Adjunctive benefits of systemic amoxicillin and metronidazole in non ...

Adjunctive benefits of systemicamoxicillin and metronidazole innon-surgical treatment ofgeneralized aggressiveperiodontitis: a randomizedplacebo-controlled clinical trialGuerrero A, Griffiths GS, Nibali L, Suvan J, Moles DR, Laurell L, Tonetti MS.Adjunctive benefits of systemic amoxicillin and metronidazole in non-surgicaltreatment of generalized aggressive periodontitis: a randomized placebo controlledclinical trial. J Clin Periodontol 2005; 32: 1096–1107. doi: 10.1111/j.1600-051X.2005.00814.x. r Blackwell Munksgaard 2005.

AbstractBackground: The objective of this study was to assess the adjunctive clinical effectof the administration of systemic amoxicillin and metronidazole in the non-surgicaltreatment of generalized aggressive periodontitis (GAP).

Methods: Forty-one systemically healthy subjects with GAP were included in this6-month double-blind, placebo-controlled, randomized clinical trial. Patients receiveda course of full-mouth non-surgical periodontal treatment delivered over a 24 h periodusing machine-driven and hand instruments. Test subjects received an adjunctivecourse of systemic antibiotic consisting of 500 mg amoxicillin and 500 mgmetronidazole three times a day for 7 days. Clinical parameters were collected atbaseline, and at 2 and 6 months post-treatment.

Results: In both the test and the placebo groups, all clinical parameters improved at2 and 6 months. In deep pockets (X7 mm), the test treatment resulted in an additional1.4 mm (95% confidence interval 0.8, 2.0 mm) in full-mouth probing pocket depth(PPD) reduction and 1 mm (0.7, 1.3 mm) of life cumulative attachment loss (LCAL)gain at 6 months. In moderate pockets (4–6 mm), the adjunctive benefit was smaller inmagnitude: PPD reduction was 0.4 mm (0.1, 0.7 mm) and LCAL gain was 0.5 mm (0.2,0.8 mm). In addition, the 6-month data showed LCAL gains X2 mm at 25% of sites intest patients compared with 16% in placebo (p 5 0.028). Similarly, PPD reductions of2 mm or more were observed in 30% of sites in test and 21% of sites in placebopatients. Seventy-four percent of pockets with PPD X5 mm at baseline were 4 mmor shallower at 6 months in the test group. This compared with 54% in the placebogroup (p 5 0.008). Disease progression at 6 months was observed at 1.5% of test and3.3% of sites in test and placebo, respectively (p 5 0.072).

Conclusions: These data indicate that a 7-day adjunctive course of systemicmetronidazole and amoxicillin significantly improved the short-term clinical outcomesof full-mouth non-surgical periodontal debridement in subjects with GAP.

Key words: antibiotics; generalized aggressiveperiodontitis; human; randomized-controlledclinical trial; treatment

Accepted for publication 1 June 2005

Adrian Guerrero1,2, Gareth S.Griffiths1, Luigi Nibali1, Jean Suvan1,David R. Moles1, Lars Laurell1

and Maurizio S. Tonetti1

1Department of Periodontology and Eastman

Clinical Investigation Centre, Eastman Dental

Institute and Hospital, University College

London, London, UK; 2Private Periodontal

Practice, Malaga, Spain

1096

J Clin Periodontol 2005; 32: 1096–1107 doi: 10.1111/j.1600-051X.2005.00814.x Copyright r Blackwell Munksgaard 2005

Generalized aggressive periodontitis(GAP) affects a minority of periodontalpatients but is highly significant becauseit is characterized by severe destructionof the supporting apparatus of the teeth,which may lead to edentulism early inlife. Because of its relatively rare occur-rence, few studies have evaluated how totreat this condition. The current notion isthat, as with most forms of periodontitis,the first step in the treatment of GAP is acause-related treatment phase aimed atthe reduction and/or elimination of thepathogenic microflora.

In recent years, two approaches havebeen introduced to improve the clinicaloutcomes of cause-related periodontaltherapy in chronic periodontitis patients:the use of adjunctive antibiotics, andperforming debridement within a 24 hperiod, the so-called ‘‘full-mouth disin-fection’’ approach (Quirynen et al. 1995).

The adjunctive use of systemic anti-biotics is supported by evidence pub-lished in systematic reviews of trialsassessing the benefit of systemic anti-biotics in cases with advanced perio-dontitis (Herrera et al. 2002, Haffajeeet al. 2003). Among the possible regi-mens, the combination of amoxicillinand metronidazole has gained increasingpopularity because of its wide spectrumof activity and effectiveness in terms ofsuppression of Actinobacillus actinomy-cetemcomitans (Van Winkelhoff et al.1989), possibly because of a synergisticeffect of the combination of amoxicillinand metronidazole against A. actinomy-cetemcomitans that has been demon-strated in vitro (Pavicic et al. 1991,1994a, b). In addition, chronic perio-dontitis patients harbouring subgingivalPorphyromonas gingivalis benefit sig-nificantly from the combined therapy(Winkel et al. 2001). Randomized-con-trolled clinical trials have reported clin-ical and microbiological improvementsin chronic periodontitis patients treatedwith these two antibiotics (Berglundhet al. 1998, Flemmig et al. 1998, Winkelet al. 2001, Rooney et al. 2002). Further-more, some clinical studies havereported good long-term clinical out-comes in patients with ‘‘severe diseasewhich was associated with A. actinomy-cetemcomitans’’ (Van Winkelhoff et al.1992, Pavicic et al. 1994a, Winkel et al.1998) and in aggressive periodontitis(Buchmann et al. 2002) patients whenperiodontal treatment was completedwith adjunctive use of amoxicillin andmetronidazole. However, because of thelack of a control group in these studies,

the benefits achieved could not be con-firmed as attributable to the adjunctiveantibiotic.

Recent investigations, performed inchronic periodontitis patients, have indi-cated that full-mouth scaling and rootplaning within 24 h (FSR) results indifferent degrees of clinical and micro-biological additional benefits (Quirynenet al. 1995, Bollen et al. 1996, Vande-kerckhove et al. 1996, Mongardini et al.1999, Apatzidou & Kinane 2004). Thebenefits of this approach have not beensystematically evaluated in aggressiveperiodontitis patients but initial data inchronic periodontitis patients suggestthat the full-mouth scaling within 24 hmay perform as well as the conven-tional treatment (Apatzidou & Kinane2004, Kinane 2005, Koshy et al. 2005,Wennstrom et al. 2005). In addition,some potential benefits, such as theapplication of a better understanding ofthe infectious process, a reduced num-ber of treatment sessions for patients, amore efficient use of treatment time anda reduced cost of therapy, may all be infavour of the FSR (Greenstein 2002).

The aim of this double-blind rando-mized placebo-controlled study was totest the null hypothesis of ‘‘no differ-ence in treatment effect of adjunctiveuse of systemic amoxicillin plus metro-nidazole during full-mouth non-surgicalcause-related periodontal treatment(FSR) performed within 24 h comparedwith FSR alone, in patients with GAPpatients at 2 and 6 months after thecompletion of active treatment.

Material and Methods

Experimental design

This study was a randomized placebo-controlled, parallel-design, double-blindclinical trial with 6-month follow-up.Ethical approval was obtained from theEastman Dental Institute UniversityCollege London Hospitals joint Re-search and Ethics Committee, and thestudy was conducted according to theprinciples outlined in the Declaration ofHelsinki on experimentation involvinghuman subjects.

Population screening

Potential subjects eligible for the studywere identified from the populationreferred to the periodontal clinic of theEastman Dental Hospital, London. Acomplete periodontal examination was

performed including a full medical anddental history, an intra-oral examinationand a full-mouth periodontal probing.A radiographic examination was under-taken using either periapicals or apantomogram. A periodontal diagnosiswas made, and subjects who fulfilled thestudy inclusion/exclusion criteria wereprovided with a written informationsheet, related to the study protocol, andthey were invited to participate in thestudy.

The study included subjects with (i)GAP (according to the criteria of the1999 international classification (Armi-tage 1999); (ii) at least 20 teeth present;(iii) good general health and (iv) agebetween 16 and 35 when first diagnosedwith aggressive periodontal disease.Subjects were excluded from the studyif they: (i) were considered to have adiagnosis of chronic periodontitis(according to the criteria of the 1999international classification (Armitage1999); (ii) were pregnant or lactatingfemales; (iii) were females of child-bearing age not using a standardaccepted method of birth control; (iv)required antibiotic pre-medication forthe performance of periodontal exami-nation and treatment; (v) suffered fromany other systemic diseases (cardiovas-cular, pulmonary, liver, cerebral, dis-eases or diabetes); (vi) had receivedantibiotic treatment in the previous 3months; (vii) were taking long-termanti-inflammatory drugs; (viii) hadreceived a course of periodontal treat-ment within the last 6 months; (ix) wereallergic to penicillin or metronidazole;and (x) were not able to provide consentto participate in the study, or they didnot accept the proposed treatment plan.Informed consent was obtained from allthe subjects to be entered in the study.

Pre-treatment

All the subjects went through motiva-tion sessions during which oral hygieneinstructions were given. The purpose ofthese sessions was to ensure that thesubjects could maintain a proper level oforal hygiene before starting active treat-ment, and this was repeated until sub-jects showed the ability to maintaingood plaque control as evidenced bypre-treatment plaque scores o20%.During these sessions, a case presenta-tion was given to the subject related tothe specific features of his/her disease,and a supragingival debridement wasperformed.

Treatment of generalized aggressive periodontitis 1097

Sample size calculation

The sample size calculation determinedthat 17 subjects per treatment arm wouldprovide 80% power to detect a truedifference of 1.0 mm between test andplacebo using probing pocket depth(PPD) reduction in pockets X7 mm asthe primary outcome variable, assumingthat the common standard deviation is1.0 mm. Accordingly, a sample of 21subjects per arm (42 in total) were to berecruited to compensate for possibledrop-out during the study period.

Randomization and allocation

concealment

Subject numbers were assigned inascending order at the enrolment visit.Subjects were randomly assigned by acomputer-generated table to receive oneof the two treatments. A balanced randompermuted block approach (4-unit blocksize) was used to prepare the randomiza-tion tables in order to avoid unequalbalance between the two treatments.Restricted randomization (minimization)took place, stratifying for smoking habits(yes or no) and number of initial pocketsX5 mm (o50, 50–80, 480).

The randomization table was sent tothe University College London (UCL)pharmacy, which prepared the medica-tion for 50 subjects (25 tests and 25controls). Fifty plastic bags containingtwo bottles each (amoxicillin, metroni-dazole or placebo tablets) were sent backto the study coordinator, who was theonly person who had access to them.Consequently, the study coordinatorcompleted the treatment assignmentand matched the code of the plastic bagwith the subject number. The researchnurse provided the subject with the plas-tic bag containing the two bottles. Therandomization code was not broken untilall data had been collected and analysed.Thus, the treatment group was concealedto the patient, the clinical examiner, thetherapist and the statistician.

Clinical parameters

Clinical parameters were assessed usinga UNC-15 periodontal probe by thecalibrated examiner at six sites/toothexcluding third molars. Full-mouth pla-que score (FMPS) was recorded byassigning a binary score to each surface(1 for plaque present, 0 for absent) andcalculating the percentage of total toothsurfaces that revealed the presence of

plaque detected by the use of a perio-dontal probe as modified by Tonettiet al. (2002). Similarly, a full-mouthpercentage bleeding score (FMBS) wascalculated after assessing dichoto-mously the presence of bleeding onprobing from the bottom of the pocketwhen probing with a manual probe witha force of 0.3 N (Tonetti et al. 2002).Full-mouth PPD and recession of thegingival margin (REC) were recorded atthe same time, with measurementsrounded to the nearest millimetre. RECwas recorded as a positive value if thefree gingival margin (FGM) occurredapical to the cemeno–enamel junction(CEJ), whereas it was recoded as anegative value if it was coronal to theCEJ. In the latter case, the examiner re-inserted the probe angled 451 into thesite in order to detect the CEJ. If the CEJwas not detectable for anatomical or re-storative reasons, the examiner adoptedclinical landmarks that were noted in thecase report forms. Lifetime cumulativeattachment loss (LCAL) was calculatedas PPD plus REC.

Investigator calibration

A total of 10 non-study subjects withaggressive periodontitis were recruitedand used for the calibration exercise.The single designated examiner (L. N.)measured full-mouth PPD and REC ofthe gingival margin for all 10 subjects.On the same day (with a minimumof 15 min separation), the examinerrepeated the examination. Upon com-pletion of all measurements, the intra-examiner repeatability for LCALmeasurement was assessed. The exam-iner was judged to be reproducible afterfulfilling the pre-determined success cri-teria (the percentage of agreement within� 2 mm between repeated measure-

ments had to be at least 98%). Theexaminer showed 99.7% reproducibility.

Non-surgical periodontal therapy

Periodontal therapy was initiated within1 month of the baseline screening exam-ination. If for any reason, the initia-tion of the therapy was delayed, a newfull-mouth periodontal examination wasperformed.

A standard cycle of periodontal ther-apy consisting of oral hygiene instruc-tions, supra- and sub-gingival mecha-nical instrumentation of the root surface(scaling and root planing) was per-formed by a single experienced therapist

(A. G.) using a piezoelectric instrumentwith fine tips (EMS, Nyon, Switzerland)and hand instruments, as appropriate.Both groups received this treatment intwo long appointments during the sameday. Two quadrants were instrumentedin a morning session, followed by theother two quadrants in an afternoonsession. A 2 h session for each appoint-ment was planned. Local anaesthesiawas used as necessary. Test subjectsreceived an adjunctive course of sys-temic antibiotics consisting of 500 mg ofamoxicillin and 500 mg of metronida-zole three times a day for 7 days, whilecontrol subjects received placebo. Sub-jects were asked to take the first dose ofthe medication before mechanicalinstrumentation had started at the firsttreatment session. All subjects used a0.2% chlorhexidine rinse (supplied toimprove complicance) twice a day for 2weeks post–treatment, and relied onstandard oral hygiene methods asinstructed at the commencement of thestudy.

Post-treatment controls

The objectives of the post-treatmentappointments were to control and rein-force the oral hygiene habits of thesubject, to monitor the early healingevents, report on any adverse events oradditional medications taken. In addi-tion, the 1-week post-treatment visitserved as a compliance control, as sub-jects were asked to return any medica-tion not taken and/or the empty bottles.The number of pills not taken by thesubject was documented.

Re-assessment examinations

Re-assessment visits occurred at 2 and 6months after the completion of the treat-ment. During these appointments, theexaminer recorded any medical historychanges, and the clinical periodontalparameters recorded at the baseline visitwere repeated. At the end of theappointment, a session of supragingivaldebridement was performed as neces-sary. No attempt was made to re-instru-ment residual periodontal pockets.

Primary and secondary outcomemeasures

The primary outcome measure of thestudy was PPD reduction in sites withinitial PPD X7 mm. Secondary out-comes included differences between

1098 Guerrero et al.

groups for the (i) changes in mean full-mouth PPD and the changes in PPD andLCAL at different initial PPD cate-gories; (ii) changes in FMPS andFMBS; (iii) percentage of sites withPPD reduction or LCAL gain ofX2 mm; (iv) percentage of sites thatshowed LCAL loss X2 mm (diseaseprogression); (v) percentage of siteswith PPD changing from X5 to44 mm and the percentage of sites withPPD changing from X4 to 43 mm(need for re-treatment); (vi) descriptionand frequency of adverse events;and (vii) compliance with the systemicmedication.

Data management and statistical analysis

Data were entered into an Excel (Micro-soft office 2000) database and wereproofed for entry errors. The databasewas subsequently locked, imported intoSPSS for Windows (SPSS Inc. version11.0) formatted and analysed. A sub-ject-level analysis was performed bycomputing a subject-level variable(full-mouth or at different PPD cate-gories) for each of the parameters.Numerical data were summarized asmeans and 95% confidence intervals(CIs), categorical data were summarizedas frequency distribution and the per-centage-based measures (e.g. FMPS)were summarized as the median of thepercentage and inter-quartile range. Thesignificance of differences between testand placebo groups in terms of numer-ical data was evaluated via univariateanalysis using the independent samplest-test. Likewise, the significance of thedifference within each group before andafter treatment was evaluated with thepaired samples t-test. Categorical datawere analysed with the w2 test, and thepercentage data between the two groupswere compared with the Mann–Whitneytest, while the within-group percentagechanges were evaluated with the Wil-coxon’s sign-rank test. The significanceof the treatment option (test or placebo)on the dependent variables PPD reduc-tion and LCAL gain at different initialPPD categories was estimated by analy-sis of covariance (ANCOVA). The modelswere adjusted for baseline values andcontrolled for smoking. The final modelwas then selected by including signifi-cant factors only. Model estimatesincluded adjusted means and 95% CIs.An intention-to-treat, last observationcarried forward analysis was performed(Hollis & Campbell 1999).

Results

Subject accountability

Figure 1 shows what happened to allpotential subjects throughout the studyfrom possible recruitment to comple-tion. Fifty-one subjects were assessedfor their eligibility before entering thestudy. Of these, 10 subjects wereexcluded; seven because they did notmeet the inclusion criteria, while theother three refused to participate. Oneof the three who refused to participatedid so after signing the consent form,but before treatment assignment hadtaken place. Thus, 41 subjects wererandomly allocated to participate in thestudy. All participants received the allo-cated intervention and one patient fromthe placebo group was lost to follow-upbetween the 2-month visit and the6-month visit because of reasons unre-lated to the study. All participants wereincluded in the analysis.

Study Schedule

Subject recruitment started in January2003 and was completed by the end ofDecember 2003. All the 6-month fol-low-up visits were completed by July

2004. Data entry of all information andstatistical analysis were performed bythe end of September 2004.

Subject characteristics at baseline

The baseline characteristics of the 41participants who were treated non-sur-gically with the adjunctive use of thetest or the placebo medication are dis-played in Table 1. The mean age of theparticipants was 31.3 � 5.2 years (SD)for the test group and 31.7 � 5.1 yearsfor the placebo group. Femalesaccounted for 80% of the test groupand 57% of the placebo group. In thetest group 25% of the participants weresmokers whereas 19% smoked in theplacebo group. Caucasians constitutedthe major ethnic group in the study,accounting for 65% of the test groupand 47.6% of the placebo group. Noneof these demographic parametersshowed a statistically significant differ-ence between groups.

Clinical characteristics

The baseline examination revealed thatthe two study groups showed similar

51 subjects assessed foreligibility

21 allocated to FSR withplacebo medication

21 received allocatedintervention

20 allocated to FSR withamoxicillin andmetronidazole

20 received allocatedintervention

Followed up atWeek 1: n=21Week 5: n=21Month 2: n=21Month 6: n=20

Followed up at Week 1: n=20 Week 5: n=20 Month 2. n=20 Month 6: n=20

20 ANALYSED

41 RANDOMIZED

21 ANALYSED

10 excluded:Reasons:Not meeting inclusioncriteria (n=7)Refused to participate(n=3)

Fig. 1. Flow chart for study patients.


characteristics for number of teeth pre-sent, percentage of pockets X5 mm,plaque and bleeding levels, with nosignificant differences between thegroups. The data show that the subjectshad retained most of their teeth, but hadapproximately a third of sites exhibit-ing pockets requiring treatment andhigh levels of bleeding, but low levelsof plaque (Fig. 2).

Mean values for clinical parameters

Mean full-mouth clinical outcomes andmean clinical outcomes at shallow

(43 mm), moderate (4–6 mm) anddeep (X7 mm) pocket categories forbaseline, and the differences betweenbaseline – 2 months and baseline – 6months are displayed in Table 2. Atbaseline, there were no significant dif-ferences between test and placebo. Allparameters, with the exception of themean LCAL gain at the initial shallowpockets, showed a statistically signifi-cant difference between baseline and2 months. This was also true betweenbaseline and 6 months except for LCALgain and PPD reduction at shallowpockets. At 2 months, there were statis-

tically significant differences (po0.02)between test and placebo in the meanPPD at moderate pockets (4–6 mm) andmean PPD at deep pockets (X7 mm). At6 months, statistically significant differ-ences were detected between test andplacebo groups in the mean PPD atmoderate pockets (po0.02), meanPPD at deep pockets (po0.001) andLCAL at deep pockets (po0.05).

The significance of this treatmenteffect between the groups at 2 and 6months (difference between the testgroup and the placebo group in themean PPD reduction and the meanLCAL gain at different pocket cate-gories) is displayed in Table 3. Multi-variate models based on linear regressionANCOVA were constructed taking intoaccount the potential sources of variabil-ity such as smoking status and baselinepocket depth. As the adjustment forbaseline PPD value could constitute aproblem related to mathematical cou-pling (Tu et al. 2004), the same analyseswere undertaken with a model that didnot include an adjustment for baselinevalues. This resulted in almost identicalresults (data not shown). When consider-ing full-mouth mean LCAL, there wereno statistically significant differencesbetween test and placebo. Similarlywhen examining pockets 43 mm, nodifferences were observed between testand placebo for either LCAL or PPD. Forease of presentation, these analyses havebeen omitted from Table 3.

There were highly significant treat-ment effects for full-mouth PPD reduc-tion, PPD reduction at 4–6 mm pocketsand PPD reduction at X7 mm pockets at2 and 6 months, with the outcomesfavouring the test treatment. For PPDreduction in 4–6 mm pockets, theadjusted differences between test andplacebo treatment were 0.5 mm at2 months and 0.4 mm at 6 months. Inthe deeper pockets X7 mm this differ-ence was much larger: 0.9 mm at 2months and 1.4 mm at 6 months.

For sites with initial PPD X7, LCALgain was also significantly better in testsubjects: an adjunctive benefit of0.6 mm at 2 months and 1.0 mm at 6months was observed. While there wasno statistically significant benefit interms of 2-month LCAL gain(p 5 0.650) at sites with initial PPD4–6 mm, a highly significant differenceof 0.50 mm in favour of the test groupwas observed at 6 months (p 5 0.001).

In addition, the effect of smoking onthe primary outcome variable (PPD

Table 1. Subject and clinical characteristics at baseline

Parameter Test group(N 5 20)

Placebo group(N 5 21)

p-value

Age 31.3 31.7 0.779Mean (95% CI) (28.8, 33.7) (29.4, 34.1) t-testFemales (percentage) 16 12 0.108

(80%) (57%) w2

Smokers (percentage) 5 4 0.719(25%) (19%) w2

Caucasians (percentage) 13 10 0.530(65%) (47.6%) w2

Teeth at baseline 25.5 26.0 0.482Mean (95% CI) (24.5, 26.6) (25.0, 27.0) t-testNumber of pockets X5 mm 60.8 58.4 0.795Mean (95% CI) (46.3, 75.3) (46.74, 70.20) t-testPercentage of pockets X5 mm 35.5 31.5 0.514Median (IQ) (26.6, 47.3) (24.4, 48.1) Mann–WhitneyFull-mouth plaque score 25.5 20.0 0.155Median (IQ) (13.3, 36.8) (10.0, 29.0) Mann–WhitneyFull-mouth bleeding score 61.5 55.0 0.175Median (IQ) (50.8, 74.8) (35.5, 66.5) Mann–Whitney

Fig. 2. Baseline clinical (a) and radiographic (b) appearance of a 21-year-old, smokingfemale (eight cigarettes per day). She presented with a plaque score of 24%, a bleeding scoreof 68% and 70 sites with pockets 5 mm or deeper.


Table 2. Mean clinical outcome variables at baseline and differences between 0–2 and 0–6 months

Clinical outcomes mean (95% CI) Group Baseline0 months

Difference between0 and 2 months


p-value paired t-test

difference0–2 months


Full-mouth mean PPD Placebo 4.1 0.8 0.7 o0.001 o0.001(3.6, 4.5) (0.6, 1.1) (0.4, 1.0)

Test 4.1 1.1 1.2 o0.001 o0.001(3.6, 4.5) (0.9, 1.4) (0.9, 1.4)

Mean PPD at pockets 43 mm Placebo 2.3 0.2 � 0.1 0.003 0.052(2.2, 2.4) (0.1, 0.3) (� 0.2, 0.0)

Test 2.3 0.2 0.0 o0.001 0.931(2.2, 2.3) (0.2, 0.3) (0.0, 0.0)

Mean PPD at pockets 4–6 mm Placebo 5.0 1.2 1.0 o0.001 o0.001(4.9, 5.1) (0.9, 1.5) (0.8, 1.3)

Test 5.02 1.7 1.5 o0.001 o0.001(4.9, 5.1) (1.6, 1.9) (1.3, 1.7)

Mean PPD at pockets X7 mm Placebo 7.7 2.1 1.8 o0.001 o0.001(7.4, 8.1) (1.6, 2.5) (1.3, 2.3)

Test 7.7 3.0 3.1 o0.001 o0.001(7.5, 7.9) (2.6, 3.3) (2.7, 3.5)

Full-mouth mean LCAL Placebo 4.8 0.5 0.5 o0.001 o0.001(4.1, 5.5) (0.3, 0.6) (0.2, 0.7)

Test 4.7 0.7 0.8 o0.001 o0.001(4.1, 5.2) (0.5, 0.8) (0.7, 0.9)

Mean LCAL at sites with initialpockets 43 mm

Placebo 3.2 0.0 0.0 0.683 0.704(2.7, 3.7) (� 0.1, 0.1) (� 0.2, 0.1)

Test 2.9 0.0 0.0 0.631 0.634(2.6, 3.1) (� 0.01, 01) (� 0.1, 0.1)

Mean LCAL at sites with initialpockets 4–6 mm

Placebo 5.7 0.8 0.8 o0.001 o0.001(5.2, 6.2) (0.5, 1.0) (0.5, 1.1)

Test 5.7 1.1 1.3 o0.001 o0.001(5.3, 6.1) (1.0, 1.2) (1.2, 1.4)

Mean LCAL at sites with initialpockets X7 mm

Placebo 8.2 1.3 1.3 o0.001 o0.001(7.5, 8.9) (1.0, 1.6) (1.0, 1.6)

Test 8.1 1.8 2.3 o0.001 o0.001(7,7, 8.4) (1.6, 2.1) (2.0, 2.5)

PPD, probing pocket depth; LCAL, life cumulative attachment loss.

Table 3. Analysis of covariance for PPD reduction and LCAL gain at 2 and 6 months in different pockets categories

Multivariate ‘‘ANCOVA’’ analysis models Parameter Difference 0–2 months Difference 0–6 months

estimate(95% CI)

p-value estimate(95% CI)

p-value

Full-mouth mean PPD reduction Treatment group (test-placebo) 0.3 0.5(0.1, 0.5) 0.002 (0.2, 0.7) 0.001

Smoking (no-yes) 0.4 0.4(0.1, 0.7) 0.007 (0.1, 0.7) 0.040

Mean PPD reduction in pockets 4–6 mm Treatment group (test-placebo) 0.5 0.4(0.2, 0.8) 0.001 (0.1, 0.7) 0.005

Smoking (no-yes) 0.4 0.2(0.0, 0.8) 0.050 (� 0.1, 0.6) 0.183

Mean PPD reduction in pockets X7 mm Treatment group (test-placebo) 0.9 1.4(0.4, 1.5) 0.001 (0.8, 2.0) o0.001

Smoking (no-yes) 0.9 1.0(0.3, 1.5) 0.007 (0.3, 1.7) 0.007

Mean LCAL gain in sites with initial PPD X7 mm Treatment group (test-placebo) 0.6 1.0(0.2, 0.9) 0.002 (0.7, 1.3) o0.001

Smoking (no-yes) 0.6 0.7(0.2, 1.0) 0.005 (0.3, 1.1) 0.001

Mean LCAL gain in sites with initial PPD 4–6 mm Treatment group (test-placebo) � 0.2 0.5(� 0.4, 0.0) 0.650 (0.2, 0.8) 0.001

Smoking (no-yes) 0.0 0.0(� 0.4, 0.2) 0.203 (� 0.3, 0.4) 0.903

PPD, probing pocket depth; LCAL, life cumulative attachment loss.


reduction at X7 mm pockets) was sta-tistically significant (p 5 0.007), and thedifference between a non-smoker and asmoker on PPD reduction at deep pock-ets was 0.9 mm (95% CI 0.3, 1.5) at 2months and 1.0 mm (0.3, 1.7) at 6months. The corresponding value forthe difference between non-smokersand smokers on PPD reduction in initialpockets of 4–6 mm was 0.4 mm (0.0,0.8), demonstrating a borderline signifi-cance (p 5 0.050) at 2 months and anon-significant difference of 0.2 mm(� 0.1, 0.6) at 6 months (p 5 0.183),whereas there were no statistically sig-nificant differences for LCAL.

Percentage of sites with pockets

The percentage of sites (median andinter-quartile range) with a PPD of aspecific threshold at baseline and thereduction in the percentage of pocketswithin groups (difference between base-line – 2 months and baseline – 6months) are reported in Table 4.The significance of the reduction in thepercentage of pockets between thegroups is also shown. At baseline, therewere no statistically significant differ-ences between the groups in any of thespecific PPD thresholds.

Analysis within groups (Wilcoxon’sSigned rank test) indicated that all PPDthresholds within each group showed ahighly statistically significant differencebetween baseline and two months and

between baseline and 6 months in bothtreatment groups. Furthermore, analysisof the differences between test andplacebo treatments for the outcome oftreatment (baseline – 2 months) showeda statistically significant difference(po0.05) for the reduction in the per-centage of pockets X5, X6 and X7 mmthat favoured the test treatment. Thestatistical significance of the differencebetween baseline and 6 months waspo0.02 for the reduction in the percen-tage of pockets X5, X6 mm, and waspo0.05 for pockets X4, X7 mm.

Oral hygiene and bleeding on probing

FMPS and FMBS at baseline, and thereduction (difference baseline – 2months and baseline – 6 months) withineach group are displayed in Table 5.

Plaque scores decreased in both treat-ments from baseline to 2 months, andthe difference was statistically signifi-cant for test and placebo groups. How-ever, the 6-month plaque scores valueswere equal to baseline values. Theeffects of both treatments had a largeimpact on bleeding, and these changeswere statistically significant at 2 and 6months (po0.001). Furthermore, therewas a statistically significant differencebetween test and placebo for theimprovement in the percentage of bleed-ing sites at 2 and 6 months (po0.02).

Percentage of sites with clinically relevant

changes

A subset analysis was carried out to testthe changes of some clinically relevantparameters at 2 and 6 months (Table 6).All the median values (inter-quartilerange) showed statistically significantdifferences favouring the test treatmentfor the percentage of sites with LCALgain X2 mm at 2 months (p 5 0.047), at6 months (p 5 0.028), the percentage ofsites with PPD reduction of X2 mm at 2months (p 5 0.029) and at 6 months(p 5 0.021), and the percentage of pock-ets that had converted from X5 mm atbaseline to 44 mm at 2 months (p 5

0.039) and at 6 months (p 5 0.008).Conversely, the percentage of siteswith LCAL loss X2 mm was higher inthe placebo group as compared with thetest group at 2 months (p 5 0.041) and at6 months (p 5 0.072).

The percentage of pockets that con-verted from X4 mm at baseline to43 mm at 2 months failed to show astatistically significant difference (p 50.112) while at 6 months the differencebetween the groups demonstrated a sta-tistical significance (p 5 0.038).

Adverse events, concomitant

antimicrobials and compliance

At the 1-week follow-up visit, 11 sub-jects (55%) in the test group and foursubjects (19%) in the placebo reported

Table 4. Percentage of pockets at baseline and differences between 0–2 and 0–6 months

Median of percentage (IQ) Group Baseline Difference between0 and 2 months


p-value Wilcoxon’s signed-ranks test



Percentage of pockets X4 mm Placebo 45.8 15.3 14.9 o0.001 o0.001(33.7, 60.0) (9.4, 24.2) (7.6, 24.8)

Test 46.3 19.6 21.3n o0.001 o0.001(37.6, 57.4) (16.1, 28.5) (14.6, 32.0)


Test 35.5 22.1n 24.1nn o0.001 o0.001(26.6, 47.3) (19.5, 30.2) (19.2, 32.8)


Test 22.1 16.4n 18.2nn o0.001 o0.001(13.2, 28.9) (11.5, 27.5) (10.7, 27.7)

Percentage of pockets X7 mm Placebo 9.0 6.0 5.3 o0.001 0.001(5.2, 17.3) (1.0, 11.5) (0.7, 10.5)

Test 12.0 10.5n 10.8n o0.001 o0.001(5.8, 19.0) (5.7, 16.6) (5.6, 17.6)

nSignificant difference between groups favoring test treatment (po0.05).nnSignificant difference between groups favoring test treatment (po0.02).


adverse events. At the 5-week follow-upvisit only two subjects (10%) in the testgroup and one subject (4.8%) in theplacebo group reported to have continu-ing adverse events. The types of adverseevents at the 1- and 5-week follow-upvisits are described in Table 7. Twosubjects (one in the test group and onein the placebo group) had a tooth extrac-tion each between the baseline visit andthe 2-month visit. The baseline values ofthese two teeth were carried forwardthrough all the analysis. One subjectfrom the test group lost three front teethbecause of an accident between the2-month visit and the 6-month visit.The 2-month values of these three teethwere carried forward to the 6-month visit.

Concomitant antimicrobial medicationduring the study period was recorded.Two subjects in the test group tookamoxicillin capsules for medical reasons,while no subject in the placebo grouphad any concomitant antimicrobials.

Compliance with the course of sys-temic medication and the number of

pills not taken by the non-compliantpatients were also documented. All sub-jects returned the medication bottles.Sixteen subjects (80%) in the test groupand 19 subjects 90.5% in the placebogroup completed the course of systemicmedication as indicated. The reasonsadvocated by the four non-compliantsubjects in the test group for not havingtaken all the pills were the following:two subjects reported diarrhoea, onesubject reported vomiting and one sub-ject failed to remember to take theprescribed medication. These four sub-jects missed 38%, 45%, 52% and 9% ofthe whole number of pills, respectively.

Discussion

This was the first randomized-controlledclinical study (RCT) designed to assessthe adjunctive effect of the metronida-zole–amoxicillin antibiotic combina-tion, originally proposed by vanWinkelhoff et al. (1989), in the treat-

ment of GAP. The data indicated thatthe experimental therapy resulted inclinically significant short-term im-provements in clinical parameters.

As all patients had pre-treatment ses-sions of oral hygiene instructions andreinforcement as necessary, FMPS werelow from the beginning of the study.There was little additional benefit toplaque reduction from the therapy at 2an 6 months, and there was no differencebetween the treatment regimes. Pre-treat-ment sessions to achieve plaque scoreso20% were included in order to reducethe impact of inadequate plaque controlin the success of non-surgical treatment(Magnusson et al. 1984). This wasimportant because full-mouth instrumen-tation was performed in two visits, andthus the therapist had fewer opportunitiesto deliver, check and reinforce the neces-sary oral hygiene instructions.

Our experimental population con-sisted of subjects with the clinical char-acteristics of GAP according to thecriteria of the 1999 international classi-

Table 5. Analysis on FMPS and FMBS at baseline (post-oral hygiene instructions) and differences between 0–2 and 0–6 months.

Median (IQ) Group Baseline Difference0–2 months

Difference0–6 months

p-value Wilcoxon’ signed-ranks test



Full-mouth plaque score (%) Placebo 20.0 3.0 0.0 0.029 0.112(10.0, 29.0) (� 1.0, 7.0) (� 2.5, 8.0)

Test 25.5 6.0 1.0 0.038 0.170(13.3, 36.8) (� 3.8, 19.0) (� 5.0, 15.0)

Full-mouth bleeding score (%) Placebo 55.0 17.0 21.0 o0.001 0.001(35.5, 66.5) (10.0, 32.5) (9.5, 28.5)

Test 61.5 34.5nn 32.0nn o0.001 o0.001(50.8, 74.8) (27.3, 34.5) (26.0, 39.0)

nnSignificant difference between groups favoring test treatment (po0.02).

FMPS, full-mouth plaque score; FMBS, full-mouth bleeding score.

Table 6. Percentage of sites with clinically relevant changes in test and placebo groups at 2 and 6 months

Median of percentage (IQ) 0–2 months data 0–6 months data

test group placebogroup

p-valueMann–Whitney test

test group placebogroup

p-valueMann–Whitney test

Percentage of sites with X2 mmof LCAL gain at 2 months

19.6 14.3 0.047 25.4 16.1 0.028(15.5, 26.2) (8.6, 21.3) (18.5, 34.1) (8.8, 24.9)

Percentage of sites with X2 mmof PPD reduction at 2 months

29.4 20.8 0.029 30.2 20.8 0.021(23.9, 43.8) (10.5, 32.7) (21.1, 46.6) (8.6, 32.7)

Percentage of sites with LCALloss X2 mm at 2 months

1.3 3.0 0.041 1.5 3.3 0.072(0.3, 3.5) (1.8, 5.4) (1.2, 2.3) (1.5, 5.5)

Percentage of pockets convertingfrom X5 mm at baseline to 44 mmafter treatment

71.2 56.6 0.039 74.1 54.2 0.008(63.3, 78.2) (30.4, 72.7) (63.7, 83.5) (29.1, 75.7)

Percentage of pockets convertingfrom X4 mm at baseline to 43 mmafter treatment

49.0 41.6 0.112 55.2 37.2 0.038(42.9, 60.6) (21.1, 58.1) (38.9, 65.2) (18.0, 56.4)

LCAL, life cumulative attachment loss.


fication (Armitage 1999). Because ofthe recently reported difficulties encoun-tered with this classification (Mombelliet al. 2002, Meyer et al. 2004), extraefforts were directed towards selecting‘‘clear cases’’. Our patients were mainlyCaucasians, with an average of 31 yearsof age, who presented with almost allteeth and with severe widespread dis-ease (an average of 33% of the sites withPPD X5 mm after probing six sitesaround each tooth). Patients, however,were not screened or selected basedupon a microbiological diagnosis. Thelack of microbiological entry criteriahad implications on the choice of anti-biotic regimen, and indicates that ourresults are applicable to subjects wherethe antibiotic is used empirically, i.e.without specific targeting based on themicrobial results (Mombelli 2005, vanWinkelhoff et al. 2005). Nevertheless,microbiological outcomes of treatmentwill be reported in a separate paper.

In this study, we prescribed 500 mg ofamoxicillin combined with 500 mg ofmetronidazole three times a day for7 days. This dosage has not beenreported in previous clinical trials. Itaims to provide a wide spectrum ofactivity and to reach and maintain serumconcentrations above the minimumeffective concentration. The rationalefor the wide spectrum has been pre-viously discussed and is based on thereported high prevalence of A. actino-mycetemcomitans and anaerobic patho-gens in GAP patients (Sasaki et al. 1989,Kamma et al. 1994, Listgarten et al.1995, Lopez et al. 1995, Tonetti andMombelli 1999, Ishikawa et al. 2002,Lee et al. 2003, Takeuchi et al. 2003).The choice of dosage comes from an

analysis of previous studies in chronicperiodontitis subjects and the lack ofsignificant adjunctive benefit reportedin studies that have used marginallyeffective doses of antibiotic (Van Win-kelhoff et al. 1992, Winkel et al. 1997,Palmer et al. 1999). Attention has beendrawn recently to the fact that theamount of metronidazole needed foreffective concentration in body fluidsamounts to 20–25 mg/kg, and that aninsufficient antibiotic concentrationwould turn into a lack of effect onclinical and microbiological parameters(Van Winkelhoff et al. 1999). Thismeans that 1400–1750 mg/day of themedication should be taken by a 70 kgadult patient (Winkel et al. 1997).Therefore, in GAP patients with a highprevalence of anaerobic and micro-aero-philic periodontal pathogens, a moder-ate dose of amoxicillin (375–500 mg)will have synergistic effects withmetronidazole and its hydroxymetabo-lite against A. actinomycetemcomitans(Pavicic et al. 1992), while a high doseof metronidazole (500 mg) will targetthe anaerobic microflora.

It is clear from other clinical trialsthat mean full-mouth PPD and LCALvalues may not be the best way todescribe the data. Shallow sites, whichare not expected to change as a result oftherapy, are likely to significantly dilutethe changes observed at the deeper sites,which are the ones of therapeutic con-cern. Therefore, the primary outcomevariable selected was the difference inPPD reduction between the treatmentgroups at deep pockets. The mean PPDreduction at 6 months was 1.8 mm (95%CI 1.3, 2.3) for the placebo group and3.1 mm (2.7, 3.5) for the test group. A

multivariate model (Table 3) determinedthat the additional benefit for test sub-jects after taking into account the poten-tial sources of variability was 1.4 mm(0.8, 2.0). It should be noted that theresults obtained in the control groupwere within the range expected fromnon-surgical periodontal treatment inchronic periodontitis patients. Cobb(1996) reviewed the most relevant clin-ical studies related to PPD reductionafter non-surgical therapy alone, andfound that at deep pockets (PPDX

7 mm), the mean PPD reduction was2.2 mm. This was in excellent agreementwith the results of our placebo group,which exhibited a mean PPD reductionof 2.1 mm at 2 months and 1.8 mm at 6months. The results are also comparablewith those of the control group in asimilar study in aggressive periodontitispatients treated with the adjunctive useof three different single antibiotic regi-mens (Sigusch et al. 2001). They showedthat in pockets 46 mm, a 2.3 mm PPDreduction was achieved 6 months aftertreatment. The similarity between theoutcomes of subgingival instrumentationat deep pockets of chronic and aggres-sive periodontitis patients is in agree-ment with reports indicating that ag-gressive periodontitis patients respondwell to mechanical instrumentationalone (Wennstrom et al. 1986).

In contrast, the adjunctive benefits aremore difficult to compare with otherstudies because of the paucity of rando-mized controlled clinical trial in GAPpatients. Recent meta-analyses by Her-rera et al. (2002) and Haffajee et al.(2003) have suggested that the adjunc-tive benefit expected from antibioticusage may be greater in aggressiveperiodontitis patients. An additionalgain in LCAL of 0.7 mm was observedin seven studies including 231 subjectsreceiving the antibiotic adjunctively tonon-surgical or surgical root instrumen-tation. In the present study, the use ofadjunctive antimicrobials resulted in anadditional benefit of 0.5 mm in LCALgain in moderate pockets (4–6 mm),while a 1.0 mm benefit was observed indeeper pockets (X7 mm) compared withnon-surgical root debridement alone.

Our test subjects showed a mean PPDreduction of 3.1 mm in pockets X7 mmat 6 months. These results are slightlyinferior but comparable with the 6-monthoutcomes reported by Sigusch et al.(2001) with the use of adjunctive metro-nidazole or clindamycin. In terms of PPDreduction at 6 months, the added benefit

Table 7. Type of adverse events at the 1- and 5-week follow-up visit

Type of adverse event number(percentage) of subjects

Time period(week)

Test group,N 5 20

Placebo group,N 5 21

Stomach upset (nausea and vomiting) 1 3(15%) 05 1(5%) 0

Gastrointestinal disorder (diarrhea) 1 3(15%) 05 0 0

Headache 1 1(5%) 05 0 0

Periodontal abscess 1 0 2 (9.5%)5 0 0

Tooth loss, tooth extraction 1 0 05 1(5%) 1(4.8%)

Metallic taste 1 1(5%) 05 0 0

Intra-oral tissue alteration 1 0 2 (9.5%)5 0 0

General unwellness (irritability, flu, etc.) 1 3 (15%) 05 0 0


that we observed was 0.4 mm for mod-erate pockets (4–6 mm) and 1.4 mm forthe deep pockets (X7 mm). This gradientof effect is consistent with the notion thatthe benefit of the antibiotic is particularlyevident at deeper pockets where mechan-ical debridement is less effective.

The multivariate analysis identifiedcigarette smoking as a significant factor(p 5 0.007): in a non–smoker, deeppockets reduced by an average of0.9 mm more than in a smoker, regard-less of the treatment group. This result isin accordance with previous studies thathave demonstrated, in chronic perio-dontitis patients, that less PPD reductionand less LCAL gain occur in smokers ascompared with non-smokers (Preber andBergstrom 1986, Jin et al. 2000) or evenformer smokers (Grossi et al. 1997).

For most clinicians, results reportedas mean full-mouth values offer littleinsight into the clinical relevance of thefindings. To illustrate tangible clinicalbenefits, after the analysis on the pri-mary outcome variable (PPD reductionin pockets X7 mm) and the other para-meters based on full-mouth mean ormedian values, secondary analyseswere carried out. Accordingly, the testtreatment significantly decreased thepercentage of pockets that remainedabove specific thresholds at 2 and 6months after subgingival debridement(Table 6). As in previous studies (Ber-glundh et al. 1998), the percentage of allsites that gained X2 mm in LCAL andthe percentage of all sites that had a PPDreduction X2 mm were statistically sig-nificantly higher in the test group at2 and 6 months. Furthermore, the per-centage of sites experiencing diseaseprogression (LCAL loss of 2 mm ormore over the 6-month observation per-iod) was significantly decreased by theantibiotic combination.

However, a critical question at re-evaluation 3–6 months after the comple-tion of non-surgical therapy is related towhat to do with residual pockets and theneed for further treatment beyond main-tenance care. A recent systematicreview on the clinical parameters usedduring re-evaluation (residual pockets,bleeding on probing and presence offurcation defects) to predict furtherattachment loss (Renvert & Persson2002) concluded that the presence ofdeep residual pockets was associatedwith further disease progression andhence decreased maintainability. Thisconclusion can be used as a rationalefor providing further treatment to

patients, e.g. pocket reduction surgery.As reported in other studies (Loescheet al. 1992, Smith et al. 2002), wecompared the reduction in the frequencyof sites in test and control patientswho would require surgical interventionfor PPD reduction at 2 or 6 months using5 mm as the discriminant value. At 2months post-therapy, we found thatthe subjects receiving the test treat-ment showed a 71% reduction in thenumber of sites in need of surgical inter-vention, while the subjects in the placebogroup had a reduction of 57%(p 5 0.039). These values were main-tained at 6 months. Using an even stricterdiscriminant value (4 mm), at 6 months,55% of the test sites with baseline pock-ets showed maintainable probing depths(3 mm or less) as compared with 37% ofthe placebo sites (p 5 0.038).

Two subjects in the placebo groupand four subjects in the test group didnot fully comply with the medication.The fact that 20% of test subjects did notcomplete the full cycle of antibiotic mayhave led to an underestimation of theadjunctive effect in our intention-to-treat analysis. On the other hand, thisfact provides the study with a higherexternal validity as lack of complianceis a reality in clinical practice (Grob1992). Furthermore, given the fact thatsome of the observed incomplete com-pliance can be attributed to the onset ofsignificant side effects, clinicians pre-scribing this regimen to their patientsshould expect less than optimal compli-ance. An additional analysis assessingthe impact of incomplete compliancewill be presented in a companionpaper focused on the microbiologicaloutcomes of the study where an ‘‘on-drug’’ analysis gives important addi-tional information.

In conclusion, the findings of thepresent study have indicated that theadjunctive use of systemic amoxicillinplus metronidazole, during full-mouthnon-surgical cause-related periodontaltreatment (FSR) performed within 24 h,has resulted in significant additionalimprovements in the clinical conditionsof GAP patients when compared withFSR alone. These observations are validfor both the 2- and 6-month evaluationsafter the completion of active treatment.

Acknowledgements

This study was supported by the Perio-dontal Research Fund of the Eastman

Dental Institute. L. N. is supported by afellowship from the Italian Society ofPeriodontology, SIdP.

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Address:

Maurizio S. Tonetti

Department of Periodontology

University of Connecticut Health Center

263 Farmington Ave

Farmington, CT 06030

USA

E-mail: [email protected]

Clinical relevance

Scientific rationale for study:Adjunctive systemic antibiotics maybenefit aggressive periodontitispatients during non-surgical therapy.Insufficient data, however, exist sup-porting this approach.

Principal findings: Subjectsreceiving the adjunctive amoxicillinand metronidazole combinationdemonstrated statistically significantadditional improvements in clinicaloutcomes with respect to debride-ment alone. The improvementswere clinically significant, as demon-

strated by the reduced prevalence ofpockets.

Practical implications: Patientswith generalized aggressive perio-dontitis may benefit from the adjunc-tive administration of amoxicillinand metronidazole during the initialphase of periodontal treatment.


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