppatients with adverseeffects:Gastrointestinalintolerance: 9Rash on the face: 1Rash on the neck: 1Nausea after alcohol: 1Diarrhea: 1

119

Slots & Ting

Table 4. Continued



Combination therapy: various combinationsAitken et al. (3) Doxycycline π Active Test: Patients were treated 7 % subjects with % positive tests:

metronidazole: periodontitis doxycycline 200 months prior with disease recurrence A. actinomycetemcomitans11 mg the first day bimonthly scaling with within 3 months E. corrodens(mean age: and then 100 mg, either 3 weeks of systemic F. nucleatumGingival attachment54 years) once daily, doxycycline or placebo. P. intermedialevel

21 days, and Patients were monitored P. gingivalisPlacebo πmetronidazole for recurrent periodontitis spirochetesmetronidazole:250 mg, three and scaled every 2 months12times daily,(mean age: Patients with continued10 days53 years) periodontal destructionPlacebo: were entered into thislactose- prospective study. Thesecontaining patients receivedplacebo, once metronidazole therapydaily, 21 daysandmetronidazole250 mg, threetimes daily10 days

Matisko & 11 (12–70 years) Refractory Test: Patients were randomly Mean plaque score Mean values not givenBissada (66) periodontitis amoxicillin/ placed into test or controlTest: Mean gingival score

A. actino- clavulanic acid antibiotic treatment groups.doxycycline and % sites:mycetemcomitans– 500 mg, three Each group was furtheramoxicillin/ Bleedingand/or P. times daily, subdivided using a split-clavulanate: 6 Suppurationgingivalis– 5 days, and then mouth technique: one-halfControl: associated doxycycline 200 of each mouth received one Mean probingdoxycycline periodontitis mg the first day session of root planning; the pocket depthonly: 5 and 100 mg, once other half mouth received

Mean probingdaily, 4 days no local therapy. Patients’attachment levelusual oral hygiene regimenControl:

was not adjusteddoxycycline 200mg the first dayand 100 mg,once daily,10 days

controls. Ng & Bissada (76) reported that 6 weeks ofsystemic doxycycline therapy significantly decreasedgingival inflammation compared with placebo. Lop-ez & co-workers (61, 62) showed that metronidazole–amoxicillin combination therapy resulted in less gin-gival bleeding for up to 12 months compared withplacebo. It might be that systemic antibiotic therapyis ineffective against gingival inflammation related tosupragingival plaque but may help decrease gingi-vitis caused by susceptible subgingival microorgan-isms.

Several systemic antibiotic therapies have no sig-nificant impact on periodontal pocket depth com-pared with controls (Table 7). However, metronida-zole and its combination with amoxicillin constitutean important exception (Table 7). Noyan et al. (79)and Elter et al. (29) reported that 7 days of metronid-azole therapy reduced pocket depth significantlycompared with controls. Winkel et al. (141) showedthat 7 days of metronidazole–amoxicillin combi-nation therapy produced greater probing depth re-duction than did control medication, especially in

120

pockets having initial depths greater than or equalto 7 mm. Loesche et al. (60) also found most probingdepth reductions in pockets greater than 6 mm. Si-gusch et al. (107) demonstrated a significant de-crease in pocket depth after systemic metronidazoleand clindamycin therapies. An important study byCollins et al. (19) revealed that a comprehensiveanti-infective therapy, including a 2-week regimen ofamoxicillin/clavulanic acid in conjunction with pro-fessional, subgingival delivery of povidone–iodine,and chlorhexidine mouthwash rinses twice daily,was effective at reducing probing pocket depth witha 56% decrease in the number of pockets greaterthan 6 mm at 6 weeks posttreatment. Systemic spira-mycin as adjunct to scaling and root planing maygive rise to significant reduction in probing depth aswell (7).

Systemic metronidazole and its combinations cansignificantly improve clinical (probing) attachmentlevel compared with controls (Table 8). Loesche etal. (57, 60) and Elter et al. (29) found that 7 days ofmetronidazole therapy significantly increased


Table 5. Effect of systemic antibiotics on supragingival dental plaque

ChangesPeriodontal Systemic antibiotic Effect on from

Study condition regime plaque Baseline baseline P-value

MacrolidesAl-Joburi Advanced adult Spiramycin 1,500,000 IU, Plaque Index

et al. (4) periodontitis twice daily, 14 days Test 1.652 weeks ⇓ 0.72Placebo, four times daily,

24 weeks ⇓ 0.3814 daysPlacebo 1.63

2 weeks ⇓ 0.8324 weeks ⇓ 0.77

NitroimidazolesGusberti Recurrent periodontal Metronidazole 250 mg, Plaque Index 0.94

et al. (40) disease three times daily, 10 days Day 10 ⇓ 0.369 months

⇓

0.06

Jenkins Advanced adult Metronidazole 200 mg, Plaque Indexet al. (45) periodontitis three times daily, 5 days Debridement only 1.4 ⇓ 0.1

Metronidazole only 1.4 ⇓ 0.1Debridement π 1.2 0metronidazole

Lindhe et al. (53) Advanced adult Metronidazole 200 mg, % sitesperiodontitis four times daily for three Plaque IndexΩ0

periods of 2 weeks Testseparated by intervals of Scaled 08 weeks 2 weeks

⇓

5850 weeks

⇓

75

Not scaled 02 weeks

⇓

3850 weeks

⇓

70

ControlScaled 0

2 weeks

⇓

6750 weeks

⇓

83

Not scaled 62 weeks

⇓

4450 weeks

⇓

69

Noyan et al. (79) Adult periodontitis Metronidazole 250 mg, Plaque Index aCompared with baseline,three times daily, 7 days Metronidazole π 0.99 ⇓ 0.55a,b P,0.05

scaling bCompared with control andMetronidazole only 1.11 ⇓ 0.64a metronidazole only, notControl 1.35 ⇓ 0.95a statistically significant

Palmer et al. (82) Moderate to advanced Metronidazole 200 mg, % sites with plaque Compared with control, foradult periodontitis three times daily, 7 days Test 21.82 all parameters, no

8 weeks ⇓ 8.17 significant differences24 weeks ⇓ 8.13

Control 18.898 weeks ⇓ 7.33

24 weeks ⇓ 6.43

Palmer et al. (83) Moderate to advanced Metronidazole 200 mg, Proportion of sites aCompared with baseline,adult periodontitis three times daily, 7 days with plaque P,0.05

SmokersTest 21.32 months ⇓ 8.46 months ⇓ 7.5

Control 18.22 months ⇓ 6.76 months ⇓ 7.0

NonsmokersTest 22.12 months ⇓ 8.16 months ⇓ 8.5


% sites with plaqueat 6 monthsSmokersTest – ⇓ 42.5a

Control – ⇓ 37.9a

NonsmokersTest – ⇓ 27.4a


121

Slots & Ting

Table 5. Continued



Söder et al. (121) Moderate to advanced Metronidazole 400 mg, Plaque Index Plaque index:periodontitis, with less three times daily, 7 days Test 2.8 aCompared with control,than three teeth with After 1 months ⇓ 0.8a PΩ0.01Placebo, three times daily,.5 mm pockets and After 6 months ⇓ 1.07 daysradiographic marginal Control 2.6alveolar bone loss after After 1 months ⇓ 0.3scaling and root After 6 months ⇓ 0.8planning

Söder et al. (122) Advanced adult Metronidazole 400 mg, % teeth with aCompared with baseline,periodontitis three times daily, 7 days Plaque IndexΩ2 P,0.05

Placebo, three times daily, Smokers7 days Test 20.5

⇓

18.6Placebo 16.0

⇓

17.1a

NonsmokersTest 14.4

⇓

11.9Placebo 12.3

⇓

13.5

% teeth withPlaque IndexΩ3SmokersTest 2.8 ⇓ 1.5Placebo 5.4 ⇓ 5.0a

NonsmokersTest 4.2 ⇓ 3.3Placebo 2.9 ⇓ 2.3

von Troil-Linden Advanced Metronidazole 500 mg, % sites with plaque 45.2 aCompared with baseline,et al. (135) periodontitis twice daily, 7 days 1 month ⇓ 33.5a statistically significant

6 month ⇓ 26.3a

Walsh et al. (138) Adult periodontitis Metronidazole Plaque Index aCompared with baseline,2 g single dose for Test 1.17 P,0.05treatment of Trichomonas 1 month

⇓

0.33b bCompared with scaling,vaginalis by medical staff 3 months

⇓

0.58 P,0.05cCompared with bothScaling 1.20control and test, P,0.051 month ⇓ 0.62a

3 months ⇓ 0.53a,c

Control 1.173 months 0

Winkel et al. (142) ‘‘Refractory’’ Metronidazole 500 mg, Plaque Index 0.5 ⇓ 0.2 aCompared with baseline,periodontitis, culture three times daily, 7 days PÆ0.0002positive for B. forsythusand negative for A.actinomycetemcomitans

PenicillinsWinkel et al. (140) Generalized adult Amoxicillin 500 mg with Plaque Index aCompared with control, no

periodontitis clavulanic acid (125 mg), Test 0.9 significant differencethree times daily, 10 days 3 months ⇓ 0.6a

12 months ⇓ 0.6a

Control 1.13 months ⇓ 0.8

12 months ⇓ 0.8

TetracyclinesAl-Joburi et al. (4) Advanced adult Tetracycline 250 mg, Plaque Index

periodontitis four times daily, 14 days Test 1.522 weeks ⇓ 0.94Placebo, four times daily,

24 weeks ⇓ 0.5814 daysPlacebo 1.63

2 weeks ⇓ 0.8324 weeks ⇓ 0.77

Ciancio et al. (17) Gingivitis and/or Group 1: minocycline-HCl Plaque Index aCompared with baseline,periodontitis 100 mg, twice daily, 8 days Group 1 1.91 statistically significant

Day 3 ⇓ 0.52aGroup 2: minocycline-HCl

Day 8 ⇓ 0.88a50 mg in the morning and100 mg in the evening for Group 2 1.708 days Day 3 ⇓ 0.02

Day 8 ⇓ 0.43a

Feres et al. (30) Adult periodontitis Doxycycline 200 mg the % sites with plaquefirst day and 100 mg each Test 63 0day thereafter for 14 days Control 69

⇓

8

122


Table 5. Continued



Hellden et al. (42) Advanced adult Tetracycline 250 mg, four % sites with aCompared with baseline,periodontitis times daily for 2 periods of Plaque IndexΩ0 P,0.001

14 days each. The first Test bCompared with post-period extended from day Scaled 13.0 tetracycline, P,0.0010 to the end of week 2 and Post-tetracycline

⇓

78.4a cCompared with not scaledthe other period from the 25 weeks

⇓

76.2a,c group, P,0.01beginning of week 7 to the Not scaled 21.8end of week 8 Post-tetracycline

⇓

56.5a

25 weeks

⇓

44.8b

ControlScaled 36.4Post-tetracycline

⇓

44.0a

25 weeks

⇓

48.7a,c

Not scaled 36.7Post-tetracycline

⇓

47.5a

25 weeks

⇓

36.2a

Lindhe et al. (52) Advanced adult Tetracycline 250 mg, four % sites withperiodontitis times daily for the first 2 Plaque IndexΩ0

weeks and once daily for Testthe next 48 weeks Scaled 0

2 weeks

⇓

6050 weeks

⇓

70

Not scaled 02 weeks

⇓

1950 weeks

⇓

86

ControlScaled 0

2 weeks

⇓

6250 weeks

⇓

75

Not scaled 22 weeks

⇓

3250 weeks

⇓

67

Listgarten Advanced adult Tetracycline-HCl 250 mg, Plaque Indexet al. (56) periodontitis four times daily for two Test

periods of 14 days each With scaling 2separated by a 4-week 8 weeks ⇓ 2interval 25 weeks ⇓ 2

Without scaling 1.58 weeks ⇓ 1.5

25 weeks ⇓ 1.5

ControlWith scaling 1

8 weeks ⇓ 125 weeks ⇓ 1

Without scaling 28 weeks ⇓ 2

25 weeks ⇓ 2

Matisko & Refractory Doxycycline 200 mg for Mean plaque score Mean plaque score:Bissada (66) periodontitis: the first day and then 100 Control All parameters compared

A. actino- mg, once daily for 10 days Root planed 0.32 with baseline, notmycetemcomitans– 1 month

⇓

0.16 statistically significantand/or P. gingivalis– 3 months

⇓

0.17 For all parameters, rootassociated Non-root planed 0.48 planed compared with non-periodontitis 1 month 0 root planed, not statistically

3 months

⇓

0.05 significant

attachment levels in periodontal pockets withgreater than 4–6 mm depth. Flemmig et al. (34), Lop-ez et al. (61, 62) and Winkel et al. (141) showed thatmetronidazole–amoxicillin combination therapy for7–14 days significantly increased the proportion ofperiodontal sites gaining clinical attachment com-pared with controls. Berglundh et al. (11) demon-strated most clinical attachment gain in periodontalpockets probing greater than 6 mm. Sigusch et al.

123

(107) found significant gain in clinical attachmentlevel after systemic metronidazole and clindamycintherapy. Aitken et al. (3) reported that systemic doxy-cycline therapy for 3 weeks followed by systemic me-tronidazole for 10 days resulted in improved attach-ment levels and reduced disease recurrence com-pared with metronidazole treatment alone. Collins etal. (19) revealed that amoxicillin/clavulanic acidalong with subgingival povidone–iodine therapy re-

Slots & Ting

Table 5. Continued



Ng & Bissada (76) Generalized moderate Doxycycline 200 mg the Plaque Indexadult periodontitis first day and then 100 mg, Doxycycline

once daily 6 weeks Scaled 0.83 weeks ⇓ 0.2Ibuprofen 800 mg, once

24 weeks 0daily, 6 weeksNot scaled 0.9Combined doxycycline

3 weeks ⇓ 0.1(200 mg the first day and24 weeks ⇓ 0.3100 mg, once daily,

thereafter) and ibuprofen Ibuprofen(800 mg), once daily, Scaled 1.06 weeks 3 weeks ⇓ 0.4

24 weeks ⇓ 0.3Placebo, once daily,6 weeks Not scaled 1.0

3 weeks ⇓ 0.324 weeks ⇓ 0.1

CombinedScaled 0.5

3 weeks ⇓ 0.124 weeks

⇓

0.3

Not scaled 0.63 weeks ⇓ 0.1

24 weeks ⇓ 0.1

PlaceboScaled 0.6

3 weeks ⇓ 0.124 weeks 0


24 weeks 0

Slots & Localized juvenile Tetracycline-HCl 250 mg, Plaque Index 1.4Rosling (117) periodontitis four times daily, 14 days Post-scaling ⇓ 0.6

Post-tetracycline ⇓ 0.7

Combination therapy: metronidazole and amoxicillinBerglundh Advanced periodontal Metronidazole 250 mg, % sites with plaque No statistical significance

et al. (11) disease three times daily π Test (with scaling) 70 between the groupsamoxicillin 375 mg, 2 months ⇓ 60twice daily, 14 days 12 months ⇓ 60

24 months ⇓ 58

Test (without scaling) 722 months ⇓ 63

12 months ⇓ 5924 months –

Control 68(with scaling)

2 months ⇓ 5912 months ⇓ 5824 months ⇓ 51

Control 68(without scaling)

2 months ⇓ 5912 months ⇓ 5724 months –

Lopez & Moderate to advanced Metronidazole 250 mg, % sites with plaqueGamonal (61) adult periodontitis three times daily π Test 62.4

amoxicillin 375 mg, 2 months ⇓ 2.5three times daily, 8 days 4 months

⇓

0.6

Placebo 62.72 months ⇓ 3.24 months

⇓

2.6

Lopez et al. (62) Moderate to advanced Metronidazole 250 mg, % sites with plaque aCompared with placebo,adult periodontitis three times daily π Test 62.2 statistically significantwith Ø2 mm amoxicillin 500 mg, 2 months ⇓ 1.2attachment loss in twice daily, 14 days 12 months ⇓ 6.5a

Øtwo sites in the Placebo, three times daily, Placebo 57.7previous 2 months 7 days 2 months ⇓ 0.4

12 months

⇓

7.3

Pavicic et al. (85) A. actino- Metronidazole 250 mg, Plaque Index 0.79mycetemcomitans– three times daily π 3 months ⇓ 0.44associated severe amoxicillin 375 mg, 24 months ⇓ 28periodontitis three times daily, 7 days

124


Table 5. Continued



Winkel et al. (143) A. actino- Metronidazole 250 mg, Plaque Index 0.5 aCompared with after initialmycetemcomitans– three times daily π After initial therapy ⇓ 0.4 therapy, PΩ0.02positive periodontitis amoxicillin 375 mg, After antibiotics ⇓ 0.2a

with either P. gingivalis, three times daily, 7 daysB. forsythus orP. intermediaco-infection

Winkel et al. (141) Generalized severe Metronidazole 250 mg, Plaque Index aCompared with baseline,adult periodontitis three times daily π Placebo 0.9 ⇓ 0.6a statistically significant

amoxicillin 375 mg, Test 1.0 ⇓ 0.6aCompared with placebo, not

three times daily, 7 days statistically significant

Combination therapy: various combinationsMatisko & Refractory Test: Mean plaque score Mean plaque score:

Bissada (66) periodontitis: Amoxicillin/clavulanic Test All parameters compared toA. actino- acid 500 mg, three times Root planed 0.77 baseline, not statisticallymycetemcomitans– daily, 5 days, and then 1 month ⇓ 0.13 significantand/or P. gingivalis– doxycycline 200 mg the 3 months

⇓

0.03 For all parameters, rootassociated first day and 100 mg, Non-root planed 0.86 planed compared with non-periodontitis once daily, 4 days 1 month ⇓ 0.21 root planed, not statistically

Control: 3 months

⇓

0.05 significantDoxycycline 200 mg the Controlfirst day and 100 mg, Root planed 0.32once daily, 10 days 1 month

⇓

0.163 months

⇓

0.17

Non-root planed 0.481 month 03 months

⇓

0.05

sulted in clinical attachment gain of at least 1 mm in41% of deep sites at 3 years posttreatment. Recently,Ramberg et al. (90) found that systemic tetracyclineadministered during a 3-week period concomitantwith nonsurgical periodontal treatment led to al-most three times greater gain in clinical attachmentthan occurred in an age- and sex-matched controlgroup.

Systemic antibiotic therapy may improve radio-graphic alveolar bone level (Table 9). Metronidazoletherapy for 7 days (135) or for 10 days (101) and te-tracycline therapy for 12 days (102) may significantlyincrease the proportion of periodontal sites demon-strating less than 25–30% alveolar bone loss and de-crease the proportion of sites showing a greateramount of bone loss. In nonsmokers but not insmokers, Söder et al. (122) found that 7-day systemicmetronidazole therapy led to increased alveolarbone height compared with baseline. In early lesionsof juvenile periodontitis, Novak et al. (78) showedthat 1 g of systemic tetracycline per day for 6 weeksresulted in marked gains in clinical attachment andalmost complete repair of alveolar bony defects, andthe clinical outcome remained stable up to 4 yearsfollowing the antibiotic therapy.

Systemic antibiotics can have a beneficial effecton periodontal disease activity, as assessed by reduc-tion in disease-progressing sites (Table 10). Com-

125

pared with pre-antibiotic findings, clindamycin-HCltherapy for 7 days caused a decrease in the pro-portion of disease-active sites per subject per month(38, 39). Also, metronidazole–amoxicillin combi-nation therapy for 1 week may significantly decreaseperiodontal disease activity compared with placebomedication (61, 62).

Systemic antibiotics may reduce periodontal sur-gical needs, as determined by a periodontist havingno knowledge of the therapy rendered (Table 11). Inadvanced adult periodontitis, Loesche et al. (57, 59)showed that systemic metronidazole for 7 days re-duced the number of teeth assigned to surgery morethan in control groups with or without the use ofa placebo. Also, Loesche et al. (58) suggested thatsystemic doxycycline therapy for 14 days might re-duce the need for periodontal surgery, although thisfinding was statistically nonsignificant comparedwith controls.

Systemic antibiotics may improve other clinicalperiodontal variables as well (Table 12). After 14 daysof systemic minocycline therapy, Atilla et al. (6)found significant decreases in the number of epi-thelial cells and salivary protease activity in peri-odontal pockets greater than 6 mm. Fourteen daysof systemic spiramycin therapy (4) or 14 days of sys-temic tetracycline therapy (4) may diminish the rateof gingival crevicular fluid flow.

Slots & Ting

Table 6. Effect of systemic antibiotics on gingivitis

ChangesPeriodontal Systemic antibiotic from

Study condition regime Effect on gingivitis Baseline baseline P-value

MacrolidesAl-Joburi Advanced adult Spiramycin 1,500,000 Number of sites with bleeding

et al. (4) periodontitis IU, twice daily, 14 days on probingTest 3.38Placebo, four times

2 weeks ⇓ 1.68daily, 14 days24 weeks ⇓ 1.91

Placebo 3.732 weeks ⇓ 1.64

24 weeks ⇓ 2.04

NitroimidazolesClark et al. (18) Destructive Metronidazole 250 mg, Gingival Index

periodontal disease three times daily, 7 days Test 1.77excluding acute 1 month ⇓ 0.27Placebo, three timesnecrotizing 3 months ⇓ 0.19daily, 7 daysulcerative gingivitis 6 months ⇓ 0.20and juvenile Control 1.81periodontosis 1 month ⇓ 0.21

3 months ⇓ 0.346 months ⇓ 0.19

Gusberti Recurrent Metronidazole 250 mg, Bleeding on probing 2.28 aCompared with baseline,et al. (40) periodontal disease three times daily, 10 days Day 10 ⇓ 1.58a statistically significant

9 months ⇓ 0.87a

Lindhe Advanced adult Metronidazole 200 mg, % siteset al. (53) periodontitis four times daily for three Gingival IndexΩ0


⇓

1050 weeks

⇓

72

Not scaled 02 weeks 0

50 weeks

⇓

20

ControlScaled 0

2 weeks 050 weeks

⇓

65


50 weeks

⇓

20

Lundström Advanced adult Metronidazole 200 mg, % bleeding siteset al. (63) periodontitis three times daily, 7 days Sufficient oral hygiene group 50

1 month ⇓ 253 months ⇓ 17

12 months ⇓ 42

Poor oral hygiene group 501 month ⇓ 253 months ⇓ 25

12 months ⇓ 33

Nieminen Advanced adult Metronidazole 250 mg, Bleeding on probing aCompared with baseline,et al. (77) periodontitis three times daily, 10 days Metronidazole 23.7 ⇓ 8.8a,b P,0.01

Surgery 20.6

⇓

0.7 bCompared to surgery,P,0.05

Noyan Adult periodontitis Metronidazole 250 mg, Gingival Index aCompared with baseline,et al. (79) three times daily, 7 days Metronidazole π scaling 1.31 ⇓ 0.92a,b P,0.05

Metronidazole only 1.35 ⇓ 0.58a bCompared with controlControl 1.80 ⇓ 1.00a and metronidazole only,

not statistically significant

Palmer Moderate to Metronidazole 200 mg, % sites bleeding Compared with control,et al. (82) advanced adult three times daily, 7 days Test 25.94 for all parameters, no

periodontitis 8 weeks ⇓ 12.00 significant difference24 weeks ⇓ 11.91


24 weeks ⇓ 7.18

126


Table 6. Continued



Palmer Moderate to Metronidazole 200 mg, Proportion of sites bleeding aCompared with baseline,et al. (83) advanced adult three times daily, 7 days on probing P,0.05

periodontitis SmokersTest 20.22 months ⇓ 9.36 months ⇓ 10.5



Control 24.22 months ⇓ 86 months ⇓ 6

% sites bleeding on probing at6 monthsSmokersTest – ⇓ 46.6a


NonsmokersTest – ⇓ 44.0a


Saxen & Localized juvenile Metronidazole 200 mg, % bleeding sitesAsikainen periodontitis three times daily, 10 days Metronidazole 30.6(101) 6 months ⇓ 21.5

18 months ⇓ 21.8


18 months ⇓ 19.2

Söder et al. Advanced adult Metronidazole 400 mg, % teeth bleeding on probing aCompared with baseline,(122) periodontitis three times daily, 7 days Smokers P,0.05

Test 91.6 ⇓ 71.8aPlacebo, three times

Placebo 87.9 ⇓ 77.8adaily, 7 days

NonsmokersTest 91.0 ⇓ 86.7a

Placebo 92.6 ⇓ 78.6a

von Troil-Linden Advanced Metronidazole 500 mg, % sites with gingival bleeding 57.2 aCompared with baseline,et al. (135) periodontitis twice daily, 7 days 1 month ⇓ 25.5a statistically significant

6 month ⇓ 23.0a

Walsh Adult periodontitis Metronidazole 2 g single Bleeding Index aCompared with baseline,et al. (138) dose for treatment of Test 2.58 P,0.05

Trichomonas vaginalis 1 month ⇓ 0.91b bCompared with scaling,by medical staff 3 months ⇓ 0.42 P,0.05

cCompared with bothScaling 2.33control and test, P,0.051 month ⇓ 1.23a



Watts et al. Adult periodontitis Metronidazole 200 mg, % bleeding sites aCompared with baseline,(139) three times daily, 7 days Test 72 PΩ0.008

1 month ⇓ 4b bCompared with control,Placebo, three times3 months ⇓ 7a,b PÆ0.03daily, 7 daysControl 801 month ⇓ 53 months ⇓ 4

Winkel ‘‘Refractory’’ Metronidazole 500 mg, Bleeding on probing 1.6 ⇓ 0.9a aCompared with baseline,et al. (142) periodontitis, three times daily, 7 days PÆ0.0002

culture positive forB. forsythus andnegative forA. actino-mycetemcomitans

127

Slots & Ting

Table 6. Continued



PenicillinsAbu Fanas Rapidly progressive Amoxicillin 250 mg with % sites bleeding on probing 68.6 aCompared with baseline,

et al. (1) periodontitis clavulanic acid (125 mg), Week 1 ⇓ 28.8a P,0.05three times daily, Week 2 ⇓ 41.6a

14 days Week 6 ⇓ 49.5a

Week 18 ⇓ 46.4a

Collins et al. Refractory Amoxicillin 250 mg with % sites bleeding on probing 29.3 ⇓ 20.5a aCompared with baseline,(19) periodontitis clavulanic acid (125 mg), PΩ0.003

four times daily, 14 days

Winkel et al. Generalized adult Amoxicillin 500 mg with Bleeding on probing aCompared with control,(140) periodontitis clavulanic acid (125 mg), Test 0.6 no significant difference

three times daily, 3 months ⇓ 0.5a

10 days 12 months ⇓ 0.4a


12 months ⇓ 0.3

Gingival IndexTest 1.2

3 months ⇓ 0.9a

12 months ⇓ 1.0a


12 months ⇓ 1.0

TetracyclinesAbu Fanas Rapidly progressive Tetracycline-HCl 250 % sites bleeding 58.0 aCompared with baseline,

et al. (1) periodontitis mg, four times daily, on probing P,0.0514 days Week 1 ⇓ 18.8

Week 2 ⇓ 28.8a

Week 6 ⇓ 37.7a

Week 18 ⇓ 34.1a

Al-Joburi Advanced adult Tetracycline 250 mg, Number of sites bleeding onet al. (4) periodontitis four times daily, 14 days probing

Test 3.49Placebo, four times2 weeks ⇓ 2.24daily, 14 days8 weeks ⇓ 2.43

12 weeks ⇓ 2.2224 weeks ⇓ 2.23

Placebo 3.732 weeks ⇓ 1.648 weeks ⇓ 1.70

12 weeks ⇓ 2.2024 weeks ⇓ 2.04

Atilla et al. (6) Moderate to Minocycline-HCl 100 Bleeding Index For probing depthΩ4–5advanced adult mg, once daily, 14 days For probing depth Ω4–5 mm mm: all parametersperiodontitis Scaling and root planning 41.0 ⇓ 33.83 compared with baseline,

Scaling, root planning and 39.2 ⇓ 32.80 not statistically significantminocycline For probing depthØ6 mm:For probing depth Ø6 mm acompared with baseline,Scaling and root planning 59.4 ⇓ 42.4 P,0.05Scaling, root planning and 62.0 ⇓ 55.0a

minocycline

Ciancio Gingivitis and/or Group 1: minocycline- Gingival Index aCompared with baseline,et al. (17) periodontitis HCl 100 mg, twice daily, Group 1 1.88 statistically significant

8 days Day 3 ⇓ 0.26a

Day 8 ⇓ 0.69aGroup 2: minocycline-HCl 50 mg in the Group 2 1.76morning and 100 mg in Day 3 ⇓ 0.05the evening for 8 days Day 8 ⇓ 0.60a

Feres et al. (30) Adult periodontitis Doxycycline 200 mg the % sites with aCompared with baseline,first day and 100 mg gingival redness P,0.05each day thereafter for Test 50 ⇓ 24a

14 days Control 45 ⇓ 6

% sites with bleedingon probingTest 21 0Control 20 ⇓ 3

% sites with suppurationTest 1.6 ⇓ 0.5Control 0.9 ⇓ 0.1

128


Table 6. Continued



Hellden Advanced adult Tetracycline 250 mg, % sites with aCompared with baseline,et al. (42) periodontitis four times daily for 2 Gingival IndexΩ0 P,0.001

periods of 14 days each. Test bCompared with post-The first period extended Scaled 1.1 tetracycline, P,0.001from day 0 to the end of Post-tetracycline

⇓

39.8a,c cCompared with notweek 2 and the other 25 weeks

⇓

65.2b,c scaled group, P,0.01period from the Not scaled 2.0beginning of week 7 to Post-tetracycline

⇓

22.8a

the end of week 8 25 weeks

⇓

37.3b

ControlScaled 13.4Post-tetracycline

⇓

36.2a,c

25 weeks

⇓

22.8b,c

Not scaled 8.5Post-tetracycline

⇓

14.9a

25 weeks

⇓

34.0b

Lindhe Advanced adult Tetracycline 250 mg, % sites withet al. (52) periodontitis four times daily for the Gingival IndexΩ0

first 2 weeks and once Testdaily for the next Scaled 048 weeks 2 weeks 0

50 weeks

⇓

49


50 weeks

⇓

10

ControlScaled 0

2 weeks

⇓

250 weeks

⇓

59


50 weeks

⇓

17

% sites bleeding on probingTestScaled 100

2 weeks ⇓ 8050 weeks ⇓ 100


50 weeks ⇓ 86

Control 100Scaled



50 weeks 0

Listgarten Advanced adult Tetracycline-HCl 250 Gingival Indexet al. (56) periodontitis mg, four times daily for Test

2 periods of 14 days With scaling 2each separated by a 4- 8 weeks ⇓ 1.5week interval 25 weeks ⇓ 2


25 weeks ⇓ 1

ControlWith scaling 2

8 weeks ⇓ 1.525 weeks ⇓ 2


25 weeks ⇓ 0.5

Lundström Advanced adult Doxycycline 100 mg, % bleeding sites 100et al. (63) periodontitis once daily, 14 days 1 month ⇓ 58

3 months ⇓ 6712 months ⇓ 75

Mandell & Localized juvenile Doxycycline 100 mg, % sites bleeding on probing 95 aCompared with baseline,Socransky (65) periodontitis twice daily for the first 3 months ⇓ 68a statistically significant

day, then 100 mg, once 12 months ⇓ 63a

daily for 13 days

129

Slots & Ting

Table 6. Continued



Matisko & Refractory Doxycycline 200 mg for Mean gingival score Mean gingival score: allBissada (66) periodontitis: the first day and then Root planed 0.39 parameters compared

A. actino- 100 mg, once daily for 1 month ⇓ 0.13 with baseline, notmycetemcomitans– 10 days 3 months ⇓ 0.06 statistically significantand/or P. gingivalis– Non-root planed 0.54 For all parameters, rootassociated 1 month ⇓ 0.12 planed compared withperiodontitis 3 months ⇓ 0.16 non-root planed, not

statistically significant% bleeding sites 551 month ⇓ 333 months ⇓ 37

% suppuration sites 121 month ⇓ 123 months ⇓ 12

Müller et al. (72) Advanced Minocycline-HCl 200 Localized juvenile periodontitis Improvement wasA. actino- mg, once daily, 21 days Bleeding on probing 1.00 significant for allmycetemcomitans– Post-scaling π minocycline ⇓ 0.53 parameters, P,0.001associated Post-surgery π minocycline ⇓ 0.41periodontitis 6 months ⇓ 0.75

Localized periodontitisBleeding on probing 1.00Post-scaling π minocycline ⇓ 0.55Post-surgery π minocycline ⇓ 0.656 months ⇓ 0.55

Generalized severe periodontitisBleeding on probing 1.00Post-scaling π minocycline ⇓ 0.56Post-surgery π minocycline ⇓ 0.696 months ⇓ 0.61

Generalized moderateperiodontitisBleeding on probing 1.00Post-scaling π minocycline ⇓ 0.73Post-surgery π minocycline ⇓ 0.616 months ⇓ 0.72

Ng & Bissada Generalized Doxycycline 200 mg the Gingival Index aCompared with placebo,(76) moderate adult first day and then Doxycycline PÆ0.05

periodontitis 100 mg, once daily, Scaled 0.96 weeks 3 weeks ⇓ 0.2

24 weeks ⇓ 0.4aIbuprofen 800 mg,once daily, 6 weeks Not scaled 0.8

3 weeks 0Combined doxycycline24 weeks ⇓ 0.2a

(200 mg the first day and100 mg, once daily, Ibuprofenthereafter) and Scaled 0.8ibuprofen (800 mg), 3 weeks

⇓

0.1once daily, 6 weeks 24 weeks

⇓

0.4

Placebo, once daily Not scaled 1.06 weeks 3 weeks 0

24 weeks

⇓

0.1

CombinedScaled 1.2

3 weeks ⇓ 0.3a

24 weeks ⇓ 0.2

Not scaled 1.03 weeks ⇓ 0.3a

24 weeks ⇓ 0.2a

PlaceboScaled 0.7

3 weeks

⇓

0.124 weeks

⇓

0.2


24 weeks

⇓

0.5

Saxen & Localized juvenile Tetracycline 250 mg, % bleeding sitesAsikainen periodontitis four times daily, 12 days Test 43.6(101) 6 months ⇓ 28.0

18 months ⇓ 32.0


18 months ⇓ 19.2

130


Table 6. Continued



Saxen et al. Localized juvenile Doxycycline 200 mg the % sites bleeding aCompared with baseline,(102) periodontitis first day, then 100 mg, Test 30.8 ⇓ 15.1a P,0.05

once daily for 14 days Placebo 28.6 ⇓ 21.9a

Placebo

Slots & Localized juvenile Tetracycline-HCl 250 Gingival Index 1.6Rosling (117) periodontitis mg, four times daily, Post-scaling ⇓ 0.4

14 days Post-tetracycline ⇓ 0.4

Combination therapy: metronidazole and amoxicillinBerglundh Advanced Metronidazole 250 mg, % sites bleeding on probing aCompared with baseline,

et al. (11) periodontal disease three times daily π Test (with scaling) 72 P,0.05amoxicillin 375 mg, 2 months ⇓ 52a

twice daily, 14 days 12 months ⇓ 55a

24 months ⇓ 58a

Test (without scaling) 652 months ⇓ 11

12 months ⇓ 1424 months –

Control 71(with scaling)

2 months ⇓ 52a

12 months ⇓ 48a

24 months ⇓ 49a

Control 70(without scaling)

2 months ⇓ 512 months ⇓ 124 months –

Lopez & Moderate to Metronidazole 250 mg, % sites bleeding on probing aCompared with baseline,Gamonal (61) advanced adult three times daily π Test 32.9 statistically significant

periodontitis amoxicillin 375 mg, 2 months ⇓ 12.5a,bbCompared with placebo,

three times daily, 8 days 4 months ⇓ 12.6a,bstatistically significant

Placebo 28.92 months

⇓

3.24 months

⇓

5.3

Lopez et al. (62) Moderate to Metronidazole 250 mg, % sites bleeding on probing aCompared with baseline,advanced adult three times daily π Test 33.2 statistically significantperiodontitis with amoxicillin 500 mg, 2 months ⇓ 12.9a

Compared with placebo,Ø2 mm attachment twice daily, 14 days 12 months ⇓ 17.1a

statistically significant forloss in Øtwo sites in Placebo, three times Placebo 29.1 all 12-month evaluationsthe previous 2 daily, 7 days 2 months

⇓

2.3months 12 months

⇓

9.1a

Pavicic et al. A. actino- Metronidazole 250 mg, Bleeding Index 1.61(85) mycetemcomitans– three times daily π 3 months ⇓ 0.80

associated severe amoxicillin 375 mg, 24 months ⇓ 1.12periodontitis three times daily, 7 days % bleeding sites 37.8

3 months ⇓ 25.824 months ⇓ 25.5

van Winkelhoff A. actino- Metronidazole 250 mg, % pockets bleeding on probing 98 ⇓ 50et al. (132) mycetemcomitans– three times daily, π

associated amoxicillin 375 mg,periodontitis three times daily, 7 daysconsisting oflocalized juvenileperiodontitis andrapidly progressiveperiodontitis

van Winkelhoff A. actino- Metronidazole 250 mg, Bleeding Index 1.7 All clinical indiceset al. (133) mycetemcomitans– three times daily π Localized juvenile periodontitis ⇓ 1.3 compared with baseline,

associated amoxicillin 375 mg, Generalized advanced adult 1.8 ⇓ 1.3 P,0.0001periodontitis three times daily, 7 days periodontitisconsisting of Refractory periodontitis 1.8 ⇓ 1.3localized juvenileperiodontitis,generalizedadvanced adultperiodontitis, andrefractoryperiodontitis

131

Slots & Ting

Table 6. Continued



Winkel A. actino- Metronidazole 250 mg, Bleeding Index 1.6 Bleeding Index:et al. (143) mycetemcomitans– three times daily π After initial therapy ⇓ 0.4 acompared with after

positive periodontitis amoxicillin 375 mg, After antibiotics ⇓ 0.9a initial therapy, PΩ0.002with either three times daily, 7 days Suppuration Index 0.6 Suppuration Index:P. gingivalis, After initial therapy ⇓ 0.3 bcompared with afterB. forsythus or After antibiotics ⇓ 0.6b initial therapy, P,0.0001P. intermediaco-infection

Winkel Generalized severe Metronidazole 250 mg π Bleeding Index aCompared with baseline,et al. (141) adult periodontitis amoxicillin 375 mg, Placebo 0.8 ⇓ 0.4a statistically significant

three times daily, 7 days Test 0.8 ⇓ 0.6a,b bCompared with placebo,statistically significant

Combination therapy: various combinationsMatisko & Refractory Test Mean gingival score Mean gingival score: all

Bissada (66) periodontitis: Amoxicillin/clavulanic Test parameters comparedA. actino- acid 500 mg, three times Root planed 0.81 with baseline, notmycetemcomitans– daily, 5 days, and then 1 month ⇓ 0.47 statistically significantand/or P. gingivalis– doxycycline 200 mg the 3 months ⇓ 0.23 For all parameters, rootassociated first day and 100 mg, Non-root planed 0.81 planed compared withperiodontitis once daily 4 days 1 month ⇓ 0.38 non-root planed, not

Control 3 months ⇓ 0.04 statistically significantDoxycycline 200 mg the Controlfirst day and 100 mg, Root planed 0.39once daily, 10 days 1 month ⇓ 0.13

3 months ⇓ 0.06

Non-root planed 0.541 month ⇓ 0.123 months ⇓ 0.16

Effect of systemic antibiotic therapyon microbiological variables

A. actinomycetemcomitans is considered an exoge-nous oral pathogen (131), and treatment aims atcompletely removing the organism from the oralcavity (118). Many systemic antibiotic therapies areunable to consistently suppress subgingival A. acti-nomycetemcomitans to undetectable levels (Table13). Single systemic therapies by metronidazole ortetracycline may markedly reduce oral A. actino-mycetemcomitans but not eradicate the organism(73, 77, 101, 102). Strains of A. actinomycetemcomit-ans serotype b, which seems to constitute the mostperiodontopathic serotype in some populations (5),may be more resistant to antibiotic therapy than A.actinomycetemcomitans serotype a (41).

Periodontal surgery may aid in eradicating A. acti-nomycetemcomitans as well as other bacteria insome types of periodontitis, especially if carried outas a pocket reduction procedure (67, 50, 67, 128). Inlocalized juvenile periodontitis patients, Slots & Ro-sling (117) showed that periodontal surgery togetherwith systemic tetracycline-HCl was able to decreaseperiodontal A. actinomycetemcomitans to below de-tectable levels in about 50% of the study patients.Kleinfelder et al. (48) reported that systemic ofloxac-in, 200 mg twice daily for 5 days, in conjunction with

132

open flap surgery was able to suppress A. actino-mycetemcomitans below detectable levels in 22 studypatients for a period of 12 months. Systemic oflox-acin therapy can also resolve periodontal A. actino-mycetemcomitans infection in Papillon-Lefevre syn-drome patients (44). Müller et al. (72) showed thatperiodontal surgery together with systemic minocyc-line caused a marked suppression of A. actinomyce-temcomitans in virtually all infected localized peri-odontitis lesions but was not as predictable in severeand generalized types of periodontitis; however, theorganism reappeared in some localized periodontitislesions at 6 months posttreatment. Müller et al. (73)also reported that systemic minocycline was unableto eliminate A. actinomycetemcomitans from buccalmucosa and saliva.

Importantly, the combination of metronidazole(250 mg) and amoxicillin (375 mg), three times dailyfor 8 days comprises an effective and low-cost ther-apy against A. actinomycetemcomitans in localizedjuvenile periodontitis, Papillon-Lefevre syndromeperiodontitis, adult-type periodontitis, rapidly pro-gressive periodontitis, generalized advanced peri-odontitis and refractory periodontitis (28, 81, 132,133). Metronidazole–amoxicillin combination ther-apy may reduce A. actinomycetemcomitans to belowdetection levels in subgingival plaque for at least 2years (85) and in oral mucous membranes, tongue


Table 7. Effect of systemic antibiotics on periodontal pocket depth


Study condition regime Effect on probing depth Baseline baseline P-value

MacrolidesAl-Joburi Advanced adult Spiramycin 1,500,000 Probing depth (mm) aCompared with baseline,

et al. (4) periodontitis IU, twice daily, 14 days For sites 4–6 mm PÆ0.05Test 5.26Placebo, four times

2 weeks ⇓ 1.21daily, 14 days24 weeks ⇓ 1.32a


24 weeks ⇓ 1.72a

For sites Ø7 mmTest 7.49

2 weeks ⇓ 2.1224 weeks ⇓ 2.57a


24 weeks ⇓ 2.85a

Gordon Adult refractory Clindamycin-HCl 150 % probing depths 1–3 mm % probing depths 1–3 mm:et al. (38) periodontitis mg, four times daily, Pre-antibiotics 52.5 aCompared with

7 days 12 months ⇓ 17.9a pre-antibiotics, P,0.0124 months ⇓ 16.7a

NitroimidazolesGusberti Recurrent Metronidazole 250 mg, Probing depth 7.72 aCompared with baseline,

et al. (40) periodontal disease three times daily, 10 days Day 10 ⇓ 1.30a statistically significant9 months ⇓ 1.45a

Jenkins Advanced adult Metronidazole 200 mg, Probing depth (mm) aCompared with baseline,et al. (45) periodontitis three times daily, 5 days Debridement only 6.2 0 PÆ0.05

Metronidazole only 5.9 ⇓ 0.4a

Debridement π metronidazole 6.4 ⇓ 0.5a

Lindhe Advanced adult Metronidazole 200 mg, % sites with probinget al. (53) periodontitis four times daily for three depth Æ4 mm


⇓

1750 weeks

⇓

75

Not scaled 02 weeks

⇓4

50 weeks

⇓

25

ControlScaled 0

2 weeks

⇓

1150 weeks

⇓

50

Not scaled 02 weeks

⇓

850 weeks 0

Loesche Advanced adult Metronidazole 250 mg, Changes for probing aCompared with control,et al. (57) periodontitis three times daily, 7 days depth (mm) P,0.01

At initial probing Æ3 mmTest – ⇓ 0.05Control – ⇓ 0.20

At initial probing 4–6 mmTest – ⇓ 1.22a

Control – ⇓ 0.75

At initial probing Ø7 mmTest – ⇓ 2.83a

Control – ⇓ 1.78

Loesche Advanced adult Metronidazole 250 mg, Probing depths (mm) Probing depths: test versuset al. (59) periodontitis three times daily, 7 days Test Æ3

⇓

0.05 control, no significantControl Æ3 ⇓ 0.02 differencePlacebo, three times

daily, 7 days Test 4–6 ⇓ 0.75Control 4–6 ⇓ 0.81

Test Ø7 ⇓ 1.91Control Ø7 ⇓ 1.50

133

Slots & Ting

Table 7. Continued



Loesche Moderate to Metronidazole 250 mg, Advanced disease test group aCompared with placebo,et al. (60) advanced adult three times daily, 7 days Number of pockets Ø7 mm 22.8 ⇓ 18.8 PÆ0.05

periodontitis per subjectsPlacebo, three timesdaily, 7 days Moderate disease test group

Number of pockets Ø7 mm 12.0 ⇓ 8.0per subjects

Pocket depth change (mm)For initial probing 4–6 mm – ⇓ 1.19For initial probing .6 mm – ⇓ 3.19a

Moderate disease placebo groupNumber of pockets Ø7 mm 8.9 ⇓ 1.2per subjects

Pocket depth change (mm)For initial probing 4–6 mm – ⇓ 1.05For initial probing .6 mm – ⇓ 1.55

Lundström Advanced adult Metronidazole 200 mg, Probing depths (mm)et al. (63) periodontitis three times daily, 7 days Sufficient oral hygiene group 6.2

1 month ⇓ 1.03 months ⇓ 1.0

12 months ⇓ 2.3

Poor oral hygiene group 6.21 month ⇓ 1.23 months ⇓ 1.2

12 months ⇓ 1.7

Nieminen Advanced adult Metronidazole 250 mg, Number of pockets aCompared with baseline,et al. (77) periodontitis three times daily, 10 days Probing depth Ø6 mm 6.6 ⇓ 4.6a P,0.01

Probing depth 4–5 mm 22.7 ⇓ 6.1a bCompared with surgery,P,0.05

Noyan Adult periodontitis Metronidazole 250 mg, Probing depth (mm) aCompared with baseline,et al. (79) three times daily, 7 days Metronidazole π scaling 5.53 ⇓ 1.91a,b P,0.05

Metronidazole only 5.43 ⇓ 1.01a bCompared with controlControl 5.19 ⇓ 1.31a and metronidazole only,

P,0.05

Palmer Moderate to Metronidazole 200 mg, % sites probing Ø7 mm Compared with control,et al. (82) advanced adult three times daily, 7 days Test 7.71 for all parameters no



24 weeks ⇓ 3.83

Palmer Moderate to Metronidazole 200 mg, Probing depth (mm) aCompared with baseline,et al. (83) advanced adult three times daily, 7 days Smokers P,0.05

periodontitis Test 5.842 months ⇓ 1.236 months ⇓ 1.20a

Control 5.732 months ⇓ 1.026 months ⇓ 1.12a

NonsmokersTest 6.102 months ⇓ 1.856 months ⇓ 1.83a

Control 5.922 months ⇓ 1.736 months ⇓ 1.98a

Saxen & Localized juvenile Metronidazole 200 mg, % sites probing Ø4 mmAsikainen periodontitis three times daily, 10 days Metronidazole 20.8(101) 6 months ⇓ 16.0

18 months ⇓ 18.213.8Control


134


Table 7. Continued



Söder Moderate and Metronidazole 400 mg, Mean number of sites Ø5 mm Mean number of siteset al. (121) advanced three times daily, 7 days Test 11.2 ⇓ 5.7a Ø5 mm: aCompared with

periodontitis with Control 10.8 ⇓ 5.6a baseline, PÆ0.001Placebo, three timesmore than three daily, 7 days Mean probing depth Mean probing depth:teeth with .5 mm Test 2.81 ⇓0.46b bCompared with baseline,pockets and Control 2.75 ⇓ 0.41b PÆ0.0001radiographic

% patients having less than % patients having lessmarginal alveolar3 teeth with pockets Ø5 mm than three teeth withbone loss afterTest 2 pockets Ø5 mm: testscaling and rootAfter 1 months

⇓

37 (after 1 month and after 6planningAfter 6 months

⇓

50 months) compared withcontrol, no significantControl 6differenceAfter 1 months

⇓

14After 6 months

⇓

36

Söder Advanced adult Metronidazole 400 mg, Subjects non-surgically treated aCompared with baseline,et al. (122) periodontitis three times daily, 7 days % teeth with pockets Ø5 mm P,0.05

SmokersPlacebo, three timesTest 25.7 ⇓ 17.3daily, 7 daysPlacebo 27.9 ⇓ 18.2


Placebo 17.9 ⇓ 10.8

Probing depth (mm)SmokersTest 2.8 ⇓ 0.6Placebo 2.9 ⇓ 0.6


Placebo 2.1 0

Subjects surgically treated% teeth with pockets Ø5 mmSmokersTest 44.3 ⇓ 9.2Placebo 37.5 ⇓ 4.7


Probing depth (mm)SmokersTest 3.4 ⇓ 0.3a

Placebo 3.1 0


von Troil-Linden Advanced Metronidazole 500 mg, % sites Æ3 mm 49.9 aCompared with baseline,et al. (135) periodontitis twice daily, 7 days 1 month

⇓

35.5a statistically significant6 month

⇓

32.4a

Walsh et al. (138) Adult periodontitis Metronidazole 2 g single Probing depth (mm) aCompared with baseline,dose for treatment of Test 5.90 P,0.05Trichomonas vaginalis 1 month 0b bCompared with scaling,by medical staff 3 months 0 P,0.05




Winkel ‘‘Refractory’’ Metronidazole 500 mg, Probing depth 6.8 ⇓ 1.5a aCompared with baseline,et al. (142) periodontitis, three times daily, 7 days PÆ0.0002


PenicillinsAbu Fanas Rapidly progressive Amoxicillin 250 mg with Mean probing pocket 4.1 aCompared with baseline,

et al. (1) periodontitis clavulanic acid (125 mg), depth (mm) P,0.05three times daily, 14 Week 1 ⇓ 0.6a

days Week 2 ⇓ 1.0a

Week 6 ⇓ 1.4a

Week 18 ⇓ 1.6a

135

Slots & Ting

Table 7. Continued



Collins Refractory Amoxicillin 250 mg with % sites probing 0–3 mm 54.3

⇓

11.8et al. (19) periodontitis clavulanic acid (125 mg), % sites probing 4–6 mm 38.4 ⇓ 7.7

four times daily, 14 days % sites probing .6 mm 7.3 ⇓ 4.1

Winkel Generalized adult Amoxicillin 500 mg with Mean probing pocket aCompared with control,et al. (140) periodontitis clavulanic acid (125 mg), depth (mm) no significant difference

three times daily, 10 Test 3.9days 3 months ⇓ 0.9a

12 months ⇓ 1.0a


12 months ⇓ 1.0

TetracyclinesAl-Joburi Advanced adult Tetracycline 250 mg, Probing depth (mm) aCompared with baseline,

et al. (4) periodontitis four times daily, 14 days For sites 4–6 mm PÆ0.05Test 5.21Placebo, four times



24 weeks ⇓ 1.72a


2 weeks ⇓ 1.9624 weeks ⇓ 3.04a


24 weeks ⇓ 2.85a

Atilla et al. (6) Moderate to Minocycline-HCl 100 For probing depth Ω4–5 mm For probing depthΩ4–5advanced adult mg, once daily, 14 days Mean probing depth (mm) mm: all parametersperiodontitis Scaling and root planning 3.26 ⇓ 1.50 compared with baseline,

Scaling, root planning and 3.11 ⇓ 1.44 not statistically significantminocycline For probing depth Ø6 mm:For probing depth Ø6 mm aCompared with baseline,Number of Ø6 mm pockets P,0.05Scaling and root planning 24.6 ⇓ 19.3a

Scaling, root planning and 23.0 ⇓ 18.1a

minocycline

Mean probing depth (mm)Scaling and root planningScaling, root planning and 4.19 ⇓ 1.74minocycline 4.17 ⇓ 2.23

Feres et al. (30) Adult periodontitis Doxycycline 200 mg the Mean pocket depth (mm) aCompared with baseline,first day and 100 mg Test 2.89 ⇓ 0.22a P,0.05each day thereafter for Control 3.12 ⇓ 0.15a

14 days

Hellden Advanced adult Tetracycline 250 mg, Probing depth (mm) aCompared with baseline,et al. (42) periodontitis four times daily for 2 Test P,0.001

periods of 14 days each. Scaled 5.8 bCompared with post-The first period Post-tetracycline ⇓ 1.8a tetracycline, P,0.001extended from day 0 to 25 weeks ⇓ 2.2a,c cCompared with notthe end of week 2 and scaled group, P,0.01Not scaled 6.0the other period from Post-tetracycline ⇓ 1.5a

the beginning of week 7 25 weeks ⇓ 1.8a

to the end of week 8ControlScaled 5.4Post-tetracycline ⇓ 1.3a

25 weeks ⇓ 1.8b,c

Not scaled 5.5Post-tetracycline ⇓ 0.6a

25 weeks ⇓ 0.8a

136


Table 7. Continued



Lindhe Advanced adult Tetracycline 250 mg, % sites probing Æ4 mmet al. (52) periodontitis four times daily for the Test

first 2 weeks and Scaled 0once daily for the next 2 weeks

⇓

548 weeks 50 weeks

⇓

71


50 weeks

⇓

28

ControlScaled 0

2 weeks

⇓

1150 weeks

⇓

50

Not scaled 02 weeks

⇓

850 weeks 0

% sites probing Ø7 mmTestScaled 67


Not scaled 582 weeks ⇓ 16

50 weeks ⇓ 58

ControlScaled 73



50 weeks ⇓ 6

Listgarten Advanced adult Tetracycline-HCl 250 Probing depth (mm)et al. (56) periodontitis mg, four times daily for Test

two periods of 14 days With scaling 7.2each separated by a 8 weeks ⇓ 2.44-week interval 25 weeks ⇓ 2.4


25 weeks ⇓ 2.3

ControlWith scaling 7.0

8 weeks ⇓ 1.725 weeks ⇓ 2.2


25 weeks ⇓ 0.5

Lundström Advanced adult Doxycycline 100 mg, Probing depths (mm) 5.4et al. (63) periodontitis once daily, 14 days 1 month ⇓ 0.7


Mandell & Localized juvenile Doxycycline 100 mg, Probing depth (mm) 7.6 aCompared with baseline,Socransky (65) periodontitis twice daily for the first 3 months ⇓ 3.8a statistically significant

day, then 100 mg, once 12 months ⇓ 3.6a

daily for 13 days

Matisko & Refractory Doxycycline 200 mg for Mean probing pocket For all parameters, rootBissada (66) periodontitis: the first day and then 100 depth (mm) planed compared with

A. actino- mg, once daily for 10 Root planed 6.4 non-root planed, notmycetemcomitans– days 1 month ⇓ 0.5a statistically significantand/or P. gingivalis– 3 months ⇓ 0.5a

Mean probing pocketassociated Non-root planed 5.8 depth: acompared withperiodontitis 1 month ⇓ 0.6a baseline, P,0.05

3 months ⇓ 0.4

137

Slots & Ting

Table 7. Continued



Müller Advanced A. actino- Minocycline-HCl 200 Localized juvenile periodontitis Improvement waset al. (72) mycetemcomitans– mg, once daily, 21 days Probing depth 7.92 significant for all

associated Post-scaling π minocycline ⇓ 3.18 parameters, P,0.001periodontitis Post-surgery π minocycline ⇓ 3.98

6 months ⇓ 3.87

Localized periodontitisProbing depth 8.93Post-scaling π minocycline ⇓ 3.9Post-surgery π minocycline ⇓ 5.036 months ⇓ 4.95

Generalized severe periodontitisProbing depth 7.75Post-scaling π minocycline ⇓ 2.92Post-surgery π minocycline ⇓ 4.146 months ⇓ 3.94

Generalized moderateperiodontitisProbing depth 7.49Post-scaling π minocycline ⇓ 2.07Post-surgery π minocycline ⇓ 3.536 months ⇓ 3.07

Ng & Generalized Doxycycline 200 mg the Probing depth (mm) aCompared wirh placebo,Bissada (76) moderate adult first day and then 100 Doxycycline PÆ0.05

periodontitis mg, once daily, 6 weeks Scaled 4.33 weeks ⇓ 0.5a

Ibuprofen 800 mg, once24 weeks ⇓ 0.3daily, 6 weeksNot scaled 4.1Combined doxycycline

3 weeks 0(200 mg the first day and24 weeks ⇓ 0.2a

100 mg, once daily,thereafter) and Ibuprofenibuprofen (800 mg), Scaled 4.0once daily, 3 weeks ⇓ 0.4a

6 weeks 24 weeks 0

Placebo, once daily, Not scaled 4.06 weeks 3 weeks ⇓ 0.3a

24 weeks 0

CombinedScaled 4.2

3 weeks ⇓ 0.5a

24 weeks ⇓ 0.7a


24 weeks ⇓ 0.5a

PlaceboScaled 4.3

3 weeks 024 weeks

⇓

0.3

Not scaled 4.53 weeks

⇓

0.124 weeks

⇓

0.5

Saxen et al. Localized juvenile Doxycycline 200 mg the % sites probing Ø4 mm aCompared with baseline,(102) periodontitis first day, then 100 mg, Test 20.4 ⇓ 14.1a P,0.05

once daily for 14 days Placebo 16.9 ⇓ 13.5a

Placebo

Abu Fanas Rapidly progressive Tetracycline-HCl 250 Mean probing pocket depth 4.3 aCompared with baseline,et al. (1) periodontitis mg, four times daily, (mm) P,0.05

14 days Week 1 ⇓ 0.1Week 2 ⇓ 0.4a

Week 6 ⇓ 1.0a

Week 18 ⇓ 1.4a

Saxen & Localized juvenile Tetracycline 250 mg, % sites probing Ø4 mmAsikainen periodontitis four times daily, 12 days Test 18.7(101) 6 months ⇓ 11.4

18 months ⇓ 14.6


18 months ⇓ 7.8

Slots & Localized juvenile Tetracycline-HCl 250 Probing depth 2.8Rosling (117) periodontitis mg, four times daily, Post-scaling ⇓ 0.3

14 days Post-tetracycline ⇓ 0.1

138


Table 7. Continued



Combination therapy: metronidazole and amoxicillinBerglundh Advanced Metronidazole 250 mg, Probing aCompared with baseline,

et al. (11) periodontal disease three times daily π Pocket depth (mm) P,0.05amoxicillin 375 mg, Test (with scaling) 4.8twice daily, 14 days 2 months ⇓ 1.6a

12 months ⇓ 1.7a

24 months ⇓ 2.1a

Test (without scaling) 4.62 months ⇓ 0.7

12 months ⇓ 1.0a

24 months –

Control (with scaling) 4.52 months ⇓ 1.3a

12 months ⇓ 1.4a

24 months ⇓ 1.6a

Control (without scaling) 4.82 months ⇓ 0.3

12 months ⇓ 0.324 months –

Lopez & Moderate to Metronidazole 250 mg, Probing depth (mm) aCompared with baseline,Gamonal (61) advanced adult three times daily π Test 2.74 statistically significant

periodontitis amoxicillin 375 mg, 2 months ⇓ 0.20a

three times daily, 8 days 4 months ⇓ 0.25a


⇓

0.154 months

⇓

0.17

Lopez et al. Moderate to Metronidazole 250 mg, Mean probing depth (mm) aCompared with baseline,(62) advanced adult three times daily π Test 2.93 statistically significant

periodontitis with amoxicillin 500 mg, 2 months ⇓ 0.29abCompared with placebo,

Ø2 mm attachment twice daily, 14 days 12 months ⇓ 0.58a,bstatistically significant

loss in Ø two sites in Placebo, three times Placebo 2.66the previous daily, 7 days 2 months

⇓

0.052 months 12 months

⇓

0.29a

Pavicic et al. A. actino- Metronidazole 250 mg, Probing depth (mm) 7.93(85) mycetemcomitans– three times daily π 3 months ⇓ 2.33

associated severe amoxicillin 375 mg, 24 months ⇓ 3.14periodontitis three times daily, 7 days % pockets ,5 mm 67.1

3 months

⇓

14.324 months

⇓

22.0

% pockets 5–8 mm 30.13 months ⇓ 13.4

24 months ⇓ 20.1

% pockets .9 mm 2.73 months ⇓ 0.77

24 months ⇓ 1.70

van Winkelhoff A. actino- Metronidazole 250 mg, Pocket depth (mm) All clinical indices,et al. (133) mycetemcomitans– three times daily π Localized juvenile periodontitis 8.0 ⇓ 2.2 compared with baseline,

associated amoxicillin 375 mg, P,0.0001Generalized advanced adult 8.1 ⇓ 2.5periodontitis three times daily, 7 days periodontitisconsisting of

Refractory periodontitis 7.6 ⇓ 2.0localized juvenileperiodontitis,generalizedadvanced adultperiodontitis andrefractoryperiodontitis

van Winkelhoff A. actino- Metronidazole 250 mg, Probing depth (mm)et al. (132) mycetemcomitans– three times daily π Subjects with prior periodontal 7.2 ⇓ 1.9

associated amoxicillin 375 mg, therapyperiodontitis three times daily, 7 days Subjects with no prior 7.4 ⇓ 1.9consisting of periodontal therapylocalized juvenileperiodontitis andrapidly progressiveperiodontitis

Winkel A. actino- Metronidazole 250 mg, Probing pocket depth 8.1 Probing pocket depth:et al. (143) mycetemcomitans– three times daily π After initial therapy ⇓ 1.4 aCompared with after

positive periodontitis amoxicillin 375 mg, After antibiotics ⇓ 2.5a initial therapy, P,0.0001with either three times daily, 7 daysP. gingivalis,B. forsythus orP. intermediaco-infection

139

Slots & Ting

Table 7. Continued



Winkel Generalized severe Metronidazole 250 mg, Mean probing pocket aCompared with baseline,et al. (141) adult periodontitis three times daily π depth (mm) statistically significant

amoxicillin 375 mg, Placebo 4.4 ⇓ 1.0a bCompared with placebo,three times daily, 7 days Test 4.4 ⇓ 1.4a,b statistically significant

% sites probing Ø5 mmPlacebo 44.6 ⇓ 23.7a

Test 43.8 ⇓ 31.8a,b

Pocket depth change (mm)PlaceboFor initial probing 0–3 mm – ⇓ 0.11For initial probing 4–6 mm – ⇓ 1.37For initial probing Ø7 mm – ⇓ 2.46

TestFor initial probing 0–3 mm – ⇓ 0.27b

For initial probing 4–6 mm – ⇓ 1.72b

For initial probingØ7 mm – ⇓ 3.18b

Combination therapy: various combinationsMatisko & Refractory Test: Mean probing pocket depth Mean probing pocket

Bissada (66) periodontitis: Amoxicillin/clavulanic (mm) depth: aCompared withA. actino- acid 500 mg, three times Test baseline, P,0.05mycetemcomitans– daily, 5 days, and then Root planed 6.2and/or P. gingivalis– doxycycline 200 mg the 1 month ⇓ 1.4a

associated first day and 100 mg, 3 months ⇓ 1.4a

periodontitis once daily, 4 days Non-root planed 6.2Control 1 month ⇓ 0.9a

Doxycycline 200 mg the 3 months ⇓ 1.2a

first day and 100 mg, Controlonce daily, 10 days Root planed 6.4

1 month ⇓ 0.5a

3 months ⇓ 0.5a

Non-root planed 5.81 month ⇓ 0.6a

3 months ⇓ 0.4

dorsum and tonsils for at least 1 year (35). However,some patients may experience re-infection of A. acti-nomycetemcomitans after 2–3 years following themetronidazole–amoxicillin therapy (14, 85) or maynot become free of the organism in all oral sites (61).The failure to remove oral A. actinomycetemcomitansfrom all patients may be due to lack of patient com-pliance with the prescribed antibiotic regimen, dueto biofilm effect or other microbial factors impedingthe effectiveness of antibiotic therapy, or due to rein-fection from other individuals. Dentists should notrely solely upon systemic antibiotic therapy for erad-icating A. actinomycetemcomitans from periodontalsites and the entire mouth but, as described else-where (113), might benefit from combining systemicmetronidazole–amoxicillin therapy with mechanicaldebridement and topical antiseptic treatment.

P. gingivalis appears also to be an exogenous oralpathogen (131), but the organism is difficult to eradi-cate from subgingival sites by antibiotic therapyalone (Table 14). Systemic metronidazole for 10 daysmay suppress subgingival P. gingivalis to very lowlevels for over 6 months in some patients (40, 47) butnot in all cases (77). Differences in treatment out-

140

come may be partly due to biofilm-associated P. gin-givalis that can be resistant to metronidazole at con-centrations that are usually attained by systemic ad-ministration (119, 144). Single antibiotic therapy byamoxicillin/clavulanic acid for 10 days may reducesubgingival levels of P. gingivalis and the number ofP. gingivalis–infected patients, but not significantlycompared with placebo (47, 140).

Metronidazole–amoxicillin therapy for 7–8 dayscan reduce subgingival levels of P. gingivalis, al-though not consistently to below detectable levels(34, 61, 85, 132, 133, 141, 143). Berglundh et al. (11)showed that subgingival scaling together with sys-temic metronidazole-amoxicillin for 14 days causedmore suppression of P. gingivalis for 12 months thanscaling without metronidazole or metronidazolewithout scaling. Metronidazole–amoxicillin seems tobe most effective in suppressing P. gingivalis inrapidly progressive adult periodontitis (132). Me-tronidazole–amoxicillin systemic therapy may alsodecrease P. gingivalis levels in oral mucous mem-branes, tongue and tonsils (35). Importantly, Collinset al. (19) showed that systemic amoxicillin/clavul-anic acid therapy combined with subgingival povi-


Table 8. Effect of systemic antibiotics on periodontal attachment level


Study condition regime attachment level Baseline baseline P-value

MacrolidesAl-Joburi Advanced adult Spiramycin 1,500,000 Attachment level (mm) aCompared with baseline,

et al. (4) periodontitis IU, twice daily, 14 days For sites 4–6 mm PÆ0.05Test 9.11Placebo, four times



24 weeks ⇓ 1.02a


2 weeks ⇓ 0.8524 weeks ⇓ 1.46a


24 weeks ⇓ 1.54a

NitroimidazolesClark et al. (18) Destructive Metronidazole 250 mg, Attachment level (mm) aCompared with baseline,

periodontal disease three times daily, 7 days Test 7.21 statistically significantexcluding acute 1 month ⇓ 0.73a bCompared with baseline,Placebo, three timesnecrotizing 3 months ⇓ 0.73 no significancedaily, 7 daysulcerative gingivitis 6 month ⇓ 0.50b

and juvenile Control 7.81periodontosis 1 month ⇓ 0.60a

3 months ⇓ 0.286 month ⇓ 0.34b

Gusberti Recurrent Metronidazole 250 mg, Attachment level (mm) 9.80 aCompared with baseline,et al. (40) periodontal disease three times daily, 10 days Day 10 ⇓ 0.72a statistically significant

9 months ⇓ 1.07a

Jenkins Advanced adult Metronidazole 200 mg, Attachment level (mm) aCompared with baseline,et al. (45) periodontitis three times daily, 5 days Debridement only – ⇓ 0.1 PÆ0.05

Metronidazole only – ⇓ 0.3a

Debridement π metronidazole – ⇓ 0.2a

Lindhe Advanced adult Metronidazole 200 mg, Attachment level (mm)et al. (53) periodontitis four times daily for Test

three periods of 2 weeks Scaled –separated by intervals of 2 weeks ⇓ 0.18 weeks 50 weeks

⇓

1.8

Not scaled –2 weeks

⇓

0.150 weeks

⇓

0.8

ControlScaled –

2 weeks

⇓

0.250 weeks

⇓

1.6

Not scaled –2 weeks

⇓

0.250 weeks ⇓ 0.3

Loesche Advanced adult Metronidazole 250 mg, Attachment level (mm) aCompared with control,et al. (57) periodontitis three times daily, 7 days For initial probing Æ3 mm P,0.01

Test –

⇓

0.04Control – ⇓ 0.33

For initial probing4–6 mmTest –

⇓

0.79a

Control –

⇓

0.32

For initial probing Ø7 mmTest –

⇓

1.69Control –

⇓

1.03

Loesche Advanced adult Metronidazole 250 mg, Attachment level (mm) Attachment level:et al. (59) periodontitis three times daily, 7 days Test Probing ⇓ 0.05 compared with control,

Control depths ⇓ 0.15 no significant differencePlacebo, three timesÆ3 mmdaily, 7 days Test

Control Probing

⇓

0.40depths

⇓

0.274–6 mmTest

Control Probing

⇓

0.86depths

⇓

0.54Ø7 mm

141

Slots & Ting

Table 8. Continued



Loesche Moderate to Metronidazole 250 mg, Advanced disease test group aCompared with placebo,et al. (60) advanced adult three times daily, 7 days Number of sites 25.3 ⇓ 10.7 PÆ0.05

periodontitis with attachmentPlacebo, three timeslossØ7 mmdaily, 7 daysModerate disease test groupNumber of sites with 9.7 ⇓ 0.9attachment lossØ7 mm

Attachment level (mm)For initial probing 4–6 mm –

⇓

0.38For initial probing .6 mm –

⇓

1.42a

Moderate disease placebo groupNumber of sites with 11.3 ⇓ 1.2attachment lossØ7 mm

Attachment level (mm)For initial probing 4–6 mm –

⇓

0.28For initial probing .6 mm –

⇓

0.23

Nieminen Advanced adult Metronidazole 250 mg, Attachment loss (mm)et al. (77) periodontitis three times daily, 10 days % patients –

⇓

33.3

Noyan et al. (79) Adult periodontitis Metronidazole 250 mg, Attachment loss (mm) aCompared with baseline,three times daily, 7 days Metronidazole π scaling 9.61 ⇓ 1.00a,b P,0.05

Metronidazole only 68 ⇓ 0.37a bCompared with controlControl 9.56 ⇓ 0.59a and metronidazole only,

P,0.05

Palmer Moderate to Metronidazole 200 mg, Attachment level (mm) Compared with control,et al. (82) advanced adult three times daily, 7 days Test – for all parameters no

periodontitis 8 weeks

⇓

0.59 significant difference24 weeks

⇓

0.67

Control –8 weeks

⇓

0.3624 weeks

⇓

0.51

Palmer et al. (83) Moderate to Metronidazole 200 mg, Attachment level (mm) aCompared with baseline,advanced adult three times daily, 7 days Smokers P,0.05periodontitis Test –

2 months

⇓

0.326 months

⇓0.43a

Control –2 months

⇓

0.266 months

⇓

0.47a

NonsmokersTest –2 months

⇓

0.726 months

⇓

0.79a

Control –2 months

⇓

0.416 months

⇓

0.53a

Söder Advanced adult Metronidazole 400 mg, Subjects non-surgically treated aCompared with baseline,et al. (122) periodontitis three times daily, 7 days Attachment level (mm) P,0.05



Placebo 6.3 ⇓ 3.3

Subjects surgically treatedAttachment level (mm)SmokersTest 4.4 0Placebo 4.1

⇓

0.1


Walsh Adult periodontitis Metronidazole 2 g single Attachment loss (mm) aCompared with baseline,et al. (138) dose for treatment of Test 5.9 P,0.05




Control3 months 6.00 ⇓ 0.20

142


Table 8. Continued



Winkel ‘‘Refractory’’ Metronidazole 500 mg, Attachment level (mm) 7.7 ⇓ 1.0a aCompared with baseline,et al. (142) periodontitis, three times daily, 7 days PÆ0.0002


PenicillinsWinkel Generalized adult Amoxicillin 500 mg with Clinical attachment level (mm) aCompared with control,

et al. (140) periodontitis clavulanic acid (125 mg), Test 7.4 no significant differencethree times daily, 10 3 months ⇓ 0.5a

days 12 months ⇓ 0.5a


12 months ⇓ 0.5

TetracyclinesAl-Joburi Advanced adult Tetracycline 250 mg, Attachment level (mm) aCompared with baseline,

et al. (4) periodontitis four times daily, 14 days For sites 4–6 mm PÆ0.05Test 9.06Placebo, four times



24 weeks ⇓ 1.02a

For pocketsØ7 mmTest 10.58

2 weeks ⇓ 0.7424 weeks ⇓ 1.46a


24 weeks ⇓ 1.79a

Feres et al. (30) Adult periodontitis Doxycycline 200 mg the Mean attachment level (mm)first day and 100 mg Test 3.13 ⇓ 0.13each day thereafter for Control 3.15

⇓

0.0414 days

Hellden Advanced adult Tetracycline 250 mg, Attachment level (mm) aCompared with notet al. (42) periodontitis four times daily for Test scaled group, P,0.05

2 periods of 14 days Scaled –each. The first period Post-tetracycline

⇓

0.25extended from day 0 to 25 weeks

⇓

0.49a

the end of week 2 and Not scaled –the other period from Post-tetracycline

⇓

0.23the beginning of week 7 25 weeks

⇓

0.32to the end of week 8

ControlScaled –Post-tetracycline

⇓

0.3125 weeks

⇓

0.30a

Not scaled –Post-tetracycline

⇓

0.0225 weeks

⇓

0.05

Lindhe Advanced adult Tetracycline 250 mg, Attachment level (mm) aCompared with baseline,et al. (52) periodontitis four times daily for the Test P,0.01

first 2 weeks and once Scaled 7.1 bCompared with baseline,daily for the next 48 10 weeks

⇓

1.0 P,0.05weeks 50 weeks

⇓

1.7a


⇓

0.250 weeks

⇓

0.7

ControlScaled 7.410 weeks

⇓

0.650 weeks

⇓

1.4b


⇓

0.150 weeks ⇓ 0.4

Mandell & Localized juvenile Doxycycline 100 mg, Attachment level (mm) 5.8 aCompared with baseline,Socransky (65) periodontitis twice daily for the first 3 months ⇓ 1.2a statistically significant

day, then 100 mg, once 12 months ⇓ 1.3a

daily for 13 days

143

Slots & Ting

Table 8. Continued



Matisko & Refractory Doxycycline 200 mg for Mean probing attachment For all parameters, rootBissada (66) periodontitis: the first day and then level (mm) planed compared with

A. actino- 100 mg, once daily for Control non-root planed, notmycetemcomitans– 10 days Root planed 7.8 statistically significantand/or P. gingivalis– 1 month ⇓ 0.5associated 3 months ⇓ 0.2periodontitis Non-root planed 7.0

1 month 03 months 0

Müller et al. (72) Advanced Minocycline-HCl 200 Attachment loss (mm) Improvement wasA. actino- mg, once daily, 21 days Localized juvenile periodontitis 8.75 significant for allmycetemcomitans– Post-scaling π minocycline ⇓ 2.16 parameters, P,0.001associated Post-surgery π minocycline ⇓ 2.46periodontitis 6 months ⇓ 2.75

Localized periodontitis 10.13Post-scaling π minocycline ⇓ 1.85Post-surgery π minocycline ⇓ 2.236 months ⇓ 2.70

Generalized severe periodontitis 9.11Post-scaling π minocycline ⇓ 1.14Post-surgery π minocycline ⇓ 1.146 months ⇓ 1.33

Generalized moderate 8.33periodontitisPost-scaling π minocycline ⇓ 1.43Post-surgery π minocycline ⇓ 2.016 months ⇓ 2.13

Ng & Bissada Generalized Doxycycline 200 mg the Attachment level (mm) aCompared with placebo,(76) moderate adult first day and then Doxycycline PÆ0.05

periodontitis 100 mg, once daily, Scaled 7.8 bCompared with6 weeks 3 weeks ⇓ 0.2 combined, PÆ0.05

24 weeks ⇓ 0.4aIbuprofen 800 mg,once daily, 6 weeks Not scaled 8.0

3 weeks

⇓

0.1bCombined doxycycline

24 weeks ⇓ 0.1b(200 mg the first day and100 mg, once daily, Ibuprofenthereafter) and Scaled 8.8ibuprofen (800 mg), 3 weeks ⇓ 0.7a

once daily, 24 weeks

⇓

0.2a

6 weeks Not scaled 8.6Placebo, once daily, 3 weeks ⇓ 0.46 weeks 24 weeks

⇓

0.6b

CombinedScaled 8.5

3 weeks ⇓ 0.7a

24 weeks ⇓ 0.5a


24 weeks ⇓ 0.3a

PlaceboScaled 9.0

3 weeks

⇓

1.324 weeks

⇓

0.9


⇓

0.524 weeks

⇓

0.9

Slots & Localized juvenile Tetracycline-HCl 250 Attachment level (mm) –Rosling (117) periodontitis mg, four times daily, Post-scaling ⇓ 0.05

14 days Post-tetracycline

⇓

0.27

144


Table 8. Continued



Combination therapy: metronidazole and amoxicillinBerglundh Advanced Metronidazole 250 mg, Probing attachment level (mm) aCompared with control,

et al. (11) periodontal disease three times daily π Test (with scaling) Probing P,0.05amoxicillin 375 mg, 2 months pocket depth

⇓

0.4twice daily, 14 days 12 months 4–5 mm

⇓

0.624 months

⇓

0.9

Control Probing(with scaling) pocket depth

2 months 4–5 mm

⇓

0.612 months

⇓

0.724 months

⇓

0.7

Test (with scaling) Probing2 months pocket depth

⇓

1.312 months Ø6 mm

⇓

1.8a

24 months

⇓

2.1a

Control Probing(with scaling) pocket depth

2 months Ø6 mm

⇓

1.012 months

⇓

1.324 months

⇓

1.5

Flemmig A. actino- Metronidazole 250 mg, Mean incidence (%) of 2 mm or aCompared with control,et al. (34) mycetemcomitans– three times daily π more probing attachment level PΩ0.03

and/or P. gingivalis– amoxicillin 375 mg, gain for subjects withpositive periodontitis three times daily, 8 days A. actinomycetemcomitans(based on microbial regardless of P. gingivalisresults for the oral Test 0cavity) 3 months

⇓

16a

12 months

⇓

29

Control 03 months

⇓

1012 months

⇓

21

Mean incidence (%) of 2 mm ormore probing attachment levelgain for subjects with ofP. gingivalis withoutA. actinomycetemcomitansTest 0 ⇓

103 months ⇓

1912 months

Control 0 ⇓

153 months ⇓

3312 months

Lopez & Moderate to Metronidazole 250 mg, % sites gaining attachment aCompared with placebo,Gamonal (61) advanced adult three times daily π Test 0 statistically significant

periodontitis amoxicillin 375 mg, 2 months

⇓

1.40a

three times daily, 8 days 4 months

⇓

2.23a

Placebo 02 months

⇓

0.594 months

⇓

0.80

Lopez et al. (62) Moderate to Metronidazole 250 mg, % sites gaining attachment % sites gainingadvanced adult three times daily π Test 0.57 attachment: aComparedperiodontitis with amoxicillin 500 mg, 2 months

⇓

0.91 with baseline, statisticallyØ2 mm attachment twice daily, 14 days 12 months

⇓

1.44a,b significantloss in Ø two sites bCompared with placebo,Placebo, three times Placebo 0.53in the previous statistically significantdaily, 7 days 2 months

⇓

0.072 months 12 months ⇓ 0.40 Mean attachment level:

cCompared with 2Mean attachment level (mm)months, statisticallyTest 0significant2 months

⇓

0.2612 months

⇓

0.46c Compared with placebo,statistically significantPlacebo 0throughout the 12-month2 months ⇓ 0.13evaluation12 months ⇓ 0.43v

Pavicic et al. (85) A. actino- Metronidazole 250 mg, Attachment level (mm) 8.05mycetemcomitans– three times daily π 3 months ⇓ 1.46associated severe amoxicillin 375 mg, 24 months ⇓ 1.62periodontitis three times daily, 7 days

145

Slots & Ting

Table 8. Continued



van Winkelhoff A. actino- Metronidazole 250 mg, Attachment level (mm) All clinical indices,et al. (133) mycetemcomitans– three times daily π Localized juvenile periodontitis 7.4 ⇓ 1.3 compared with baseline,

associated amoxicillin 375 mg, Generalized advanced adult 8.2 ⇓ 1.2 P,0.0001periodontitis three times daily, 7 days periodontitisconsisting of Refractory periodontitis 7.8 ⇓ 1.4localized juvenileperiodontitis,generalizedadvanced adultperiodontitis andrefractoryperiodontitis

Winkel A. actino- Metronidazole 250 mg, Attachment level (mm) 8.6 Attachment level:et al. (143) mycetemcomitans– three times daily π After initial therapy ⇓ 1.1 aCompared with after

positive periodontitis amoxicillin 375 mg, After antibiotics ⇓ 2.0a initial therapy, P,0.0001with either three times daily, 7 daysP. gingivalis,B. forsythus orP. intermediaco-infection

Winkel Generalized severe Metronidazole 250 mg, Clinical attachment level (mm) aCompared with placebo,et al. (141) adult periodontitis three times daily π Placebo 4.0

⇓

0.4 statistically significantamoxicillin 375 mg, Test 3.9

⇓

0.7a

three times daily, 7 days Attachment level change (mm)PlaceboFor initial probing 0–3 mm – ⇓ 0.31For initial probing 4–6 mm –

⇓

0.68For initial probing Ø7 mm –

⇓

1.46

TestFor initial probing 0–3 mm – ⇓ 0.14a

For initial probing 4–6 mm –

⇓

0.88For initial probing Ø7 mm –

⇓

1.97a

Combination therapy: various combinationsAitken et al. (3) Active periodontitis Test Attachment level (mm) Attachment level:

Doxycycline 200 mg the Placebo π metronidazole –

⇓

,2 aCompared with placebo,first day and then Doxycycline π metronidazole –

⇓

.4a P,0.001100 mg, once daily, 21days, and metronidazole250 mg, three timesdaily, 10 days

PlaceboLactose-containingplacebo, once daily, 21days and metronidazole250 mg, three times daily,10 days

done–iodine application reduced subgingival P. gin-givalis to below detectable levels in 10 of 11 culture-positive refractory periodontitis patients. Also, Si-gusch et al. (107) showed an almost complete eradi-cation of subgingival P. gingivalis after comprehen-sive subgingival scaling and systemic metronidazoleor clindamycin therapy. It may be that predictableand long-term eradication of subgingival P. gingivalisfrom deep periodontal sites requires a combined ap-proach of systemic antibiotic therapy, careful rootdebridement possibly in conjunction with peri-odontal surgery and professional and self-care ad-ministration of subgingival antiseptics (118).

Systemic metronidazole, amoxicillin/clavulanicacid, tetracycline and metronidazole–amoxicillincombined therapy may reduce subgingival levels ofB. forsythus (Table 15); however, compared with pla-

146

cebo, the proportional occurrence of B. forsythus andnumber of infected subjects were significantly re-duced only immediately after the termination of themetronidazole–amoxicillin therapy (141).

P. intermedia is an indigenous organism that can-not be expected to be eradicated from the oral cavity(131). Subgingival P. intermedia seems to be most ef-fectively reduced by metronidazole with or withoutamoxicillin (Table 16). Metronidazole single drugtherapy for 7–10 days may reduce subgingival P. in-termedia counts (3, 46, 57, 59, 60, 142). Metronida-zole–amoxicillin for 7 days may significantly de-crease the proportion of P. intermedia–infected sites(61). Amoxicillin without metronidazole or com-bined with clavulanic acid was not effective in de-creasing subgingival P. intermedia levels (41, 140).Doxycycline used in combination with metronidazo-


Table 9. Effect on systemic antibiotics on alveolar bone level


Study condition regime Effect on bone loss Baseline baseline P-value

NitroimidazolesSöder et al. (122) Advanced adult Metronidazole 400 mg, Subjects non-surgically treated aCompared with baseline,

periodontitis three times daily, 7 days % bone height P ,0.05SmokersPlacebo, three timesTest 77.3

⇓

2.9daily, 7 daysPlacebo 80.8 ⇓ 1.2

NonsmokersTest 79.7

⇓

2.6a

Placebo 82.0

⇓

2.2

Subjects surgically treated% bone heightSmokersTest 74.1

⇓

1.6Placebo 75.9 ⇓1.1

NonsmokersTest 80.5

⇓

2.2a

Placebo 81.1

⇓

1.7

von Troil-Linden Advanced Metronidazole 500 mg, % siteset al. (135) periodontitis twice daily, 7 days With alveolar bone loss ,1/3 41.5

6 months

⇓

3.7

% sitesWith alveolar bone loss Ø1/2 15.86 months ⇓6.2

Saxen & Localized juvenile Metronidazole 200 mg, Number of sitesAsikainen periodontitis three times daily, 10 days With ,25% bone loss(101) Metronidazole 6

18 months

⇓

8

Control 518 months

⇓

12

Number of sitesWith 25–48% bone lossMetronidazole 1218 months ⇓ 7

Control 818 months ⇓ 4

TetracyclinesSaxen & Localized juvenile Tetracycline 250 mg, Number of sites

Asikainen periodontitis four times daily, 12 days With ,25% bone loss(101) Test 3

18 months

⇓

5

Control 518 months

⇓

12

Number of sitesWith 25–48% bone lossTest 1018 months ⇓ 3


le caused an increase rather than a decrease in sub-gingival P. intermedia counts (3).

Most systemic antibiotics can reduce levels of sub-gingival spirochetes but not permanently eradicatethe organisms (Table 17). Compared with placebo,spiramycin for 14 days significantly reduced subgin-gival spirochete levels. Clindamycin for 7 days (39)and metronidazole for 7–10 days (18, 40) can alsosignificantly decrease subgingival spirochete counts.However, Lindhe et al. (53) found that systemic me-tronidazole without scaling did not significantly re-duce subgingival spirochetes compared with base-line. Tetracyclines seem to be more effective againstsubgingival spirochetes. Tetracycline-HCl for two

147

periods of 14 days separated by a 4-week interval(56) and tetracycline for 1 year (52) suppressedspirochetes below detectable levels. Doxycycline for14 days reduced spirochetes in advanced peri-odontitis lesions to below detectable levels for atleast 3 months (63). Azithromycin in doses of 500 mgonce daily for 3 days can also significantly decreasesubgingival spirochete counts (103, 104).

Other bacteria of potential periodontopathic sig-nificance are also affected by systemic antibiotictherapy (Table 18). Metronidazole can reduce levelsof total obligate anaerobes, Fusobacterium species,Selenomonas species, Eikenella corrodens, Campylo-bacter rectus and Peptostreptococcus micros. The ef-

Slots & Ting

Table 10. Effect of systemic antibiotics on periodontal disease activity


Study condition regime Effect on active sites Baseline baseline P-value

LincosamidesGordon Adult refractory Clindamycin-HCl 150 Number of active sites % active sites per subject

et al. (38) periodontitis mg, four times daily, Pre-antibiotics 54 per month, compared with7 days Post-antibiotics ⇓ 30 pre-antibiotics, *P,0.001

% active sites per subjectPre-antibiotics 1.9Post-antibiotics ⇓ 1.0

% active sites per subjectper monthPre-antibiotics 0.7Post-antibiotics ⇓ 0.65a

Gordon Refractory Clindamycin-HCl 150 Number of active sites % active sites per subjectet al. (39) periodontitis mg, four times daily, Pre-antibiotics 29 per month, compared with

7 days Post-antibiotics ⇓ 23 pre-antibiotics, *P,0.01

% active sites per subjectPre-antibiotics 2.5Post-antibiotics ⇓ 2.1

% active sites per subjectper monthPre-antibiotics 0.9Post-antibiotics ⇓ 0.86a

Combination therapy: metronidazole and amoxicillinLopez & Moderate to Metronidazole 250 mg, % active sites aCompared with baseline,

Gamonal (61) advanced adult three times daily π Test 3.10 statistically significantperiodontitis amoxicillin 375 mg, 2 months ⇓ 1.92a,b bCompared with placebo,

three times daily, 8 days 4 months ⇓ 2.12a,b statistically significant


⇓

0.074 months

⇓

0.77

Lopez et al. (62) Moderate to Metronidazole 250 mg, % active sites aCompared with baseline,advanced adult three times daily π Test 3.3 statistically significantperiodontitis with amoxicillin 500 mg, 2 months ⇓ 2.17a Compared with placebo,Ø2 mm attachment twice daily, 14 days 12 months ⇓ 2.35a statistically significantloss in two or more throughout the 12-monthPlacebo, three times Placebo 3.14sites in the previous evaluationdaily, 7 days 2 months ⇓ 0.082 months 12 months

⇓0.22

Table 11. Effect of systemic antibiotics on periodontal surgical need


Study condition regime Effect on surgical need Baseline baseline P-value

NitroimidazolesLoesche Advanced adult Metronidazole 250 mg, Number of teeth needing aCompared with control,

et al. (57) periodontitis three times daily, 7 days surgery P,0.01Test – ⇓ 8.4a,b bCompared with baseline,Control – ⇓ 2.6 P,0.05

% teeth needing surgeryTest – ⇓ 62Control – ⇓ 21

Loesche Advanced adult Metronidazole 250 mg, % teeth requiring surgery % of teeth requiringet al. (59) periodontitis three times daily, 7 days Test 77 ⇓ 31 surgery: compared with

Placebo, three times Control 64 ⇓ 11 control, PÆ0.05daily, 7 days

TetracyclinesLoesche Advanced adult Placebo, twice daily for Number of teeth requiring

et al. (58) periodontitis 14 days simultaneously periodontal surgery andwith doxycycline 100 extractionmg, once daily, 14 days Test 11.0 ⇓ 7.5

Control 7.1 ⇓ 6.8Placebo, twice daily,14 days simultaneouslywith another placebo,once daily, 14 days

148


Table 12. Effect of systemic antibiotics on other clinical periodontal parameters

Effect onother clinical Changes

Periodontal Systemic antibiotic periodontal fromStudy condition regime parameters Baseline baseline P-value

MacrolidesAl-Joburi Advanced adult Spiramycin 1,500,000 Periotron readings of

et al. (4) periodontitis IU, twice daily, 14 days crevicular fluidsTest 45.83Placebo, four times



24 weeks ⇓ 18.71

NitroimidazolesAitken et al. (3) Periodontitis patients Metronidazole 250 mg, % subjects with disease

previously treated three times daily, 10 days recurrence within 3 monthswith placebo or Placebo π metronidazole 0

⇓

42doxycycline 7 monthsago with continuedgingival attachmentgreater than 2 mm

TetracyclinesAl-Joburi Advanced adult Tetracycline 250 mg, Periotron readings of crevicular

et al. (4) periodontitis four times daily, 14 days fluidsTest 34.87Placebo, four times


12 weeks ⇓ 11.8924 weeks ⇓ 13.69

⇓ 16.71Placebo 37.422 weeks8 weeks ⇓ 15.44

12 weeks ⇓ 19.2224 weeks ⇓ 18.71

Atilla et al. (6) Moderate to Minocycline-HCl 100 For probing depthΩ4–5 mm For probing depthΩ4–5advanced adult mg, once daily, 14 days Number of epithelial cells mmperiodontitis (unit space) All parameters compared

Scaling and root planning 163.7 ⇓ 77.4 with baseline, notScaling, root planning and 195.0 ⇓ 104.2 statistically significantminocycline For probing depthØ6 mmSalivary protease activity aCompared with baseline,(units/ml) P,0.05Scaling and root planning 2.05 ⇓ 0.64Scaling, root planning and 2.08 ⇓ 0.76minocycline

For probing depth Ø6 mmNumber of epithelial cells(unit space)Scaling and root planning 267.0 ⇓ 70.6Scaling, root planning and 260.0 ⇓ 157.8a

minocycline

Salivary protease activity(unit/ml)Scaling and root planning 2.78 ⇓ 0.62Scaling, root planning and 3.30 ⇓ 1.49a

minocycline

Combination therapy: various combinationsAitken et al. (3) Active periodontitis Test % subjects with disease % subjects with disease

Doxycycline 200 mg the recurrence within 3 months recurrence within 3first day and then 100 Placebo π metronidazole 0

⇓

42 months compared withmg, once daily, 21 days, Doxycycline π metronidazole 0

⇓

9a placebo, aP,0.096and metronidazole 250mg, three times daily,10 days

PlaceboLactose-containingplacebo, once daily, 21days and metronidazole250 mg, three times daily,10 days

149

Slots & Ting

Table 13. Effect of systemic antibiotics on subgingival A. actinomycetemcomitans

ChangesPeriodontal Systemic antibiotic Effect on A. from

Study condition regime actinomycetemcomitans Baseline baseline P-value

NitroimidazolesAitken et al. (3) Periodontitis patients Metronidazole 250 mg, A. actinomycetemcomitans Not calculated

previously treated three times daily, 10 days % positive testswith placebo or Active sites 65Data for placebo πdoxycycline 7 months 1 month

⇓

10metronidazole presentedago with continued 7 months

⇓

6gingival attachment Control sitesgreater than 2 mm 1 month 44

⇓

207 months

⇓

1

Loesche Advanced adult Metronidazole 250 mg, Proportions ofet al. (57) periodontitis three times daily, 7 days A. actinomycetemcomitans

Test ,0.1Post-debridement 0Post-medication 0Hygiene phase 0

Control,0.1Post-debridement

⇓

0.3Post-medication

⇓

1.4Hygiene phase 0

Loesche Advanced adult Metronidazole 250 mg, % A. actinomycetemcomitanset al. (59) periodontitis three times daily, 7 days Test ,0.01

1–3 days

⇓

,0.1Placebo, three times3–6 months 0daily, 7 daysControl ,0.011–3 days 03–6 months 0

Nieminen Advanced adult Metronidazole 250 mg, A. actinomycetemcomitanset al. (77) periodontitis three times daily, 10 days Metronidazole

% subjects 55.6 ⇓ 11.1% microflora 2.3 ⇓ 2.0

Surgery% subjects 46.7

⇓

6.7% microflora 5.2 ⇓ 4.4

Saxen & Localized juvenile Metronidazole 200 mg, A. actinomycetemcomitansAsikainen periodontitis three times daily, 10 days % subjects(101) Metronidazole 100

6 months ⇓ 88.918 months ⇓ 100

Control6 months 100 ⇓ 33.3

18 months ⇓ 66.7

Söder Moderate and Metronidazole 400 mg, Number ofet al. (121) advanced three times daily, 7 days A. actinomycetemcomitans–

periodontitis, with positive sitesPlacebo, three timesmore than three Test 4daily, 7 daysteeth with .5 mm After 6 months

⇓

2pockets and Control 5radiographic After 6 months ⇓ 3marginal alveolarbone loss afterscaling and rootplanning

Söder Advanced adult Metronidazole 400 mg, A. actinomycetemcomitanset al. (122) periodontitis three times daily, 7 days % subjects

Smokers 6.3 0Placebo, three timesTest 14.3 ⇓ 9.5daily, 7 daysPlacebo

Nonsmokers 25.0 ⇓ 6.3Test 27.3 ⇓ 18.2Placebo

von Troil-Linden Advanced Metronidazole 500 mg, A. actinomycetemcomitanset al. (135) periodontitis twice daily 7 days % patients 6

1 month ⇓ 606 month ⇓ 40

PenicillinsCollins et al. (19) Refractory Amoxicillin 250 mg with A. actinomycetemcomitans

periodontitis clavulanic acid (125 mg), % subjects 3.3 0four times daily, 14 days

Haffajee Mild to moderate Amoxicillin 250 mg with % siteset al. (41) periodontitis clavulanic acid (125 mg), A. actinomycetemcomitans

three times daily, serotype a 8.0 ⇓ 4.630 days A. actinomycetemcomitansPlacebo serotype b 13.8 ⇓ 2.5250 mg sucrose, threetimes daily, 30 days


Table 13. Continued


Study condition regime actinomycetemcomitans Baseline baseline P-valueWinkel Generalized adult Amoxicillin 500 mg with A. actinomycetemcomitans aCompared with control,

et al. (140) periodontitis clavulanic acid (125 mg), % subjects no significant differencethree times daily, Test 2010 days 3 months ⇓ 20a

12 months ⇓ 10a

Control 93 months

⇓

912 months –

% microfloraTest ,1

3 months ⇓ ∞1a

12 months 0

Control ,13 months

⇓

∞112 months –

TetracyclinesHaffajee Mild to moderate Tetracycline 250 mg, % sites

et al. (41) periodontitis three times daily, 30 days A. actinomycetemcomitansserotype a 13.8 ⇓ 3.2Placebo: 250 mg

sucrose, three times A. actinomycetemcomitansdaily, 30 days serotype b 10.7

⇓

2.1

Mandell & Localized juvenile Doxycycline 100 mg, A. actinomycetemcomitansSocransky (65) periodontitis twice daily for the first % patients 100 ⇓ 50

day, then 100 mg, % sites 100 ⇓ 77.3once daily for 13 days

Müller et al. (72) Advanced Minocycline-HCl 200 A. actinomycetemcomitans % subjects: significantA. actino- mg, once daily, 21 days Localized juvenile periodontitis differences between themycetemcomitans– % subjects 100 groups post-surgery πassociated Post-scaling π minocycline ⇓ 75 minocycline, P,0.05periodontitis Post-surgery π minocycline ⇓ 100 % sites: significant

6 months ⇓ 88 differences between the% sites 100 groups post-surgery πPost-scaling π minocycline ⇓ 88 minocycline, P,0.001;Post-surgery π minocycline ⇓ 100 and at 6 months, P,0.016 months ⇓ 2

% microflora: significant% microflora 63.73 differences between thePost-scaling π minocycline ⇓ 63.72 groups at baseline, P,0.01Post-surgery π minocycline –6 months ⇓ 63.73

Localized periodontitis% subjects 100Post-scaling π minocycline ⇓ 70Post-surgery π minocycline ⇓ 806 months ⇓ 80

% sites 100Post-scaling π minocycline ⇓ 80Post-surgery π minocycline ⇓ 956 months ⇓ 95

% microflora 16.12Post-scaling π minocycline

⇓

0.02Post-surgery π minocycline ⇓ 16.096 months ⇓ 16.07

Generalized severe periodontitis% subjects 100Post-scaling π minocycline ⇓ 44Post-surgery π minocycline ⇓ 336 months ⇓ 33

% sites 100Post-scaling π minocycline ⇓ 56Post-surgery π minocycline ⇓ 506 months ⇓ 50

% microflora 33.26Post-scaling π minocycline ⇓ 13.33Post-surgery π minocycline ⇓ 18.706 months ⇓ 31.58

Generalized moderateperiodontitis% subjects 100

⇓ 50Post-scaling π minocycline⇓ 50Post-surgery π minocycline⇓ 506 months

% sites 100⇓ 62Post-scaling π minocycline⇓ 54Post-surgery π minocycline⇓ 546 months

% microflora 7.75 ⇓

6.83Post-scaling π minocycline ⇓

1.45Post-surgery π minocycline ⇓

5.156 months

151

Slots & Ting

Table 13. Continued



Saxen & Localized juvenile Tetracycline 250 mg, A. actinomycetemcomitansAsikainen periodontitis four times daily, 12 days % subjects(101) Test 100

6 months ⇓ 55.618 months ⇓ 44.4100Control

6 months ⇓ 33.318 months ⇓ 66.7

Saxen Localized juvenile Doxycycline 200 mg the A. actinomycetemcomitans Compared with baseline,et al. (102) periodontitis first day, then 100 mg, % sites aP,0.05, bP,0.001

once daily for 14 days TestDiseased sites 57Placebo

2 months ⇓ 158 months ⇓ 50b

20 months ⇓ 21

Healthy sites 432 months ⇓ 368 months ⇓ 43a

20 months ⇓ 30

PlaceboDiseased sites 57

2 months ⇓ 218 months ⇓ 32a

20 months ⇓ 36

Healthy sites 362 months 08 months

⇓

420 months ⇓ 29

Slots & Localized juvenile Tetracycline-HCl A. actinomycetemcomitansRosling (117) periodontitis 250 mg, four times daily, % patients 100

14 days Post-scaling 0Post-BetadineA 0Post-tetracycline ⇓ 83.336 weeks ⇓ 50

% sites 100Deep pocketsPost-scaling 0Post-BetadineA 0Post-tetracycline ⇓ 4.836 weeks ⇓ 80

Shallow pockets 20Post-scaling

⇓

30Post-BetadineA

⇓

10Post-tetracycline ⇓ 2036 weeks ⇓ 10

Number of infected sites 16during therapy

1 day ⇓ 13 days ⇓ 36 days ⇓ 79 days ⇓ 12

13 days ⇓ 1514 days ⇓ 16

Combination therapy: Metronidazole and amoxicillinBerglundh Advanced Metronidazole 250 mg, % A. actinomycetemcomitans

et al. (11) periodontal disease three times daily π Test (with scaling) 0.1amoxicillin 375 mg, 2 months ⇓ 0.1twice daily, 14 days 12 months ⇓ 0.1


12 months ⇓ 0.1

Control (with scaling) 0.52 months ⇓ 0.4

12 months ⇓ 0.4


12 months ⇓ 2.7

152


Table 13. Continued



Flemmig A. actino- Metronidazole 250 mg, Number of patientset al. (34) mycetemcomitans– three times daily π Test

and/or P. gingivalis– amoxicillin 375 mg, A. actinomycetemcomitans only 0positive periodontitis three times daily, 8 days 12 months 0(based on microbial A. actinomycetemcomitans and 10results for the oral P. gingivaliscavity) 12 months ⇓ 10

Control 3A. actinomycetemcomitans only12 months 0

A. actinomycetemcomitans and 10P. gingivalis12 months ⇓ 4

Flemmig A. actino- Metronidazole 250 mg, Number of A. Oral cavityet al. (35) mycetemcomitans– three times daily π actinomycetemcomitans– aCompared with control,

and/or P. gingivalis– amoxicillin 375 mg, positive subjects PΩ0.0005positive periodontitis three times daily, 8 days Oral cavity Subgingival plaque

Test 10 compared with control,10 days ⇓ 8 bPΩ0.045

3 months ⇓ 8 cPΩ0.00912 months ⇓ 10a

Oral mucous membranesControl 13 compared with control,10 days ⇓ 5 dPΩ0.001

3 months ⇓ 5Tongue compared with12 months ⇓ 3control, ePΩ0.001

Subgingival plaqueTest 910 days ⇓ 8

3 months ⇓ 8b

12 months ⇓ 9c

Control 1210 days ⇓ 6


Oral mucous membranesTest 610 days ⇓ 5

3 months ⇓ 412 months ⇓ 6d


3 months ⇓ 312 months 0

TongueTest 510 days ⇓ 4

3 months ⇓ 412 months ⇓ 5e


3 months ⇓ 512 months

⇓

2

TonsilsTest 410 days ⇓ 4


Control 110 days

⇓

23 months

⇓

112 months 0

Buccal mucosaTest 010 days 0

3 months 012 months 0


3 months ⇓ 112 months

⇓

2

Lopez & Moderate to Metronidazole 250 mg, A. actinomycetemcomitansGamonal (61) advanced adult three times daily π % sites

periodontitis amoxicillin 375 mg, Test 6.81 ⇓ 1.55three times daily, 8 days Placebo 2.77

⇓

0.56

153

Slots & Ting

Table 13. Continued



Pavicic et al. (85) A. actino- Metronidazole 250 mg, A. actinomycetemcomitansmycetemcomitans– three times daily π % subjects 100associated severe amoxicillin 375 mg, 3 months ⇓ 100periodontitis three times daily, 7 days 24 months ⇓ 97.9

van Winkelhoff A. actino- Metronidazole 250 mg, A. actinomycetemcomitanset al. (132) mycetemcomitans– three times daily π % subjects

associated amoxicillin 375 mg, Localized juvenile periodontitis 100 ⇓ 90.9periodontitis three times daily, 7 days Rapidly progressively 100 ⇓ 100consisting of periodontitislocalized juvenileperiodontitis andrapidly progressiveperiodontitis

van Winkelhoff A. actino- Metronidazole 250 mg, A. actinomycetemcomitanset al. (133) mycetemcomitans– three times daily π Localized juvenile periodontitis

associated amoxicillin 375 mg, % subjects 100 ⇓ 93periodontitis three times daily, 7 days % microflora 16 ⇓ 15.6consisting of colony-forming units ¿105/ml 24 ⇓ 23.7localized juvenile Generalized advanced adultperiodontitis, periodontitisgeneralized % subjects 100 ⇓ 98advanced adult % microflora 7 ⇓ 6.9994periodontitis and colony-forming units ¿105/ml 10 ⇓ 9.9998refractory

Refractory periodontitisperiodontitis% subjects 100 ⇓ 97.5% microflora 15 ⇓ 14.93colony-forming units ¿105/ml 19 ⇓ 18.6

Winkel A. actino- Metronidazole 250 mg, A. actinomycetemcomitans A. actinomycetemcomitans:et al. (143) mycetemcomitans– three times daily π Number of subjects 22 aCompared with after

positive periodontitis amoxicillin 375 mg, After initial therapy ⇓ 1 initial therapy, PΩ0.005with either three times daily, 7 days After antibiotics ⇓ 19P. gingivalis, Mean % microflora 3.4B. forsythus or After initial therapy ⇓ 1.2P. intermedia After antibiotics ⇓ 3.3a

co-infection

Winkel et al. (141) Generalized severe Metronidazole 250 mg, A. actinomycetemcomitansadult periodontitis three times daily π Number of subjects

amoxicillin 375 mg, Placebo 5 ⇓ 2three times daily, 7 days Test 4 ⇓ 4

% microfloraPlacebo 0.8 ⇓ 0.5Test 0.6 ⇓ 0.6

Combination therapy: various combinationsAitken et al. (3) Active periodontitis Test A. actinomycetemcomitans

Doxycycline 200 mg the % positivefirst day and then 100 Placebo π metronidazolemg, once daily, 21 days, Active sites 65and metronidazole 250 1 month

⇓

10mg, three times daily, 7 months

⇓

610 days Control sites 44Placebo 1 month

⇓

20Lactose-containing 7 months

⇓

1placebo, once daily, 21 Doxycycline π metronidazoledays and metronidazole Active sites 67250 mg, three times daily, 1 month ⇓ 1610 days 7 months ⇓ 19

Control sites 281 month ⇓ 47 months

⇓

2

fect of metronidazole on Veillonella, a non-peri-odontopathic species, is not consistent. Amoxicillinwith clavulanic acid may reduce subgingival levels ofCapnocytophaga, Fusobacterium nucleatum, E.corrodens and C. recta and increase levels of Capno-cytophaga ochracea and P. micros. Tetracyclines maydecrease subgingival Fusobacterium nucleatum andC. ochracea. The metronidazole–amoxicillin combi-

154

nation (1, 140) but apparently not amoxicillin–clavu-lanic acid (47) has the potential of reducing subgin-gival levels of F. nucleatum.

In addition to reducing levels of periodontopath-ic bacteria, systemic antibiotic therapy may lead toincreased levels of antibiotic-resistant, innocent orbeneficial bacteria such as streptococci or Acti-nomyces (31, 103, 114). Metronidazole for 7–10


Table 14. Effect of systemic antibiotics on subgingival P. gingivalis


Study condition regime Effect on P. gingivalis Baseline baseline P-value

NitroimidazolesAitken et al. (3) Periodontitis patients Metronidazole 250 mg, P. gingivalis Not done

previously treated three times daily, 10 days % positive testswith placebo or Active sites 35Data for placebo πdoxycycline 7 months 1 month ⇓ 15metronidazole presentedago with continued 7 months

⇓

10gingival attachment Control sites 24greater than 2 mm 1 month ⇓ 10

7 months

⇓

4

Gusberti Recurrent Metronidazole 250 mg, % P. gingivalis 16.37 aCompared with baseline,et al. (40) periodontal disease three times daily, 10 days Day 10 ⇓ 16.15a statistically significant

9 months ⇓ 15.74a

Loesche Advanced adult Metronidazole 250 mg, Proportions of P. gingivaliset al. (57) periodontitis three times daily, 7 days Test 0.1

Post-debridement ⇓ ,0.1Post-medication ⇓ ,0.1Hygiene phase ⇓ ,0.1

Control 0.4Post-debridement ⇓ 0.1Post-medication

⇓

1.0Hygiene phase ⇓ 0.1

Loesche Advanced adult Metronidazole 250 mg, % P. gingivalis % P. gingivalis: aComparedet al. (59) periodontitis three times daily, 7 days Test 0.5 with baseline, PÆ0.05

1–3 days ⇓ .0.4aPlacebo, three times

3–6 months 0daily, 7 daysControl 3.01–3 days ⇓ 2.93–6 months ⇓ 2.8

Loesche Moderate to Metronidazole 250 mg, % P. gingivalis aCompared with baseline,et al. (60) advanced adult three times daily, 7 days Advanced disease test group 3.8 statistically significant

periodontitis 0–2 weeks ⇓ 3.7aPlacebo, three times

15–30 weeks ⇓ 2.4adaily, 7 days

Moderate disease test group 5.90–2 weeks ⇓ 5.6a

15–30 weeks ⇓ 5.0a

Moderate disease placebo group 5.80–2 weeks ⇓ 4.4

15–30 weeks ⇓ 8

Nieminen Advanced adult Metronidazole 250 mg, P. gingivaliset al. (77) periodontitis three times daily, 10 days Metronidazole

% subjects 11.1

⇓

5.6% microflora 1.5 ⇓ 0.6

Surgery% subjects 60 ⇓ 6.7% microflora 3.3 ⇓ 2.7

Söder Moderate and Metronidazole 400 mg, Number of P. gingivalis–positive Number of P. gingivalis–et al. (121) advanced three times daily, 7 days patients positive patients:

periodontitis, with Test 8 compared with control, noPlacebo, three times. three teeth with After 1 month ⇓ 7 significant differencedaily, 7 days.5 mm pockets and After 6 months ⇓ 5radiographic Control 9marginal alveolar After 1 month ⇓ 3bone loss after After 6 months ⇓ 6scaling and rootplanning

Söder Advanced adult Metronidazole 400 mg, P. gingivaliset al. (122) periodontitis three times daily, 7 days % subjects

Smokers 31.3 ⇓ 31.3Placebo, three timesTest 14.3 ⇓ 14.3daily, 7 daysPlacebo

Nonsmokers 25.0 ⇓ 18.8Test 45.5 ⇓ 36.4Placebo

von Troil-Linden Advanced Metronidazole 500 mg, P. gingivaliset al. (135) periodontitis twice daily, 7 days % patients 70


155

Slots & Ting

Table 14. Continued



Winkel ‘‘Refractory’’ Metronidazole 500 mg, Posttreatment P. gingivalis inet al. (142) periodontitis, three times daily, 7 days pretreatment P. gingivalis–

culture-positive for positive subjectsB. forsythus and % subjects 55.6 ⇓ 33.3negative for % microflora 31.8 ⇓ 6.3A. actino- Posttreatment P. gingivalis inmycetemcomitans pretreatment P. gingivalis–

negative subjects% subjects 44.4 ⇓ 25.9% microflora 0

⇓

6.9

PenicillinsCollins et al. (19) Refractory Amoxicillin 250 mg with % subjects aCompared with baseline,

periodontitis clavulanic acid (125 mg), P. gingivalis 36.7 ⇓ 33.3a P,0.01four times daily, 14 days

Haffajee Mild to moderate Amoxicillin 250 mg with P. gingivaliset al. (41) periodontitis clavulanic acid (125 mg), % sites 23.3 ⇓ 3.9

three times daily,30 days

Placebo250 mg sucrose, threetimes daily, 30 days

Winkel Generalized adult Amoxicillin 500 mg with P. gingivalis aCompared with control,et al. (140) periodontitis clavulanic acid (125 mg), % subjects no significant difference

three times daily, 10 Test 40days 3 months ⇓ 20a

12 months 0a


12 months ⇓ 45

% microfloraTest 31

3 months ⇓ 19a

12 months ⇓ 16a


12 months ⇓ 10

TetracyclinesHaffajee Mild to moderate Tetracycline 250 mg, P. gingivalis

et al. (41) periodontitis three times daily, 30 days % sites 31.3 ⇓ 9.5

Placebo: 250 mgsucrose, three timesdaily, 30 days

Combination therapy: metronidazole and amoxicillinBerglundh Advanced Metronidazole 250 mg, % P. gingivalis



12 months ⇓ 23.2


12 months ⇓ 8.0


12 months ⇓ 7.4

156


Table 14. Continued



Flemmig A. actino- Metronidazole 250 mg, Number of P. gingivalis–positive Oral cavity: comparedet al. (35) mycetemcomitans– three times daily π subjects with control, aPΩ0.0006

and/or P. gingivalis– amoxicillin 375 mg, Oral cavity Subgingival plaque:positive periodontitis three times daily, 8 days Test 18 compared with control,

10 days ⇓ 11abPΩ0.00001

3 months ⇓ 3Oral mucous membranes:12 months ⇓ 2compared with control,

Control 17 cPΩ0.0008, dPΩ0.00210 days

⇓

1Tongue: compared with3 months

⇓

2control, ePΩ0.0002,12 months

⇓

2fPΩ0.003

Subgingival plaqueTonsils: compared withTest 15control, gPΩ0.0007,10 days ⇓ 12b

hPΩ0.033 months ⇓ 412 months ⇓ 2 Buccal mucosa: compared

with control,Control 12iPΩ0.00810 days

⇓

53 months

⇓

612 months

⇓

7

Oral mucous membranesTest 1510 days ⇓ 9c

3 months ⇓ 7d

12 months ⇓ 1

Control 1710 days 0

3 months

⇓

112 months

⇓

1

TongueTest 1410 days ⇓ 10

3 months ⇓ 8e

12 months ⇓ 3f

Control 1610 days 0

3 months 012 months

⇓

1

TonsilsTest 1310 days ⇓ 9g

3 months ⇓ 9h

12 months

⇓

1



Buccal mucosaTest 910 days ⇓ 6

3 months ⇓ 7i

12 months ⇓ 2


3 months 012 months

⇓

1

Flemmig A. actino- Metronidazole 250 mg, Number of patientset al. (34) mycetemcomitans– three times daily π Test

and/or P. gingivalis– amoxicillin 375 mg, A. actinomycetemcomitans and 10positive periodontitis three times daily, 8 days P. gingivalis(based on microbial 12 months ⇓ 10results for the oral P. gingivalis only 8cavity) 12 months

⇓

8

ControlA. actinomycetemcomitans and 10P. gingivalis ⇓ 412 months

P. gingivalis only 712 months

⇓

4

Lopez & Moderate to Metronidazole 250 mg, P. gingivalis aCompared with placebo,Gamonal (61) advanced adult three times daily π % sites statistically significant

periodontitis amoxicillin 375 mg, Test 72.72 ⇓ 12.20a

three times daily, 8 days Placebo 77.77

⇓

8.89

157

Slots & Ting

Table 14. Continued



Pavicic et al. (85) A. actino- Metronidazole 250 mg, P. gingivalismycetemcomitans– three times daily π % subjects 37.5associated severe amoxicillin 375 mg, 3 months ⇓ 33.3periodontitis three times daily, 7 days 24 months ⇓ 33.3

van Winkelhoff A. actino- Metronidazole 250 mg, P. gingivaliset al. (132) mycetemcomitans– three times daily π % subjects

associated amoxicillin 375 mg, Localized juvenile periodontitis 9.1 0periodontitis three times daily, 7 days Rapidly progressively 27.3 ⇓ 27.3consisting of periodontitislocalized juvenileperiodontitis andrapidly progressiveperiodontitis

van Winkelhoff A. actino- Metronidazole 250 mg, P. gingivaliset al. (133) mycetemcomitans– three times daily π Localized juvenile periodontitis

associated amoxicillin 375 mg, % subjects 18 ⇓ 11periodontitis three times daily, 7 days % microflora 18 ⇓ 3consisting of colony-forming units ¿105/ml 68 ⇓ 57localized juvenile Generalized advanced adultperiodontitis, periodontitisgeneralized % subjects 40 ⇓ 38advanced adult % microflora 28 ⇓ 16periodontitis and colony-forming units ¿105/ml 416 ⇓ 414refractory

Refractory periodontitisperiodontitis% subjects 23 ⇓ 15.5% microflora 31 ⇓ 26colony-forming units ¿105/ml 317 ⇓ 292

Winkel A. actino- Metronidazole 250 mg, P. gingivalis P. gingivalis: aComparedet al. (143) mycetemcomitans– three times daily π Number of subjects 17 with after initial therapy,

positive periodontitis amoxicillin 375 mg, After initial therapy ⇓ 4 PΩ0.02with either three times daily, 7 days After antibiotics ⇓ 13P. gingivalis, Mean % microflora 32.7B. forsythus, or After initial therapy ⇓ 3.6P. intermedia After antibiotics ⇓ 15.2a

co-infection

Winkel Generalized severe Metronidazole 250 mg, P. gingivalis aCompared with baseline,et al. (141) adult periodontitis three times daily π Number of subjects statistically significant

amoxicillin 375 mg, Placebo 13 ⇓ 2 bCompared with placebo,three times daily, 7 days Test 13 ⇓ 10a,b statistically significant

% microfloraPlacebo 39.9 ⇓ 21.3Test 25.0 ⇓ 14.4a,b

Combination therapy: various combinationsAitken et al. (3) Active periodontitis Test P. gingivalis

Doxycycline 200 mg the % positive testsfirst day and then 100 Placebo π metronidazolemg, once daily, 21 days, Active sites 35and metronidazole 250 1 month ⇓ 15mg, three times daily, 7 months

⇓

1010 days Control sites 24Placebo 1 month ⇓ 10Lactose-containing 7 months

⇓

4placebo, once daily, 21 Doxycycline π metronidazoledays and metronidazole Active sites 43250 mg, three times daily, 1 month ⇓ 1110 days 7 months

⇓

8


⇓

5

days increased subgingival proportions of Strepto-coccus sanguis and Streptococcus mutans (Table 19)and of Actinomyces naeslundii, Actinomyces odon-tolyticus and Actinomyces viscosus (Table 20). Also,following treatment with azithromycin, numbers oforal streptococci increased (103). Subgingival over-growth of periodontally harmless bacteria may oc-cupy niches previously inhabited by periodontal

158

pathogens and, because of antagonistic bacterialinteractions (15), delay or prevent major pathogensfrom re-colonizing subgingival sites. However,overgrowth of mutans streptococci on exposed rootsurfaces might also increase the risk of dentalcaries and argue for prophylactic application oftopical fluoride concomitant with anti-infectiveperiodontal therapy.


Table 15. Effect of systemic antibiotics on subgingival B. forsythus


Study condition regime Effect on B. forsythus Baseline baseline P-value

NitroimidazolesWinkel ‘‘Refractory’’ Metronidazole 500 mg, Posttreatment B. forsythus in

et al. (142) periodontitis, three times daily, 7 days pretreatment B. forsythus–culture-positive for positive subjectsB. forsythus and % subjects 100.0 ⇓ 63.0negative for % microflora 16.1 ⇓ 5.5A. actinomyce-temcomitans

PenicillinsHaffajee Mild to moderate Amoxicillin 250 mg with % sites

et al. (41) periodontitis clavulanic acid (125 mg), B. forsythus 17.6 ⇓ 1.4three times daily,30 days


Winkel Generalized adult Amoxicillin 500 mg with B. forsythus aCompared with control,et al. (140) periodontitis clavulanic acid (125 mg), % subjects no significant difference

three times daily, Test 8010 days 3 months ⇓ 10a

12 months ⇓ 10a


12 months ⇓ 18

% microfloraTest 9

3 months

⇓

2a

12 months ⇓ 2a

Control 103 months

⇓

212 months

⇓

2


et al. (41) periodontitis three times daily, 30 days B. forsythus 23.9 ⇓ 8.7


Combination therapy: metronidazole and amoxicillinWinkel A. actino- Metronidazole 250 mg, B. forsythus aCompared with after

et al. (143) mycetemcomitans– three times daily π Number of subjects 14 initial therapy, PΩ0.001positive periodontitis amoxicillin 375 mg, After initial therapy ⇓ 3with either three times daily, 7 days After antibiotics ⇓ 13P. gingivalis, Mean % microflora 20.3B. forsythus, or After initial therapy 1.4P. intermedia After antibiotics ⇓ 14.7a

co-infection

Winkel Generalized severe Metronidazole 250 mg, B. forsythus aCompared with baseline,et al. (141) adult periodontitis three times daily π Number of subjects statistically significant

amoxicillin 375 mg, Placebo 22 ⇓ 6 bCompared with placebo,three times daily, 7 days Test 19 ⇓ 16a,b statistically significant

% microfloraPlacebo 10.4 ⇓ 0.3Test 7.5 4.5b

Conclusion and recommendations

Actively progressing periodontitis is virtually alwaysassociated with specific bacterial infections andoften requires the adjunctive use of systemic anti-biotic therapy. Systemic antibiotics may inhibit orkill periodontal pathogens located subgingivally out-side the reach of dental instruments and topicalantiseptics as well as pathogens invading gingivaltissue or residing in non-periodontal sites of the oralcavity. Decreasing periodontal pathogen counts in

159

the entire oral cavity may delay subgingival recolon-ization of pathogens and ensure prolonged prophy-lactic benefits. The tetracyclines have the additionaladvantage of inhibiting collagenases (99).

A conservative and highly selective approach isrecommended for periodontal antibiotic therapy. In-discriminate antibiotic administration is contrary tosound clinical practice and unnecessarily increasesin vivo resistance to antimicrobial agents that arevaluable in potentially fatal medical infections (96,115) or may cause overgrowth of intrinsically resis-

Slots & Ting

Table 16. Effect of systemic antibiotics on subgingival P. intermedia


Study condition regime Effect on P. intermedia Baseline baseline P-value

NitroimidazolesAitken Periodontitis patients Metronidazole 250 mg, Placebo π metronidazole Not done

et al. (3) previously treated three times daily, 10 days (% positive tests)with placebo or P. intermediadoxycycline 7 months Active sites 55ago with continued 1 month ⇓ 15gingival attachment 7 months ⇓ 7greater than 2 mm Control sites 33

1 month

⇓

267 months ⇓ 7

Gusberti Recurrent Metronidazole 250 mg, % P. intermedia 9.72 aCompared with baseline,et al. (40) periodontal disease three times daily, 10 days Day 10 ⇓ 3.34a statistically significant

9 months

⇓

6.06

Loesche Advanced adult Metronidazole 250 mg, Proportions of P. intermedia aCompared with control,et al. (57) periodontitis three times daily, 7 days Test 13.5 statistically significant

Post-debridement ⇓ 8.3Post-medication ⇓ 11.9a

Hygiene phase ⇓ 7.6


⇓


Loesche Advanced adult Metronidazole 250 mg, % P. intermedia aCompared with baseline,et al. (59) periodontitis three times daily, 7 days Test 7.2 PÆ0.05

1–3 days ⇓ 4.3a,b bCompared with control,Placebo, three times3–6 months ⇓ 3.0a PΩ0.05daily, 7 daysControl 6.11–3 days ⇓ 0.33–6 months

⇓

0.4

Loesche Moderate to Metronidazole 250 mg, % P. intermedia aCompared with baseline,et al. (60) advanced adult three times daily, 7 days Advanced disease test group 15.8 statistically significant


15–30 weeks ⇓ 12.7adaily, 7 days

Moderate disease test group 10.00–2 weeks ⇓ 7.5

15–30 weeks ⇓ 4.1


15–30 weeks ⇓ 1.0

Söder Advanced adult Metronidazole 400 mg, P. intermediaet al. (122) periodontitis three times daily, 7 days % subjects


NonsmokersTest 100.0 ⇓ 37.5Placebo 45.5

⇓

36.4

von Troil-Linden Advanced Metronidazole 500 mg, P. intermedia/P. nigrescenset al. (135) periodontitis twice daily, 7 days % patients 100


Winkel ‘‘Refractory’’ Metronidazole 500 mg, Posttreatment P. intermedia inet al. (142) periodontitis, three times daily, 7 days pretreatment P. intermedia–

culture-positive for positive subjectsB. forsythus and % subjects 77.8 ⇓ 51.9negative for % microflora 3.1 ⇓ 1.2A. actino- Posttreatment P. intermedia inmycetemcomitans pretreatment P. intermedia–

negative subjects% subjects 22.2 ⇓ 11.2% microflora 0

⇓

1.3

PenicillinsHaffajee Mild to moderate Amoxicillin 250 mg with % sites

et al. (41) periodontitis clavulanic acid (125 mg), P. intermedia 20.0

⇓

2.0three times daily, P. nigrescens 14.9

⇓

9.130 days


160


Table 16. Continued



Winkel Generalized adult Amoxicillin 500 mg with P. intermedia aCompared with control,et al. (140) periodontitis clavulanic acid (125 mg), % subjects no significant difference

three times daily, Test 10010 days 3 months

⇓

20a

12 months ⇓ 20a


12 months ⇓ 18


et al. (41) periodontitis three times daily, 30 days P. intermedia 29.9 ⇓ 6.5

Placebo: 250 mg P. nigrescens 29.4 ⇓ 2.8sucrose, three timesdaily, 30 days

Combination therapy: metronidazole and amoxicillinBerglundh Advanced Metronidazole 250 mg, % P. intermedia



12 months ⇓ 3.0


12 months ⇓ 1.5

Control (without scaling) 2.22 months

⇓

0.312 months

⇓

0.3

Lopez & Moderate to Metronidazole 250 mg, P. intermedia aCompared with placebo,Gamonal (61) advanced adult three times daily π % sites statistically significant

periodontitis amoxicillin 375 mg, Test 45.45 ⇓ 21.77a

three times daily, 8 days Placebo 50.00

⇓

20.00

Pavicic A. actino- Metronidazole 250 mg, P. intermediaet al. (85) mycetemcomitans– three times daily π % subjects 50

associated severe amoxicillin 375 mg, 3 months ⇓ 27.1periodontitis three times daily, 7 days 24 months

⇓14.6

van Winkelhoff A. actino- Metronidazole 250 mg, P. intermediaet al. (132) mycetemcomitans– three times daily π % subjects

associated amoxicillin 375 mg, Localized juvenile periodontitis 18.2 ⇓ 9.1periodontitis three times daily, 7 days Rapidly progressively 45.5 ⇓ 18.2consisting of periodontitislocalized juvenileperiodontitis andrapidly progressiveperiodontitis

van Winkelhoff A. actino- Metronidazole 250 mg, P. intermediaet al. (133) mycetemcomitans– three times daily π Localized juvenile periodontitis

associated amoxicillin 375 mg, % subjects 47 ⇓ 22periodontitis three times daily, 7 days % microflora 8

⇓

1consisting of colony-forming units ¿105/ml 56

⇓

109localized juvenile Generalized advanced adultperiodontitis, periodontitisgeneralized % subjects 72 ⇓ 42advanced adult % microflora 7

⇓

1periodontitis and colony-forming units ¿105/ml 92 ⇓ 80refractory

Refractory periodontitisperiodontitis% subjects 48 ⇓ 23% microflora 5

⇓

4colony-forming units ¿105/ml 90 ⇓ 67

Winkel A. actino- Metronidazole 250 mg, P. intermediaet al. (143) mycetemcomitans– three times daily π Number of subjects 16

positive periodontitis amoxicillin 375 mg, After initial therapy ⇓ 6with either three times daily, 7 days After antibiotics ⇓ 5P. gingivalis, Mean % microflora 1.3B. forsythus After initial therapy

⇓

3.0or P. intermedia After antibiotics 0co-infection

161

Slots & Ting

Table 16. Continued



Winkel Generalized severe Metronidazole 250 mg, P. intermedia aCompared with baseline,et al. (141) adult periodontitis three times daily π Number of subjects statistically significant

amoxicillin 375 mg, Placebo 24 ⇓ 6 bCompared with placebo,three times daily, 7 days Test 19 ⇓ 10a statistically significant

% microfloraPlacebo 4.4 ⇓ 1.0Test 4.5 ⇓ 0.4

Combination therapy: various combinationsAitken et al. (3) Active periodontitis Test P. intermedia

Doxycycline 200 mg the % positive testsfirst day and then 100 Placebo π metronidazolemg, once daily, 21 days, Active sites 55and metronidazole 250 1 month ⇓ 15mg, three times daily, 7 months ⇓ 710 days Control sites 33Placebo 1 month

⇓

26Lactose-containing 7 months ⇓ 7placebo, once daily, 21 Doxycycline π metronidazoledays and metronidazole Active sites 33250 mg, three times daily, 1 month

⇓

1610 days 7 months

⇓

15

Control sites 241 month 07 months ⇓ 7

tant pathogens (80, 92). However, we consider severeperiodontal infections to represent such a threat tooral and possibly systemic health that prudent useof effective antibiotics is ethically permissible in ap-propriately selected patients.

Prescription of systemic antibiotic therapy in peri-odontics should be based upon scientific data and notupon personal biases. Empirical antibiotic therapymay be used for periodontal diseases with known mi-crobial causes, such as acute necrotizing ulcerativegingivitis, which is caused by anaerobic organismsand can be cured by metronidazole (25), and earlylocalized juvenile periodontitis, mostly involving A.actinomycetemcomitans, which can be controlled oreradicated by systemic metronidazole–amoxicillincombination therapy (127, 132). However, even themost careful clinical examination cannot delineatethe likely microbial pathogens in most cases of peri-odontitis, and since the group of periodontal patho-gens exhibits diverse antimicrobial susceptibility(137), microbiological analysis is sometimes necess-ary for proper selection of antibiotic therapy. Be-cause antibiotic resistance constitutes an increasingproblem in the periodontal microbiota (55, 137),especially in countries permitting over-the-countersale of antibiotics (130), a number of authors recom-mend antimicrobial susceptibility testing of isolatedpathogens from non-responding patients (9, 21, 26,32, 54, 91, 124, 126). Based on microbial analysis andconsideration of the patient’s medical status and

162

current medications, an appropriate antibiotic ther-apy to supplement other types of periodontal anti-infective treatment can be prescribed.

If microbiological testing is unavailable, metroni-dazole–amoxicillin combination therapy (250–500mg of each, three times daily for 8 days) may be areasonable antibiotic first choice in periodontics.Unpublished data from our laboratory suggest thatthe metronidazole–amoxicillin combination is anappropriate choice in about 70% of advanced peri-odontitis patients. However, the metronidazole–amoxicillin combination does not affect Pseudomon-as or enteric gram-negative rods that inhabit ap-proximately 14% of advanced periodontitis lesionsin the United States (111) and more in developingcountries (8), and the post-antibiotic composition ofthe subgingival microbiota is unpredictable. The riskexists that resistant pathogens may proliferate andaggravate existing disease. Another valuable sys-temic antibiotic therapy in periodontics is the com-bination of metronidazole and ciprofloxacin (500 mgof each, twice daily for 8 days), which can cure an-aerobic, enteric rod and A. actinomycetemcomitansperiodontal infections and promote subgingivalovergrowth of streptococci able to inhibit gram-negative pathogens (111, 112). However, if poten-tially pathogenic beta-hemolytic streptococci colon-ize subgingival sites, their overgrowth after antibiotictherapy might lead to recurrence of disease (36).Also, the presence of Candida albicans or other resis-


Table 17. Effect of systemic antibiotics on subgingival spirochetes


Study condition regime Effect on spirochetes Baseline baseline P-value

LincosamidesGordon Refractory Clindamycin-HCl 150 % spirochetes 35 Compared with baseline,

et al. (39) periodontitis mg, four times daily, 7 1 month ⇓ 31a aP,0.01days 3 months ⇓ 25a

6 months ⇓ 26a

12 months ⇓ 27a

MacrolidesAl-Joburi Advanced adult Spiramycin 1,500,000 % spirochetes aCompared with placebo,

et al. (4) periodontitis IU, twice daily, 14 days Test 28 statistically significant2 weeks ⇓ 27.94a

Placebo, four times24 weeks ⇓ 25a

daily, 14 daysPlacebo 30


NitroimidazolesAitken et al. (3) Periodontitis patients Metronidazole 250 mg, Placebo π metronidazole Not done

previously treated three times daily, 10 days (% positive tests)with placebo or Spirochetes 61doxycycline 7 months Active sites 1⇓ 31ago with continued 1 month ⇓ 1gingival attachment 7 monthsgreater than 2 mm Control sites 23

1 month ⇓ 147 months

⇓

2

Clark et al. (18) Destructive Metronidazole 250 mg, % spirochetes aCompared with baseline,periodontal disease three times daily, 7 days Test 36.18 statistically significantexcluding acute 1 month ⇓ 23.22a bCompared with baseline,Placebo, three timesnecrotizing 3 months ⇓ 20.05 no significancedaily, 7 daysulcerative gingivitis 6 month ⇓ 13.30b

and juvenile Control 36.18periodontosis 1 month ⇓ 16.07a

3 months ⇓ 12.806 month ⇓13.29b

Gusberti Recurrent Metronidazole 250 mg, % spirochetes 44.43 aCompared with baseline,et al. (40) periodontal disease three times daily, 10 days Day 10 ⇓ 41.38a statistically significant

9 months ⇓ 19.68a

Jenkins Advanced adult Metronidazole 200 mg, % spirochetes aCompared with baseline,et al. (45) periodontitis three times daily, 5 days Debridement only 11.5 ⇓ 6.6a PÆ0.05

Metronidazole only 3.9 ⇓ 1.1Debridement π metronidazole 5.6 ⇓ 3.1a

Lindhe Advanced adult Metronidazole 200 mg, % spirocheteset al. (53) periodontitis four times daily for Test 35

three periods of 2 weeks Scaled ⇓ 35separated by intervals of 2 weeks ⇓ 348 weeks 50 weeks


50 weeks ⇓ 22

ControlScaled 38



50 weeks ⇓ 13

Loesche Advanced adult Metronidazole 250 mg, Proportions of Treponema spp.et al. (57) periodontitis three times daily, 7 days Test 0.2

Post-debridement ⇓ 0.2Post-medication ⇓ 0.2Hygiene phase

⇓

0.9

Control , 0.1Post-debridement

⇓

0.3Post-medication

⇓

1.4Hygiene phase 0

Lundström Advanced adult Metronidazole 200 mg, % spirochetes50et al. (63) periodontitis three times daily, 7 days Sufficient oral hygiene group


12 months ⇓ 4250Poor oral hygiene group


12 months ⇓ 8

163

Slots & Ting

Table 17. Continued



Palmer Moderate to Metronidazole 200 mg, % spirochetes Compared with control,et al. (82) advanced adult three times daily, 7 days Test 47.1 for all parameters no



24 weeks ⇓ 21.6

Palmer Moderate to Metronidazole 200 mg, Proportion of spirochetes aCompared with baseline,et al. (83) advanced adult three times daily, 7 days Smokersb P,0.05

periodontitis Test 47.2 bSmokers compared with2 months ⇓ 17.1 nonsmokers, P,0.056 months ⇓ 18.3




% spirochetes at 6 monthsSmokersb –Test – ⇓ 39.3a

Control ⇓ 29.9a

Nonsmokers –Test – ⇓ 45.7a

Control ⇓ 46.3a

Söder Advanced adult Metronidazole 400 mg, % spirocheteset al. (122) periodontitis three times daily, 7 days Smokers

Test 19.9 ⇓ 13.1Placebo, three timesPlacebo 20.2 ⇓ 15.2daily, 7 daysNonsmokersTest 15.7 ⇓ 5.7Placebo 19.3 ⇓ 6.8

Söder Moderate and Metronidazole 400 mg, Number of spirochetes per unit Compared with baseline,et al. (121) advanced three times daily, 7 days Test 6.69 ⇓ 2.34 and compared with

periodontitis, with Control 7.65

⇓

0.21 control, no significantPlacebo, three timesmore than three differencedaily, 7 daysteeth with .5 mmpockets andradiographicmarginal alveolarbone loss afterscaling and rootplanning

Walsh Adult periodontitis Metronidazole 2 g single % spirochetes aCompared with baseline,et al. (138) dose for treatment of Test 38.1 P,0.01





Watts Adult periodontitis Metronidazole 200 mg, % spirochetes aCompared with control,et al. (139) three times daily, 7 days Test 17.0 P,0.05

1 month ⇓ 6.5aPlacebo, three times

3 months ⇓ 3.3daily, 7 daysControl 20.31 month ⇓ 0.13 months ⇓ 0.1

164


Table 17. Effect of systemic antibiotics on subgingival spirochetes



PenicillinsWinkel Generalized adult Amoxicillin 500 mg with Spirochetes aCompared with control,

et al. (140) periodontitis clavulanic acid (125 mg), % subjects no significant differencethree times daily, Test 10010 days 3 months ⇓ 70a

12 months ⇓ 60a


12 months ⇓ 36

% microfloraTest 7

3 months ⇓ 6a

12 months ⇓ 6a


12 months ⇓ 11

TetracyclinesLindhe Advanced adult Tetracycline 250 mg, % spirochetes

et al. (52) periodontitis four times daily for the Testfirst 2 weeks and Scaled 48once daily for the next 2 weeks ⇓ 4848 weeks 50 weeks ⇓ 48


50 weeks ⇓ 39

ControlScaled 37



50 weeks ⇓ 13

Listgarten Advanced adult Tetracycline-HCl 250 % spirocheteset al. (56) periodontitis mg, four times daily for Test

2 periods of 14 days With scaling 36.3each separated by a 8 weeks ⇓ 36.34-week interval 25 weeks ⇓ 29.8


25 weeks ⇓ 17.1

ControlWith scaling 34.8

8 weeks ⇓ 24.125 weeks ⇓ 28.5

Without scaling 38.78 weeks

⇓

0.525 weeks

⇓

6.0

Lundström Advanced adult Doxycycline 100 mg, % spirochetes 100et al. (63) periodontitis once daily, 14 days 1 month ⇓ 100


tant pathogens in periodontal sites may pose a prob-lem with systemic antibiotic therapy. Some of the in-herent risks with antibiotic-resistant pathogens maybe partly overcome by concomitant subgingival ad-ministration of antiseptic agents capable of sup-pressing antibiotic-resistant pathogenic organisms(113). The risk still exists that antibiotic-resistantpathogens may overgrow in various oral sites andsubsequently reinfect periodontal pockets. As dis-cussed above, the best way to reduce or avoid ad-verse effects from antibiotic therapy is to prescribeantibiotics based on the findings of microbial analy-

165

sis. In addition, microbial sampling post-treatmentcan provide valuable information on the effective-ness of the antimicrobial therapy rendered. As em-phasized by Dahlen (22), microbiological testing isalso important in treating periodontal and endodon-tic acute infections and abscesses.

In conclusion, systemic antibiotic therapy that isproperly prescribed to patients with aggressiveperiodontitis can give rise to striking clinical out-comes. The value of systemic antibiotics in pa-tients with chronic periodontitis is not as clear.Based on the studies reviewed here, dental prac-

Slots & Ting

Table 18. Effect of systemic antibiotics on various putative periodontopathic bacteria

Effect on ChangesPeriodontal Systemic antibiotic other periodontal from

Study condition regime microorganisms Baseline baseline P-value

NitroimidazolesAitken et al. (3) Periodontitis patients Metronidazole 250 mg, % positive tests Not calculated

previously treated three times daily, 10 days E. corrodenswith placebo or Data for placebo π Active sites 51doxycycline 7 months metronidazole presented 1 month ⇓ 36ago with continued 7 months ⇓ 1gingival attachment Control sites 42greater than 2 mm 1 month ⇓ 15

7 months ⇓ 17

F. nucleatumActive sites 591 month ⇓ 297 months ⇓ 11

Control sites 411 month ⇓ 147 months ⇓ 5

Gusberti Recurrent Metronidazole 250 mg, % Fusobacterium spp. 17.31 aCompared with baseline,et al. (40) periodontal disease three times daily, 10 days Day 10 ⇓ 16.13a statistically significant

9 months ⇓ 6.63

% E. corrodens 3.06Day 10 ⇓ 2.99a

9 months ⇓ 0.59

% Capnocytophaga spp. 0.67Day 10

⇓

0.749 months

⇓

0.35

Loesche Advanced adult Metronidazole 250 mg, Proportions of Fusobacteria spp. aCompared with control,et al. (57) periodontitis three times daily, 7 days Test 3.6 statistically significant

Post-debridement ⇓ 1.3Post-medication ⇓ 2.4a

Hygiene phase ⇓ 1.1

Control 5.4Post-debridement ⇓ 2.4Post-medication ⇓ 0.1Hygiene phase ⇓ 1.0

Proportions ofSelenomonas spp.Test 0.4Post-debridement ⇓ 0.2Post-medication ⇓ 0.3Hygiene phase ⇓ 0.1

Control 0.4Post-debridement

⇓

0.1Post-medication

⇓


Proportions of Veillonella spp.Test 0.6a

Post-debridement

⇓

0.4a

Post-medication

⇓

0.6Hygiene phase

⇓

2.6


⇓

1.4Post-medication

⇓


Loesche Advanced adult Metronidazole 250 mg, % F. nucleatum % F. nucleatum:et al. (59) periodontitis three times daily, 7 days Test 3.6 acompared with baseline,

1–3 days ⇓ 2.4a PÆ0.05Placebo, three times3–6 months ⇓ 1.5daily, 7 days % Selenomonas spp.:Control 3.3 bcompared with baseline,1–3 days

⇓

2.0 PÆ0.053–6 months

⇓

0.4

% SelenomonasTest 1.21–3 days ⇓ 1.0a,b

3–6 months ⇓ 0.5

Control 1.41–3 days ⇓ 0.73–6 months ⇓ 0.9b

166


Table 18. Continued



Loesche Moderate to Metronidazole 250 mg, % F. nucleatum aCompared with baseline,et al. (60) advanced adult three times daily, 7 days Advanced disease test group 3.6 statistically significant


15–30 weeks

⇓

0.6adaily, 7 days


15–30 weeks

⇓

6.4a


15–30 weeks ⇓ 1.6

% Veillonella spp.Advanced disease test group 2.4

0–2 weeks ⇓ 1.515–30 weeks ⇓ 0.5


15–30 weeks

⇓

0.9


15–30 weeks 0

% Capnocytophaga spp.Advanced disease test group 1.0

0–2 weeks ⇓ 0.115–30 weeks

⇓

0.4


15–30 weeks ⇓ 1.6

Moderate disease placebo group 1.40–2 weeks

⇓

0.415–30 weeks

⇓

1.0

Noyan et al. (79) Adult periodontitis Metronidazole 250 mg, Obligate anaerobesthree times daily, 7 days % total viable counts

Metronidazole π scaling 61.59 ⇓ 42.17Metronidazole only 51.75 ⇓ 30.66Control 55.04 ⇓ 21.74

von Troil-Linden Advanced Metronidazole 500 mg, C. rectus 100et al. (135) periodontitis twice daily, 7 days 1 month ⇓ 60

6 month ⇓ 40

P. micros 701 month ⇓ 106 month 0

Walsh Adult periodontitis Metronidazole 2 g single % Fusobacterium spp. aCompared with baseline,et al. (138) dose for treatment of Test 0.63 P,0.01

Trichomonas vaginalis 1 month ⇓ 0.11 bCompared with scaling,by medical staff 3 months ⇓ 0.21 P,0.01

cCompared with bothScaling 0.46control and test, P,0.011 month

⇓

0.573 months ⇓ 0.27

Control 0.503 months

⇓

0.12

% obligate anaerobesTest 80.401 month ⇓ 11.7b

3 months

⇓

0.84

Scaling 71.801 month ⇓ 37.6a



PenicillinsAbu Fanas Rapidly progressive Amoxicillin 250 mg with Proportion of F. nucleatum 20.2 Compared with baseline,

et al. (1) periodontitis clavulanic acid (125 mg), Week 1 ⇓ 20.09b aP,0.05, bP,0.01three times daily, 14 Week 2 ⇓ 20.2b

days Week 6 ⇓ 17.5b

Week 18 ⇓ 17.7a

Collins Refractory Amoxicillin 250 mg with % subjectset al. (19) periodontitis clavulanic acid (125 mg), E. corrodens 43.3 ⇓ 23.3

four times daily, 14 days F. nucleatum 73.3 ⇓ 16.7

Capnocytophaga spp. 43.3 ⇓ 1.0

C. recta 46.7 ⇓ 0

167

Slots & Ting

Table 18. Continued



Haffajee Mild to moderate Amoxicillin 250 mg with % siteset al. (41) periodontitis clavulanic acid (125 mg), C. ochracea 17.2

⇓

21.8three times daily,30 days


Winkel Generalized adult Amoxicillin 500 mg with F. nucleatum aCompared with control,et al. (140) periodontitis clavulanic acid (125 mg), % subjects no significant difference

three times daily, Test 10010 days 3 months ⇓ 10a

12 months 0a


12 months 0

% microfloraTest 7

3 months 0a

12 months 0a


12 months ⇓ 1

P. micros% subjectsTest 60

3 months

⇓

30a

12 months

⇓

40a

Control 733 months

⇓

912 months

⇓

9

% microfloraTest 4

3 months

⇓

5a

12 months

⇓

4a

Control 63 months

⇓1

12 months ⇓ 1

TetracyclinesAbu Fanas Rapidly progressive Tetracycline-HCl 250 Proportion of F. nucleatum 15.7 Compared with baseline,

et al. (1) periodontitis mg, four times daily, Week 1 ⇓ 11.5 aP,0.0514 days Week 2 ⇓ 15.7a

Week 6 ⇓ 14.5a

Week 18 ⇓ 12.6a

Haffajee et al. Mild to moderate Tetracycline 250 mg, % sites(41) periodontitis three times daily, 30 days C. ochracea 28.9 ⇓ 1.4


Preus et al. (88) Moderate to Minocycline-HCl 50 mg % colony forming unitsadvanced adult in the morning and 100 Aerobic minocycline-resistant 0.5periodontitis mg in the evening for 10 strains

days 2 weeks

⇓

2.81 month ⇓ 0.49 months ⇓ 0.4

12 months ⇓ 0.4

Anaerobic minocycline-resistant 0.12strains

2 weeks

⇓

0.331 month

⇓

0.289 months

⇓

0.00512 months

⇓

0.02

168


Table 18. Continued



Combination therapy: metronidazole and amoxicillinWinkel A. actino- Metronidazole 250 mg, P. micros

et al. (143) mycetemcomitans– three times daily π Number of subjects 4positive periodontitis amoxicillin 375 mg, After initial therapy

⇓

7with either three times daily, 7 days After antibiotics

⇓

6P. gingivalis, Mean % microflora 23.6B. forsythus or After initial therapy ⇓ 13.8P. intermedia After antibiotics ⇓ 16.9co-infection

F. nucleatumNumber of subjects 3After initial therapy

⇓

4After antibiotics

⇓

6

Mean % microflora 16.0After initial therapy ⇓ 3.4After antibiotics ⇓ 10.2

Winkel Generalized severe Metronidazole 250 mg, P. micros aCompared with placebo,et al. (141) adult periodontitis three times daily π Number of subjects statistically significant

amoxicillin 375 mg, Placebo 15 ⇓ 2three times daily, 7 days Test 18 ⇓ 8a

% microfloraPlacebo 8.1 ⇓ 1.6Test 6.4

⇓

1.5a

F. nucleatumNumber of subjectsPlacebo 22 ⇓ 2Test 21 ⇓ 2

% microfloraPlacebo 8.7 ⇓ 2.6Test 3.8

⇓

0.1

Combination therapy: various combinationsAitken et al. (3) Active periodontitis Test: % positive tests

Doxycycline 200 mg the Placebo π metronidazolefirst day and then E. corrodens100 mg, once daily, Active sites 5121 days, and 1 month ⇓ 36metronidazole 250 mg, 7 months ⇓ 1three times daily, Control sites 4210 days 1 month ⇓ 15Placebo: 7 months ⇓ 17Lactose-containing F. nucleatumplacebo, once daily, Active sites 5921 days and 1 month ⇓ 29metronidazole 250 mg, 7 months ⇓ 11three times daily,

Control sites 4110 days1 month ⇓ 147 months ⇓ 5

Doxycycline π metronidazoleE. corrodensActive sites 431 month ⇓ 57 months

⇓

8

Control sites 161 month ⇓ 47 months ⇓ 3

F. nucleatumActive sites 521 month ⇓ 287 months ⇓ 1


⇓

8

169

Slots & Ting

Table 19. Effect of systemic antibiotics on subgingival streptoccocci


Study condition regime Effect on streptococci Baseline baseline P-value

NitroimidazolesJenkins Advanced adult Metronidazole 200 mg, % Streptococcus

et al. (45) periodontitis three times daily, 5 days Debridement only 4.7

⇓

4.1Metronidazole only 8.9

⇓

3.6Debridement π metronidazole 8.7 ⇓ 0.9

Loesche Advanced adult Metronidazole 250 mg, Proportions of S. sanguis aCompared with control,et al. (57) periodontitis three times daily, 7 days Test 0.9 P,0.01

Post-debridement

⇓

6.3a

Post-medication

⇓

8.5Hygiene phase

⇓

6.9


⇓

8.0Post-medication

⇓

10.0Hygiene phase

⇓

5.2

Proportions of S. mutansTest 0.6Post-debridement

⇓

0.1Post-medication

⇓

0.4Hygiene phase

⇓

1.3


⇓


Loesche Advanced adult Metronidazole 250 mg, % S. sanguis % S. sanguis: aComparedet al. (59) periodontitis three times daily, 7 days Test 1.0 with baseline, PÆ0.05

1–3 days

⇓

2.0Placebo, three times % S. mutans: bCompared3–6 months

⇓

2.4adaily, 7 days with baseline, PΩ0.05

Control 1.11–3 days

⇓

4.4a

3–6 months

⇓

0.7

% S. mutansTest 0.31–3 days

⇓

0.43–6 months

⇓

0.7b


⇓0.2

3–6 months

⇓

0.1

Loesche Moderate to Metronidazole 250 mg, % S. sanguis aCompared with baseline,et al. (60) advanced adult three times daily, 7 days Advanced disease test group 4.1 statistically significant

periodontitis 0–2 weeks

⇓

11.2aPlacebo, three times

15–30 weeks

⇓

2.7adaily, 7 days

Moderate disease test group 2.00–2 weeks

⇓

12.115–30 weeks ⇓ 0.1


⇓

6.9a

15–30 weeks ⇓ 0.8

% S. mutansAdvanced disease test group 0.2

0–2 weeks

⇓

0.915–30 weeks

⇓

0.3


⇓

17.315–30 weeks

⇓

4.9


⇓

0.815–30 weeks 0

titioners should be able to choose an appropriatesystemic antibiotic therapy in the treatment of de-structive periodontal disease. However, manage-ment of severe types of periodontitis should notrely solely on systemic antibiotics but upon a com-bination of mechanical debridement possibly inconjunction with surgery, subgingival administra-tion of antiseptics by dental professionals and pa-

170

tients, patients’ oral hygiene efforts and effectiveand safe systemic antibiotics (19, 109, 113). Rec-ommendations for periodontal anti-infective ther-apy will undoubtedly be continually revised alongwith the development of even better understand-ing of the pathogenic periodontal microbiota andthe availability of new and more effective drugs tocontrol or possibly cure periodontal infections.


Table 20. Effect of systemic antibiotics on subgingival Actinomyces


Study condition regime Effect on Actinomyces Baseline baseline P-valueNitroimidazolesGusberti Recurrent Metronidazole 250 mg, % A. naeslundii 1.21

et al. (40) periodontal disease three times daily, Day 10

⇓

5.4910 days 9 months

⇓

8.15

% A. odontolyticus 0Day 10

⇓

0.839 months

⇓

032

Loesche Advanced adult Metronidazole 250 mg, Proportions of A. naeslundiiet al. (57) periodontitis three times daily, 7 days Test 1.2

Post-debridement

⇓

2.2Post-medication

⇓

2.7Hygiene phase

⇓

0.9


⇓

2.7Post-medication

⇓

5.3Hygiene phase

⇓

2.1

Proportions of A. odontolyticusTest 0.5Post-debridement

⇓

2.6Post-medication

⇓

5.2Hygiene phase

⇓

2.7


⇓

1.0Post-medication

⇓

3.1Hygiene phase

⇓

1.4

Proportions of A. viscosusTest 0.4Post-debridement

⇓

2.8Post-medication

⇓

3.2Hygiene phase

⇓

2.6


⇓

5.1Post-medication

⇓

4.8Hygiene phase

⇓

4.0

Loesche Advanced adult Metronidazole 250 mg, % A. naeslundii % A. viscosus:et al. (59) periodontitis three times daily, 7 days Test 1.6 aCompared with

1–3 days

⇓

3.4 baseline, PÆ0.05Placebo, three times3–6 months

⇓

1.3daily, 7 daysControl 1.21–3 days

⇓

0.23–6 months

⇓

0.4

% A. viscosusTest 3.11–3 days

⇓

3.5a

3–6 months

⇓

3.3a


⇓

1.63–6 months

⇓

2.3

Loesche Moderate to Metronidazole 250 mg, % A. odontolyticus aCompared withet al. (60) advanced adult three times daily, 7 days Advanced disease test group 2.0 baseline, statistically

periodontitis 0–2 weeks

⇓

2.0a significantPlacebo, three times15–30 weeks ⇓ 1.4a

daily, 7 daysModerate disease test group 1.3

0–2 weeks

⇓

0.4a

15–30 weeks

⇓

1.6a


⇓

1.615–30 weeks ⇓ 0.1

% A. viscosusAdvanced disease test group 0.7

0–2 weeks

⇓

1.315–30 weeks

⇓

0.2


⇓

2.615–30 weeks ⇓ 0.4


⇓

1.715–30 weeks

⇓

0.7

% A. naeslundiiAdvanced disease test group 0.02

0–2 weeks

⇓

0.4815–30 weeks

⇓

1.98

Moderate disease test group 0.30–2 weeks 0

15–30 weeks

⇓

2.2


⇓

1.015–30 weeks ⇓ 0.1

171

Slots & Ting

References

1. Abu Fanas SH, Drucker DB, Hull PS. Amoxycillin with cla-vulanic acid and tetracycline in periodontal therapy. J Dent1991: 19: 97–99.

2. Adriaens PA, De Boever JA, Loesche WJ. Bacterial invasionin root cementum and radicular dentin of periodontallydiseased teeth in humans. A reservoir of periodontopathicbacteria. J Periodontol 1988: 59: 222–230.

3. Aitken S, Birek P, Kulkarni GV, Lee WL, McCulloch CA. Serialdoxycycline and metronidazole in prevention of recurrentperiodontitis in high-risk patients. J Periodontol 1992: 63:87–92.

4. Al-Joburi W, Quee TC, Lautar C, Iugovaz I, Bourgouin J, De-lorme F, Chan EC. Effects of adjunctive treatment of peri-odontitis with tetracycline and spiramycin. J Periodontol1989: 60: 533–539.

5. Asikainen S, Lai CH, Alaluusua S, Slots J. Distribution ofActinobacillus actinomycetemcomitans serotypes in peri-odontal health and disease. Oral Microbiol Immunol 1991:6: 115–118.

6. Atilla G, Balcan M, Bicakci N, Kazandi A. The effect of non-surgical periodontal and adjunctive minocycline-HCLtreatments on the activity of salivary proteases. J Peri-odontol 1996: 67: 1–6.

7. Bain CA, Beagrie GS, Bourgoin J, Delorme F, Holthuis A,Landry RG, Roy S, Schuller P, Singer D, Turnbull R. The ef-fects of spiramycin and/or scaling on advanced peri-odontitis in humans. J Can Dent Assoc 1994: 60: 209, 212–227–127.

8. Barbosa FCB, Mayer MPA, Saba-Chujfi E, Cai S. Subgingivaloccurrence and antimicrobial susceptibility of enteric rodsand pseudomonads from Brazilian periodontitis patients.Oral Microbiol Immunol 2001: 16: 306–310.

9. Barone A, Sbordone L, Ramaglia L, Ciaglia RN. Microbioticaassociated with refractory periodontitis. Prevalence andantibiotic susceptibility. Minerva Stomatol 1999: 48: 191–201.

10. Bedeschi G, Beltrame M, Baldin C, Confente G, Guerra L,Fostini R. Pharmacokinetics of a new oral antibacterialagent, ofloxacin, in dentistry and oral surgery. Int J ClinPharmacol Ther Toxicol 1988: 26: 162–164.

11. Berglundh T, Krok L, Liljenberg B, Westfelt E, Serino G,Lindhe J. The use of metronidazole and amoxicillin in thetreatment of advanced periodontal disease. A prospective,controlled clinical trial. J Clin Periodontol 1998: 25: 354–362.

12. Blandizzi C, Malizia T, Lupetti A, Pesce D, Gabriele M, Giu-ca MR, Campa M, Del Tacca M, Senesi S. Periodontal tissuedisposition of azithromycin in patients affected by chronicinflammatory periodontal diseases. J Periodontol 1999: 70:960–966.

13. Britt MR, Pohlod DJ. Serum and crevicular fluid concen-trations after a single oral dose of metronidazole. J Peri-odontol 1986: 57: 104–107.

14. Buchmann R, Müller RF, Heinecke A, Lange DE. Actino-bacillus actinomycetemcomitans in destructive periodontaldisease. Three-year follow-up results. J Periodontol 2000:71: 444–453.

15. Chen C, Slots J. The current status and future prospects ofaltering the pathogenic microflora of periodontal disease.Curr Opin Periodontol 1993: 71–77.

172

16. Christersson LA, Albini B, Zambon JJ, Wikesjö UM, GencoRJ. Tissue localization of Actinobacillus actinomycetem-comitans in human periodontitis. I. Light, immunofluor-escence and electron microscopic studies. J Periodontol1987: 58: 529–539.

17. Ciancio SG, Mather ML, McMullen JA. An evaluation of mi-nocycline in patients with periodontal disease. J Peri-odontol 1980: 51: 530–534.

18. Clark CD, Shenker S, Stulginski P, Schwartz S. Effectivenessof routine periodontal treatment with and without adjunc-tive metronidazole therapy in a sample of mentally re-tarded adolescents. J Periodontol 1983: 54: 658–665.

19. Collins JG, Offenbacher S, Arnold RR. Effects of a combi-nation therapy to eliminate Porphyromonas gingivalis inrefractory periodontitis. J Periodontol 1993: 64: 998–1007.

20. Conway TB, Beck FM, Walters JD. Gingival fluid ciproflox-acin levels at healthy and inflamed human periodontalsites. J Periodontol 2000: 71: 1448–1452.

21. Dahlen G. Role of suspected periodontopathogens inmicrobiological monitoring of periodontitis. Adv Dent Res1993: 7: 163–174.

22. Dahlen G. Microbiology and treatment of dental abscessesand periodontal-endodontic lesions. Periodontol 20002002: 28: 206–239.

23. Del Tacca M, Danesi R, Bernardini N, Ducci M, Zolfino I,Senesi S, Panattoni E, Gabriele M, Marcucci M, Lazzarini Aet al. Roxithromycin penetration into gingiva and alveolarbone of odontoiatric patients. Chemotherapy 1990: 36:332–336.

24. Dzink JL, Gibbons RJ, Childs WC 3rd, Socransky SS. Thepredominant cultivable microbiota of crevicular epithelialcells. Oral Microbiol Immunol 1989: 4: 1–5.

25. Duckworth R, Waterhouse JP, Britton DE, Nuki K, SheihamA, Winter R, Blake GC. Acute ulcerative gingivitis. Adouble-blind controlled clinical trial of metronidazole. BrDent J 1966: 120: 599–602.

26. Edlund C, Hedberg M, Nord CE. Antimicrobial treatmentof periodontal diseases disturbs the human ecology: a re-view. J Chemother 1996: 8: 331–341.

27. Edwardsson S, Bing M, Axtelius B, Lindberg B, SöderfeldtB, Attström R. The microbiota of periodontal pockets withdifferent depths in therapy-resistant periodontitis. J ClinPeriodontol 1999: 26: 143–152.

28. Eickholz P, Kugel B, Pohl S, Naher H, Staehle HJ. Combinedmechanical and antibiotic periodontal therapy in a case ofPapillon-Lefevre syndrome. J Periodontol 2001: 72: 542–549.

29. Elter JR, Lawrence HP, Offenbacher S, Beck JD. Meta-analy-sis of the effect of systemic metronidazole as an adjunct toscaling and root planing for adult periodontitis. J Peri-odontal Res 1997: 32: 487–496.

30. Feres M, Haffajee AD, Goncalves C, Allard KA, Som S, SmithC, Goodson JM, Socransky SS. Systemic doxycycline ad-ministration in the treatment of periodontal infections. I.Effect on the subgingival microbiota. J Clin Periodontol1999: 26: 775–783.

31. Feres M, Haffajee AD, Goncalves C, Allard KA, Som S, SmithC, Goodson JM, Socransky SS. Systemic doxycycline ad-ministration in the treatment of periodontal infections. II.Effect on antibiotic resistance of subgingival species. J ClinPeriodontol 1999: 26: 784–792.

32. Fine DH. Microbial identification and antibiotic sensi-tivity testing, an aid for patients refractory to periodontal


therapy. A report of 3 cases. J Clin Periodontol 1994: 21:98–106.

33. Fives-Taylor PM, Meyer DH, Mintz KP, Brissette C. Viru-lence factors of Actinobacillus actinomycetemcomitans.Periodontol 2000 1999: 20: 136–167.

34. Flemmig TF, Milian E, Karch H, Klaiber B. Differential clin-ical treatment outcome after systemic metronidazole andamoxicillin in patients harboring Actinobacillus actino-mycetemcomitans and/or Porphyromonas gingivalis. J ClinPeriodontol 1998: 25: 380–387.

35. Flemmig TF, Milian E, Kopp C, Karch H, Klaiber B. Differen-tial effects of systemic metronidazole and amoxicillin onActinobacillus actinomycetemcomitans and Porphyromonasgingivalis in intraoral habitats. J Clin Periodontol 1998: 25:1–10.

36. Flynn MJ, Slots J. Beta-hemolytic streptococci in advancedperiodontitis. Oral Microbiol Immunol 1993: 8: 295–297.

37. Giuliana G, Ammatuna P, Pizzo G, Capone F, D’Angelo M.Occurrence of invading bacteria in radicular dentin of peri-odontally diseased teeth: microbiological findings. J ClinPeriodontol 1997: 24: 478–485.

38. Gordon J, Walker C, Holviaras C, Socransky S. Efficacy ofclindamycin hydrochloride in refractory periodontitis: 24-month results. J Periodontol 1990: 61: 686–691.

39. Gordon J, Walker C, Lamster I, West T, Socransky S, SeigerM, Fasciano R. Efficacy of clindamycin hydrochloride in re-fractory periodontitis. 12-months results. J Periodontol1985: 56: S75–S80.

40. Gusberti FA, Syed SA, Lang NP. Combined antibiotic (me-tronidazole) and mechanical treatment effects on the sub-gingival bacterial flora of sites with recurrent periodontaldisease. J Clin Periodontol 1988: 15: 353–359.

41. Haffajee AD, Socransky SS, Dibart S, Kent RL Jr. Responseto periodontal therapy in patients with high or low levelsof P. gingivalis, P. intermedia, P. nigrescens and B. forsythus.J Clin Periodontol 1996: 23: 336–345.

42. Hellden LB, Listgarten MA, Lindhe J. The effect of tetracy-cline and/or scaling on human periodontal disease. J ClinPeriodontol 1979: 6: 222–230.

43. Higashi K, Seike M, Mitani Y, Morisaki K, Hayashi S, Kita-mura M, Fujimoto N, Kimura S, Ebisu S, Okada H. Concen-tration of ofloxacin in human gingival crevicular fluid afteroral administration of TarividA. J Periodontal Res 1989: 24:409–411.

44. Ishikawa I, Umeda M, Laosrisin N. Clinical, bacteriological,and immunological examinations and the treatment pro-cess of two Papillon-Lefevre syndrome patients. J Peri-odontol 1994: 65: 364–371.

45. Jenkins WM, MacFarlane TW, Gilmour WH, Ramsay I, Mac-Kenzie D. Systemic metronidazole in the treatment of peri-odontitis. J Clin Periodontol 1989: 16: 443–450.

46. Kamma JJ, Nakou M, Mitsis FJ. The clinical and microbio-logical effects of systemic ornidazole in sites with and with-out subgingival debridement in early-onset periodontitispatients. J Periodontol 2000: 71: 1862–1873.

47. Kleinfelder JW, Müller RF, Lange DE. Bacterial susceptibilityto amoxicillin and potassium clavulanate in advanced peri-odontitis patients not responding to mechanical therapy. JClin Periodontol 2000: 27: 846–853.

48. Kleinfelder JW, Müller RF, Lange DE. Fluoroquinolones inthe treatment of Actinobacillus actinomycetemcomitans-as-sociated periodontitis. J Periodontol 2000: 71: 202–208.

49. Lamont RJ, Jenkinson HF. Subgingival colonization by Por-

173

phyromonas gingivalis. Oral Microbiol Immunol 2000: 15:341–349.

50. Levy RM, Giannobile WV, Feres M, Haffajee AD, Smith C,Socransky SS. The short-term effect of apically reposi-tioned flap surgery on the composition of the subgingivalmicrobiota. Int J Periodontics Restorative Dent 1999: 19:555–567.

51. Liew V, Mack G, Tseng P, Cvejic M, Hayden M, BuchananN. Single-dose concentrations of tinidazole in gingival cre-vicular fluid, serum, and gingival tissue in adults with peri-odontitis. J Dent Res 1991: 70: 910–912.

52. Lindhe J, Liljenberg B, Adielson B, Adielson B. Long-termtetracycline therapy on human periodontal disease. J ClinPeriodontol 1983: 10: 590–601.

53. Lindhe J, Liljenberg B, Adielson B, Börjesson I. Use of me-tronidazole as a probe in the study of human periodontaldisease. J Clin Periodontol 1983: 10: 100–112.

54. Listgarten MA. Monitoring the periodontal microbiota asan adjunct to periodontal therapy: rationale, interpretationof test results and application to patient management. Al-pha Omegan 1992: 5: 49–53.

55. Listgarten MA, Lai CH, Young V. Microbial composition andpattern of antibiotic resistance in subgingival microbialsamples from patients with refractory periodontitis. J Peri-odontol 1993: 64: 155–161.

56. Listgarten MA, Lindhe J, Hellden LB. Effect of tetracyclineand/or scaling on human periodontal disease: clinical,microbiological and histological observations. J Clin Peri-odontol 1978: 5: 246–271.

57. Loesche WJ, Giordano JR, Hujoel P, Schwarcz J, Smith BA.Metronidazole in periodontitis: reduced need for surgery. JClin Periodontol 1992: 19: 103–112.

58. Loesche WJ, Giordano J, Soebren S, Hutchinson R, Rau CP,Walsh L, Schork MA. Nonsurgical treatment of patientswith periodontal disease. Oral Surg Oral Med Oral PatholOral Radiol Endod 1996: 81: 533–543.

59. Loesche WJ, Schmidt E, Smith BA, Morrison EC, CaffesseR, Hujoel PP. Effects of metronidazole on periodontal treat-ment needs. J Periodontol 1991: 62: 247–257.

60. Loesche WJ, Syed SA, Morrison EC, Kerry GA, Higgins T,Stoll J. Metronidazole in periodontitis. I. Clinical and bac-teriological results after 15 to 30 weeks. J Periodontol 1984:55: 325–335.

61. Lopez NJ, Gamonal JA. Effects of metronidazole plusamoxicillin in progressive untreated adult periodontitis: re-sults of a single 1-week course after 2 and 4 months. J Peri-odontol 1998: 69: 1291–1298.

62. Lopez NJ, Gamonal JA, Martinez B. Repeated metronidazo-le and amoxicillin treatment of periodontitis. A follow-upstudy. J Periodontol 2000: 71: 79–89.

63. Lundström Å, Johansson LÅ, Hamp SE. Effect of combinedsystemic antimicrobial therapy and mechanical plaquecontrol in patients with recurrent periodontal disease. JClin Periodontol 1984: 11: 321–330.

64. Malizia T, Tejada MR, Ghelardi E, Senesi S, Gabriele M, Giu-ca MR, Blandizzi C, Danesi R, Campa M, Del Tacca M. Peri-odontal tissue disposition of azithromycin. J Periodontol1997: 68: 1206–1209.

65. Mandell RL, Socransky SS. Microbiological and clinical ef-fects of surgery plus doxycycline on juvenile periodontitis.J Periodontol 1988: 59: 373–379.

66. Matisko MW, Bissada NF. Short-term sequential adminis-tration of amoxicillin/clavulanate potassium and doxycy-

Slots & Ting

cline in the treatment of recurrent/progressive peri-odontitis. J Periodontol 1993: 64: 553–558.

67. Mombelli A, Nyman S, Bragger U, Wennström J, Lang NP.Clinical and microbiological changes associated with an al-tered subgingival environment induced by periodontalpocket reduction. J Clin Periodontol 1995: 22: 780–787.

68. Mombelli A, Schmid B, Rutar A, Lang NP. Persistence pat-terns of Porphyromonas gingivalis, Prevotella intermedia/nigrescens, and Actinobacillus actinomycetemcomitans aftermechanical therapy of periodontal disease. J Periodontol2000: 71: 14–21.

69. Müller HP, Heinecke A, Borneff M, Kiencke C, Knopf A, PohlS. Eradication of Actinobacillus actinomycetemcomitansfrom the oral cavity in adult periodontitis. J Periodontal Res1998: 33: 49–58.

70. Müller HP, Heinecke A, Borneff M, Knopf A, Kiencke C, PohlS. Microbial ecology of Actinobacillus actinomycetemcomit-ans, Eikenella corrodens and Capnocytophaga spp. in adultperiodontitis. J Periodontal Res 1997: 32: 530–542.

71. Müller HP, Heinecke A, Borneff M, Kiencke C, Knopf A, PohlS. Eradication of Actinobacillus actinomycetemcomitansfrom the oral cavity in adult periodontitis. J Periodontal Res1998: 33: 49–58.

72. Müller HP, Lange DE, Müller RF. A 2-year study of adjunc-tive minocycline-HCl in Actinobacillus actinomycetem-comitans-associated periodontitis. J Periodontol 1993: 64:509–519.

73. Müller HP, Lange DE, Müller RF. Failure of adjunctive mino-cycline-HCl to eliminate oral Actinobacillus actinomyce-temcomitans. J Clin Periodontol 1993: 20: 498–504.

74. Müller HP, Lange DE, Müller RF. Actinobacillus actinomyce-temcomitans recovery from extracrevicular locations of themouth. Oral Microbiol Immunol 1993: 8: 344–348.

75. Naito Y, Gibbons RJ. Attachment of Bacteroides gingivalisto collagenous substrata. J Dent Res 1988: 67: 1075–1080.

76. Ng VW, Bissada NF. Clinical evaluation of systemic doxycy-cline and ibuprofen administration as an adjunctive treat-ment for adult periodontitis. J Periodontol 1998: 69: 772–776.

77. Nieminen A, Asikainen S, Torkko H, Kari K, Uitto VJ, SaxenL. Value of some laboratory and clinical measurements inthe treatment plan for advanced periodontitis. J Clin Peri-odontol 1996: 23: 572–581.

78. Novak MJ, Stamatelakys C, Adair SM. Resolution of earlylesions of juvenile periodontitis with tetracycline therapyalone: long-term observations of 4 cases. J Periodontol1991: 62: 628–633.

79. Noyan Ü, Yilmaz S, Kuru B, Kadir T, Acar O, Büget E. Aclinical and microbiological evaluation of systemic and lo-cal metronidazole delivery in adult periodontitis patients. JClin Periodontol 1997: 24: 158–165.

80. Olsvik B, Hansen BF, Tenover FC, Olsen I. Tetracycline-re-sistant micro-organisms recovered from patients with re-fractory periodontal disease. J Clin Periodontol 1995: 22:391–396.

81. Pacheco JJ, Coelho C, Salazar F, Contreras A, Slots J, VelazcoCH. Treatment of Papillon-Lefevre syndrome periodontitis.J Clin Periodontol (in press).

82. Palmer RM, Matthews JP, Wilson RF. Adjunctive systemicand locally delivered metronidazole in the treatment ofperiodontitis: a controlled clinical study. Br Dent J 1998:184: 548–552.

83. Palmer RM, Matthews JP, Wilson RF. Non-surgical peri-

174

odontal treatment with and without adjunctive metronid-azole in smokers and non-smokers. J Clin Periodontol1999: 26: 158–163.

84. Pappalardo G, Bianchi A, Scire Scappuzzo G, Mirone M,Salomone S. Preliminary pharmacokinetic and clinicalevaluation of ofloxacin in dental and oral cavity diseases.Int J Clin Pharmacol Res 1989: 9: 229–232.

85. Pavicic MJAMP, van Winkelhoff AJ, Douque NH, SteuresRWR, de Graaff J. Microbiological and clinical effects ofmetronidazole and amoxicillin in Actinobacillus actino-mycetemcomitans-associated periodontitis. A 2-yearevaluation. J Clin Periodontol 1994: 21: 107–112.

86. Pertuiset JH, Saglie FR, Lofthus J, Rezende M, Sanz M.Recurrent periodontal disease and bacterial presence inthe gingiva. J Periodontol 1987: 58: 553–558.

87. Petersilka GJ, Ehmke B, Flemmig TF. Antimicrobial effectsof mechanical debridement. Periodontol 2000 2002: 28:56–71.

88. Preus HR, Lassen J, Aass AM, Ciancio SG. Bacterial re-sistance following subgingival and systemic administra-tion of minocycline. J Clin Periodontol 1995: 22: 380–384.

89. Quirynen M, De Soete M, Dierickx K, van Steenberghe D.The intra-oral translocation of periodontopathogensjeopardises the outcome of periodontal therapy. A reviewof the literature. J Clin Periodontol 2001: 28: 499–507.

90. Ramberg P, Rosling B, Serino G, Hellström MK, SocranskySS, Lindhe J. The long-term effect of systemic tetracyclineused as an adjunct to non-surgical treatment of advancedperiodontitis. J Clin Periodontol 2001: 28: 446–452.

91. Rams TE. Availability of laboratory testing services foridentification of periodontal pathogens in dental plaque.Clin Prev Dent 1989: 11: 18–21.

92. Rams TE, Babalola OO, Slots J. Subgingival occurrence ofenteric rods, yeasts and staphylococci after systemicdoxycycline therapy. Oral Microbiol Immunol 1990: 5:166–168.

93. Rams TE, Feik D, Listgarten MA, Slots J. Peptostreptoc-occus micros in human periodontitis. Oral Microbiol Im-munol 1992: 7: 1––6.

94. Rams TE, Feik D, Slots J. Campylobacter rectus in humanperiodontitis. Oral Microbiol Immunol 1993: 8: 230–235.

95. Renvert S, Wikström M, Dahlen G, Slots J, Egelberg J. Onthe inability of root debridement and periodontal surgeryto eliminate Actinobacillus actinomycetemcomitans fromperiodontal pockets. J Clin Periodontol 1990: 17: 351–355.

96. Roberts MC. Antibiotic toxicity, interactions and resistancedevelopment. Periodontol 2000 2002: 28: 280–297.

97. Rotzetter PA, Le Liboux A, Pichard E, Cimasoni G. Kineticsof spiramycin/metronidazole (Rodogyl) in human gingi-val crevicular fluid, saliva and blood. J Clin Periodontol1994: 21: 595–600.

98. Rudney JD, Chen R, Sedgewick GJ. Intracellular Actino-bacillus actinomycetemcomitans and Porphyromonas gin-givalis in buccal epithelial cells collected from humansubjects. Infect Immun 2001: 69: 2700–2707.

99. Ryan ME, Golub LM. Modulation of matrix metallopro-teinase activities in periodontitis as a treatment strategy.Periodontol 2000 2000: 24: 226–238.

100. Sakellari D, Goodson JM, Kolokotronis A, KonstantinidisA. Concentration of 3 tetracyclines in plasma, gingivalcrevice fluid and saliva. J Clin Periodontol 2000: 27: 53–60.

101. Saxen L, Asikainen S. Metronidazole in the treatment of


localized juvenile periodontitis. J Clin Periodontol 1993:20: 166–171.

102. Saxen L, Asikainen S, Kanervo A, Kari K, Jousimies-SomerH. The long-term efficacy of systemic doxycycline medi-cation in the treatment of localized juvenile periodontitis.Arch Oral Biol 1990: 35(suppl): 227S–229S.

103. Sefton AM. Macrolides and changes in the oral flora. Int JAntimicrob Agents 1999: 11(suppl 1): S23–S29; discussionS31–S32.

104. Sefton AM, Maskell JP, Beighton D, Whiley A, Shain H,Foyle D, Smith SR, Smales FC, Williams JD. Azithromycinin the treatment of periodontal disease. Effect on mi-crobial flora. J Clin Periodontol 1996: 23: 998–1003.

105. Serino G, Rosling B, Ramberg P, Hellström MK, SocranskySS, Lindhe J. The effect of systemic antibiotics in thetreatment of patients with recurrent periodontitis. J ClinPeriodontol 2001: 28: 411–418.

106. Shiloah J, Patters MR, Dean JW 3rd, Bland P, Toledo G.The prevalence of Actinobacillus actinomycetemcomitans,Porphyromonas gingivalis, and Bacteroides forsythus inhumans 1 year after 4 randomized treatment modalities.J Periodontol 1998: 69: 1364–1372.

107. Sigusch B, Beier M, Klinger G, Pfister W, Glockmann E. A2-step non-surgical procedure and systemic antibiotics inthe treatment of rapidly progressive periodontitis. J Peri-odontol 2001: 72: 275–283.

108. Slots J. Systemic antibiotics in periodontics (Am Acad Peri-odontol position paper). J Periodontol 1996: 67: 831–838.

109. Slots J. Primer for antimicrobial periodontal therapy. JPeriodontal Res 2000: 35: 108–114. Translated into Span-ish: Compendio de terapeutica antimicrobiana peri-odontal. Acta Dent Int 2000: 1: 295–302.

110. Slots J, Chen C. The oral microflora and human peri-odontal disease. In: Tannock GW, ed. Medical importanceof the normal microflora. London: Kluwer Academic Pub-lishers, 1999: 101–127.

111. Slots J, Feik D, Rams TE. Prevalence and antimicrobialsusceptibility of Enterobacteriaceae, Pseudomonadaceaeand Acinetobacter in human periodontitis. Oral MicrobiolImmunol 1990: 5: 149–154.

112. Slots J, Feik D, Rams TE. In vitro antimicrobial sensitivityof enteric rods and pseudomonads from advanced adultperiodontitis. Oral Microbiol Immunol 1990: 5: 298–301.

113. Slots J, Jorgensen MG. Effective, safe, practical and af-fordable periodontal antimicrobial therapy: where are wegoing, and are we there yet? Periodontol 2000 2002: 28:298–312.

114. Slots J, Mashimo P, Levine MJ, Genco RJ. Periodontal ther-apy in humans. I. Microbiological and clinical effects of asingle course of periodontal scaling and root planing, andof adjunctive tetracycline therapy. J Periodontol 1979: 50:495–509.

115. Slots J, Pallasch TJ. Dentists’ role in halting antimicrobialresistance. J Dent Res 1996: 75: 1338–1341.

116. Slots J, Rams TE. Systemic and topical antimicrobial ther-apy in periodontics. Periodontol 2000 1996: 10: 5–159.

117. Slots J, Rosling B. Suppression of the periodontopathicmicroflora in localized juvenile periodontitis by systemictetracycline. J Clin Periodontol 1983: 10: 465–486.

118. Slots J, Ting M. Actinobacillus actinomycetemcomitansand Porphyromonas gingivalis in human periodontal dis-ease: occurrence and treatment. Periodontol 2000 1999:20: 82–121.

175

119. Socransky SS, Haffajee AD. Dental biofilms: difficulttherapeutic targets. Periodontol 2000 2002: 28: 12–55.

120. Socransky SS, Haffajee AD, Ximenez-Fyvie LA, Feres M,Mager D. Ecological considerations in the treatment ofActinobacillus actinomycetemcomitans and Porphyro-monas gingivalis periodontal infections. Periodontol 20001999: 20: 341–362.

121. Söder PÖ, Frithiof L, Wikner S, Wouters F, Engström PE,Rubin B, Nedlich U, Söder B. The effect of systemic me-tronidazole after non-surgical treatment in moderate andadvanced periodontitis in young adults. J Periodontol1990: 61: 281–288.

122. Söder B, Nedlich U, Jin LJ. Longitudinal effect of non-surgical treatment and systemic metronidazole for 1 weekin smokers and non-smokers with refractory peri-odontitis: a 5-year study. J Periodontol 1999: 70: 761–771.

123. Takamatsu N, Yano K, He T, Umeda M, Ishikawa I. Effectof initial periodontal therapy on the frequency of de-tecting Bacteroides forsythus, Porphyromonas gingivalis,and Actinobacillus actinomycetemcomitans. J Periodontol1999: 70: 574–580.

124. Tanner A, Stillman N. Oral and dental infections with an-aerobic bacteria: clinical features, predominant patho-gens, and treatment. Clin Infect Dis 1993: 16(suppl 4):S304–S309.

125. Tenenbaum H, Jehl F, Gallion C, Dahan M. Amoxicillinand clavulanic acid concentrations in gingival crevicularfluid. J Clin Periodontol 1997: 24: 804–807.

126. Ting M, Slots J. Microbiological diagnostics in peri-odontics. Compendium Contin Educ Dent 1997: 18: 861–878. Translated into German: Mikrobiologische Testver-fahren: Wann, wie, warum? Ästhet Zahnmed 1998: 1: 146–156.

127. Tinoco EM, Beldi MI, Campedelli F, Lana M, Loureiro CA,Bellini HT, Rams TE, Tinoco NM, Gjermo P, Preus HR.Clinical and microbiological effects of adjunctive anti-biotics in treatment of localized juvenile periodontitis. Acontrolled clinical trial. J Periodontol 1998: 69: 1355–1363.

128. Tuan M-C, Nowzari H, Slots J. Clinical and microbiologicstudy of periodontal surgery by means of apically posi-tioned flaps with and without osseous recontouring. Int JPeriodontics Restorative Dent 2000: 20: 469–475. Trans-lated into German: Parodontalchirurgie mit apikalen po-sitioniertem Lappen mit und ohne Osteoplastik: klinischeund mikrobiologische Studie. Int J Paradontol Restaur-ative Zahnheilkd 2000: 20: 453–459.

129. Van Oosten MA, Notten FJ, Mikx FH. Metronidazole con-centrations in human plasma, saliva, and gingival crevicefluid after a single dose. J Dent Res 1986: 65: 1420–1423.

130. van Winkelhoff AJ, Herrera Gonzales D, Winkel EG, Delle-mijn-Kippuw N, Vandenbroucke-Grauls CM, Sanz M.Antimicrobial resistance in the subgingival microflora inpatients with adult periodontitis. A comparison betweenthe Netherlands and Spain. J Clin Periodontol 2000: 27:79–86.

131. van Winkelhoff AJ, Rams TE, Slots J. Systemic antibiotictherapy in periodontics. Periodontol 2000 1996: 10: 45–78.

132. van Winkelhoff AJ, Rodenburg JP, Goene RJ, Abbas F, Win-kel EG, de Graaff J. Metronidazole plus amoxycillin in thetreatment of Actinobacillus actinomycetemcomitans as-sociated periodontitis. J Clin Periodontol 1989: 16: 128–131.

133. van Winkelhoff AJ, Tijhof CJ, de Graaff J. Microbiological

Slots & Ting

and clinical results of metronidazole plus amoxicillin inActinobacillus actinomycetemcomitans–associated peri-odontitis. J Periodontol 1992: 63: 52–57.

134. van Winkelhoff AJ, Winkel EG, Vandenbroucke-GraulsCMJE. On the dosage of antibiotics in clinical trials. J ClinPeriodontol 1999: 26: 764–766.

135. von Troil-Linden B, Alaluusua S, Wolf J, Jousimies-SomerH, Torppa J, Asikainen S. Periodontitis patient and thespouse: periodontal bacteria before and after treatment.J Clin Periodontol 1997: 24: 893–899.

136. Walker CB. Selected antimicrobial agents: mechanisms ofaction, side effects and drug interactions. Periodontol2000 1996: 10: 12–28.

137. Walker CB. The acquisition of antibiotic resistance in theperiodontal microflora. Periodontol 2000 1996: 10: 79–88.

138. Walsh MM, Buchanan SA, Hoover CI, Newbrun E, TaggartEJ, Armitage GC, Robertson PB. Clinical and microbiolog-ic effects of single-dose metronidazole or scaling and rootplaning in treatment of adult periodontitis. J Clin Peri-odontol 1986: 13: 151–157.

139. Watts T, Palmer R, Floyd P. Metronidazole: a double-blindtrial in untreated human periodontal disease. J Clin Peri-odontol 1986: 13: 939–943.

176

140. Winkel EG, van Winkelhoff AJ, Barendregt DS, van derWeijden GA, Timmerman MF, van der Velden U. Clinicaland microbiological effects of initial periodontal therapyin conjunction with amoxicillin and clavulanic acid in pa-tients with adult periodontitis. A randomised double-blind, placebo-controlled study. J Clin Periodontol 1999:26: 461–468.

141. Winkel EG, van Winkelhoff AJ, Timmerman MF, van derVelden U, van der Weijden GA. Amoxicillin plus metronid-azole in the treatment of adult periodontitis patients. Adouble-blind placebo-controlled study. J Clin Periodontol2001: 28: 296–305.

142. Winkel EG, van Winkelhoff AJ, Timmerman MF, VangstedT, van der Velden U. Effects of metronidazole in patientswith ‘‘refractory’’ periodontitis associated with Bacter-oides forsythus. J Clin Periodontol 1997: 24: 573–579.

143. Winkel EG, van Winkelhoff AJ, van der Velden U. Ad-ditional clinical and microbiological effects of amoxicillinand metronidazole after initial periodontal therapy. J ClinPeriodontol 1998: 25: 857–864.

144. Wright TL, Ellen RP, Lacroix JM, Sinnadurai S, MittelmanMW. Effects of metronidazole on Porphyromonas gingi-valis biofilms. J Periodontal Res 1997: 32: 473–477.

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