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Ann Periodontol

Systemic Anti-Infective Periodontal Therapy.A Systematic Review

Anne D. Haffajee,* Sigmund S. Socransky,* and John C. Gunsolley†

* Department of Periodontology, The Forsyth Institute, Boston, Massachusetts.† Department of Periodontics, College of Dental Surgery, University of Maryland, Baltimore, Maryland.

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Background: Periodontal diseases are infections and thus systemically administered antibiotics are oftenemployed as adjuncts for their control. There are conflicting reports as to whether these agents provide a ther-apeutic benefit.

Rationale: The purpose of this systematic review is to determine whether systemically administeredantibiotics improve a primary clinical outcome measure, periodontal attachment level change.

Focused Question: In patients with periodontitis, what is the effect of systemically administered antibi-otics as compared to controls on clinical measures of attachment level?

Search Protocol: The PubMed database was searched from 1966 to May 2002. Searches were limitedto human studies published in English. Hand searches were performed on the Journal of Clinical Peri-odontology, Journal of Periodontology, and Journal of Periodontal Research. References in relevant papersand review articles were also examined.

Selection CriteriaInclusion criteria: Trials were selected if they met the following criteria: randomized controlled clinical

trials, quasi-experimental studies, and cohort studies of >1 month duration with a comparison group; sub-jects with aggressive, chronic, or recurrent periodontitis and periodontal abscess; use of a single or a com-bination of systemically administered antibiotics(s) versus non-antibiotic therapy; and a primary outcomeof mean attachment level change (AL).

Exclusion criteria: Studies involving the use of low-dose doxyclycline, combinations of locally plus sys-temic antibiotics, or where the control group included a systemically administered antibiotic were excluded.

Data Collection and Analysis: A mean difference in AL between groups was available for all papers used inthe meta-analysis. A standard deviation (SD) for the difference was used if provided or calculated from the SDor standard error of the mean (SEM) when provided for single measurements. Data were subset by antibioticemployed, type of adjunctive therapy, and disease type. Results were assessed with both fixed-effects andrandom-effects models.

Main Results1. Twenty-nine studies, 26 RCTs and 3 quasi-experimental (36 comparisons), met the entry criteria.

Total study population, both control and test groups, was estimated at over 1,200.2. Twenty-two studies (27 comparisons) were used in the meta-analysis, evaluating if the antibiotics pro-

vided a consistent benefit in mean AL change for different patient populations, for different therapies, and fordifferent antibiotics.

3. For the majority of the comparisons, systemically administered antibiotics exhibited a more positiveattachment level change than the control group in the study. The combined results were statistically significant(P <0.001).

4. The systemic antibiotics were uniformly beneficial in providing an improvement in AL when used asadjuncts to scaling and root planing (SRP) and were consistently beneficial, although of borderline signifi-cance, when used as adjuncts to SRP plus surgery or as a stand alone therapy.

5. When examining the effects of individual or combinations of antibiotics, it was found that there were sta-tistically significant improvements in AL for tetracycline, metronidazole, and an effect of borderline statisticalsignificance for the combination of amoxicillin plus metronidazole.

6. Improvements in mean AL were consistent for both chronic and aggressive periodontitis subjects, althoughthe aggressive periodontitis patients benefited more from the antibiotics.

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Systemic Anti-Infective Therapy Volume 8 • Number 1 • December 2003

BACKGROUNDPeriodontal diseases constitute a series of infectionscaused by the microorganisms that colonize at or belowthe gingival margin. These infections commonly leadto periodontal inflammation and often result in thedestruction of the supporting tissues of the teeth. Sincemost periodontal pathology is caused by bacteria, it isnot surprising that systemically administered antibi-otics have often been employed as adjuncts to aid intheir control. The organisms that cause these diseasesreside in unique structures termed biofilms that offerpartial protection to the colonizing organisms from thedefense mechanisms of the host as well as from theantibiotics used for their treatment.

The literature is replete with studies that havedescribed the effects of systemically administeredantibiotics on periodontal diseases. These reports rangefrom case reports to randomized clinical trials (RCTs).Most reports suggest benefits resulting from antibioticuse, although often these benefits were not “statisticallysignificantly better” than comparison groups. Unfortu-nately, the reports in the literature are quite heteroge-neous in terms of antibiotics employed, dosage, dura-tion, nature of adjunctive therapy, time of follow up,subject population, and the choice of outcome vari-ables.

RATIONALEThe purpose of this systematic review was to examinethe added effects, if any, of systemically administeredantibiotics on one commonly accepted primary outcomevariable, clinically determined gain in periodontal attach-ment level (AL).

FOCUSED QUESTIONThis systematic review attempted to answer the focusedquestion: “in patients with periodontitis, what is the effectof systemically administered antibiotics as comparedto controls on clinical measures of attachment level?”

SEARCH PROTOCOLData Sources and Search StrategiesPubMed was the primary database searched from 1966to May 2002.

The following search terms were used:For clinical conditions: periodontitis; periodontal dis-

eases; periodontal attachment loss; periodontitis juvenile;recurrent periodontitis; refractory periodontitis; alveolarbone loss; periodontal abscess; periodontal pocket; peri-odontics; tooth loss; and tooth mobility.

For periodontal treatment: antibiotic; antibiotics; amox-icillin; amoxycillin; amoxicillin-potassium clavulanatecombination; amoxicillin + clavulanic acid; penicillin;ampicillin; doxycline; tetracycline; minocycline; metron-idazole; flagyl; clindamycin; spiramycin; rovamycin;azithromycin; erythromycin; kanamycin; rifampin; rifam-picin; chloramphenicol; and ciprofloxacin.

Searches were limited to human studies in the Eng-lish language. Available abstracts were reviewed andsuitable papers requested. In addition, potentially suit-able papers without abstracts and publications thatcould not be adequately evaluated from the abstractwere also requested. Hand searches of Journal of Clin-ical Periodontology, Journal of Periodontology, andJournal of Periodontal Research and examination ofreferences in relevant papers and review articles wereused to supplement the search.

Selection Criteria: InclusionStudy types: The studies were limited to randomizedcontrolled clinical trials, quasi-experimental studies, andcohort studies of >1 month duration. A comparison groupwas mandatory.

Study populations: Participants included subjectswith aggressive periodontitis, chronic periodontitis,recurrent periodontitis, and periodontal abscess.

Intervention: Studies were limited to those using asingle systemically administered antibiotic versus non-antibiotic therapy or therapy using combined system-ically administered antibiotics versus non-antibiotictherapy. Antibiotic therapies could be stand-alone orcombined with mechanical therapies such as scalingand root planing (SRP) or periodontal surgery.

Selection Criteria: ExclusionStudies involving the use of low-dose doxycycline,local + systemic antibiotics, and where the control groupincluded a systemically administered antibiotic wereexcluded, as were animal and in vitro studies.

OutcomesThe primary outcome measured in the studies had tobe clinically determined attachment level (AL) change

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Reviewers’ Conclusions1. The use of systemically administered adjunc-

tive antibiotics with and without SRP and/or surgeryappeared to provide a greater clinical improvementin AL than therapies not employing these agents.

2. The data supported similar effect sizes forthe majority of the antibiotics; therefore, the selec-tion for an individual patient has to be made basedon other factors.

3. Due to a lack of sufficient sample size formany of the antibiotics tested, it is difficult to pro-vide guidance as to the more effective ones.Ann Periodontol 2003;8:115-181.

KEY WORDSClinical trials, controlled; antibiotics/therapeutic use; periodontal diseases/drugtherapy; periodontal attachment level/drugtherapy; periodontal diseases/therapy;periodontal attachment level/therapy; reviewliterature; meta-analysis.

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Ann Periodontol Haffajee, Socransky, Gunsolley

(e.g., mean AL change, % of sites exhibiting AL changeover a given threshold). Studies without this outcomewere excluded.

Methods of ReviewEach reviewer (ADH, SSS) independently examined thetitles and abstracts of the search output for the follow-ing criteria: 1) Was it a human study? 2) Of periodon-titis? 3) Involving a systemically administered antibiotic?4) Was it a randomized clinical trial, quasi-experimental,or cohort study? 5) Was there a comparison group?6) Was there a clinically determined attachment levelmeasure outcome? A “No” to any of these questionswould exclude the study.

The agreement between the 2 reviewers for eachpaper was tabulated in a 2 × 2 table. A paper was dis-carded at this stage if both reviewers agreed. Thesenumbers were recorded. If either reviewer “accepted”the paper, it was entered into a full-text review.

All possibly relevant full-text papers were screened byboth reviewers using the screening criteria outlinedabove. Reasons for exclusion were recorded. If there wasdisagreement, the reasons were discussed and resolved.

Data Collection and AnalysisData were independently abstracted from all eligiblefull-text papers using a review form by the reviewers.

Study Quality AssessmentThe following measures were used to insure quality ofdata collection. There was duplicate independentscreening and data abstraction; agreement scores werechecked using kappa statistics; a log of all studiesscreened and accepted or rejected was kept; the num-bers achieved from the initial search were recordedas well as the number of publications accepted andrejected. Reasons for rejection of studies at the full-textreview stage were recorded.

The following questions were asked of each study.Was assignment to treatment groups random? Wasthe treatment allocation concealed? Were the groupssimilar at baseline in terms of level of disease? Wereinclusion and exclusion criteria specified? Were out-come assessors masked to the treatment allocation?Was the care provider masked? Was the patientmasked? Were the point estimates and measure of vari-ability presented for the primary outcome measure?Did the analyses include an intention-to-treat analy-sis? Were drop-out rates presented and explained? Wereadverse events reported? Was compliance measured?

Data AnalysisA mean difference in AL between groups was availablefor all the studies employed in the meta-analyses. Astandard deviation (SD) for the difference was calculatedusing the following strategy. All standard errors (SE)were converted to SD. If there was a standard error ordeviation for the change, that was used. If only a stan-

dard error or deviation of an individual measure wasavailable, then it was assumed that the covariance was0 and the variance of the change was computed as thesum of the variance of the 2 measures. The same for-mula was applied in order to obtain the variance of thedifferences in changes between groups.

The outcome nearest to the 6-month time point wasused for the analysis, although this was not possible forall studies. Studies that examined only 1 or 2 sites werenot included in the analysis. It was assumed that theadjunctive effect to different mechanical therapies wouldresult in similar differences between groups. This wasexamined in one of the analyses. In different analyses,the data were subset according to systemic antibioticemployed, type of adjunctive therapy, and disease type.

The data were analyzed using a standardized differ-ence as described by Fleiss.1 The results were checkedwith both a fixed-effects model and a random-effectsmodel and the results were consistent. To test for het-erogeneity both Cohen’s d (unadjusted)2 and Hedges’sg (adjusted)3 were used. Both tests had to be non-significant to support the lack of heterogeneity.

Details of Included StudiesThe search strategy outlined above identified 526studies; 446 of which met the established inclusioncriteria. Of these, the reviewers agreed on 68 for full-text review. There was disagreement on 12 studiesthat were also acquired in full-text format. Thus, therewas a 97.7% agreement between reviewers on theselection of the studies. After full-text review, 29 werefound to meet all inclusion and exclusion criteria,7 of the 29 were excluded from the meta-analysis forreasons described below. Thus, a total of 22 studiesproviding 27 comparisons, since some studies eval-uated more than a single agent, were analyzed in themeta-analysis.

Rationale for excluding the other 51 studies whichmet the defined criteria is explained immediately beforethe Results section.

The design of the 29 (36 comparisons) includedstudies is presented in Table 1 (page 118). The stud-ies are subset according to the systemically adminis-tered antibiotic(s). There was a single study employ-ing amoxicillin (AMOX),4 5 comparisons4-8 evaluatedAMOX plus metronidazole (MET), 4 comparisons9-12

evaluated AMOX + clavulanic acid (AMOX + CA), 2comparisons10,13 evaluated clindamycin (CLIN), 3comparisons13-15 evaluated doxycycline (DOXY) attherapeutic levels, 12 comparisons4,13,16-25 evaluatedMET, 1 comparison26 evaluated penicillin (PEN), 2comparisons27,28 evaluated spiramycin (SPIR), and 6comparisons12,27,29-32 tetracycline (TET). All studiesincluded either placebo (PLAC), SRP, or surgery (SURG)in either the control or test groups.

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Table 1.

Design of Included Studies

TreatmentStudyDesign/ N

Reference Duration Groups Test Control Setting Funding Ranking*

AMOXICILLIN

Rooney et al.4 2002 RCT 6 months 4 AMOX + MET + SRP; 2 PLAC + SRP University Not stated IMET + PLAC + SRP; UKAMOX + PLAC + SRP:

AMOXICILLIN + METRONIDAZOLE

Lopez et al.5 2000 RCT 12 months 2 MET & AMOX PLAC University Government IChile

Berglundh et al.6 RCT 24 months 4 MET & AMOX + PLAC + SRP; University Government/ I1998 SRP; MET & AMOX PLAC Sweden industry

Winkel et al.7 2001 RCT 3 months 2 MET + AMOX + PLAC + SRP University Not stated ISRP The Netherlands

Rooney et al.4 2002 RCT 6 months 4 AMOX + MET + SRP; 2 PLAC + SRP University Not stated IMET + PLAC + SRP: UKAMOX + PLAC + SRP:

Tinoco et al.8 1998 RCT 12 months 2 AMOX + MET + SRP PLAC + SRP Multi-center Government IBrazil

AMOXICILLIN + CLAVULANIC ACID

Winkel et al.9 1999 RCT 12 months 2 AMOX + CA + SRP PLAC + SRP University Industry IThe Netherlands

Magnusson et al.10 Quasi 3 AMOX + CA + SRP; PLAC + SRP University Government II-11994 24 months CLIND + SRP USA

Purucker et al.11 RCT 54 weeks 2 AMOX + CA + SRP Local TET University Industry II-12001 fibers + SRP Germany

Haffajee et al.12 RCT 10 months 3 TET + SRP + MWF or PLAC + SRP + University Government I1995 AMOX + CA + MWF USA

SRP + MWF†

CLINDAMYCIN

Sigusch et al.13 2001 RCT 24 months 4 DOXY + SRP; MET + SRP University Not stated II-1SRP; CLIND + SRP Germany

Magnusson et al.10 Quasi 3 AMOX + CA + SRP; PLAC + SRP University Government II-11994 24 months CLIND + SRP USA

DOXYCYCLINE

Ng and Bissada14 1998 RCT 24 weeks 4 DOXY + SRP; DOXY PLAC + SRP; PLAC Unclear Not stated IUSA

Feres et al.15 1999 RCT 90 days 2 DOXY + SRP SRP University Government II-1USA

Sigusch et al.13 2001 RCT 24 months 4 DOXY + SRP; MET + SRP University Not stated II-1SRP; CLIND + SRP Germany

METRONIDAZOLE

Yilmaz et al.16 1996 RCT 42 days 4 MET; MET + SRP None; SRP University Industry II-1Turkey

Noyan et al.17 1997 RCT 42 days 4 MET; MET + SRP None; SRP Unclear Industry II-1Turkey

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Table 1. (continued)



Reference Duration Groups Test Control Setting Funding Ranking

Lindhe et al.18 1983 RCT 50 weeks 4 MET + SRP; MET SRP; none University Government II-1Sweden

Walsh et al.19 1986 Quasi 3 months 3 MET SRP or none University Government/ II-1USA industry

Sigusch et al.13 RCT 24 months 4 DOXY + SRP; MET + SRP University Not stated II-12001 SRP; CLIND + SRP Germany

Loesche et al.20 RCT 4-6 weeks 2 MET + SRP PLAC + SRP University Government I1992 after completion USA

of debridement

Loesche et al.21 RCT 4-6 weeks 2 MET + SRP PLAC + SRP University Government I1991 after completion USA

of debridement

Rooney et al.4 RCT 6 months 4 AMOX + MET + SRP; 2 PLACS + SRP University Not stated I2002 MET + PLAC + SRP; UK

AMOX + PLAC + SRP

Clark et al.22 1983 RCT 6 months 2 MET + prophy PLAC + prophy Unclear Not stated II-1Canada

Soder et al.23 RCT 5 years 8 MET + SRP smokers; PLAC + SRP smokers Unclear Not stated II-11999 MET + SRP non- PLAC + SRP non- Sweden

smokers; MET + smokers; PLAC +SRP + SURG smokers; SRP + SURGMET + SRP + SURG smokers; PLAC +non-smokers SRP + SURG

non-smokers

Palmer et al.24 RCT 24 weeks 3 MET + SRP SRP; SRP + MET gel University Government II-11998 UK

Palmer et al.25 RCT 6 months 3 MET + SRP SRP; SRP + MET gel University Government II-11999 UK

PENICILLIN

Kunihira et al.26 RCT 62 weeks; 98 2 PEN + SRP + SURG SRP + SURG + PLAC Unclear Not stated I1985 weeks for subset USA

SPIRAMYCIN

Al-Joburi et al.27 RCT 24 weeks 3 SPIRA + SRP;TET + SRP PLAC + SRP Unclear Industry I1989 Canada

Bain et al.28 1994 RCT 24 weeks 2 SPIRA + SRP PLAC + SRP Multi-center Industry ICanada

TETRACYCLINE

Hellden et al.29 RCT 25 weeks 4 TET + SRP;TET SRP; none University Not stated II-11979 Sweden

Lindhe et al.30 RCT 50 weeks 4 TET + SRP;TET PLAC + SRP; PLAC University Government I1983 Sweden

Al-Joburi et al.27 RCT 24 weeks 3 SPIRA + SRP;TET + SRP PLAC + SRP Unclear Industry I1989 Canada (continued)

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Reference Duration Groups Test Control Setting Funding Ranking

Ramberg et al.31 Quasi 13 years 2 TET + SRP SRP University Government II-12001 (numeric data for Sweden

1 year only)

Haffajee et al.12 RCT 10 months 3 TET + SRP + MWF PLAC + SRP + University Government I1995 or AMOX + CA + MWF USA

SRP + MWF

Palmer et al.32 RCT 12 months 2 TET + SRP followed PLAC + SRP followed University Not stated I1996 by SURG by SURG UK

* I: RCT; II-1: controlled trial without randomization.† Modified Widman flap.

Table 2.

Quality Assessment

Randomization Masking

Reference Randomization Method Allocation Concealment Patient Therapist Examiner

AMOXICILLIN

4 According to subject number Coded packages dispensed by hospital pharmacy Yes Yes Yes


5 Unclear Coded labels Yes Yes Yes

6 Unclear Unclear Yes Unclear Unclear

7 Unclear Unclear Yes Unclear Yes




9 Unclear Coded labels Yes Unclear Yes

10 Unclear Unclear Unclear Unclear Unclear

11 Unclear Unclear No No Unclear

12 Random number table Unclear Yes Unclear Yes

CLINDAMYCIN

13 Unclear Unclear No Unclear Yes


DOXYCYCLINE


15 Random number table Unclear No No Yes


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Twenty-six comparisons were RCTs and 3 werequasi-experimental. Twenty-seven of the compari-sons took place in a university setting, 2 were multi-center studies, and the location of 7 was unclear. Fif-teen comparisons were funded by government, 7 byindustry, 2 by government and industry, and the fund-ing source was unknown for the remaining studies.The duration of the studies ranged from 6 weeks to5 years. The studies were carried out in 9 countries;10 in the United States, 6 each in United Kingdom andSweden, 4 each in Canada and Germany, 2 each inTurkey and The Netherlands, and 1 each in Brazil andChile.

Quality AssessmentQuality assessment of the studies is summarized inTable 2 (page 120). While randomization was employedin 26 studies, only 11 of the comparisons described the

method of randomization and just 6 defined allocationand concealment procedures. Masking of the subjectstook place in 20 of the comparisons, of the therapist in9, and of the examiner in 26. Masking was not done orwas unclear for the remainder of the studies. One exam-iner was employed in 8 studies and examiner calibra-tion was described in 9 of the comparisons. Inclusioncriteria were defined for all but 1 comparison and exclu-sion criteria were described for all studies. The numberof subjects completing the studies was documented inall studies but the reason for dropouts was usually notdescribed. In addition, the handling of dropouts in thedata analysis of many studies was not explicitly stated,although many studies appeared to employ only thesubjects that were retained to the end of the study inthe analyses.

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Quality Assessment

Subject Selection Defined Completion

Calibration Inclusion Criteria Exclusion Criteria Patients Acounted at End Dropouts in Analyses?

AMOXICILLIN

1 examiner Yes Yes Yes No


Yes Yes Yes Yes No

Unclear No Yes Yes N/A*

Unclear Yes Yes Yes N/A





Unclear Yes Yes Yes No

1 examiner Yes Yes Yes Unclear

Yes Yes Yes Yes N/A

CLINDAMYCIN

Yes Yes Yes Yes N/A


DOXYCYCLINE


Yes Yes Yes Yes N/A

Yes Yes Yes Yes N/A

(continued)

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Table 2. (continued) Table 2. (continued)

Quality Assessment

Randomization Masking

Reference Randomization Method Allocation Concealment Patient Therapist Examiner

METRONIDAZOLE



18 Not stated Not stated Yes Unclear Yes

19 None N/A No No Yes


20 Random number table Unclear Yes No Yes



22 Not stated Sealed packages with coded numbers Yes Unclear Yes

23 Computer generated list in Sealed envelopes Yes Yes Yesblocks of 10

24 Random number table Unclear No No Yesafter stratification

25 Unclear Unclear No No Yes

PENICILLIN

26 Matched pairs and Not stated Yes Yes Yespharmacologistrandomly assigned drugs

SPIRAMYCIN

27 Unclear Unclear Yes Yes Yes

28 Coded envelopes from drug Coded envelopes from drug manufacturer Yes Yes Yesmanufacturer

TETRACYCLINE

29 Unclear Unclear No Unclear Unclear

30 Not stated Not stated Yes Unclear Yes

27 Unclear Unclear Yes Yes Yes

31 None N/A No No No

12 Random number table Unclear Yes Unclear Yes


* Not applicable or not available.

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Quality Assessment

Subject Selection Defined Completion

Calibration Inclusion Criteria Exclusion Criteria Patients Acounted at End Dropouts in Analyses?

METRONIDAZOLE




Unclear No Yes Yes N/A

Yes Yes Yes Yes N/A




2 examiners measured everyone Yes Yes Yes N/A



Unclear Yes Yes Yes? No

PENICILLIN

1 examiner Yes Yes Yes N/A

SPIRAMYCIN

Not stated Yes Yes Yes No


TETRACYCLINE

Yes Yes Yes Yes N/A


Not stated Yes Yes Yes No

Yes Yes Yes Yes Unclear

Yes Yes Yes Yes N/A


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Table 3.

Subject Populations

N Test Group N Control Group

Reference Baseline Completion Baseline Completion Disease % Males

AMOXICILLIN

4 66 overall 4 lost AMOX + MET = 15 66 overall PLAC = 15 Advanced Not statedMET = 16 4 lost chronicAMOX = 16


5 23 20 23 19 Active 15.3

6 8 8 8 8 Advanced 38

7 23 23 26 26 Chronic 43

4 66 overall 4 lost AMOX + MET = 15 66 overall PLAC = 15 Advanced Not statedMET = 16 4 lost chronicAMOX = 16

8 25 total in 10 25 total in 10 Aggressive Not statedboth groups both groups (LJP)


9 10 10 11 11 Chronic 29

10 AMOX + CA = 13 AMOX + CA = 12 4 4 Refractory Not statedCLIND = 4 CLIND = 4

11 15 13 15 15 Generalized Unclearaggressive

12 TET = 13 TET = 13 11 11 Active 55 PLAC, 62 TET;AMOX + CA = 10 AMOX + CA = 10 40 AMOX + CA

CLINDAMYCIN

13 DOXY = 12 DOXY = 12 10 10 Generalized 42MET = 15 MET = 15 aggressiveCLIND = 11 CLIND = 11

10 AMOX + CA = 12 AMOX + CA = 12 4 4 Refractory Not statedCLIND = 4 CLIND = 4

DOXYCYCLINE

14 8 (split mouth) 8 8 (split-mouth) 8 Chronic 56

15 10 10 10 10 Chronic 60% in both groups


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125


Subject Populations

Mean AgeRacial/

% SmokersSystemically

Test Control All Age Range Ethnic Group Test Control Healthy

AMOXICILLIN

Not stated Not stated Not stated 20-45 Not stated Not stated Not stated Yes


46.7 44.1 Not stated 36-68 No 40 42.1 Yes

Not stated Not stated Not stated 35-58 No Not stated Not stated Yes

42 28-63 No 61 69 Yes


Not stated Not stated Not stated 12-19 Unclear Not stated Not stated Yes


49 39 44 28-66 No 50 45 Yes

Not stated Not stated 46 35-62 Not stated 16/21 (76%) 16/21 (76%) Yesoverall overall

Not stated Not stated 32 20-40 Caucasian Not stated Not stated Yes

44 TET; 48 Not stated 14-71 No Not stated Not stated Yes53 AMOX + CA

CLINDAMYCIN

Not stated Not stated 32.4 Not stated Not stated No smokers No smokers Yes

Not stated Not stated 46 35-62 Not stated 16/21 (76%) 16/21 (76%) Yesoverall overall

DOXYCYCLINE

Not stated Not stated Not stated 32-72 Not stated Unclear Unclear Yes

49 54 Not stated ≥20 years Not stated Not stated Not stated Yes


(continued)

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Subject Populations



METRONIDAZOLE

16 6 6 6 6 Aggressive 33(EOP)

17 5 5 5 5 Chronic 30

18 8 8 8 8 Chronic 44advanced

19 6 6 6, 6 6, 6 Chronic? 0


20 46 both groups 15 46 both groups 18 Advanced 52chronic (high spiros and/or BANApositive)

21 50 both groups 17 50 both groups 19 Chronic 51

4 66 overall 4 lost AMOX + MET = 15 66 overall 4 lost PLAC = 15 Advanced Not statedMET = 16 ` chronicAMOX = 16

22 12 12 11 11 Chronic Not stated

23 98 in all groups MET + SRP smokers = 3; 98 in all groups PLAC + SRP Chronic 50at start MET + SRP non-smokers = 9; at start smokers = 3;

MET + SURG smokers = 13; PLAC + SRP non-smokers = 1;MET + SURG non-smokers = 7 PLAC + SURG

smokers = 18;PLAC + SURG

non-smokers = 10

24 Unclear 31 Unclear 27 SRP 26 MET gel Chronic 48

25 90 in all groups 10 smokers; 21 non-smokers 90 in all groups SRP: 9 smokers + Moderate to 4818 non-smokers; advanced

SRP + MET gel: chronic9 smokers +18 non-smokers

PENICILLIN

26 8 8 8 8 Aggressive Not stated

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127


Subject Populations

Mean AgeRacial/



METRONIDAZOLE

Not stated Not stated 25.7 19-35 Not stated Not stated Not stated Yes



37.3 37.2, 37.0 37.2 23-59 No Not stated Not stated No; trichomonasinfection intest group


Not stated Not stated Not stated Not stated Not stated Not stated Not stated Yes

Not stated Not stated Not stated Not stated Not stated Not stated Not stated Yes


Adolescents Adolescents Not stated Not stated Not stated Not stated Not stated Mentallyretardedadolescents

36.5 36.1 Not stated Not stated Not stated MET = 50% PLAC = 66% Yes

44.7 50.5 SRP; Not stated 35-65 No 32 33 SRP; Yes48.1 SRP + 35 SRP + MET gel MET gel

42.1 smokers; SRP 50 smokers, Not stated 35-65 No Stratifed by Stratifed by Yes46 non-smokers 50.7 non-smokers; smoking smoking

SRP + MET gel 48.3 smokers,48 non-smokers

PENICILLIN

Not stated Not stated Not stated <30 years No Not stated Not stated Yes

(continued)

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Subject PopulationOver 600 subjects were recruited in each of the test andcontrol groups (Table 3; page 124). The uncertainty isdue to the fact that in some studies the total number ofsubjects was reported, but it was not clear how manysubjects were assigned to the test and control groups.The designation of the disease type by the investigatorswas not entirely clear reflecting the change in the clas-sification of periodontal diseases over time. The major-ity of studies appeared to include subjects who would beclassified as chronic periodontitis today, although 8 stud-ies included subjects with “aggressive disease” and 2studies involved “refractory” periodontitis. The male-female ratio was described in 22 of the comparisons andaveraged about 41% males across studies. All but 3 ofthe comparisons provided either an overall mean age,mean age for subjects in each group, or an age range.One study described the participants as “adolescents.”In general, the racial/ethnic characteristics of the subjectpopulation were not described, while the smoking char-acteristics of the subjects were described for 10 com-parisons. Subjects in the majority of studies were sys-temically healthy, although test subjects in one studyhad a trichomonas infection and one study examinedmentally retarded subjects.

Clinical MeasurementsThe nature of the clinical measurements performed inthe studies varied (Table 4; page 130). Twenty studiesreported on measurements on all teeth in the oral cav-ity (which may or may not have included third molars),while 2 comparisons reported on measurements from8 teeth, 5 on measurements from 4 teeth, 4 compar-isons on measurements from 1 tooth and in 3 com-parisons the numbers of teeth reported in the analyseswere unclear. When subsets of teeth were employed,selection was frequently based on baseline probingdepth (11 comparisons), with or without concomitantdemonstration of bone loss (3 comparisons). The num-ber of sites examined per tooth differed, ranging from1 to 6. Three comparisons employed the Florida probe,4 a constant force probe, and the rest a manual probe.Stents were employed in 13 comparisons, while dupli-cate measures of probing depth and attachment levelat each site were employed in 8 comparisons.

TherapyThe therapeutic procedures employed in the studies wereremarkably heterogeneous (Table 5; page 132). Nineantibiotics or antibiotic combinations were employed,although MET alone (12 comparisons) or in combina-

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Subject Populations



SPIRAMYCIN

27 96 in all groups TET = 27; SPIRA = 28 96 in all groups 24 Chronic Unclearadvanced

28 96 93 97 96 Chronic Not stated

TETRACYCLINE

29 6 6 6 6 Aggressive 58

30 7 7 7 7 Chronic 43

27 Unclear TET = 27; SPIRA = 28 Unclear 24 Chronic Unclearadvanced

31 42 35 99 80 Advanced 47

12 TET = 13 TET = 13 11 11 Active 55 PLAC, 62 TET;AMOX + AMOX + CA = 10 40 AMOX + CA

CA = 10

32 19 19 completed TET + 19 19 completed PLAC + Aggressive (LJP + GJP) 37SRP phase; SRP phase;

13 completed 13 completed SURG phase SURG phase

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tion with AMOX (5 comparisons) was the most frequentlytested agent. The dosage and duration varied even withinindividual antibiotic regimens. MET was prescribed atdoses of 200 mg tid, 250 mg tid, 200 mg qid, 2 gmsonce, 200 mg per day, and 400 mg tid for durations thatincluded, 1, 7, 8, and 14 days. AMOX was administeredat dosages of 250 mg tid; 375 mg bid; 375 mg tid; and500 mg tid for 7, 8, or 14 days. AMOX + AC was givenat the dosage of 250 mg tid; 375 mg tid; 500 mg tid; or625 mg tid for 10, 14, or 30 days. CLIN was adminis-tered at the dosage of 150 mg qid for 8 days. DOXYwas given at the dosage of 100 mg per day for 14 or42 days (with a loading dose of 200 mg on Day 1), or200 mg a day for 8 days. PEN was administered at thedosage of 250 mg qid for 10 days. SPIR was given at thedosage of 1,500,000 IU bid for 14 days in 2 studies. TETwas prescribed at the dosage of 250 mg tid or 250 mgqid for 14, 21, or 30 days. One study employed 250 mgqid for 14 days followed by 250 mg once a day for 48weeks. In 3 studies, the antibiotic regimen was repeatedfrom 1 to 3 times. Mechanical debridement took placeafter antibiotic administration in 18 comparisons and wasgiven at the same time as SRP in 14 comparisons. Inthe remaining comparisons, there was either no mechan-ical debridement or the timing was unclear. Seven stud-

ies utilized a split-mouth design. The concomitantmechanical debridement also differed among studies.Eight comparisons involved no mechanical debridement(including 5 of the split-mouth studies). Six comparisonsinvolved surgical procedures and the remaining utilizedSRP as the concomitant and control therapy.

Compliance and Adverse EventsCompliance and adverse events were often not reportedin the cited studies (Table 6; page 136). Compliancewas measured in 11 comparisons using techniques thatincluded asking the patient, keeping a diary, pill counts,and supervised usage. Adverse events were recordedin 17 of the comparisons. They ranged from none in 6comparisons to 39% of subjects in the test groupexhibiting diarrhea when provided with AMOX plusMET. The most frequently reported adverse eventappeared to be diarrhea.

Excluded StudiesAs noted above, 51 of the full-text studies reviewed werenot included in the review. Studies were excluded for thefollowing reasons: 29 because they contained no attach-

129


Subject Populations

Mean AgeRacial/



SPIRAMYCIN

Not stated Not stated 46 ≥35 No Not stated Not stated Yes

48.5 47.3 Not stated ≥35 No Not stated Not stated Yes

TETRACYCLINE

Not stated Not stated 34 27-42 No Not stated Not stated Yes

Not stated Not stated Not stated 37-52 Not stated N/A N/A Yes

Not stated Not stated 46 ≥35 No Not stated Not stated Yes

41.2 42.1 41.7 24-60 No 60 56 Yes

44 TET; 48 Not stated 14-71 No Not stated Not stated Yes53 AMOX + CA

20.5 18.5 19.5 12-25 Not stated Not stated Not stated Yes


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130

Table 4.

Clinical Assessment of Probing Depth and Attachment Levels

Number Teeth Selection Number Stent DuplicateReference Examined Criteria of Sites/ Tooth Type of Probe Used? Measures

AMOXICILLIN

4 All* N/A† 4 Manual No No


5 All N/A 6 Florida No Yes

6 All N/A 4 Manual Yes No

7 All N/A 6 Constant force No No

4 All N/A 4 Manual No No

8 All (only those See previous 4 Manual No Nowith PD ≥5 or CAL >2 in analyses)


9 All N/A 6 Constant force Yes No

10 1 active site Active = 1 active site Florida probe Yes Yesand 1 matched AL >3 SDs‡ and 1 matchednon-active site for the subject non-active site

11 4 Tooth with 6 Controlled force Unclear Yesdeepest PD electronicin each quadrant

12 All N/A 6 Manual No Yes

CLINDAMYCIN


10 1 active site Active = 1 active site Florida Yes Yesand 1 matched AL >3 SDs and 1 matchednon-active site for the subject non-active site

DOXYCYCLINE

14 All (or 10)? Unclear 6 Manual Yes No



METRONIDAZOLE

16 4 1 site with 6 Manual Yes Nobaseline (BPD) ≥5 mm

17 4 1 site with 6 Manual Yes NoBPD ≥5 mm

18 8 BPD ≥6 mm; 1 Manual No No≥50% bone loss

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131


Clinical Assessment of Probing Depth and Attachment Levels

Number Teeth Selection Number Stent DuplicateReference Examined Criteria of Sites/ Tooth Type of Probe Used? Measures

19 2 BPD ≥5 mm 1 Manual No No





22 2 1 site on each 1 Manual Yes Yestooth withdeepest BPD of ≥5


24 All N/A 6 Florida No No

25 All, but only deep BPD ≥4.6 Unclear Florida No NoPD reported (Florida) or

≥5 mm manual

PENICILLIN


SPIRAMYCIN

27 4 1 pocket ≥7 mm 2 Manual (Williams) Yes No

28 2 BPD ≥7 mm 1 Manual Yes No

TETRACYCLINE


30 8 BPD ≥6 mm; 1 Manual No No≥40% bone loss; premolars and/or incissors

27 4 1 pocket ≥7 mm 2 Manual (Williams) Yes No



32 Affected Affected teeth 6 Constant force No Noteeth (PD ≥4 mm,

AL ≥2 mm;bone loss ≥4 mm)

* At least 28 teeth if present.† Not applicable or not available.‡ Standard deviations.

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132

Table 5.

Antibiotic and Mechanical Debridement Procedures

Total dosage Reference Antibiotic 1 Dosage Duration (gms) Repeated? And/or Antibiotic 2 Dosage

AMOXICILLIN

4 AMOX 250 mg tid* 7 days 5.25 No Or MET (see 200 mg tidbelow)


5 MET 250 mg tid 7 days 5.25 (×3) = 15.75 Yes And AMOX 500 mg tid

6 MET 250 tid 14 days? 10.5 No And AMOX 375 mg bid

7 MET 250 mg tid 7 days 5.25 No And AMOX 375 mg tid

4 MET 200 mg tid 7 days 4.2 No And AMOX 250 mg tid

8 MET 750 mg/day 8 days 6.0 No And AMOX 1500 mg/day


9 AMOX + CA 625 mg tid 10 days 18.75 No – N/A N/A

10 AMOX + CA 250 mg AMOX + 14 days 15.75 No Or CLIND qid;‡ No dosage given125 mg CA tid

11 AMOX + CA 500 mg tid 14 days 21.0 No – N/A§ N/A

12 AMOX + CA 375 mg tid 30 days 33.75 No Or TET 250 mg tid (see below)

CLINDAMYCIN

13 CLIND 150 mg qid 8 days 4.8 No – N/A N/A

10 CLIND qid; no dosage 14 days – No Or AMOX + CA 250 mg AMOX + given 125 mg clavulanic

acid tid

DOXYCYCLINE

14 DOXY 200 mg day 1 6 weeks 4.3 No – N/A N/Athen 100 mgper day

15 DOXY 200 mg loading 14 days 1.5 No – N/A N/Adose, 100 mgper day

13 DOXY 200 mg/day 8 days 1.6 No Or MET 500 mg bid

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133



Total dosage When Versus Concomitant Control Duration (gms) Repeated? Debridement Split Mouth? Therapy Therapy Maintenance?

AMOXICILLIN

7 days – No After No PLAC + SRP PLAC + UnclearPLAC + SRP


7 days 10.5 (×3) Yes (0, 4, N/A No None PLAC No= 31.5 8 months)

14 days 10.5 No During Yes SRP/None PLAC + SRP/None Unclear

7 days 7.9 No After (6 weeks) No SRP PLAC No

7 days 5.25 No After No SRP PLAC + UnclearPLAC + SRP

8 days 12.0 No After No SRP + Widman PLAC + SRP + OHI† + supra flap at deep Widman flap at and subgingival sites deep sites scaling at 1,

3 months andthen every3 months


N/A – N/A After (6 weeks) No SRP PLAC + SRP Yes 3 monthsintervals

10 days – No After No SRP PLAC + SRP Not stated

N/A – N/A After (2 months) No SRP SRP + local TET fibers Yes 3-4‡ weekintervals

30 days – No During active No SRP + MWF SRP + MWF Yes every treatment 3 months

CLINDAMYCIN

N/A – N/A After enhanced No SRP followed SRP followed by YesSRP by enhanced enhanced SRP

SRP

10 days No After No SRP PLAC + SRP Not stated

DOXYCYCLINE

N/A – N/A After Yes None; SRP PLAC; SRP Unclear

N/A – N/A During SRP No SRP SRP No

8 days – No After enhanced No SRP followed by SRP followed by YesSRP enhanced SRP enhanced SRP (continued)

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134




METRONIDAZOLE

16 MET 250 mg tid 7 days 5.25 No – N/A N/A


18 MET 200 mg qid 14 days 11.2 (×3) Yes 0, 10, – N/A N/A= 33.6 20 weeks

19 MET 2 gm once Single dose 2.0 No – N/A N/A

13 MET 500 mg bid� 8 days 8.0 No Or DOXY 200 mg/day



4 MET 200 mg tid 7 days 4.2 No Or AMOX (see 250 mg tidabove)





PENICILLIN

26 PEN (phenoxymethyl) 250 mg qid 10 days 10.0 (×5) Yes at – N/A N/A(week 13) = 50 weeks 26,

38, 50and 62

SPIRAMYCIN

27 SPIRA 1,500,000 IU¶ 14 days 42,000,000 IU No Or TET 250 mg qidbid

28 SPIRA 1,500,000 IU 14 days 42,000,000 IU No – N/A N/Abid

TETRACYCLINE

29 TET 250 mg qid 14 days 14.0 (× 2) Yes; 5 weeks – N/A N/A= 28 later

30 TET 250 mg qid for 14 days then 98.0 No – N/A N/A14 days then 48 weeks250 mg oncea day for48 weeks

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135




METRONIDAZOLE

N/A – N/A During SRP Yes None; SRP None; SRP OHI every2 weeks

N/A – N/A During SRP Yes None; SRP None; SRP OHI every2 weeks

N/A – N/A During Yes SRP; none SRP; none OHI at each monitoring visit

N/A – N/A No SRP No None SRP or none No

8 days – No After enhanced No SRP followed by SRP followed by YesSRP enhanced SRP enhanced SRP

N/A – N/A After SRP No SRP PLAC + SRP No

N/A – N/A During SRP No SRP PLAC + SRP No

7 days – No After No PLAC + SRP PLAC + PLAC + SRP Unclear

N/A – N/A After prophylaxis No Prophylaxis PLAC + prophylaxis Not stated

N/A – N/A After No SRP; SRP + SURG PLAC + SRP; PLAC + OHI + SRP everySRP + SURG 6 months

N/A – N/A Started on the No SRP SRP; SRP + MET gel Yes; prophylaxis +2nd of 2 SRP OHI at visits 4 weeks only

N/A – N/A After SRP No SRP SRP; SRP + MET gel Not stated(twice)

PENICILLIN

N/A – N/A During flap No SRP + flap surgery SRP + flap surgery + Yes every surgery and PLAC 3 monthsat recall visits

SPIRAMYCIN

14 days – No During SRP No SRP SRP + PLAC Not stated

N/A – N/A During SRP No SRP SRP + PLAC Not stated

TETRACYCLINE

N/A – N/A During first Yes SRP or none SRP or none Yesadministration

N/A – N/A During Yes SRP; none PLAC + SRP; OHI at each PLAC + none monitoring visit

(continued)

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136




27 TET 250 mg qid 14 days 14.0 No Or SPIRA 1,500,000 IU bid

31 TET 250 mg qid 21 days 21.0 No – N/A N/A

12 TET 250 mg tid 30 days 22.5 No Or AMOX + CA 375 mg tid

32 TET 250 mg qid 14 days 14.0 No – N/A N/A

* 3 times a day.† Oral hygiene index.‡ 4 times a day.§ Not applicable or not available.� 2 times a day.¶ International units.# Modified Widman flap.

Table 6.

Description of Compliance and Adverse Events

Compliance Reference Measured How? Adverse Events (AE) AE % Affected Test AE % Affected Control

AMOXICILLIN

4 Yes Asked patient Reported None None


5 Yes Pill count Reported None None

6 No N/A* Not stated N/A N/A

7 Yes Pill count Diarrhea 39 None

7 Rash 9 4

7 Nausea after alcohol 4 None

7 Softened stools 0 8


8 Yes Daily supervision Reported None None


9 Yes Diary, returned Diarrhea 20 18.2meds, phone for compliance,AEs

10 No N/A No N/A N/A

11 No N/A Yes “Few” had “mild “Few” reported “pressure”GI symptoms” from fibers

12 No N/A Not stated N/A N/A

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137




14 days – No During SRP No SRP SRP + PLAC Not stated

N/A – N/A During No SRP SRP Yes

30 days – No During active No SRP + MWF SRP + MWF# Yes every treatment 3 months

N/A – N/A After No SRP + SURG at PLAC + SRP + SURG Not statedsites with PD at sites with PD ≥5 mm + BOP ≥5 mm + BOP




CLINDAMYCIN

13 No N/A Not reported N/A N/A


DOXYCYCLINE

14 Yes? Reinforced verbally Reported None None



METRONIDAZOLE




19 Unclear Unclear Not stated N/A N/A


20 Yes Oral report by subject Yes Occasional metallic taste Unclear

21 Yes Oral report by subject Yes Legs cramps 6% None


22 Yes Supervised usage Not reported N/A N/A




PENICILLIN

26 Unclear N/A Not stated N/A N/A (continued)

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138




SPIRAMYCIN

27 Yes Pill count Reported 3.7 TET Not stated

28 Yes Pill count Reported 1.1 periodontal symtoms; 1.0 periodontalGI upset/diarrhea 2.2 symptoms

TETRACYCLINE



27 Yes Pill count Reported 3.7 TET Not stated

31 No N/A None reported N/A N/A



* Not available.

Figure 1.Meta-analysis of mean attachment level changes by patient periodontal disease diagnosis (aggressive or chronic).

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139

ment level measurements or included uninterpretabledata;33-61 11 because there was no comparison groupor that group included another antibiotic;62-72 5 becauseguided tissue regeneration barriers or other materialswere inserted into the defects;73-77 3 because another ver-sion of the same study and data were selected;78-80 and3 because they were reviews or meta-analyses.81-83

MAIN RESULTSTwenty-nine studies involving 36 comparisons werefound to be eligible for inclusion after review (Table 1;page 118).4-32 Tables 7 through 12 present the attach-ment level and probing depth findings from these stud-ies.

Meta-Analysis Results Using Mean AttachmentLevel ChangeOf the 36 comparisons described in the tables, only27 were selected for meta-analyses. One study4 involv-ing 3 comparisons and a second study8 involving onecomparison were omitted because the attachmentlevel change was provided only as percent of sites. Twostudies were excluded because no SD or SEM were pro-vided.17,29 Two studies that evaluated 1 site per subjectwere excluded.10,19 Finally, one study that provided data

only at 5 years after treatment was excluded.23 Themeta-analyses emphasized full-mouth mean attachmentlevel change rather than change at selected subsets ofsites that may have been provided by the authors. Threemeta-analyses were carried out to evaluate the data.The analyses evaluated if antibiotics were consistentlyadjunctive for different patient populations, adjunctiveto different therapies, and different antibiotics.

Figure 1 (page 138) is the forest plot of the analy-sis divided by patient population. For all of the stud-ies and for the 2 sets of studies divided by the popu-lation studied, the antibiotic groups showed statisticallysignificantly better results than the control groups. Alltests of heterogeneity were not significant, indicatingthat the outcomes of the studies were consistent. Addi-tionally, the results were significantly different betweenpatient populations, indicating that the aggressive peri-odontitis groups had a larger adjunctive benefit.

Figure 2 separates the adjunctive effect by themechanical therapy employed. In the case of therapiesadjunctive to SRP, there was a significant benefit for theuse of antibiotics and the studies provided a consis-tent finding as indicated by a non-significant test forheterogeneity. The analysis was less clear for the

Figure 2.Meta-analysis of mean attachment level change grouped by type of mechanical therapy.

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140

Figure 3.Meta-analysis of mean attachment level changes grouped by type of antibiotic used.

Table 7.

Mean Attachment Level and/or Mean Attachment Level Change at Different Post-Treatment Time

Control

Mean AL Mean AL Reference Time Site Type Treatment Baseline SD/SEM at End SD/SEM Change*


5 2 months All PLAC −0.13 ± 0.18 sd




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141

adjunctive effect of antibiotics to either no other mechan-ical therapy or adjunctive to SRP plus surgery. In the 4studies with no mechanical therapy,5,7,18,22 there was asignificant test for heterogeneity and a significant dif-ference between groups for the random-effects model of0.093. While one may question combining these 4 stud-ies due to the significant test for heterogeneity, all of thestudies favored the antibiotic groups and the overall testfor significance was borderline. The significance levelfor studies adjunctive to SRP and surgical therapy was0.055. While a borderline significance level, the studieswere consistent by a lack of a significant test for het-erogeneity. Thus the data did support a case for anadjunctive effect in these 4 studies.

Figure 3 shows the results by the type of antibiotic.While it would have been desirable to determine whichantibiotic was the most effective, it is difficult becauseof the number of antibiotics (8) for the 27 comparisonsin the analysis. The combination of all of the studies wassignificant and the studies were consistent as noted pre-viously. Furthermore, the effect for studies grouped bythe type of antibiotic was similar ranging from 0.188 to0.555, excluding the 2 studies that used SPIR that hadan effect of 0.06.27,28 It appears that statistical powerdetermined which antibiotics demonstrated a significantadjunctive effect. There were significant adjunctive effectsfor TET (5 studies; 135 subjects)12,27,30-32 and MET (9studies; 125 subjects)13,16,18,20-22,24,25 with non-signifi-cant tests of heterogeneity. The remaining antibiotics inwhich the number of studies ranged from 1 to 3 and thenumber of subjects ranged from 8 to 120 lacked signif-icance, with a borderline effect for AMOX plus MET.Only the 2 studies of SPIR had sufficient subjects(i.e., 120) to suggest that the adjunctive effect of theantibiotic was ineffective.27,28

Mean Attachment Level ChangeThe data describing mean attachment level change atall sites and subsets of sites are presented in Table 7

(page 140). The meta-analyses describing the overallchanges in the subjects were presented above. Severalstudies reported mean AL changes at sites subsetaccording to baseline probing depth. In some instances,the data were provided at multiple time points. Basedon data closest to the 6-month time point and usingany of the antibiotics, it was found that at sites withshallow baseline probing depths (<4 mm), the test wasfavored over the control in 7 of 8 comparisons (87%,mean benefit 0.29 mm), for intermediate pockets of 4to 5 or 4 to 6 mm the test was favored over the con-trol in 8 of 10 comparisons (80%, mean benefit 0.29mm) while in deep pockets (≥6 mm) the test wasfavored over the control in 19 of 23 comparisons (83%,mean benefit 0.45 mm).

Change in Percent of Sites Gaining or LosingPeriodontal AttachmentTable 8 (page 152) presents the percent of sites that“gained” or lost periodontal attachment over certainthreshold levels. Only 8 comparisons (6 studies) pre-sented data in this format.5,6,8,10,12,26 As in the previ-ous section, we focused on data that were closest tothe 6-month post-therapy monitoring visit. For sitesthat lost attachment over certain thresholds (typically≥2 mm), the test group was favored over the control in6 of 7 comparisons (1 study did not present losses).For sites that “gained” attachment over certain thresh-olds, the test group was favored over the control in all8 comparisons.

Percent of Sites in Different Attachment LevelCategoriesAnother method of data presentation was to describethe percent of sites in different attachment level cate-gories at baseline and at different time points after



Test

Mean AL Mean ALTreatment Baseline SD/SEM at end SD/SEM Change* Difference†


AMOX + MET 0.26 ± 0.27 sd 0.39

AMOX + MET 0.25 ± 0.22 sd 0.48

AMOX + MET 0.35 ± 0.29 sd 0.67

AMOX + MET 0.39 ± 0.31 sd 0.71(continued)


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142



Control




6 2 months All SRP + PLAC 0.6 ± 0.2 sd





6 2 months BPD 4-5 mm SRP + PLAC 0.6 ± 0.2 sd



6 2 months BPD >5 mm SRP + PLAC 1.0 ± 0.2 sd



7 3 months All PLAC 4.0 1.3 sd 3.6 1.1 sd 0.4

7 3 months BPD 0-3 mm PLAC −0.31 ± 0.29 sd

7 3 months BPD 4-6 mm PLAC 0.68 ± 0.44 sd

7 3 months BPD >6 mm PLAC 1.46 ± 0.70 sd


9 3 months All SRP 7.3 0.3 sd 6.8 0.3 sd 0.5



9 12 months BPD 0-3 mm SRP 0.1

9 12 months BPD 4-6 mm SRP 0.6

9 12 months BPD >6 mm SRP 1.7

10 2 years 1 active PLAC + SRP 0.84 ± 0.43 sd

10 2 years 1 control PLAC + SRP −0.35 ± 0.19 sd

11 15 weeks 4 teeth SRP + Local TET 12.0 1.8 sd 11.6 1.8 sd 0.4




12 10 months All SRP + MWF‡ + PLAC 0.02 ± 0.11 sem

12 10 months BPD <4 mm SRP + MWF + PLAC −0.25 ± 0.12 sem

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143



Test

Mean AL Mean ALTreatment Baseline SD/SEM at End SD/SEM Change* Difference†

AMOX + MET 0.45 ± 0.35 sd 0.83

AMOX + MET 0.46 ± 0.38 sd 0.89

MET + AMOX + SRP 0.6 ± 0.4 sd 0

MET + AMOX + SRP 0.8 ± 0.4 sd 0.1

MET + AMOX + SRP 1.1 ± 0.3 sd 0.3

MET + AMOX 0.2 ± 0.2 sd 0.3

MET + AMOX 0.2 ± 0.2 sd 0.5

MET + AMOX + SRP 0.4 ± 0.3 sd −0.2

MET + AMOX + SRP 0.6 ± 0.3 sd −0.1

MET + AMOX + SRP 0.9 ± 0.3 sd 0.2

MET + AMOX + SRP 1.3 ± 0.6 sd 0.3

MET + AMOX + SRP 1.8 ± 0.5 sd 0.5

MET + AMOX + SRP 2.1 ± 0.4 sd 0.6

AMOX + MET 3.9 1.1 sd 3.2 1.0 sd 0.7 0.3

AMOX + MET −0.14 ± 0.32 sd 0.17

AMOX + MET 0.88 ± 0.38 sd 0.20

AMOX + MET 1.97 ± 0.79 sd 0.51


AMOX + CA + SRP 7.4 0.9 sd 6.9 0.8 sd 0.5 0

AMOX + CA + SRP 7.4 0.9 sd 6.8 0.8 sd 0.6 0

AMOX + CA + SRP 7.4 0.9 sd 6.9 0.9 sd 0.5 0

AMOX + CA + SRP 0.1 0

AMOX + CA + SRP 0.7 0.1

AMOX + CA + SRP 1.1 −0.6

AMOX + CA + SRP 1.0 ± 1.42 sd 0.16

AMOX + CA + SRP −0.13 ± 1.29 sd 0.22

SRP + AMOX + CA 12.3 1.5 sd 12.1 1.5 sd 0.2 −0.2

SRP + AMOX + CA 12.3 1.5 sd 11.4 1.1 sd 0.9 0.4

SRP + AMOX + CA 12.3 1.5 sd 11.4 1.2 sd 0.9 −0.4

SRP + AMOX + CA 12.3 1.5 sd 11.2 1.2 sd 1.1 0.4

AMOX + CA + SRP + MWF‡ 0.68 ± 0.23 sem 0.66

AMOX + CA + SRP + MWF 0.16 ± 0.20 sem 0.41

(continued)

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144



Control


12 10 months BPD 4-6 mm SRP + MWF + PLAC 0.27 ± 0.20 sem

12 10 months BPD >6 mm SRP + MWF + PLAC 1.73 ± 0.44 sem

CLINDAMYCIN



13 6 months BPD ≥6 mm SRP 9.6 0.86 sd 8.2 0.77 sd 1.4




DOXYCYCLINE

14 3 weeks All PLAC + SRP 9.0 1.9 sd 10.3 2.4 sd −1.3




14 3 weeks All PLAC 9.5 2.3 sd 10.0 1.1 sd −0.5

14 6 weeks All PLAC 9.5 2.3 sd 9.2 0.4 sd 0.3



15 90 days All SRP 3.15 0.93 sd 3.19 1.17 sd −0.04





METRONIDAZOLE

16 42 days 24 sites None 9.0 1.2 sd 9.1 1.5 sd −0.1 ± 0.3 sdmeasured

16 42 days 24 sites SRP 9.1 2.0 sd 8.4 2.1 sd 0.8 ± 0.3 sdmeasured

17 42 days 24 sites None 8.73 – 8.72 – 0.01measured

17 42 days 24 sites SRP 9.56 – 8.97 – 0.59measured

18 2 weeks BPD ≥6 mm SRP 0.2 ± 0.2 sem

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Test




CLINDAMYCIN

CLIND + SRP 6.1 0.96 sd 4.4 1.00 sd 1.7 1.1

CLIND + SRP 6.1 0.96 sd 4.2 0.87 sd 1.9 1.5

CLIND + SRP 10.4 1.04 sd 7.4 1.00 sd 3.0 1.6

CLIND + SRP 10.4 1.04 sd 7.5 1.17 sd 2.9 2.4

CLIND + SRP −0.15 ± 0.14 sd −0.99

CLIND + SRP −0.48 ± 0.61 sd −0.13

DOXYCYCLINE

DOXY + SRP 7.8 1.2 sd 7.6 0.4 sd 0.2 1.5

DOXY + SRP 7.8 1.2 sd 7.5 0.6 sd 0.3 0.9

DOXY + SRP 7.8 1.2 sd 7.5 0.5 sd 0.3 0.8

DOXY + SRP 7.8 1.2 sd 7.4 0.5 sd 0.4 1.3

DOXY 8.0 1.1 sd 8.1 0.7 sd −0.1 0.4

DOXY 8.0 1.1 sd 8.0 0.4 sd 0 −0.3

DOXY 8.0 1.1 sd 7.9 0.4 sd 0.1 0.6

DOXY 8.0 1.1 sd 7.9 0.8 sd 0.1 1.0

DOXY + SRP 3.13 0.89 sd 3.00 0.84 sd 0.13 0.17

DOXY + SRP 6.0 1.05 sd 4.8 0.83 sd 1.2 0.6

DOXY + SRP 6.0 1.05 sd 5.1 0.9 sd 0.9 0.5

DOXY + SRP 10.1 1.21 sd 8.1 0.83 sd 2.0 0.6

DOXY + SRP 10.1 1.21 sd 8.7 1.02 sd 1.4 0.9

METRONIDAZOLE

MET 8.9 1.1 sd 8.6 1.2 sd 0.3 ± 0.3 sd 0.4

MET + SRP 8.7 1.1 sd 7.9 1.4 sd 0.8 ± 0.4 sd 0

MET 8.68 – 8.31 – 0.37 0.36

MET + SRP 9.61 – 8.61 – 1.0 0.41

MET + SRP −0.1 ± 0.1 sem −0.3

(continued)

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Control






18 2 weeks BPD ≥6 mm None 0.2 ± 0.4 sem

18 10 weeks BPD ≥6 mm None 0.1 ± 0.1 sem

18 20 weeks BPD ≥6 mm None −0.1 ± 0.3 sem



19 1 month All (2 sites) SRP 5.5 2.3 sd 4.5 1.7 sd 1.0

19 3 months All (2 sites) SRP 5.5 2.3 sd 4.3 1.5 sd 1.2

19 3 months All (2 sites) None 6.0 1.2 sd 5.8 1.3 sd 0.2



13 6 months BPD ≥6 SRP 9.6 0.86 sd 8.2 0.77 sd 1.4


20 4-6 weeks BPD ≤3 mm SRP −0.33 ± 0.19 sem

20 4-6 weeks BPD 4-6 mm SRP 0.32 ± 0.16 sem

20 4-6 weeks BPD ≥7 mm SRP 1.03 ± 0.33 sem

21 4-6 weeks BPD ≤3 mm SRP −0.15 ± 0.09 sem



22 1 month 2 sites PLAC + prophylaxis 7.81 1.29 sd 7.21 1.17 sd 0.6

22 3 months 2 sites PLAC + prophylaxis 7.81 1.29 sd 7.53 1.37 sd 0.28

22 6 months 2 sites PLAC + prophylaxis 7.81 1.29 sd 7.47 1.63 sd 0.34

23 5 years All smokers PLAC + SRP 4.2 0.7 sd 3.3 0.4 sd 0.9

23 5 years All Non-smokers PLAC + SRP 6.3 Only 1 3.0 3.3subject

23 5 years All smokers PLAC + SRP + SURG 4.1 0.8 sd 4.2 0.9 sd −0.1

23 5 years All Non-smokers PLAC + SRP + SURG 4.6 0.7 sd 3.6 0.6 sd 1.0

24 8 weeks BPD ≥5 mm SRP 0.36 ± 0.35 sd

24 8 weeks BPD ≥5 mm SRP + MET gel 0.39 ± 0.52 sd

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147



Test


MET + SRP 0.4 ± 0.1 sem −0.3

MET + SRP 0.9 ± 0.2 sem −0.2

MET + SRP 1.5 ± 0.2 sem 0.2

MET + SRP 1.8 ± 0.2 sem 0.2

MET 0.1 ± 0.1 sem −0.1

MET 0.2 ± 0.1 sem 0.1

MET 0.4 ± 0.2 sem 0.5

MET 0.5 ± 0.1 sem 0.8

MET 0.8 ± 0.2 sem 1.1

MET 5.9 1.0 sd 5.8 1.3 sd 0.1 −0.9

MET 5.9 1.0 sd 5.4 1.0 sd 0.5 −0.7

MET 5.9 1.0 sd 5.4 1.0 sd 0.5 0.3

MET + SRP 6.2 1.00 sd 4.3 0.74 sd 1.9 1.3

MET + SRP 6.2 1.00 sd 4.0 1.07 sd 2.2 1.8

MET + SRP 9.8 1.62 sd 6.7 1.22 sd 3.1 1.7

MET + SRP 9.8 1.62 sd 6.4 1.12 sd 3.4 2.9

MET + SRP 0.04 ± 0.19 sem 0.37

MET + SRP 0.79 ± 0.16 sem 0.47

MET + SRP 1.69 ± 0.33 sem 0.66

MET + SRP −0.05 ± 0.09 sem 0.10

MET + SRP 0.40 ± 0.16 sem 0.13

MET + SRP 0.86 ± 0.26 sem 0.32

MET + Prophylaxis 7.21 0.85 sd 6.48 0.82 sd 0.73 0.13



MET + SRP smokers 4.2 0.6 sd 3.2 0.7 sd 1.0 0.1

MET + SRP non-smokers 3.8 0.4 sd 3.1 0.4 sd 0.7 −2.6

MET + SRP + SURG smokers 4.4 0.5 sd 4.4 0.8 sd 0 0.1

MET + SRP + SURG 4.0 0.4 sd 3.8 0.7 sd 0.2 −0.8

MET + SRP 0.59 ± 0.51 sd 0.23

MET + SRP 0.59 ± 0.51 sd 0.20

(continued)

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148



Control


24 24 weeks BPD ≥5 mm SRP 0.51 ± 0.43 sd

24 24 weeks BPD ≥5 mm SRP + MET gel 0.47 ± 0.65 sd

25 2 months BPD ≥5 Smokers SRP 0.26 ± 0.47 sd

25 6 months BPD ≥5 Smokers SRP 0.47 ± 0.46 sd

25 2 months BPD ≥5 Smokers SRP + MET gel 0.50 ± 0.26 sd

25 6 months BPD ≥5 Smokers SRP + MET gel 0.46 ± 0.25 sd

25 2 months BPD ≥5 Non- SRP 0.41 ± 0.28 sdsmokers

25 6 months BPD ≥5 Non- SRP 0.53 ± 0.43 sdsmokers

25 2 months BPD ≥5 Non- SRP + MET gel 0.34 ± 0.60 sdsmokers

25 6 months BPD ≥5 Non- SRP + MET gel 0.48 ± 0.80 sdsmokers

PENICILLIN

26 26 weeks All SRP + SURG 0.93 0.19 sem 0.83 0.24 sem 0.10




26 26 weeks BAL ≥2 mm SRP + SURG 3.68 0.34 sem 2.49 0.39 sem 1.19




26 62 weeks BPD ≥6 mm SRP + SURG 2.52 ± 0.32 sem

26 62 weeks BPD ≤5 mm SRP + SURG 1.08 ± 0.17 sem

SPIRAMYCIN

27 2 weeks BPD 1-3 mm PLAC + SRP 7.50 0.84 sem 7.90 0.93 sem −0.40


27 12 weeks BPD 1-3 mm PLAC + SRP 7.50 0.84 sem 7.36 0.90 sem 0.14





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149



Test


MET + SRP 0.67 ± 0.67 sd 0.16

MET + SRP 0.67 ± 0.67 sd 0.20

MET + SRP 0.32 ± 0.26 sd 0.06

MET + SRP 0.43 ± 0.57 sd −0.04

MET + SRP 0.32 ± 0.26 sd −0.18

MET + SRP 0.43 ± 0.57 sd −0.03

MET + SRP 0.72 ± 0.55 sd 0.31

MET + SRP 0.79 ± 0.70 sd 0.26

MET + SRP 0.72 ± 0.55 sd 0.38

MET + SRP 0.79 ± 0.70 sd 0.31

PENICILLIN

PEN + SRP + SURG 1.39 0.21 sem 1.05 0.16 sem 0.34 0.24



PEN + SRP + SURG 1.39 0.21 sem 1.00 0.20 sem 0.39 −0.07





PEN + SRP + SURG 2.50 ± 0.25 sem −0.02

PEN + SRP + SURG 0.73 ± 0.14 sem −0.35

SPIRAMYCIN

SPIR + SRP 7.29 0.57 sem 7.08 0.50 sem 0.21 0.61

SPIR + SRP 7.29 0.57 sem 6.94 0.49 sem 0.35 0.55

SPIR + SRP 7.29 0.57 sem 6.75 0.49 sem 0.54 0.40

SPIR + SRP 7.29 0.57 sem 6.67 0.67 sem 0.62 0.92

SPIR + SRP 9.11 0.27 sem 8.80 0.26 sem 0.31 0.00

SPIR + SRP 9.11 0.27 sem 8.09 0.30 sem 1.02 0.39

SPIR + SRP 9.11 0.27 sem 8.32 0.30 sem 0.79 −0.14

(continued)

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150



Control



27 2 weeks BPD ≥7 mm PLAC + SRP 10.75 0.29 sem 9.81 0.29 sem 0.94








TETRACYCLINE

29 8 weeks All None 0.02

29 8 weeks All SRP 0.31

29 25 weeks All None 0.05

29 25 weeks All SRP 0.30

30 10 weeks BPD ≥6 mm PLAC + SRP 0.6 ± 0.2 sem




30 10 weeks BPD ≥6 mm PLAC 0.1 ± 0.2 sem

30 20 weeks BPD ≥6 mm PLAC 0.0 ± 0.3 sem

30 30 weeks BPD ≥6 mm PLAC −0.1 ± 0.3 sem

30 50 weeks BPD ≥6 mm PLAC −0.4 ± 0.4 sem



27 12 weeks BPD 1-3 PLAC + SRP 7.50 0.84 sem 7.36 0.90 sem 0.14

27 24 weeks BPD 1-3 PLAC + SRP 7.50 0.84 sem 7.80 0.82 sem −0.30





27 2 weeks BPD ≥7 PLAC + SRP 10.75 0.29 sem 9.81 0.29 sem 0.94


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151



Test


SPIR + SRP 9.11 0.27 sem 8.31 0.30 sem 0.80 −0.22

SPIR + SRP 10.60 0.27 sem 9.75 0.30 sem 0.85 −0.09

SPIR + SRP 10.60 0.27 sem 9.30 0.29 sem 1.30 0.18

SPIR + SRP 10.60 0.27 sem 9.14 0.28 sem 1.46 0.02

SPIR + SRP 10.60 0.27 sem 9.14 0.26 sem 1.46 −0.08

SPIRA + SRP 10.72 0.15 sem 9.74 0.16 sem 0.98 0.21

SPIRA + SRP 10.72 0.15 sem 9.13 0.18 sem 1.59 0.32

SPIRA + SRP 10.72 0.15 sem 8.87 0.20 sem 1.85 0.46

SPIRA + SRP 10.72 0.15 sem 8.85 0.16 sem 1.87 0.29

TETRACYCLINE

TET 0.23 0.21

TET + SRP 0.25 −0.06

TET 0.32 0.27

TET + SRP 0.49 0.19

TET + SRP 1.0 ± 0.5 sem 0.4

TET + SRP 1.3 ± 0.4 sem 0.2

TET + SRP 1.4 ± 0.6 sem 0.0

TET + SRP 1.7 ± 0.3 sem 0.3

TET 0.2 ± 0.3 sem 0.1

TET 0.4 ± 0.3 sem 0.4

TET 0.6 ± 0.4 sem 0.7

TET 0.7 ± 0.3 sem 1.1

TET + SRP 7.25 0.46 sem 7.81 0.46 sem −0.56 −0.16

TET + SRP 7.25 0.46 sem 7.14 0.45 sem 0.11 0.31

TET + SRP 7.25 0.46 sem 7.31 0.45 sem −0.06 −0.20

TET + SRP 7.25 0.46 sem 7.06 0.55 sem 0.19 0.49

TET + SRP 9.06 0.26 sem 8.76 0.31 sem 0.30 −0.01

TET + SRP 9.06 0.26 sem 8.24 0.27 sem 0.82 0.19

TET + SRP 9.06 0.26 sem 8.19 0.29 sem 0.87 −0.06

TET + SRP 9.06 0.26 sem 8.00 0.27 sem 1.06 0.04

TET + SRP 10.58 0.25 sem 9.82 0.28 sem 0.76 −0.18

TET + SRP 10.58 0.25 sem 8.90 0.28 sem 1.68 0.56

(continued)

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152



Control




31 12 months All SRP 0.16 ± 0.5 sd

12 10 months All SRP + MWF + PLAC 0.02 ± 0.11 sem

12 10 months BPD <4 SRP + MWF + PLAC −0.25 ± 0.12 sem

12 10 months BPD 4-6 SRP + MWF + PLAC 0.27 ± 0.20 sem

12 10 months BPD >6 SRP + MWF + PLAC 1.73 ± 0.44 sem

32 3 months All affected teeth PLAC + SRP 2.66 1.18 sd 2.31 1.27 sd 0.35

32 3 months All affected teeth PLAC + SRP + SURG 2.62 0.90 sd 2.31 1.07 sd 0.31



32 3 months Proximal sites of PLAC + SRP 3.22 1.25 sd 2.74 1.36 sd 0.48affected teeth

32 3 months Proximal sites of PLAC + SRP + SURG 3.25 0.99 sd 2.77 1.13 sd 0.48affected teeth



* A negative value in the Change column indicates improvement.† A positive value in the Difference column favors test over control.‡ Modified Widman Flap.

Table 8.

Percent of Sites Gaining or Losing Attachment Over Various Thresholds at Different Times

Control Test

Reference Time Site Type Threshold Treatment % Sites SD/SEM Treatment % Sites SD/SEM


5 Baseline All AL loss ≥2 mm PLAC 3.14 1.45 sd AMOX + MET 3.3 1.63 sd

5 2 months All AL loss ≥2 mm PLAC 3.06 2.09 sd AMOX + MET 1.17 1.24 sd





8006.qxd 12/30/03 3:21 PM Page 152


therapy (Table 9; page 156). Only one study with 3comparisons presented data in this format.4 The dataindicated that AMOX alone, MET alone, or the 2 antimi-crobials used in combination reduced the percent ofsites with attachment level >6 mm and increased thepercent of sites with attachment level <3 mm morethan the control at 17 of 18 agent/time points reported.

Mean Probing Depth ChangeThe data describing mean probing depth change at allsites monitored as well as subsets of sites are pre-sented in Table 10 (page 158). For 103 of 132 (78%)of comparison involving multiple time points the testgroup was favored over the control. This did not takeinto consideration the antibiotic(s) and dosages ofantibiotics employed, the duration of the monitoring,concomitant mechanical debridement, or whether allor subsets of pockets were examined.

153



Test


TET + SRP 10.58 0.25 sem 9.05 0.29 sem 1.53 0.09

TET + SRP 10.58 0.25 sem 8.79 0.26 sem 1.79 0.25

TET 0.47 ± 0.6 sd 0.31

TET + SRP + MWF 0.49 ± 0.20 sem 0.47

TET + SRP + MWF −0.05 ± 0.12 sem 0.20

TET + SRP + MWF 0.86 ± 0.26 sem 0.59

TET + SRP + MWF 2.01 ± 0.48 sem 0.28

TET + SRP 3.02 1.86 sd 2.21 1.71 sd 0.81 0.46

TET + SRP + SURG 3.29 2.05 sd 2.49 1.90 sd 0.80 0.49

TET + SRP + SURG 3.29 2.05 sd 1.96 1.72 sd 1.33 0.57

TET + SRP + SURG 3.29 2.05 sd 2.07 1.85 sd 1.22 0.43

TET + SRP 3.68 2.10 sd 2.66 1.92 sd 1.02 0.54

TET + SRP + SURG 4.07 2.34 sd 3.03 2.12 sd 1.04 0.56

TET + SRP + SURG 4.07 2.34 sd 2.25 1.19 sd 1.82 0.76

TET + SRP + SURG 4.07 2.34 sd 2.33 2.01 sd 1.74 0.61


Percent of Sites Gaining or Losing AttachmentOver Various Thresholds At Different Times

Difference* Clinically Favors Test/Control


−0.16 Control

1.89 Test

1.85 Test

3.12 Test

1.73 Test

2.17 Test (continued)

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154



Control Test



5 Baseline All AL gain ≥2 mm PLAC 0.53 0.78 sd AMOX + MET 0.57 1.03 sd

5 2 months All AL gain ≥2 mm PLAC 0.60 1.35 sd AMOX + MET 1.48 1.18 sd






6 2 months BPD 4-5 mm AL gain ≥2 mm SRP + 11 7 sd MET + AMOX + 7 7 sdPLAC SRP



6 2 months BPD >5 mm AL gain ≥2 mm SRP + 21 7 sd MET + AMOX + 40 18 sdPLAC SRP



8 12 months All “diseased AL gain >2 mm PLAC + 15.82 7.53 sd AMOX + MET + 34.70 11.67 sdsites” MWF + SRP + MWF†

SRP

8 12 months All “diseased AL loss >2 mm PLAC + 24.32 19.98 sd AMOX + MET + 10.04 11.59 sdsites” SRP + SRP + MWF

MWF


10 24 months All AL loss ≥3 SDs + PLAC + 11.3 (N 5.7 sd AMOX + CA + 4.1 (N 5.7 sd0.5 mm SRP not %) SRP not %)increase in PD

10 24 months All AL gain ≥3 SD + PLAC + 0.3 (N 6.0 sd AMOX + CA + 7.4 (N 6.0 sd0.5 mm SRP not %) SRP not %)decrease in PD

12 10 months All AL loss ≥2 mm SRP + 7.74 2.40 sem AMOX + CA + 3.83 1.70 semMWF + SRP + MWFPLAC

12 10 months All AL gain ≥2 mm SRP + 7.27 1.47 sem AMOX + CA + 23.44 6.61 semMWF + SRP + MWFPLAC

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155



Difference* Clincally Favors Test/Control

2.41 Test

0.04 Test

0.88 Test

1.44 Test

0.75 Test

1.04 Test

1.67 Test

1.88 Test

−4 Control

0 Same

3 Test

19 Test

18 Test

21 Test

18.88 Test

14.28 Test


7.2 Test

7.1 Test

3.91 Test

16.17 Test

(continued)

Change in Percent of Sites Increasing or Decreasingin Probing DepthTwo studies8,12 (with 3 comparisons) described dataas the percentage of sites that showed probing depthincreasing or decreasing over certain millimeter thresh-olds (Table 11; page 168). All comparisons presentedfavored the test over the control.

Percent of Sites in Different Probing DepthCategoriesTable 12 (page 170) presents the percentage of sitesin different probing depth categories at baseline and atdifferent time-points post-therapy. Eight studies with 10comparisons provided data in this for-mat.4,7,9,18,24,30,31,32 When data were limited to obser-vations closest to 6 months, the test was favored overthe control in 9 of 9 comparisons examining an increasein percentage of shallow pockets and in 8 of 12instances reporting a decrease in percentage of pock-ets ≥5 mm.

DISCUSSIONOutcome MeasureThe primary outcome measure employed in this reviewwas clinically determined attachment level. This variableappears to be the most commonly employed for studiesof the usefulness of adjunctive antimicrobial therapyand has gained universal acceptance by the profes-sion. A secondary outcome of probing depth was alsoincluded although no formal meta-analyses were car-ried out using this parameter. Other secondary clinicalmeasurements, such as plaque, gingival redness, sup-puration, or bleeding on probing, were not includedsince they were less consistently reported and may beof less importance. Another widely accepted primaryoutcome variable would be change in alveolar boneheight or density. However, since this variable was infre-quently assessed in clinical trials involving systemicadministration of antibiotics, it was not evaluated. Aninitial attempt was made to evaluate microbiologicalchanges that accompanied the use of systemicallyadministered antimicrobial agents. However, the datawere sparse in that limited numbers of studies, sam-ples, and species were reported. The interested readermay seek a recent comprehensive review by Slots andTing.84

Experimental DesignOne distressing feature of performing this systematicreview was the heterogeneity of the experimentaldesigns employed to assess the efficacy of systemicallyadministered antimicrobial agents. The designs variedenormously in terms of the antibiotics or antibioticcombinations employed; the dosage and duration ofadministration; whether the antibiotic administrationwas repeated or sustained over a long period of time;

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156



Control Test


CLINDAMYCIN

10 24 months All AL loss ≥3 SD + PLAC + SRP 11.3 (N 5.7 sd CLIND + SRP 7.0 (N 5.7 sd0.5 mm not %) not %)increase in PD

10 24 months All AL gain ≥3 SD + PLAC + SRP 0.3 (N 6.0 sd CLIND + SRP 5.5 (N 6.0 sd0.5 mm not %) not %)decrease in PD

PENICILLIN

26 26 weeks BAL ≥2 mm AL gain ≥2 mm SRP + SURG 44.8 9.4 sem PEN + SRP + SURG 50.0 7.8 sem




26 26 weeks BAL ≥2 mm AL loss ≥2 mm SRP + SURG 6.4 2.3 sem PEN + SRP + SURG 9.2 2.2 sem




TETRACYCLINE

12 10 months All AL loss ≥2 mm SRP + MWF + 7.74 2.40 sem TET + SRP + MWF 4.08 1.33 semPLAC

12 10 months All AL gain ≥2 mm SRP + MWF + 7.27 1.47 sem TET + SRP + MWF 15.73 4.92 semPLAC

* A positive value in the Difference column favors test over control.† Modified Widman flap.

Table 9.

Percent Sites in Different Attachment Level Categories at Different Times

Control

Reference Time point Site Type Treatment % at Baseline SD/SEM % at End SD/SEM Change*

AMOXICILLIN

4 1 month AL ≤3 mm PLAC + PLAC + SRP 48.0 20.7 sd 55.1 22.2 sd 7.1

4 3 months AL ≤3 mm PLAC + PLAC + SRP 48.0 20.7 sd 51.6 21.8 sd 3.6


4 1 month AL ≥6 mm PLAC + PLAC + SRP 24.3 13.8 sd 18.4 12.4 sd 5.9

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the nature of concomitant mechanical debridement;the timing of mechanical therapy in relation to antimi-crobial usage; the duration and timing of post-therapymonitoring; the number of subjects and the number ofsites evaluated per subject and the nature of sitesselected; the nature of the periodontal diseases beingtreated; severity of disease; the subject population eval-uated; the nature of the probing techniques; the use ofsplit-mouth designs; and the degree to which mask-ing of subject, therapist, and examiner was carried out.This formidable list of differences among studies com-plicated data analysis and led to data aggregationsthat may not have been entirely optimal. Thus, analy-ses performed examined all of the antibiotics togetheras well as subsets of antibiotics. Another problem wasthat the duration of monitoring differed and somestudies provided multiple time points of post-therapymonitoring. A time of 6 months was chosen for themeta-analysis since this was close to the median valuefor the time-points provided. Unfortunately, not all stud-ies provided 6-month data and thus, the closest datato that time point were employed.

Number of SubjectsThe number of subjects in the studies examined in thisreview ranged widely from 4 to 96 subjects per groupwith a median value of 13 subjects per group. Manyof the studies concluded that there was no “statisti-cally significant” difference between test and controlgroups although there were frequently better outcomesfor the test group, as summarized in this review. Thelack of statistical significance for the studies may havebeen due to too few subjects; i.e., the studies wereunder-powered. This led to the meta-analyses per-formed in the present review. The low number of sub-

157



Difference* Clincally Favors Test/Control

CLINDAMYCIN

4.3 Test

5.2 Test

PENICILLIN

5.2 Test

4.8 Test

1.2 Test

−6.2 Control

−2.8 Control

−3.0 Control

−1.9 Control

−5.4 Control

TETRACYCLINE

3.66 Test

8.46 Test



Test

Treatment % at Baseline SD/SEM % at End SD/SEM Change* Difference†

AMOXICILLIN

AMOX + PLAC + SRP 55.8 14.8 sd 63.4 19.6 sd 7.6 0.5




(continued)


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Control

Reference Time point Site Type Treatment % at Baseline SD/SEM % at End SD/SEM Change*

4 3 months AL ≥6 mm PLAC + PLAC + SRP 24.3 13.8 sd 20.6 13.9 sd 3.7


AMOXICILLIN + METRONIDAZOLE AMOXICILLIN + METRONIDAZOLE







METRONIDAZOLEMETRONIDAZOLE







* A negative value in the Change column indicates improvement.† A positive value in the Difference column favors test over control.


158

Table 10.

Mean Probing Depths or Probing Depth Changes at Different Times

Control

Mean PD Mean PD Reference Time Site Type Treatment Baseline SD/SEM at End SD/SEM Change*


5 2 months All PLAC 2.66 0.66 sd 2.71 0.64 sd −0.05



5 8 months All PLAC 2.66 0.66 sd 2.84 0.72 −0.18



6 2 months All SRP + PLAC 4.5 0.8 sd 3.2 0.4 sd 1.3

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Test




AMOX + MET + SRP 56.9 17.7 sd 70.7 20.6 sd 13.8 6.7

AMOX + MET + SRP 56.9 17.7 sd 72.9 21.3 sd 16.0 12.4

AMOX + MET + SRP 56.9 17.7 sd 72.5 25.8 sd 15.6 7.3

AMOX + MET + SRP 17.1 11.0 sd 7.0 8.5 sd 10.1 4.2

AMOX + MET + SRP 17.1 11.0 sd 5.4 6.8 sd 11.7 8.0

AMOX + MET + SRP 17.1 11.0 sd 6.5 11.5 sd 10.6 4.5

MET + PLAC + SRP 55.1 17.4 sd 63.9 19.7 sd 8.8 1.7

MET + PLAC + SRP 55.1 17.4 sd 69.5 17.0 sd 14.4 10.8

MET + PLAC + SRP 55.1 17.4 sd 69.9 17.9 sd 14.8 6.5

MET + PLAC + SRP 18.2 10.9 sd 13.5 12.0 sd 4.7 −1.2

MET + PLAC + SRP 18.2 10.9 sd 9.1 8.0 sd 9.1 5.4

MET + PLAC + SRP 18.2 10.9 sd 8.8 6.8 sd 9.4 3.3


159



Test

Mean PD Mean PD Treatment Baseline SD/SEM at End SD/SEM Change* Difference†


AMOX + MET 2.93 0.92 sd 2.64 0.81 sd 0.29 0.34

AMOX + MET 2.93 0.92 sd 2.57 0.71 sd 0.36 0.42

AMOX + MET 2.93 0.92 sd 2.42 0.65 sd 0.51 0.59

AMOX + MET 2.93 0.92 sd 2.42 0.58 sd 0.51 0.69

AMOX + MET 2.93 0.92 sd 2.38 0.61 sd 0.55 0.72

AMOX + MET 2.93 0.92 sd 2.35 0.60 sd 0.58 0.87

AMOX + MET + SRP 4.8 0.7 sd 3.2 0.3 sd 1.6 0.3

(continued)

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160



Control









7 3 months BPD >6 PLAC 2.46 ± 0.89 sd







11 15 weeks 4 teeth SRP + local TET 6.2 1.5 sd 5.2 1.6 sd 1.0





CLINDAMYCIN







DOXYCYCLINE

14 3 weeks All PLAC + SRP 4.3 0.9 sd 4.3 0.3 sd 0.0


14 12 weeks All PLAC + SRP 4.3 0.9 sd 4.1 0.4 sd 0.2



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161



Test


AMOX + MET + SRP 4.8 0.7 sd 3.1 0.3 sd 1.7 0.3

AMOX + MET + SRP 4.8 0.7 sd 2.7 0.2 sd 2.1 0.5

AMOX + MET 4.6 0.6 sd 3.9 0.4 sd 0.7 0.4

AMOX + MET 4.6 0.6 sd 3.6 0.3 sd 1.0 0.7

AMOX + MET 4.4 0.6 sd 3.0 0.4 sd 1.4 0.4

AMOX + MET 0.27 ± 0.14 sd 0.16

AMOX + MET 1.72 ± 0.42 sd 0.35

AMOX + MET 3.18 ± 0.92 sd 0.72


AMOX + CA + SRP 3.9 0.4 sd 3.0 0.2 sd 0.9 −0.1

AMOX + CA + SRP 3.9 0.4 sd 2.8 0.1 sd 1.1 0.1

AMOX + CA + SRP 3.9 0.4 sd 2.9 0.2 sd 1.0 0

AMOX + CA + SRP 1.55 ± 1.26 sd 0.82

AMOX + CA + SRP 1.18 ± 0.90 sd 1.71

SRP + AMOX + CA 6.5 1.4 sd 5.6 1.1 sd 0.9 −0.1

SRP + AMOX + CA 6.5 1.4 sd 4.5 0.7 sd 2.0 0.6

SRP + AMOX + CA 6.5 1.4 sd 4.3 0.8 sd 2.2 0.6

SRP + AMOX + CA 6.5 1.4 sd 4.2 0.6 sd 2.3 0.8


CLINDAMYCIN

CLIND + SRP 5.7 1.06 sd 3.5 0.96 sd 2.2 0.9

CLIND + SRP 5.7 1.06 sd 3.4 0.8 sd 2.3 1.6

CLIND + SRP 8.4 0.76 sd 4.2 1.06 sd 4.2 1.9

CLIND + SRP 8.4 0.76 sd 3.6 0.98 sd 4.8 3.6

CLIND + SRP 0.93 ± 0.57 sd 0.20

CLIND + SRP 0.80 ± 1.04 sd 1.33

DOXYCYCLINE

DOXY + SRP 4.3 0.9 sd 3.8 0.6 sd 0.5 0.5

DOXY + SRP 4.3 0.9 sd 3.8 0.6 sd 0.5 0.6

DOXY + SRP 4.3 0.9 sd 3.8 0.6 sd 0.5 0.3

DOXY + SRP 4.3 0.9 sd 4.0 0.6 sd 0.3 0.6

DOXY 4.1 0.7 sd 4.1 0.4 sd 0.0 −0.1

(continued)

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162



Control





15 90 days All SRP 3.12 0.44 sd 2.97 0.33 sd 0.15


13 24 months All SRP 5.9 0.7 sd 5.2 0.77 0.7



METRONIDAZOLE

16 42 days 24 sites measured None 5.8 1.2 sd 5.6 1.2 sd 0.2 ± 0.3 sd

16 42 days 24 sites measured SRP 5.9 0.6 sd 4.5 1.0 sd 1.4 ± 0.6 sd

17 42 days 24 sites measured None 5.08 – 4.74 – 0.34

17 42 days 24 sites measured SRP 5.19 – 3.88 – 1.31

19 1 month All (2 sites) SRP 6.1 1.7 sd 4.2 1.1 sd 1.9

19 3 months All (2 sites) SRP 6.1 1.7 sd 4.4 1.1 sd 1.7

19 3 months All (2 sites) None 6.2 0.8 5.2 1.4 sd 1.0





20 4-6 weeks BPD ≤3 mm SRP 0.20 ± 0.13 sem



21 4-6 weeks BPD ≤3 mm SRP 0.02 ± 0.08 sem



23 5 years All smokers PLAC + SRP 2.9 0.4 sd 2.3 0.3 sd 0.6

23 5 years All non-smokers PLAC + SRP 2.1 Only 1 subject 2.1 0.0

23 5 years All smokers PLAC + SRP + SURG 3.1 0.6 sd 3.1 1.0 sd 0.0

23 5 years All non-smokers PLAC + SRP + SURG 2.8 0.4 sd 2.5 0.4 sd 0.3

25 2 months BPD ≥5 mm smokers SRP 5.73 0.51 sd 4.71 0.51 sd 1.02

25 6 months BPD ≥5 mm smokers SRP 5.73 0.51 sd 4.61 0.70 sd 1.12

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DOXY 4.1 0.7 sd 4.0 0.3 sd 0.1 0.3

DOXY 4.1 0.7 sd 3.8 0.5 sd 0.3 0.8

DOXY 4.1 0.7 sd 3.9 0.5 sd 0.2 0.7

DOXY + SRP 2.89 0.29 sd 2.67 0.36 sd 0.22 0.07

DOXY + SRP 5.5 0.62 sd 3.9 0.84 sd 1.6 0.3

DOXY + SRP 5.5 0.62 sd 4.2 1.1 sd 1.3 0.6

DOXY + SRP 8.6 1.21 sd 5.2 0.79 sd 3.4 1.1

DOXY + SRP 8.6 1.21 sd 6.6 0.87 sd 2.0 0.8

METRONIDAZOLE

MET 5.9 1.0 sd 5.1 1.2 sd 0.8 ± 0.5 sd 0.6

MET + SRP 6.3 1.1 sd 4.7 1.1 sd 1.6 ± 0.7 sd 0.2

MET 5.43 – 4.42 – 1.01 0.67

MET + SRP 5.53 – 3.62 – 1.91 0.60

MET 5.9 1.0 sd 5.9 1.2 0.0 −1.9

MET 5.9 1.0 sd 5.9 1.2 0.0 −1.7

MET 5.9 1.0 sd 5.9 1.2 0.0 −1.0

MET + SRP 5.8 0.73 sd 3.6 0.78 sd 2.2 0.9

MET + SRP 5.8 0.73 sd 3.2 0.65 sd 2.6 1.9

MET + SRP 8.1 1.07 sd 3.6 1.14 sd 4.5 2.2

MET + SRP 8.1 1.07 sd 3.3 1.09 sd 4.8 3.6

MET + SRP 0.05 ± 0.13 sem −0.15

MET + SRP 1.22 ± 0.16 sem 0.47

MET + SRP 2.83 ± 0.33 sem 1.05

MET + SRP −0.05 ± 0.08 sem −0.07

MET + SRP 0.75 ± 0.19 sem −0.06

MET + SRP 1.91 ± 0.30 sem 0.41

MET + SRP smokers 2.8 0.2 sd 2.2 0.6 sd 0.6 0.0

MET + SRP non-smokers 2.8 0.2 sd 2.1 0.4 sd 0.7 0.7

MET + SRP + SURG smokers 3.4 0.6 sd 3.1 0.6 sd 0.3 0.3

MET + SRP + SURG smokers 3.0 0.6 sd 2.6 0.6 sd 0.4 0.1

MET + SRP 5.84 0.43 sd 4.61 0.61 sd 1.23 0.21

MET + SRP 5.84 0.43 sd 4.64 0.61 sd 1.2 0.08

(continued)

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Control


25 2 months BPD ≥5 mm smokers SRP + MET gel 5.69 0.42 sd 4.31 0.66 sd 1.38

25 6 months BPD ≥5 mm smokers SRP + MET gel 5.69 0.42 sd 4.38 0.69 sd 1.31

25 2 months BPD ≥5 mm non-smokers SRP 5.92 0.49 sd 4.19 0.63 sd 1.73

25 6 months BPD ≥5 mm non-smokers SRP 5.92 0.49 sd 3.96 0.37 sd 1.96

25 2 months BPD ≥5 mm non-smokers SRP + MET gel 6.04 0.75 sd 4.11 0.66 sd 1.93

25 6 months BPD ≥5 mm non-smokers SRP + MET gel 6.04 0.75 sd 4.11 0.63 1.93

PENICILLIN









26 62 weeks BPD ≥6 mm SRP + SURG 4.12 ± 0.32 sem

26 62 weeks BPD ≤5 mm SRP + SURG 1.10 ± 0.12 sem

SPIRAMYCIN














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MET + SRP 5.84 0.43 sd 4.61 0.61 sd 1.23 −0.15

MET + SRP 5.84 0.43 sd 4.64 0.61 sd 1.20 −0.11

MET + SRP 6.10 0.57 sd 4.25 0.56 sd 1.85 0.12

MET + SRP 6.10 0.57 sd 4.27 0.55 sd 1.83 −0.13

MET + SRP 6.10 0.57 sd 4.25 0.56 sd 1.85 −0.08

MET + SRP 6.10 0.57 sd 4.27 0.55 sd 1.83 −0.10

PENICILLIN









PEN + SRP + SURG 4.01 ± 0.19 sem −0.11

PEN + SRP + SURG 0.89 ± 0.09 sem −0.21

SPIRAMYCIN

SPIR + SRP 3.00 0.00 sem 3.15 0.31 sem −0.15 −0.15

SPIR + SRP 3.00 0.00 sem 2.90 0.33 sem 0.10 −0.30

SPIR + SRP 3.00 0.00 sem 2.50 0.27 sem 0.50 −0.12

SPIR + SRP 3.00 0.00 sem 2.58 0.34 sem 0.42 0.42

SPIR + SRP 5.26 0.11 sem 4.05 0.12 sem 1.21 0.21

SPIR + SRP 5.26 0.11 sem 3.78 0.16 sem 1.48 0.12

SPIR + SRP 5.26 0.11 sem 3.64 0.17 sem 1.62 −0.08

SPIR + SRP 5.26 0.11 sem 3.94 0.20 sem 1.32 −0.40

SPIR + SRP 7.49 0.13 sem 5.37 0.19 sem 2.12 0.32

SPIR + SRP 7.49 0.13 sem 4.95 0.22 sem 2.54 0.21

SPIR + SRP 7.49 0.13 sem 4.72 0.18 sem 2.77 0.05

SPIR + SRP 7.49 0.13 sem 4.92 0.21 sem 2.57 −0.28

SPIRA + SRP 7.60 0.08 sem 5.76 0.12 sem 1.84 0.38

(continued)

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Control





TETRACYCLINE

29 8 weeks All None 5.5 4.9 0.6

29 8 weeks All SRP 5.4 4.1 1.3

29 25 weeks All None 5.5 4.7 0.8

29 25 weeks All SRP 5.4 3.6 1.8






30 2 weeks BPD ≥6 mm PLAC 7.7 0.5 sem 6.8 0.3 sem 0.9


















31 12 months All SRP 0.7 ± 0.7 sd

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Test


SPIRA + SRP 7.60 0.08 sem 5.06 0.12 sem 2.54 0.50

SPIRA + SRP 7.60 0.08 sem 4.91 0.12 sem 2.69 0.50

SPIRA + SRP 7.60 0.08 sem 4.73 0.11 sem 2.87 0.47

TETRACYCLINE

TET 6.0 4.5 1.5 0.9

TET + SRP 5.8 4.0 1.8 0.5

TET 6.0 4.2 1.8 1.0

TET + SRP 5.8 3.6 2.2 0.4

TET + SRP 7.5 0.3 sem 6.3 0.2 sem 1.2 0.1

TET + SRP 7.5 0.3 sem 5.1 0.2 sem 2.4 0.5

TET + SRP 7.5 0.3 sem 4.9 0.1 sem 2.6 0.3

TET + SRP 7.5 0.3 sem 4.3 0.2 sem 3.2 0.9

TET + SRP 7.5 0.3 sem 4.4 0.1 sem 3.1 0.8

TET 6.9 0.5 sem 6.5 0.2 sem 0.4 −0.5

TET 6.9 0.5 sem 5.3 0.3 sem 1.6 0.8

TET 6.9 0.5 sem 5.1 0.2 sem 1.8 1.0

TET 6.9 0.5 sem 4.9 0.3 sem 2.0 1.1

TET 6.9 0.5 sem 5.0 0.3 sem 1.9 1.0

TET + SRP 3.00 0.00 sem 3.50 0.38 sem −0.50 −0.50

TET + SRP 3.00 0.00 sem 3.14 0.26 sem −0.14 −0.54

TET + SRP 3.00 0.00 sem 3.38 0.32 sem −0.38 −1.00

TET + SRP 3.00 0.00 sem 2.88 0.22 sem 0.12 0.12

TET + SRP 5.21 0.08 sem 4.34 0.25 sem 0.87 −0.13

TET + SRP 5.21 0.08 sem 3.69 0.17 sem 1.52 0.16

TET + SRP 5.21 0.08 sem 3.68 0.18 sem 1.53 −0.17

TET + SRP 5.21 0.08 sem 3.54 0.14 sem 1.67 −0.05

TET + SRP 7.40 0.11 sem 5.44 0.25 sem 1.94 0.14

TET + SRP 7.40 0.11 sem 4.53 0.21 sem 1.87 −0.46

TET + SRP 7.40 0.11 sem 4.64 0.27 sem 2.76 0.04

TET + SRP 7.40 0.11 sem 4.36 0.21 sem 3.04 0.19

TET + SRP + MWF 0.75 ± 0.19 sem 0.29

TET + SRP 1.0 ± 0.8 sd 0.3

(continued)

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Control

Mean PD Mean PD Reference Time Site Type Treatment Baseline SD/SEM at End SD/SEM Change

32 3 months All affected teeth PLAC + SRP 4.44 1.23 sd 3.63 1.11 sd 0.81




32 3 months Proximal sites of PLAC + SRP 5.27 1.19 sd 4.29 1.19 0.98affected teeth




* A negative value in the Change column indicates improvement.† A positive value in the Difference columns favors test over control.‡ Modified Widman flap.

Table 11.

Percent of Sites Increasing or Decreasing in Probing Depth over Various Threshold

Control Test

Reference Time Site Type Threshold Treatment % Sites SD/SEM Treatment % Sites SD/SEM Difference*


8 12 months All diseased PD decreases PLAC + SRP + 40.69 31.36 sd AMOX + MET+ 74.29 17.13 sd 33.60sites >2 mm MWF† SRP + MWF

8 12 months All diseased PD deepens PLAC + SRP + 18.95 19.06 sd AMOX + MET + 4.49 10.41 sd 14.46sites >2 mm MWF SRP + MWF


12 10 months All PD deepens SRP + MWF + 1.14 0.56 sem AMOX + CA + 2.51 1.46 sem −1.37≥2 mm PLAC SRP + MWF

12 10 months All PD decreases SRP + MWF + 10.78 2.36 sem AMOX + CA + 21.71 6.05 sem 10.93≥2 mm PLAC SRP + MWF

TETRACYCLINE

12 10 months All PD deepens SRP + MWF + 1.14 0.56 sem TET + SRP + 1.51 1.01 sem −0.37≥2 mm PLAC MWF

12 10 months All PD decreases SRP + MWF + 10.78 2.36 sem TET + SRP + 19.39 4.97 sem 8.61≥2 mm PLAC MWF

* A positive value in the Difference column favors test over control.† Modified Widman flap.

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TET + SRP 4.40 1.10 sd 3.10 0.79 sd 1.30 0.49

TET + SRP + SURG 4.59 1.19 sd 3.22 0.85 sd 1.37 0.59

TET + SRP + SURG 4.59 1.19 sd 1.89 1.18 sd 2.70 0.75

TET + SRP + SURG 4.59 1.19 sd 2.00 1.28 sd 2.59 0.57

TET + SRP 5.34 1.27 sd 3.76 0.96 sd 1.58 0.60

TET + SRP + SURG 5.60 1.39 sd 3.94 1.03 sd 1.66 0.67

TET + SRP + SURG 5.60 1.39 sd 2.26 1.38 sd 3.34 0.93

TET + SRP + SURG 5.60 1.39 sd 2.39 1.49 sd 3.21 0.68

jects in some of the studies is probably of historicalinterest in that the size of differences between test andcontrol groups were probably not known in early stud-ies and power calculations were probably less com-monly employed than they are today.

Efficacy of Systemically Administered AntimicrobialAgents in the Treatment of Periodontal InfectionsDespite the caveats concerning the heterogeneity ofexperimental designs, the meta-analyses and inspec-tion of the tables indicate that systemically adminis-tered antibiotics provide a more positive attachmentlevel change after therapy than may be observed incomparison groups. The magnitude of these changesvaried from agent to agent and study to study, but aver-aged about 0.45 mm of attachment level gain (range0.09 to 1.10 mm) for the 8 antimicrobial agents exam-ined in the meta-analysis (Table 13; page 176). Theantimicrobial agents differed in their suggested efficacy.A single study that employed CLIN suggested a meanadded benefit of 1.1 mm. DOXY provided the next bestadded benefit with a mean of 0.69 mm (3 studies). SPIRand PEN appeared to provide the least benefit at 0.09mm and 0.24 mm, respectively. Although not formallyexamined by meta-analyses, Tables 7 through 12 sug-gest that benefit may be obtained at sites when the ini-tial probing depths were ≤3, 4 to 6 or ≥7 mm. In addi-tion, benefit was observed for the antimicrobial agent

groups even when no mechanical debridement, SRP, orsurgery was performed as the comparison and con-comitant therapy. The meta-analysis suggested thatsubjects with aggressive periodontitis may have receivedgreater benefit from systemically administered agentsthan those who had chronic periodontitis, although sig-nificant benefit appeared to have occurred in the lattergroup.

Clinical ImplicationsThe data indicate that systemically administered antibi-otics can improve clinically determined periodontalattachment level beyond that achieved by comparisongroups that received no therapy, SRP, or surgery. Themean “gain” in attachment of about 0.3 to 0.4 mm formost studies may appear to be small, but it was basedon change throughout the mouth including sites withshallow probing depths whose post-therapy improve-ment would be expected to be modest. As a benchmark, one might consider that periodontitis subjectsmonitored after treatment and on maintenance ther-apy for about 12 years only experienced an averageannual full-mouth mean attachment loss of 0.042 mm(normal-susceptibility subjects) to 0.067 mm (high-susceptibility subjects).85 Thus, an attachment level“gain” of 0.3 mm would be equivalent to reversing 4 to


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170

Table 12.

Percent Sites in Different Probing Depth Categories at Different Times

Control

Reference Time Site Type Treatment % at Baseline SD/SEM % at End SD/SEM Change*

AMOXICILLIN

4 1 month PD ≤3 mm PLAC + PLAC + SRP 53.9 18.1 sd 66.4 18.6 sd 12.5

4 3 months PD ≤3 mm PLAC + PLAC + SRP 53.9 18.1 sd 64.5 18.3 sd 10.6


4 1 month PD ≥6 mm PLAC + PLAC + SRP 19.3 11.2 sd 12.1 9.1 sd 7.2

4 3 months PD ≥6 mm PLAC + PLAC + SRP 19.3 11.2 sd 13.6 11.5 sd 5.7









7 3 months PD ≥5 mm PLAC + SRP 44.6 11.4 sd 20.9 12.0 sd 23.7


9 3 months PD 1-3 mm PLAC + SRP 54 13 sd 78 13 sd 24



9 3 months PD = 4 mm PLAC + SRP 12 5 sd 11 8 sd 1






9 3 months PD ≥7 mm PLAC + SRP 11 8 sd 2 3 sd 9



METRONIDAZOLE



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AMOXICILLIN








AMOX + MET + SRP 62.6 14.5 sd 83.6 10.4 sd 21 8.5

AMOX + MET + SRP 62.6 14.5 sd 87.4 8.6 sd 24.8 14.2

AMOX + MET + SRP 62.6 14.5 sd 87.2 11.3 sd 24.6 12.1

AMOX + MET + SRP 15.9 12.7 sd 2.2 3.1 sd 13.7 6.5

AMOX + MET + SRP 15.9 12.7 sd 1.2 2.0 sd 14.7 9.0

AMOX + MET + SRP 15.9 12.7 sd 1.3 2.6 sd 14.6 7.7

AMOX + MET + SRP 43.8 16.8 sd 12.0 10.3 sd 31.8 8.1


AMOX + CA + SRP 49 11 sd 76 7 sd 27 3

AMOX + CA + SRP 49 11 sd 78 6 sd 29 3

AMOX + CA + SRP 49 11 sd 75 7 sd 26 2

AMOX + CA + SRP 15 6 sd 13 4 sd 2 1

AMOX + CA + SRP 15 6 sd 12 4 sd 3 1

AMOX + CA + SRP 15 6 sd 12 4 sd 3 0

AMOX + CA + SRP 26 9 sd 10 5 sd 16 1

AMOX + CA + SRP 26 9 sd 9 4 sd 17 2

AMOX + CA + SRP 26 9 sd 11 4 sd 15 3

AMOX + CA + SRP 10 7 sd 1 1 sd 9 0

AMOX + CA + SRP 10 7 sd 1 1 sd 9 0

AMOX + CA + SRP 10 7 sd 1 1 sd 9 0

METRONIDAZOLE

MET + PLAC + SRP 60.3 13.1 sd 73.8 13.1 sd 13.5 1.0

MET + PLAC + SRP 60.3 13.1 sd 78.4 6.2 sd 18.1 7.5

(continued)

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Control






18 2 weeks PD ≤4 mm SRP 0 11 11

18 10 weeks PD ≤4 mm SRP 0 33 33

18 20 weeks PD ≤4 mm SRP 0 43 43

18 30 weeks PD ≤4 mm SRP 0 50 50

18 50 weeks PD ≤4 mm SRP 0 50 50

18 2 weeks PD >6 mm SRP 72 33 39

18 10 weeks PD >6 mm SRP 72 8 64

18 20 weeks PD >6 mm SRP 72 8 64

18 30 weeks PD >6 mm SRP 72 0 72

18 50 weeks PD >6 mm SRP 72 0 72

18 2 weeks PD ≤4 mm None 0 8 8





18 2 weeks PD >6 mm None 73 56 17

18 10 weeks PD >6 mm None 73 70 3

18 20 weeks PD >6 mm None 73 50 23

18 30 weeks PD >6 mm None 73 67 6

18 50 weeks PD >6 mm None 73 67 6

24 8 weeks BPD ≥5 mm SRP 19.3 10.8 sd 9.4 8.4 sd 9.9

24 8 weeks BPD ≥5 mm SRP + MET gel 20.4 10.0 sd 9.7 8.6 sd 10.7







30 2 weeks PD ≤4 mm PLAC + SRP 0 11 11

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MET + PLAC + SRP 60.3 13.1 sd 79.6 8.0 sd 19.3 6.8

MET + PLAC + SRP 15.6 7.4 sd 7.3 5.6 sd 8.3 1.1

MET + PLAC + SRP 15.6 7.4 sd 5.7 5.5 sd 9.9 4.2

MET + PLAC + SRP 15.6 7.4 sd 4.8 4.4 sd 10.8 3.9

MET + SRP 0 17 17 6

MET + SRP 0 44 44 11

MET + SRP 0 52 52 9

MET + SRP 0 63 63 13

MET + SRP 0 75 75 25

MET + SRP 66 25 41 2

MET + SRP 66 6 60 −4

MET + SRP 66 6 60 −4

MET + SRP 66 0 66 −6

MET + SRP 66 0 66 −6

MET 0 4 4 −4

MET 0 13 13 5

MET 0 19 19 11

MET 0 25 25 25

MET 0 25 25 25

MET 70 30 40 23

MET 70 19 51 48

MET 70 19 51 28

MET 70 13 57 51

MET 70 0 70 64

MET + SRP 20.9 10.1 sd 10.2 7.4 sd 10.7 0.8

MET + SRP 20.9 10.1 sd 10.2 7.4 sd 10.7 0.0

MET + SRP 20.9 10.1 sd 10.2 8.2 sd 10.7 0.4

MET + SRP 20.9 10.1 sd 10.2 8.2 sd 10.7 −0.3

MET + SRP 7.7 8.2 sd 2.5 3.6 sd 5.2 1.8

MET + SRP 7.7 8.2 sd 2.5 3.6 sd 5.2 −0.1

MET + SRP 7.7 8.2 sd 2.2 2.3 sd 5.5 1.6

MET + SRP 7.7 8.2 sd 2.2 2.3 sd 5.5 −0.1

TET + SRP 0 5 5 −6

(continued)

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Control


TETRACYCLINE






30 2 weeks PD >6 mm PLAC + SRP 73 23 50





30 2 weeks PD ≤4 mm PLAC 0 8 8





30 2 weeks PD >6 mm PLAC 73 56 17

30 10 weeks PD >6 mm PLAC 73 70 3

30 20 weeks PD >6 mm PLAC 73 50 23

30 30 weeks PD >6 mm PLAC 73 67 6

30 50 weeks PD >6 mm PLAC 73 67 6

31 12 months PD ≤3 mm SRP 49 67 18

31 12 months PD 4-6 mm SRP 39 29 10

31 12 months PD ≥7 mm SRP 12 4 8

32 3 months PD ≥5 mm PLAC + SRP 25.32 17.93 sd 14.74 12.35 sd 10.58

32 3 months PD ≥5 mm PLAC + SRP + SURG 19.92 13.58 sd 13.69 8.60 sd 6.23



* A negative value in the Change column indicates improvement.† A positive value in the Difference column favors test over control.

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Test


TETRACYCLINE

MET + SRP 7.7 8.2 sd 2.2 2.3 sd 5.5 −0.1

TET + SRP 0 44 44 11

TET + SRP 0 44 44 1

TET + SRP 0 71 71 21

TET + SRP 0 71 71 21

TET + SRP 67 33 34 −16

TET + SRP 67 6 61 −4

TET + SRP 67 6 61 −4

TET + SRP 67 0 67 −6

TET + SRP 67 0 67 −6

TET 0 0 0 −8

TET 0 28 28 20

TET 0 28 28 20

TET 0 28 28 28

TET 0 28 28 28

TET 58 42 16 −1

TET 58 7 51 48

TET 58 7 51 28

TET 58 0 58 52

TET 58 0 58 52

TET + SRP 43 62 19 1

TET + SRP 42 34 8 −2

TET + SRP 15 4 11 3

TET + SRP 20.12 21.90 sd 9.58 12.80 sd 10.54 −0.04

TET + SRP + SURG 13.08 12.30 sd 8.62 9.72 sd 4.46 −1.77

TET + SRP + SURG 13.08 12.30 sd 4.00 6.68 sd 9.08 −3.99

TET + SRP + SURG 13.08 12.30 sd 5.00 7.28 sd 8.08 −5.69

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7 years of disease progression in a treated and main-tained population.

Treatment of a bacterial infection whether in theoral cavity or elsewhere in the body can be achievedby multiple means. An infection of the hand may betreated by debridement, locally administered antisep-tics or antibiotics, or “soaking in hot salt solutions.”Alternatively, if the infection is severe enough, sys-temic antibiotics might be employed. In the situationwhere systemically administered antibiotics are notemployed, healing might have been more rapid ifsystemic antibiotics had been administered. How-ever, antibiotic administration might not be employedbecause other means could achieve the treatmentgoal at a lower cost and with fewer possible side effectsto the patient or society (in terms of antibiotic resis-tance). The same is true for periodontal infections.There may be instances where systemically adminis-tered antimicrobial agents are clearly warranted, aswell as situations in which other means can achievethe desired therapeutic outcome. As always, the clin-ician in concert with the patient must make the finaldecision. In any individual case, one must considernot only the benefits that might accrue from the useof the systemically administered antimicrobial agentsbut also the risks that may be involved. Adverse eventsrelated to the taking of an antimicrobial agent pre-sent potential hazards. Unfortunately, many of thestudies included in this review did not report adverseevents (Table 6). However, examination of Table 6suggests that adverse events were infrequent and usu-ally took the form of gastrointestinal upsets. A secondmajor concern is the development of antibiotic resis-tance of species within the subjects being treated,

as well as the possible emergence of new resis-tant species that might provide a threat to soci-ety. The magnitude of this hazard is not known,although the subgingival microbiota tends torevert to similar proportions of antibiotic resis-tant isolates 3 months post-therapy.86 Anotherconcern in the administration of antimicrobialagents is the cost of the agents and thewillingness of patients to comply with the pre-scribed therapy. Thus, the treatment of the indi-vidual subject must be based on that subject’sclinical status, the nature of the colonizingmicrobiota, and the possible risks associatedwith the prescribed treatment plan. The dataprovided in this review indicate that whena systemic antibiotic is employed it is likely tobe of benefit to the patient for the treatment ofhis/her periodontal infection.

Biological ImplicationsIt is not surprising that systemically adminis-tered antimicrobial agents may be helpful in the

treatment of periodontal infections. The infections arecaused by organisms living in biofilms at or below thegingival margin. The biofilms that adhere to the toothsurface appear to be substantially different in the natureof the colonizing species than species that form thebiofilm lining the periodontal pocket wall.87 There islegitimate concern that antibiotics are less effective incombating species growing in the glycocalyx that formsthe backbone of the biofilm than the same speciesgrowing in a planktonic (free living) state. It seemslikely that the efficacy of systemically administeredantibiotics described in the studies in this review may bedue to greater susceptibility of the species that colo-nize the biofilm attached to the epithelial cell surfaceof the periodontal pocket. These species include mem-bers of the “red complex” that is comprised of speciessuch as Porphyromonas gingivalis, Tannerella forsythen-sis (Bacteroides forsythus), and Treponema denticola.This group of organisms that is associated with, andmay cause periodontal disease, is quite susceptible toantimicrobial agents. Thus, susceptibility of many sub-gingival pathogens, their proximity to the gingivalcrevice fluid containing the antibiotic that emanatesfrom the pocket wall, and the likely absence of a thickglycocalyx protecting these organisms may be key tothe described efficacy of these agents.

REVIEWERS’ CONCLUSIONSWhile there are sufficient data to suggest that antibioticscan help in the treatment of chronic or aggressive peri-odontitis, the optimum method of employment has notbeen clearly defined. This review suggests that antimi-crobial agents may be useful additions in the treatmentof periodontal infections. What is not clear from this

176

Table 13.

Mean Attachment Level Change (mm) GroupedAccording to Antibiotic

Number Antibiotic of Studies Mean ± SD*

Amoxicillin + metronidazole 3 0.36 ± 0.29

Amoxicillin + clavulanic acid 3 0.35 ± 0.33

Clindamycin 1 1.10

Doxycycline 3 0.69 ± 0.57

Metronidazole 9 0.35 ± 0.44

Penicillin 1 0.24

Spiramycin 3 0.09 ± 0.28

Tetracycline 5 0.40 ± 0.26

* Standard deviation of all the studies.

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review, or any available data source, is which agent(s)should be used for which infection, what is the optimumdosage and duration of these agents, which subjectswould most benefit from systemic antibiotics, whenshould subjects receive antibiotics in relation to mechan-ical debridement, how long should we expect the admin-istration to provide a clinically useful outcome, and thenature of hazards such as antibiotic resistance orunwanted alteration of the oral microbiota as a result ofantibiotic administration. Clearly, more research is nec-essary to answer these questions to provide the perio-dontal patient with optimum care.

ACKNOWLEDGMENTSThe authors thank Susan Orlando, Director of LibraryServices, The Forsyth Institute, and Mr. Dan McCloskey,Librarian, The Forsyth Institute, for their help in per-forming the searches of the databases, assembling thereferences, and providing the full-text articles.

REFERENCES1. Fleiss JL. The statistical basis of meta-analysis. Stat

Methods Med Res 1993;2:121-45.2. Katerndahl DA, Cohen PA. Quantitatively reviewing the

literature: The application of meta-analysis. Fam PractRes J 1987;6(3):123-129.

3. Hedges L, Olkin I. Statistical Methods of Meta-AnalysisOrlando: Academic Press; 1985.

4. Rooney J, Wade WG, Sprague SV, Newcombe RG, AddyM. Adjunctive effects to non-surgical periodontal ther-apy of systemic metronidazole and amoxycillin aloneand combined. A placebo controlled study. J Clin Peri-odontol 2002;29:342-350.

5. Lopez NJ, Gamonal JA, Martinez B. Repeated metron-idazole and amoxicillin treatment of periodontitis. A follow-up study. J Periodontol 2000;71:79-89.

6. 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.

7. Winkel EG, Van Winkelhoff AJ, Timmerman MF, Van derVelden U, Van der Weijden GA. Amoxicillin plus metron-idazole in the treatment of adult periodontitis patients.A double-blind placebo-controlled study. J Clin Peri-odontol 2001;28:296-305.

8. Tinoco EMB, Beldi MI, Campedelli F, et al. Clinical andmicrobiological effects of adjunctive antibiotics in treat-ment of localized juvenile periodontitis. A controlled clin-ical trial. J Periodontol 1998;69:1355-1363.

9. Winkel EG, Van Winkelhoff AJ, Barendregt DS, Van derWeijden GA, Timmerman MF, Van der Velden U. Clini-cal and microbiological effects of initial periodontal ther-apy in conjunction with amoxicillin and clavulanic acidin patients with adult periodontitis. A randomised double-blind, placebo-controlled study. J Clin Periodontol 1999;26:461-468.

10. Magnusson I, Low SB, McArthur WP, et al. Treatment ofsubjects with refractory periodontal disease. J Clin Peri-odontol 1994;21:628-637.

11. Purucker P, Mertes H, Goodson JM, Bernimoulin J-P.Local versus systemic adjunctive antibiotic therapy in 28patients with generalized aggressive periodontitis. J Peri-odontol 2001;72:1241-1245.

12. Haffajee AD, Dibart S, Kent RL Jr, Socransky SS. Clin-ical and microbiological changes associated with the

use of 4 adjunctive systemically administered agents inthe treatment of periodontal infections. J Clin Periodon-tol 1995;22:618-627.

13. Sigusch B, Beier M, Klinger G, Pfister W, Glockmann E.A 2-step non-surgical procedure and systemic antibi-otics in the treatment of rapidly progressive periodonti-tis. J Periodontol 2001;72:275-283.

14. Ng VWK, Bissada NF. Clinical evaluation of systemicdoxycycline and ibuprofen administration as an adjunc-tive treatment for adult periodontitis. J Periodontol 1998;69:772-776.

15. Feres M, Haffajee AD, Goncalves C, et al. Systemic doxy-cycline administration in the treatment of periodontalinfections (I). Effect on the subgingival microbiota. J ClinPeriodontol 1999;26:775-783.

16. Yilmaz S, Kuru B, Noyan U, Kadir T, Acar O, Buget E.A clinical and microbiological evaluation of systemicand local metronidazole delivery in early onset peri-odontitis patients. J Marmara Univ Dent Fac 1996;2:500-509.

17. Noyan U, Yilmaz S, Kuru B, Kadir T, Acar O, Buget E.A clinical and microbiological evaluation of systemic andlocal metronidazole delivery in adult periodontitis patients.J Clin Periodontol 1997;24:158-165.

18. Lindhe J, Liljenberg B, Adielson B, Borjesson I. Use ofmetronidazole as a probe in the study of human peri-odontal disease. J Clin Periodontol 1983;10:100-112.

19. Walsh MM, Buchanan SA, Hoover CI, et al. Clinical andmicrobiologic effects of single-dose metronidazole orscaling and root planing in treatment of adult peri-odontitis. J Clin Periodontol 1986;13:151-157.

20. Loesche WJ, Giordano JR, Hujoel P, Schwarcz J, SmithBA. Metronidazole in periodontitis: Reduced need forsurgery. J Clin Periodontol 1992;19:103-112.

21. Loesche WJ, Schmidt E, Smith BA, Morrison EC, CaffesseR, Hujoel PP. Effects of metronidazole on periodontaltreatment needs. J Periodontol 1991;62:247-257.

22. Clark DC, Shenker S, Stulginski P, Schwartz S. Effec-tiveness of routine periodontal treatment with andwithout adjunctive metronidazole therapy in a sampleof mentally retarded adolescents. J Periodontol 1983;54:658-665.

23. Soder B, Nedlich U, Jin LJ. Longitudinal effect ofnon-surgical treatment and systemic metronidazole for1 week in smokers and non-smokers with refractoryperiodontitis: A 5-year study. J Periodontol 1999;70:761-771.

24. 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.

25. Palmer RM, Matthews JP, Wilson RF. Non-surgical peri-odontal treatment with and without adjunctive metro-nidazole in smokers and non-smokers. J Clin Periodon-tol 1999;26:158-163.

26. Kunihira DM, Caine FA, Palcanis KG, Best AM, RanneyRR. A clinical trial of phenoxymethyl pencillin for adjunc-tive treatment of juvenile periodontitis. J Periodontol 1985;56:352-358.

27. Al-Joburi W, Quee TC, Lautar C, et al. Effects of adjunc-tive treatment of periodontitis with tetracycline and spi-ramycin. J Periodontol 1989;60:533-539.

28. Bain CA, Beagrie GS, Bourgoin J, et al. The effects ofspiramycin and/or scaling on advanced periodontitis inhumans. J Can Dent Assoc 1994;60:209-217.

29. Hellden LB, Listgarten MA, Lindhe, J. The effect of tetra-cycline and/or scaling on human periodontal disease.J Clin Periodontol 1979;6:222-230.

177

8006.qxd 12/30/03 3:21 PM Page 177


30. Lindhe J, Liljenberg B, Adielson B. Effect of long-termtetracycline therapy on human periodontal disease. J ClinPeriodontol 1983;10:590-601.

31. Ramberg P, Rosling B, Serino G, Hellstrom M-K,Socransky SS, Lindhe J. The long-term effect of systemictetracycline used as an adjunct to non-surgical treat-ment of advanced periodontitis. J Clin Periodontol 2001;28:446-452.

32. Palmer RM, Watts TLP, Wilson RF. A double-blind trialof tetracycline in the management of early onset peri-odontitis. J Clin Periodontol 1996;23:670-674.

33. Fanas SH, Drucker DB, Hull PS. Amoxycillin with clavu-lanic acid and tetracycline in periodontal therapy. J Dent1991;19:97-99.

34. Aitken S, Birek P, Kulkarni GV, Lee WL, McCulloch CA.Serial doxycycline and metronidazole in prevention ofrecurrent periodontitis in high-risk patients. J Periodon-tol 1992;63:87-92.

35. Asikainen S, Jousimies-Somer H, Kanervo A, Saxén L.The immediate efficacy of adjunctive doxycycline intreatment of localized juvenile periodontitis. Arch OralBiol 1990;35(Suppl.):231S-234S.

36. Atilla G, Balcan M, Biçakçi N, Kazandi A. The effect ofnon-surgical periodontal and adjunctive minocycline-HCltreatments on the activity of salivary proteases. J Peri-odontol 1996;67:1-6.

37. Colombo AP, Haffajee AD, Dewhirst FE, et al. Clinicaland microbiological features of refractory periodontitissubjects. J Clin Periodontol 1998;25:169-180.

38. Colombo AP, Sakellari D, Haffajee AD, Tanner A, CuginiMA, Socransky SS. Serum antibodies reacting with sub-gingival species in refractory periodontitis subjects. J ClinPeriodontol 1998;25:596-604.

39. de Graaff J, Van Winkelhoff AJ, Goene RJ. The role ofActinobacillus actinomycetemcomitans in periodontaldisease. Infection 1989;17:269-271.

40. Demolon IA, Persson GR, Ammons WF, Johnson RH.Effects of antibiotic treatment on clinical conditions withguided tissue regeneration: One-year results. J Periodontol1994;65:713-717.

41. Eisenberg L, Suchow R, Coles RS, Deasy MJ. The effectsof metronidazole administration on clinical and microbi-ologic parameters of periodontal disease. Clin Prev Dent1991;13:28-34.

42. Flemmig TF, Milian E, Karch H, Klaiber B. Differentialclinical outcome after systemic metronidazole and amox-icillin in patients harboring Actinobacillus actinomy-cetemcomitans and/or Porphyromonas gingivalis. J ClinPeriodontol 1998;25:380-387.

43. Freeman E, Ellen RP, Thompson G, Weinberg SE, Song M,Lazarus RH. Gingival crevicular fluid concentration andside effects of minocycline: A comparison of two dose regi-mens. J Periodontol 1992;63:13-18.

44. Groselj D, Grabec I. Statistical modeling of tooth mobilityafter treating adult periodontitis. Clin Oral Investig 2002;6:28-38.

45. Grossi SG, Skrepcinski FB, DeCaro T, et al. Treatment ofperiodontal disease in diabetics reduces glycated hemo-globin. J Periodontol 1997;68:713-719.

46. Herrera D, Roldán S, O’Connor A, Sanz M. The periodontalabscess (II). Short-term clinical and microbiological effi-cacy of 2 systemic antibiotic regimes. J Clin Periodontol2000;27:395-404.

47. Joyston-Bechal S, Smales FC, Duckworth R. A follow-up study 3 years after metronidazole therapy for chronicperiodontal disease. J Clin Periodontol 1986;13:944-949.

48. Kulkarni GV, Lee WK, Aitken S, Birek P, McCulloch CA.A randomized, placebo-controlled trial of doxycycline:

Effect on the microflora of recurrent periodontitis lesionsin high risk patients. J Periodontol 1991;62:197-202.

49. Lee W, Aitken S, Kulkarni G, et al. Collagenase activity inrecurrent periodontitis: Relationship to disease progressionand doxycycline therapy. J Periodont Res 1991;26:479-485.

50. Listgarten MA, Lindhe J, Hellden L. Effect of tetracyclineand/or scaling on human periodontal disease. Clinical,microbiological, and histological observations. J Clin Peri-odontol 1978;5:246-271.

51. Loesche WJ, Giordano J, Hujoel PP. The utility of theBANA test for monitoring anaerobic infections due tospirochetes (Treponema denticola) in periodontal dis-ease. J Dent Res 1990;69:1696-1702.

52. Loesche WJ, Schmidt E, Smith BA, Caffesse R, Stoll J.Metranidazole therapy for periodontitis. J Periodontal Res1987;22:224-226.

53. López NJ, Gamonal JA. Effects of MET plus amoxicillinin progressive untreated adult periodontitis: Results of asingle 1-week course after 2 and 4 months. J Periodontol1998;69:1291-1298.

54. Lundström Å, Johansson L-Å, Hamp S-E. Effect of com-bined systemic antimicrobial therapy and mechanicalplaque control in patients with recurrent periodontal dis-ease. J Clin Periodontol 1984;11:321-330.

55. McCulloch CAG, Birek P, Overall C, Aitken S, Lee W,Kulkarni G. Randomized controlled trial of doxycycline inprevention of recurrent periodontitis in high-risk patients:Antimicrobial activity and collagenase inhibition. J ClinPeriodontol 1990;17:616-622.

56. Quee TC, Al-Joburi W, Lautar-Lemay C, et al. Compar-ison of spiramycin and tetracycline used adjunctively inthe treatment of advanced chronic periodontitis. J Antimi-crob Chemother 1988;22(Suppl. B):171-177.

57. Quee TC, Chan ECS, Clark C, et al. The role of adjunc-tive rodogyl therapy in the treatment of advancedperiodontal disease. A longitudinal clinical and micro-biological study. J Periodontol 1987;58:594-601.

58. Smith SR, Foyle DM, Daniels J, et al. A double-blindplacebo-controlled trial of azithromycin as an adjunct tonon-surgical treatment of periodontitis in adults: Clinicalresults. J Clin Periodontol 2002;29:54-61.

59. Söder P-Ö, Frithiof L, Wikner S, et al. The effect of sys-temic metronidazole after non-surgical treatment inmoderate and advanced periodontitis in young adults.J Periodontol 1990;61:281-288.

60. Trieger N, Mark L, McKitrick J, Fiorillo J, Van Horn K, MotylM. Clindomycin v. tetracycline in the surgical treatment ofadvanced periodontitis: A double blind study with applic-ability for implant salvage. Int J Oral Implant 1991;7:31-38.

61. Watts T, Palmer R, Floyd P. Metronidazole: A double-blind trial in untreated human periodontal disease. J ClinPeriodontol 1986;13:939-943.

62. Feres M, Haffajee AD, Allard K, Som S, Socransky SS.Change in subgingival microbial profiles in adult periodontitissubjects receiving either systemically-administered amox-icillin or metronidazole. J Clin Periodontol 2001;28:597-609.

63. Haffajee AD, Dibart S, Kent RL Jr, Socransky SS. Fac-tors associated with different responses to periodontaltherapy. J Clin Periodontol 1995;22:628-636.

64. Jenkins WM, MacFarlane TW, Gilmour WH, Ramsay I,MacKenzie D. Systemic metronidazole in the treatmentof periodontitis. J Clin Periodontol 1989;16:443-450.

65. Lindhe J, Liljenberg B. Treatment of localized juvenile peri-odontitis. Results after 5 years. J Clin Periodontol 1984;11:399-410.

66. Mahmood MM, Dolby AE. The value of systemicallyadministered metronidazole in the modified Widman flapprocedure. J Periodontol 1987;58:147-152.

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67. Mandell RL, Tripodi LS, Savitt E, Goodson JM, SocranskySS. The effect of treatment on Actinobacillus actino-mycetemcomitans in localized juvenile periodontitis. J Peri-odontol 1986;57:94-99.

68. Matisko MW, Bissada NF. Short-term sequential adminis-tration of amoxicillin/clavulanate potassium and doxycy-cline in the treatment of recurrent/progressive periodontitis.J Periodontol 1993;64:553-558.

69. Serino G, Rosling B, Ramberg P, Hellström M-K, SocranskySS, Lindhe J. The effect of systemic antibiotics in the treat-ment of patients with recurrent periodontitis. J Clin Peri-odontol 2001;28:411-418.

70. Slots J, Rosling BG. Suppression of the periodontopathicmicroflora in localized juvenile periodontitis by systemictetracycline. J Clin Periodontol 1983;10:465-486.

71. Winkel EG, Van Winkelhoff AJ, Timmerman MF, VangstedT, Van der Velden U. Effects of MET in patients with “refrac-tory” periodontitis associated with Bacteroides forsythus.J Clin Periodontol 1997;24:573-579.

72. Winkel EG, Van Winkelhoff AJ, Van der Velden U. Addi-tional clinical and microbiological effects of amoxicillinand metronidazole after initial periodontal therapy. J ClinPeriodontol 1998;25:857-864.

73. Mabry TW, Yukna RA, Sepe WW. Freeze-dried bone allo-graphs combined with tetracycline in the treatment ofjuvenile periodontitis. J Periodontol 1985;56:74-81.

74. Minabe M, Kodama T, Kogou T, et al. Clinical significanceof antibiotic therapy in guided tissue regeneration with aresorbable membrane. Periodontal Clin Investig 2001;23:20-30.

75. Mowzari H, Matian F, Slots J. Periodontal pathogens onpolytetrafluoroethylene membrane for guided tissue regen-eration inhibit healing. J Clin Periodontol 1995;22:469-474.

76. Sculean A, Blaes A, Arweiler N, Reich E, Donos N, BrecxM. The effect of post-surgical antibiotics on the healingof infrabony defects following treatment with enamelmatrix proteins. J Periodontol 2001;72:190-194.

77. Zucchelli G, Sforza NM, Clauser C, Cesari C, De Sanctis M.Topical and systemic antimicrobial therapy in guided tis-sue regeneration therapy. J Periodontol 1999;70:239-247.

78. Haffajee AD, Socransky SS, Dibart S, Kent RL Jr.Response to periodontal therapy in patients with highor low levels of P. gingivalis, P. intermedia, P. nigrescensand B. forsythus. J Clin Periodontol 1996;23:336-345.

79. Loesche WJ, Giordano JR. Metronidazole in periodonti-tis V: Debridement should precede medication. Com-pendium 1994;15:1198-1217.

80. Loesche WJ, Syed SA, Morrison EC, Kerry GA, HigginsT, Stoll J. Metronidazole in periodontitis. I. Clinical andbacteriological results after 15 to 30 weeks. J Periodontol1984;55:325-335.

81. Elter JR, Lawrence HP, Offenbacher S, Beck JD. Meta-analysis of the effect of systemic metronidazole as anadjunct to scaling and root planing for adult periodon-titis. J Periodontal Res 1997;32:487-496.

82. Hayes C, Antczak-Bouckoms A, Burdick E. Quality assess-ment and meta-analysis of systemic tetracycline usein chronic adult periodontitis. J. Clin Periodontol 1992;19:164-168.

83. Walker CB, Gordon JM, Magnusson I, Clark WB. A rolefor antibiotics in the treatment of periodontitis. J Peri-odontol 1993:64;772-781.

84. Slots J, Ting M. Systemic antibiotics in the treat-ment of periodontal disease. Periodontol 2000 2002;28:106-176.

85. Rosling B, Serino G, Hellstrom M-K, Socransky SS, LindheJ. Longitudinal periodontal tissue alterations during sup-portive therapy. Findings from subjects with normal and

high susceptibility to periodontal disease. J Clin Periodon-tol 2001;28:241-249.

86. Feres M, Haffajee AD, Allard K, Goodson JM, SocranskySS. Antibiotic resistance of subgingival species dur-ing and after antibiotic therapy. J Clin Periodontol 2002;28:724-735.

87. Socransky SS, Haffajee AD. Dental biofilms: Difficulttherapeutic targets. Periodontol 2000 2002;28:12-55.

Correspondence: Dr. Anne Haffajee, Department of Periodon-tology, The Forsyth Institute, 140 The Fenway, Boston, MA02115. Fax: 617/262-4021; e-mail: [email protected].

Accepted for publication August 9, 2003.

APPENDIX ACONSENSUS REPORT

Members of the Section evaluated the review titled “Sys-temic Anti-Infective Periodontal Therapy. A SystematicReview” by Anne D. Haffajee, Sigmund S. Socransky,and John C. Gunsolley. The focused PICO questionaddressed by this evidence-based systematic reviewis: “In patients with periodontitis, what is the effect ofsystemically administered antibiotics as compared tocontrols on clinical measures of attachment level.”

IntroductionAntibiotics have been used in the treatment of peri-odontal diseases for more than 50 years. This evidence-based review represents a comprehensive search andevaluation of studies conducted from 1966 through May2002. The members of this Section discussed andweighed the following points from the review: 1) Theanalysis focused on patients with chronic or aggressiveperiodontitis. 2) Interventions in the analysis includedsingle and combination antibiotics, systemically deliveredand used adjunctively or as monotherapies. 3) Studieswere heterogeneous with respect to controls and includedno treatment, placebo, scaling and root planing (SRP)(with and without placebo) and/or surgical flap proce-dures. 4) The selected outcome for the analysis was themeasure, clinical attachment level (CAL). There wereinsufficient data on microbial and patient-centered out-comes to be included in the analysis.

1. Does the Section agree that the evidence-basedsystematic review is complete and accurate?With regard to inclusion/exclusion criteria: The sectionagreed that the review was complete and accurate interms of the evaluation of the clinical effect of systemicantibiotics on AL. However, the Section acknowledgedthat there was insufficient evidence to determine effectson microbiological and patient-centered outcomes.

Issues were raised with regard to inclusion/exclusioncriteria, populations, comparison with control groups,heterogeneity of interventions, and outcome measures.

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The analysis was limited a priori to randomized con-trolled clinical trials (RCT) to capture level I or level IIevidence. This strategy yielded a suitable number ofcitations for inclusion and, therefore, exclusion of caseand cohort studies was appropriate.

It was not the focus of this review to evaluate thosestudies utilizing systemic antibiotics in conjunction withperiodontal regenerative therapy.

The analysis was performed with the realization thatdetails regarding mechanical therapy in many of thestudies were unknown.

Conclusions and interpretation of results are basedon measurement of AL in studies with a time frame of6 months duration. The time frame of 6 months yieldedthe greatest amount of comparable data between stud-ies.

2. Has any new information been generated ordiscovered since the evidence-based searchcut-off date?Although data from published abstracts and directlyfrom investigators are available, there was a consen-sus that only peer-reviewed published papers should beincluded in the database. It should be noted, however,that Herrera et al. have recently published a systematicreview on the effect of systemic antimicrobials as anadjunct to SRP in periodontitis patients. Their resultsconfirm those of the present review.1

3. Does the Section agree with the interpretationsand conclusions of the reviewers?The Section members agree with the conclusions, inter-pretations, and final comments as presented by thereviewers. The 22 studies included in the meta-analysiswere sufficient and of adequate quality to determinethe short-term (6-month) effect of systemic antibioticson AL. The data indicate that patients with chronic oraggressive periodontitis demonstrate improved AL over6 months when treated with systemic antibiotics ascompared to controls. Further, aggressive periodontitispatients show greater clinical improvements than thosewith chronic periodontitis.

4. What further research needs to be done relative tothe focused questions of the evidence-based review?Conclusions of this review support the use of adjunc-tive systemic antibiotics in the treatment of chronic andaggressive periodontitis. However, further research isnecessary to identify specific best-practices guiding clin-icians who decide to integrate systemic antibiotics intothe ongoing management of periodontitis. The Sectionidentified the following unanswered research questions:

1. Given the clinical recognition that most peri-odontitis patients respond well to therapies that do notinclude systemic antibiotics, which patients wouldreceive the greatest benefit from such agents?

2. For patients who would benefit from adjunctivesystemic antibiotics, which antibiotic(s) would be mostclinically efficacious and cost-effective? What dosageand duration would be most appropriate?

3. What concomitant therapy should be employedand what is the timing of the adjunctive use of systemicantibiotic therapy?

4. Will diagnostic microbiological testing be of benefitin selecting systemic antibiotics? There is a need todevelop laboratory methods to identify which systemicantibiotics would be most appropriate for patientsrequiring these drugs for the treatment of periodonti-tis. Utilizing molecular techniques, time and cost-effec-tive laboratory tests need to be developed to defineantibiotic sensitivity.

5. What are the effects of systemic antibiotics onpatient-centered outcomes?

6. What are the effects of systemic antibiotics on rel-evant (i.e., clinical, microbiological, and patient-centered)outcomes beyond 6 months?

A second set of issues concerning future studies,their design, and methods were raised: Randomizeddouble-blinded placebo controlled clinical trials of ade-quate size and statistical power should be performed.Drug dosage, timing with intervention of therapy, andduration should be examined. Description of studypopulations including examination of different typesof periodontitis, subgingival microbial profiles, med-ical profile, and life-style habits of individual patientsshould be included.

The Section acknowledges that the quality andpower of the data have improved over time due tochanges in experimental design and the reporting ofstudies: There were limited data available concerningprevious patient history of antibiotic use. Studies didnot measure or evaluate antibiotic sensitivity and/orresistance. Indeed, this may result in underestimatingthe effect of the antibiotics.

New antibiotics need to be tested with the evidence-based design in order to evaluate application to peri-odontal therapies.

5. How can the information from the evidence-based review be applied to patient management?The purpose of this systematic review was not to pro-vide guidelines for the use of systemically adminis-tered antibiotics in clinical practice. Rather, this reviewanswered a focused PICO question as to whether theadjunctive use of systemic antibiotics provided anadded benefit to one primary clinical outcome, AL.The results indicated that the use of systemic antibi-otics provided an added gain in AL compared withtherapies not employing antibiotics. The reader mayask whether antibiotics should be used to treat all casesof periodontitis. Clearly, the answer to this question isno. First, from a methodological standpoint only one

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outcome variable was evaluated in the systematicreview. Periodontal treatment planning involves a num-ber of patient- and disease-specific variables. AlthoughAL is the most commonly employed outcome variablein periodontal clinical trials, it does not cover all aspectsof disease assessment.

Secondly, there are a number of pertinent issues notdirectly addressed in this review that relate to the useof antibiotics in periodontal treatment. These includeidentification of patients who would most benefit fromantibiotic therapy; the optimal antibiotic; and determi-nation of optimal dosage, duration, and timing of thistherapy. At the present time, the data are insufficientto provide detailed protocols for antibiotic treatment ofvarious types of periodontitis in individual patients.

Thirdly, it must be recognized that administration ofsystemic antibiotics confers potential risks that arelisted below. Despite these caveats, the following arethe findings of this focused review:

A. In patients with chronic or aggressive periodon-titis, clinicians can expect enhanced improvement inAL for at least 6 months with adjunctive use of sys-temic antibiotics.

Level of Evidence:2 Strong.Rationale: The strength of this evidence is based

on multiple (22) properly designed randomized con-trolled trials.

B. With adjunctive use of systemic antibiotics therewas a greater improvement in AL in patients withaggressive periodontitis than in those with chronicperiodontitis.

Level of Evidence: Strong.Rationale: The strength of this evidence is based


C. With adjunctive use of systemic antibiotics, theclinician can expect a greater improvement in ALregardless of baseline probing depth.

Level of Evidence: Strong.Rationale: The strength of this evidence is based


D. With adjunctive use of systemic antibiotics, theclinician can expect greater improvement in AL in siteswith ≥6 mm probing depth than in shallower sites.

Level of Evidence: Moderate.Rationale: A “moderate” level of evidence was

assigned due to the small number of studies that ana-lyzed data in different initial probing depth categoriesand magnitude of improvement in AL.

E. When examining the effects of individual or com-binations of antibiotics, it was found that there were sta-tistically significant improvements in AL for tetracy-cline and metronidazole. Initial data of the combinationof amoxicillin plus metronidazole showed positive clin-ical effects.

Level of Evidence: Moderate.Rationale: A “moderate” level of evidence was

assigned because of the small number of studies eval-uating the individual antibiotic regimens.

F. There is incomplete evidence to support specificrecommendations regarding optimal dosage and dura-tion of systemic antibiotics.

Level of Evidence: Incomplete.Rationale: “Incomplete” was assigned because the

regimens were so diverse that the number of studiesfor a specific antibiotic was not sufficient to performmeta-analysis.

G. There is insufficient evidence to support the useof systemic antibiotics as a monotherapy in periodon-titis patients.

Level of Evidence: Insufficient.Rationale: “Insufficient” was assigned because of

the lack of studies to allow statistical analysis.

Adverse EffectsIt was outside the scope of this meta-analysis to reviewthe adverse events occurring with the use of systemicantibiotics. Such risks (e.g., allergy, adverse gastroin-testinal effects, superinfections, and overgrowth ofresistant bacterial strains, etc.) are documented else-where. The clinician is responsible for being informedregarding adverse effects, contraindications, and poten-tial drug interactions for specific antibiotics.

CONCLUDING REMARKSThe question asked in the evidence-based review waswhether systemically administered antibiotics can im-prove AL. The answer to this question appears to be yes.

This review found that systemically administeredantibiotics can be of benefit when added to other formsof periodontal therapy including SRP and/or periodon-tal surgery in patients with periodontitis. The magni-tude of the added benefit, in many cases, was doublethat achieved by mechanical forms of therapy alone.However, given that there are risks involved in the useof antimicrobial agents, the clinician must carefullyassess the risk/benefit ratio on a case-by-case basis.

REFERENCES1. Herrera D, Sanz M, Jepsen S, Needleman I, Roldán S. A

systematic review on the effect of systemic antimicrobialsas an adjunct to scaling and root planing in periodontitispatients. J Clin Periodontol 2002;29(Suppl. 3):136-159.

2. Newman MG, Caton J, Gunsolley JC. The use of the evi-dence-based approach in a periodontal therapy contem-porary science workshop. Ann Periodontol 2003;8:1-11.

SECTION MEMBERSGary Armitage, Group Leader Ira LamsterJoan Otomo-Corgel, Chair Theresa MaddenAnne D. Haffajee, Reviewer Robert O’NealSigmund S. Socransky, Reviewer David PaquetteGeorgia Johnson Jorgen Slots

Clay Walker

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systemic anti-infective periodontal therapy. a systematic ... · systemic anti-infective therapy...

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