antibióticos podem melhorar tratamento dentário

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Short-term benefits of theadjunctive use of metronidazoleplus amoxicillin in the microbialprofileandintheclinicalparametersof subjects with generalized

aggressive periodontitis

Mestnik MJ, Feres M, Figueiredo LC, Duarte PM, Lira EAG, Faveri M. Short-termbenefits of the adjunctive use of metronidazole plus amoxicillin in the microbial profileand in clinical parameters of subjects with generalized aggressive periodontitis. J ClinPeriodontol 2010; 37: 353365. doi: 10.1111/j.1600-051X.2010.01538.x

Abstract

Aim: The aim of this study was to evaluate the clinical and microbiological effects ofscaling and root planing (SRP) alone or combined with metronidazole (MTZ) andamoxicillin (AMX) in the treatment of subjects with generalized aggressive

periodontitis (GAgP).Materials and Methods: A double-blind, placebo-controlled, randomized clinicaltrial was conducted in 30 subjects receiving SRP alone or combined with MTZ(400mg 3 per day) and AMX (500 mg 3 per day) for 14 days. Clinical and

microbiological examinations were performed at baseline and 3 months post-SRP.Nine subgingival plaque samples per subject were analysed using checkerboardDNADNA hybridization.

Results: Subjects receiving MTZ and AMX showed the greatest improvements in themean full-mouth probing depth and clinical attachment level and at initially

intermediate and deep sites. The most beneficial changes in the microbial profile werealso observed in the MTZ1AMX group, which showed the lowest proportions of thered complex as well as a significant decrease in the proportions of the orange complexafter treatment. The antibiotic therapy also reduced the levels of Aggregatibacter

actinomycetemcomitans at initially deep sites.

Conclusion:Subjects with GAgP significantly benefit from the adjunctive use ofMTZ and AMX. The short-term advantages are observed in the clinical and

microbiological parameters.

Key words: dental plaque; generalizedaggressive periodontitis; periodontal disease;

scaling and root planing

Accepted for publication 10 December 2009

Aggressive periodontitis (AgP) is char-acterized by a rapid loss of clinicalattachment and alveolar bone andnormally affects subjects younger than30 years old (Ranney 1993, Albandaret al. 1997, Lang et al. 1999, Tonetti &Mombelli 1999). These infections aresubdivided into localized or generalized,

according to the extent of the periodontaldestruction (Armitage 1999, Lang et al.1999, Lindhe et al. 1999). As opposed tochronic periodontitis, the amount ofbiofilm and calculus accumulation inAgP subjects is inconsistent with theseverity and progression of the perio-dontal destruction (Lang et al. 1999).

Maria Josefa Mestnik, Magda Feres,Luciene Cristina Figueiredo, Poliana

Mendes Duarte, Eisla Alline Gomes

Lira and Marcelo Faveri

Department of Periodontology, Dental

Research Division, Guarulhos University,

Guarulhos, Sao Paulo, Brazil

Conflict of interest and source offunding statement

The authors declare that they have no

conflict of interests.This study was supported in part byResearch Grants 2007/56413-0 from Fun-dacao de Amparo a Pesquisa do Estado de

Sao Paulo (FAPESP, Brazil).

J Clin Periodontol 2010; 37: 353365 doi: 10.1111/j.1600-051X.2010.01538.x

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The benefits of systemic antibiotics inthe treatment of AgP have recently beenreported in two systematic reviews (Her-rera et al. 2002, Haffajee et al. 2003);however, the most effective agents andtreatment protocols are still to be defined.The association of metronidazole (MTZ)

and amoxicillin (AMX) in the treatmentof AgP has gained recognition mostlydue to its effectiveness against Aggrega-tibacter actinomycetemcomitans (vanWinkelhoff et al. 1989, Pavicic et al.1992, 1994, Winkel et al. 2001), a perio-dontal pathogen closely associated withthe aetiology of these infections. How-ever, recent reports have demonstratedthat other periodontal pathogens such asTannerella forsythia, Porphyromonasgingivalis, Treponema denticola, Campy-lobacter rectus, as well as Prevotella andSelenomonas species may have an

important role in the aetiology and pro-gression of AgP (Mullally et al. 2000,Gajardo et al. 2005, Ximenez-Fyvie et al.2006, Thiha et al. 2007, Faveri et al.2008, 2009). In addition, a recent reportfrom our group (Faveri et al. 2009)showed that the proportions of the host-compatible Actinomyces species mightbe reduced in these subjects. Therefore,effective treatment of AgP would involvenot only a reduction in periodontal patho-gens but also an increase in the Actino-myces species. However, the effect ofdifferent antibiotic regimens, including

the association of MTZ and AMX withscaling and root planing (SRP), in chan-ging the microbial profile of AgP sub-jects has not yet been investigated.

Interestingly, the first randomizedplacebo-controlled clinical trial (RCT)that evaluated the clinical effects ofMTZ and AMX combined with SRPwas only recently published (Guerreroet al. 2005). The authors showed thatthis treatment led to a better clinicalresponse than that observed with SRPalone. Afterwards, the benefits of thiscombination of drugs in the clinical

parameters of generalized aggressiveperiodontitis (GAgP) subjects were cor-roborated by two other reports (Kaneret al. 2007, Machtei & Younis 2008).However, no microbiological data fromthese studies were described. In fact, sofar, only one RCT has evaluated theeffect of this antibiotic regimen onfour periodontal pathogens in the treat-ment of GAgP subjects (Xajigeorgiouet al. 2006). The authors reported thatthe adjunctive use of MTZ plus AMX toSRP significantly reduced the levels of

A. actinomycetemcomitans, P. gingiva-

lis, T. forsythia and T. denticola in deeppockets of subjects with GAgP for 6months post-SRP.

Given that no studies to date havethoroughly evaluated the changes thatoccur in the subgingival microbialprofile when systemic antibiotics are

used as part of the periodontal treatmentof subjects with GAgP, the aim of thepresent study was to evaluate the clin-ical and microbiological effects of SRPcombined with systemic MTZ andAMX in the treatment of GAgP.

Materials and Methods

Sample size calculation

The ideal sample size to assure adequatepower for the microbiological data ofthis clinical trial was calculated consi-

dering differences of at least 6.6%between groups for the proportion ofthe red complex species and a standarddeviation of 5.0% (Matarazzo et al.2008). It was determined that 13 sub-jects per group would be necessary toprovide 80% power with an a of 0.05.Based on the mean drop-out rate of 15%from our previous studies, 15 subjectswere included in each group.

Subject population

Subjects recruitment started in July2007 and was completed by the end ofSeptember 2008. Thirty subjects withpreviously untreated periodontitis wereselected from the population referred tothe Periodontal Clinic of GuarulhosUniversity (Guarulhos, SP, Brazil).Detailed medical and dental historieswere obtained. Subjects who fulfilledthe inclusion criteria were invited toparticipate in the study. All eligiblesubjects were thoroughly informed ofthe nature, potential risks and benefits oftheir participation in the study andsigned a Term of Informed Consent.This study protocol was approved pre-viously by Guarulhos University EthicsCommitte in clinical research.

Inclusion and exclusion criteria

All subjects were in good general healthand had presented with at least 20 teethexcluding third molars and teeth indica-ted for extraction. All subjects werediagnosed with GAgP, based on the cur-rent International classification of theAmerican Academy of Periodontology

(Armitage 1999). The inclusion criteriawere as follows:

430 years of age; Minimum of six permanent teeth in-

cluding incisors and/or first molarswith at least one site each with prob-

ing depth (PD) and clinical attach-ment level (CAL)X5 mm and aminimum of six teeth other than firstmolars and incisors with at least onesite each with PD and CALX5mm;and

Familial aggregation (during the an-amneses, the subjects were askedwhether they had at least one othermember of the family presenting orwith a history of periodontal dis-ease).

The exclusion criteria were as fol-

lows: previous subgingival periodontaltherapy, smoking, pregnancy, systemicdiseases that could affect the progres-sion of periodontal disease (e.g. diabetesand immunological disorders), long-term administration of anti-inflamma-tory medication, need for antibioticcoverage for routine dental therapy,antibiotic therapy in the previous 6months and allergy to chlorhexidine(CHX), AMX and MTZ.

Experimental design

In this double-blinded, RCT, subjectswere randomly assigned using a compu-ter-generated table to one of the follow-ing treatment groups: Control (C): SRP1Placebo and Test (T): SRP1systemicMTZ at the dosage of 400 mg and AMXat the dosage of 500 mg. Subjects in theControl group received MTZ and AMXplacebos. Both antibiotics and placeboswere administered 3 per day for 14days. Supragingival biofilm control inboth groups was achieved by rinsingwith a 0.12% CHX solution. All sub-jects were instructed to gargle with

15 ml of CHX twice a day for 60 daysfor 1 min., i.e., in the morning, 30 min.after breakfast and tooth brushing, andat night, before going to sleep. Theantibiotic or placebo therapies and theCHX rinses started immediately afterthe first session of mechanical instru-mentation. Guarulhos University Phar-macy prepared the antibiotic andplacebo capsules for 30 subjects. Onehundred and twenty identical opaqueplastic packs with 21 capsules (30 packswith MTZ 400 mg, 30 with AMX500 mg, 30 MTZ placebo and 30 AMX

354 Mestnik et al.

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placebo) were sent to the study coordi-nator (M. Fa.), who marked the codenumber of each subject on a set oftwo packs, according to the therapyassigned. All the capsules in the placeboand antibiotics packs were identical.The coded packs were given to the

examiner (M. J. M.), who at no timeduring the study had any access toinformation about the contents of thetubes or the assignment of subjects tothe two therapies. In addition, all studypersonnel, including the biostatisticiansand participants, were blinded to treat-ment assignment during the study.

Before the study began, all subjectsreceived full-mouth supragingival scal-ing and instruction on proper home-caretechniques. They were also given thesame dentifrice to use during the periodof the study (Colgate Totals, Anakol

Ind. Com. Ltda- Kolynos do Brasil Colgate Palmolive Co., Sao Bernardodo Campo, SP, Brazil). All subjectsreceived full-mouth SRP performedunder local anaesthesia in a maximumof six appointments lasting approxi-mately 1 h each. Treatment of the entireoral cavity was completed in a max-imum period of 14 days. SRP wasperformed by one trained periodontistusing manual instruments. All subjectsreceived microbiological and clinicalmonitoring at baseline and at 3 monthspost-therapy.

Compliance and adverse events

The subjects were asked to bring thepacks containing the medication once aweek when compliance was checked.The packs contained 21 capsules ofeach placebo or antibiotic, enough for1 week of medication (21 capsules, 3 per day for 7 days). During these visits,subjects returned the old pack contain-ing the placebo or the antibiotic andreceived a new pack of medication/placebo. They also answered a questio-

nanaire about any self-perceived side-effects of the medication/placebo. Twostudy assistants conducted this inquiry,and were also responsible for calling thesubjects every 2 days to monitor com-pliance.

Clinical monitoring

Clinical monitoring was performed byone calibrated examiner (see Investi-gators Calibration) and the treatmentwas carried out by another clinician.Thus, the examiner and the clinician

were masked as to the nature ofthe treatment groups. Subjects wereclinically monitored at baseline and at3 months post-therapy. Visible plaque,gingival bleeding, bleeding on probing(BOP), suppuration, PD (mm) and CAL(mm) were measured at six sites per

tooth (mesiobuccal, buccal, distobuccal,distolingual, lingual and mesiolingual)in all teeth, excluding third molars.First, visible plaque was scored as pre-sent if a film of plaque was visible to thenaked eye after drying the tooth with ablast air. Gingival bleeding was scoredas present or absent by running theprobe 12 mm into the gingival crevice.Subsequently, the PD and CAL mea-surements were recorded to the nearestmillimetre using a North Carolina perio-dontal probe (Hu-Friedy, Chicago, IL,USA). The cemento-enamel junction

was detected by probing the cervicalarea of each tooth and was used tocalculate the CAL. BOP and supurationwere recorded as present or absent afterPD and CAL measurements.

Investigators calibration

The examiner participated in a calibra-tion exercise that was performed in 10non-study subjects with periodontitis.The examiner measured one quadrantper subject. The quadrant chosen had atleast six teeth. If a quadrant presented

fewer than six teeth, a second quadrantwas chosen. For better standardization,quadrant #1 was the first choice, fol-lowed by #2, #3 and #4, respectively.Initially, the examiner measured PD andCAL in a given quadrant and 60 min.later, this same protocol was repeated.Therefore, all 10 subjects were probedtwice in the same visit by the examiner.Upon completion of all measurements,the intra-examiner variabilities for PDand CAL measurements were assessed.Calibration was conducted according tothe protocol developed by Araujo et al.

(2003), and the standard error of mea-surement (SE) was calculated. The intra-examiner variability was 0.15 mm forPD and 0.19 mm for CAL.

Microbiological monitoring

Sample collection

Subgingival plaque samples were col-lected at baseline and at 3 monthspost-SRP from nine non-contiguousinter-proximal sites per subject. Theselected sites were randomized into dif-

ferent quadrants and subsets accordingto baseline PD, three samples in eachof the following categories: shallow(PD43 mm), intermediate (PD 46 mm) and deep (PDX7 mm). Afterthe clinical parameters had been re-corded, the supragingival plaque was

removed and the subgingival sampleswere taken with individual sterile mini-Gracey curettes (#1112) and immedi-ately placed in separate Eppendorf tubescontaining 0.15 ml of TE (10 mM Tris-HCl, 1 mM EDTA, pH 7.6). One hun-dred microlitres of 0.5 M NaOH wasadded to each tube and the sampleswere dispersed using a vortex mixer.

Checkerboard DNADNAhybridization

Counts of 40 bacterial species were

determined in each sample, using thecheckerboard DNADNA hybridizationtechnique (Socransky et al. 1994, Matar-azzo et al. 2008). The microbiologicalanalysis was entirely performed at theLaboratory of Microbiology of GuarulhosUniversity. The samples were boiled for10 min. and neutralized using 0.8 ml of5 M ammonium acetate. The releasedDNA was then placed into the extendedslots of a Minislot 30 apparatus (Immu-netics, Cambridge, MA, USA), concen-trated on a 15 15 cm positively chargednylon membrane (Boehringer Mannheim,

Indianapolis, IN, USA) and fixed to themembrane by baking it at 1201C for20 min. The membrane was placed in aMiniblotter 45 (Immunetics) with thelanes of DNA at 901 to the lanes of thedevice. Digoxigenin-labelled whole geno-mic DNA probes for 40 bacterial specieswere hybridized in individual lanes of theMiniblotter. After hybridization, themembranes were washed at high strin-gency and the DNA probes were detectedusing the antibody to digoxigenin conju-gated with alkaline phosphatase and che-miluminescence detection. The last two

lanes in each run contained standards atconcentrations of 105 and 10

6cells of

each species. Signals were evaluatedvisually by comparison with the standardsat 105 and 106 bacterial cells for the testspecies on the same membrane by acalibrated examiner (k test593%).They were recorded as: 05not detected;15o105 cells; 25 $ 105 cells;35105106 cells; 45 $ 106 cells; or55410

6cells. The sensitivity of this

assay was adjusted to allow detection of104 cells of a given species by adjustingthe concentration of each DNA probe.

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This procedure was carried out in order toprovide the same sensitivity of detectionfor each species. Failure to detect a signalwas recorded as zero, although conceiva-bly, counts in the 11000 ranges couldhave been present.

Primary and secondary outcome variables

This study compared the microbiologi-cal and clinical effects of two differentperiodontal therapies. The primary out-come variable of the study was changesin the mean proportion of the redcomplex species. Secondary outcomevariables included differences betweentherapies for the mean changes in themean levels and proportion of the 40bacterial species analysed, changes inthe mean percentage of sites colonizedby A. actinomycetemcomitans, P. gingi-

valis, T. forsythia and T. denticola,changes in the mean full-mouth PDand CAL, as well as in different initialPD categories and the percentage ofsites with PD changing from PDX5 mmto o5mm.

Statistical analysis

The mean percentage of sites with visi-ble plaque, gingival bleeding, BOP andsuppuration, as well as mean PD andCAL were computed for each subjectand then averaged across subjects in

both groups. Similarly, the changes inPD, CAL and BOP over time wereexamined in subsets of sites accordingto the initial PD of 43, 46 andX7 mm. Values for each clinical para-meter were averaged separately withinthe three PD categories in each subjectand then averaged across subjects in thetreatment groups. The mean counts( 105) of individual bacterial specieswere averaged within each subject andthen across subjects in both groups. Thepercentage of the total DNA probecounts was determined initially in each

site, then per subject and averagedacross subjects in the two groups. Theprevalence of A. actinomycetemcomi-tans, T. forsythia, P. gingivalis andT. denticola was computed by determin-ing the percentage of sites per subjectcolonized by each species and thenaveraging across subjects in the twogroups. The significance of differencesbetween the two groups for age and theclinical and microbiological parameterswas determined using the MannWhit-ney U-test. The Wilcoxon test was usedto detect statistically significant differ-

ences within each group between thetwo time points. Adjustments for multi-ple comparisons (Socransky et al. 1991)were performed when the 40 bacterialspecies were evaluated simultaneously.The chi-square test was used to comparethe differences in the frequency of gen-

der. The level of significance was set at5%.

Results

Subject retention

There were no drop-outs during thecourse of the experimental period. Allsubjects returned for the 3-month fol-low-up visit. Thus, a total of 30 subjectscompleted the study, 15 in the Controlgroup (SRP1Placebo) and 15 in theTest group (SRP1MTZ1AMX). Figure 1

presents the flow chart of the studydesign.

Adverse effects and compliance

All subjects who finished the studyreported full adherence to the prescribedcourse of the antibiotic/placebo and theCHX rinses. Two subjects, one from theTest group and one from the Controlgroup, reported adverse events (diar-rhoea and vomiting) during the study.All subjects reported that the medica-tions did not cause any major distur-

bance in their daily routine and thatthey would start the treatment again ifnecessary.

Microbiological findings

The two groups were microbiologicallyhomogeneous at the beginning of thestudy. No significant differences wereobserved between them in the meancounts and proportions of any of thetest species at baseline (data not shown,

p40.05). Figure 2 presents the meancounts ( 105) of the 40 species evalu-

ated over the course of the study. Thespecies were grouped according to themicrobial complexes described bySocransky et al. (1998). In general, thecounts of most of the host-compatiblespecies did not change significantlyfrom baseline to 3 months post-therapy(blue, purple, yellow and green com-plexes). Actinomyces naelsundi 2 pre-sented a significant increase in levels inboth groups and there was a significantreduction in the levels of Capnocyto-

phaga sputigena in the Test group. Areduction in the mean counts of several

periodontal pathogens from the red andorange complexes was observed, mainlyin the Test group (po0.05). Eubacter-ium nodatum was the only species fromthe orange complex that was reduced inthe Control group, while five species(C. rectus, E. nodatum, Fusobacterium

nucleatum ss. nucleatum, Parvimonasmicra and Prevotella intermedia) werereduced in the Test group. The counts ofthe three pathogens from the red com-plex, T. forsythia, P. gingivalis andT. denticola, were significantly reducedin the Test group, while SRP alone didnot significantly affect the levels ofT. denticola at 3 months (po0.05). Inaddition, four bacterial species notgrouped into complexes (Others)were also significantly reduced bythe antibiotic treatment (Eubacteriumsaburreum, Leptotrichia buccalis, Pro-

pionibacterium acnes and Treponemasocranskii).Figure 3 presents the mean percen-

tage of the DNA probe counts of the 40individual species evaluated at baselineand 3 months post-SRP. The proportionsof seven periodontal pathogens weresignificantly reduced in the Test group(C. rectus, E. nodatum, F. nucleatum ssnucleatum, P. intermedia, T. forsythia,P. gingivalis and T. denticola), whilefour periodontal pathogens werereduced in the Control group (E. noda-tum, T. forsythia, P. gingivalis and

T. denticola). In general, the proportionsof the putative periodontal pathogensfrom the orange complex were not pro-found affected by SRP alone. There wasan overall trend towards increasing pro-portions of the majority of the host-compatible microorganisms, such asthe Actinomyces species as well as thepurple, yellow and green complexesafter treatments, especially in the Testgroup. These changes were statisticallysignificant for A. naeslundi 2 and Strep-tococcus sanguinis in both treatmentgroups, for Actinomyces odontolyticus

and Veilonella parvula in the Test groupand for Streptococcus gordonii in theSRP group.

Figure 4 shows the changes in theproportions of the microbial complexesin the two groups at baseline and 3months post-treatments. The microbialprofiles were profoundly affected bytreatments, and the most beneficialchanges were observed in subjects whoreceived MTZ and AMX as part of thetreatment. These subjects showed a sig-nificant reduction in the proportions ofred and orange complexes from baseline

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to 3 months post-therapy as well as anincrease in the proportion of beneficial

Actinomyces species (blue complex),purple and yellow complexes. SRPalone led to a significant reduction inthe proportions of red complex and asignificant increase in the proportions ofblue, yellow and purple complexes.

Even though no differences in the pro-portions of the microbial complexeswere observed between the two groupsat baseline, at 3 months post-treatment,there was a significantly lower propor-tion of the red complex species in theTest group in comparison with the Con-trol group (po0.05).

Figure 5 presents the mean changebetween baseline and 3 months post-SRP in the mean counts ( 10

5) of A.

actinomycetemcomitans according tothe initial PD categories (43mm, 46mm and X7 mm). An overall reduc-

tion in the mean counts was observedfor both treatments in the three PDcategories. However, subjects in theTest group showed a significantly great-er reduction in the levels of this patho-gen in the initially deep sites (X7 mm),in comparison with the Control group(po0.05).

The mean percentages of sites colo-nized by A. actinomycetemcomitans andthe red complex species (T. forsyhtia,P. gingivalis and T. denticola) at baselineand at 3 months after treatments arepresented in Table 1. Both therapies ledto a statistically significant decrease in themean percentage of sites colonized bythese species, with the exception of

A. actinomycetemcomitans in the Controlgroup (p40.05). At 3 months post-SRP,the mean percentages of sites colonizedby these four bacterial species were sig-nificantly lower in the Test group in

comparison with the Control group forall the species analysed (po0.05).

Table 2 presents the frequency ofsubjects (nine sites per/subject) colonizedby A. actinomycetemcomitans at baselineand at 3 months post-SRP in the twotreatment groups. At baseline, all subjectsfrom the Control and Test groups were

colonized by A. actinomycetemcomitans.At 3 months after treatment, four subjectsin the Test group tested negative for A.actinomycetemcomitans and eight sub-jects presented this species in only onesite. On the other hand, in the Controlgroup, only two subjects tested negativefor A. actinomycetemcomitans after treat-ment and colonization by this species wasshown in two other subjects in only onesite. In addition, none of the subjects whotook antibiotics showed heavy coloniza-tion (X5 mm sites) by this pathogen aftertreatment.

Fig.1. Flow chart of the study design.




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Clinical findings

The demographic characteristics and thefull-mouth mean values of periodontalclinical parameters at baseline and at 3months after treatments are presented inTable 3. No statistically significant dif-

ferences were observed between groupsfor any parameter at baseline (p40.05).All therapies led to a statistically sig-nificant decrease in the mean PD, CALand in the percentage of sites withvisible plaque, gingival bleeding, BOPand suppuration. At 3 months post-SRP,the full-mouth mean PD was signifi-cantly lower in the Test group in com-parison with the Control group (Table 3)(po0.05). The mean changes in PD andCAL between baseline and 3 monthspost-therapy are presented in Fig. 6.These two parameters were more strik-

ingly reduced by the antibiotic therapy(po0.05; Fig. 6).

In order to better understand theeffect of the therapies and to allowmore comprehensive comparisonsbetween the groups, the sites were sub-set into baseline PD categories of shal-

low (43 mm), intermediate (46 mm)and deep (X7 mm), and the statisticalanalysis was repeated (Fig. 7). Thecombination of MTZ and AMX wasmore effective than SRP alone inimproving PD and CAL in all the cate-gories of PD. All these differences werestatistically significant, except for CALin initially shallow sites.

Figure 8 presents changes in the meanfull-mouth CAL for individual subjectsfrom all treatment groups at 3 monthspost-SRP. The median of CAL changein the 30 subjects of the study was

0.96 mm. The number of subjects show-ing CAL gain within or above this value(0.962.12) was 12 and 3 in the Test andControl groups, respectively. Conver-sely, the number of subjects presentingCAL change below 0.96 (0.92 to 0.04) was 3 and 12 for the Test and

Control groups, respectively.Table 4 presents the mean percentage

of sites with PDo5 or X5 mm at base-line and at 3 months post-treatments.The two groups were homogeneous forthese PD categories at baseline(p40.05). The percentage of sites withPDo5 mm increased significantly, andthose with PDX5 mm significantlydecreased in both treatment groupsover the course of the study. However,at 3 months post-treatment, the Testgroup showed significantly fewer siteswith PDX5 mm and more sites with

Fig.2. Mean counts ( 105

) of the 40 test species at baseline and 3 months post-SRP in the two treatment groups. The species were orderedaccording to the microbial complexes described by Socransky et al. (1998). The counts of individual species were averaged within a subjectand then across subjects in each treatment group at each time point. The significance of differences between baseline and 3 months post-SRPwas assessed using the Wilcoxon test (npo0.05), and adjusted for 40 comparisons (Socransky et al. 1991). SRP, scaling and root planing;MTZ, metronidazole; AMX, amoxicillin.

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PDo5 mm than the Control group. Thechanges observed in the mean percen-tage of sites with PDo5 mm or X5 mmbetween baseline and 3 months weremore striking in the Test group in com-parison with the Control group.

Discussion

Previous studies have reported addi-tional clinical benefits when systemicantibiotics, in particular the combinationof MTZ and AMX, are implemented aspart of the periodontal treatment ofsubjects with GAgP (Guerrero et al.2005, Xajigeorgiou et al. 2006, Kaneret al. 2007, Machtei & Younis 2008).Nonetheless, the effect of this therapeu-tic protocol on the microbial profile hasnot yet been established. Therefore, toour knowledge, the present study is thefirst RCT that has systematically eval-

uated changes occurring in the subgin-gival microbiota with the use of MTZand AMX in association with SRP forthe treatment of non-smoker subjectswith GAgP.

The Test group presented the mostfavourable changes in the subgingivalmicrobial profile after treatment. Thelevels and proportions of the red com-

plex pathogens (T. forsythia, P. gingi-valis and T. denticola) were morestrikingly reduced when the antibioticswere used. At 3 months post-SRP, theproportion of this complex was signifi-cantly reduced in the Test group (2.8%)in comparison with the Control group(8.1%) (Fig. 4). In addition, this therapyled to a significant reduction in theproportions of the putative pathogensfrom the orange complex, which wasnot observed in subjects who receivedonly SRP (Fig. 4). The only speciesfrom this complex affected by SRP

alone was E. nodatum (Figs 2 and 3).These results are in agreement with thedata reported by Xajigeorgiou et al.(2006), who also observed a significantreduction in the levels of the threespecies from the red complex 6 monthsafter the administration of MTZ andAMX.

A. actinomycetemcomitans is an

important periodontal pathogen impli-cated in the aetiology of AgP (Slots1976, Yang et al. 2004, Fine et al.2007, Haubek et al. 2008, Faveri et al.2009). There is a general agreement thatSRP alone cannot eliminate or strikinglysuppress the levels of this pathogen insubjects with periodontal disease(Renvert et al. 1990, Takamatsu et al.1999, Mombelli et al. 2000). Winkel etal. (1998) reported the beneficial effectsof the combination of MTZ and AMX inthe treatment of subjects colonized by

A. actinomycetemcomitans and Pavicic

Fig.3. Mean percentage of DNA probe counts of the 40 test species at baseline and 3 months post-therapy in the two treatment groups. Thespecies were ordered according to the microbial complexes described by Socransky et al. (1998). The proportion of each species in the totalDNA probe count was determined at each site, and then averaged within and across subjects in each treatment group at each time point.Significance testing is as described in Fig. 2. SRP, scaling and root planing; MTZ, metronidazole; AMX, amoxicillin.




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et al. (1992, 1994) suggested a possiblesynergistic effect of this combination ofdrugs in inhibiting this periodontalpathogen. Therefore, the combinationof AMX and MTZ was originally pro-posed for the elimination or the suppres-sion A. actinomycetemcomitans (van

Winkelhoff et al. 1989). Overall, in thepresent study, the two therapies did notsignificantly change the mean levels andproportion of A. actinomycetemcomi-tans when samples from all PD cate-gories were analysed (Figs 2 and 3).However, when the samples weredivided according to the initial PD cate-gories, the Test group presented a sig-nificant reduction in the levels of

A. actinomycetemcomitans in initiallydeep sites (X7 mm) compared with theControl group. In addition, there was asignificantly lower mean percentage andnumber of subjects colonized by

A. actinomycetemcomitans in the Testgroup in comparison with the Control

group (po

0.05) at 3 months post-ther-apy (Tables 1 and 2). These results arein agreement with previous studiesshowing that the success of periodontaltherapy in subjects with AgP was asso-ciated with the reduction of this bacter-ial species (Haffajee et al. 1984,Mandell et al. 1986; Xajigeorgiou etal. 2006). Nevertheless, it is importantto note that only four subjects in the test

group were negative for A. actinomyce-temcomitans after therapy. These resultsdiffer from previous studies that showedcomplete suppression of this pathogenin all subjects treated with SRP plusMTZ and AMX (van Winkelhoff et al.1989, Berglundh et al. 1998, Winkel et

al. 2001). However, in agreement withour data, Xajigeorgiou et al. (2006) didnot observe complete elimination of

A. actinomycemtecomitans in 10 deepperiodontal sites of GAgP subjects trea-ted with this combination of drugs. Theauthors treated 10 subjects with GAgPwith AMX plus MTZ and only onesubject tested negative for A. actinomy-cemtecomitans at approximately 5months after the antibiotic treatment.Likewise, Cortelli et al. (2009) chose50 subjects colonized by A. actinomy-cemtecomitans and treated them with

SRP plus MTZ, AMX and periodontalsurgery. The authors reported that only18 subjects tested negative for A. acti-nomycemtecomitans 12 months post-therapy. Some hypothesis could beraised to explain these conflicting resultsregarding the elimination of A. actino-mycetemcomitans. The first possibilityto be considered would be differences inthe microbiological test used by differ-ent authors, such as bacterial culture(van Winkelhoff et al. 1989, Berglundhet al. 1998, Winkel et al. 2001), poly-merase chain reaction (PCR) (Cortelli et

al. 2009) and checkerboard DNADNAhybridization (Xajigeorgiou et al. 2006)and the present study). However, it isimportant to highlight that these threediagnostic tests have excellent (PCR) tovery good (Bacterial culture and check-erboard DNADNA hybridization) sen-sitivity, and therefore they would all beeffective in detecting A. actinomycetem-comitans. It should also be consideredthat variations in the composition and in

Fig.4. Pie charts of the mean proportion of each microbial complex at baseline and 3 monthspost-SRP in the two treatment groups. The colours represent different microbial complexes(Socransky et al. 1998). The areas of the pies were adjusted to reflect the mean total counts ateach time point. The significance of differences between baseline and 3 months was assessedusing the Wilcoxon test (npo0.05). The significance of differences between treatment groupsat baseline and 3 months post-therapy was assessed using the MannWhitney U-test(po0.05; different letters indicate statistically significant differences). SRP, scaling androot planing; MTZ, metronidazole; AMX, amoxicillin.

Fig.5. Bar charts of the mean changes in mean levels ( 105) of Aggregatibacter actinomycetemcomitans at sites with initial probing depths43, 46 andX7 mm between baseline and 3 months post-SRP in the two treatment groups. The whiskers represent the SD. The significanceof difference between the two treatment groups was assessed using the MannWhitney U-test (npo0.05). SRP, scaling and root planing;MTZ, metronidazole; AMX, amoxicillin.

360 Mestnik et al.



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the complexity of the subgingival micro-biota (Haffajee et al. 2004, 2005) as wellas in the antibiotic susceptibility of perio-dontal pathogens (van Winkelhoff et al.2005) in distinct geographic locationsmay also contribute to differences in theeffectiveness of systemic antibiotics.

The proportions of the host-compati-ble species were also affected by treat-ments. Both groups showed a significantincrease in the proportions of the purple,yellow and especially in the Actino-myces species (blue complex) at 3months after SRP. It has been suggestedpreviously that in addition to the reduc-tion in pathogens, an increase in bene-ficial species is necessary to achieve asuccessful treatment outcome (Teles etal. 2006). This may be an even moreimportant requirement when dealingwith AgP. In a recent study conducted

by our group (Faveri et al. 2009), the

subgingival microbial composition ofsubjects with localized AgP and GAgPwas evaluated and compared with thatof periodontally healthy individualsor those with chronic periodontitis. Sub-jects with AgP presented reducedproportions of the host-compatible Acti-

nomyces species compared with thosewho had chronic periodontitis. The lowproportions of this microbial group(around 9%) were also confirmed inthe present investigation. Therefore,increased proportions of this microbialgroup may be necessary for a successfultherapeutic outcome. It should be notedthat the increase in the proportions ofthe Actinomyces species observed inboth treatment groups in the presentinvestigation was more striking thanthat observed in other studies that eval-uated the effect of these therapies in

chronic periodontitis subjects (Carvalho

et al. 2005, Matarazzo et al. 2008). Thiseffect may be attributed to the CHXrinsing that was used by all subjects inthe present study. Feres et al. (2009)have shown that the use of this antisep-tic during the SRP and the healing phasemay cause a drastic increase in the

proportions of Actinomyces species at3 months post-therapy.Both treatments used in the present

study improved the majority of theclinical parameters evaluated. However,in agreement with the microbiologicalfindings, the combination of MTZ andAMX with SRP yielded significant clin-ical benefits over SRP alone. Overall,benefits of the combined treatmentswere observed in the full-mouth dataanalyses (Table 3 and Fig. 6) and in allinitial PD categories, especially in theintermediate (46mm) and deep

(X7 mm) sites (Fig. 7). In addition, theindividual changes in mean CAL aftertreatments (Fig. 8) re-inforce the bene-fits of the test treatment also at a subjectlevel. Another important observation ofthe present study was the lower percen-tage of sites with PDX5 mm detectedafter treatment in the Test group, incomparison with the Control group(Table 1). Renvert & Persson (2002)reported that the presence of deep resi-dual pockets after treatment was asso-ciated with further disease progression.In addition, Matuliene et al. (2008)

stated that more than eight sites withPDX5 mm represent a risk factor foradditional attachment or tooth loss withan odds ratio of 5.8. Therefore, residualsites with PDX5 mm could be used as ameasure of need for further treat-

Table 1. Mean percentage of sites colonized by Aggregatibacter actinomycetemcomitans,

Tannerella forsythia, Porphyromonas gingivalis and Treponema denticola at baseline and 3

months post-SRP in the two treatment groups

Variable Time point Treatment groups

SRP (n5 15) SRP1MTZ1AMX (n5 15)

A. actinomycetemcomitans Baseline 62.6 28.0a 61.4 31.0a

3 monthsn 35.6 27.6a 14.0 14.8b

T. forsythia Baseline 81.6 28.0a 77.7 29.8a

3 monthsn 40.4 33.3b 5.9 10.1b

P. gingivalis Baseline 84.0 17.8a 81.3 25.3a

3 months

n

58.6

27.7

b

35.5

30.8

b

T. denticola Baseline 75.3 27.6a 69.5 24.8a

3 monthsn 38.0 33.9b 13.2 13.4b

The significance of differences between time points was assessed using the Wilcoxon test (different

small letters indicate po0.05). Significance of difference between groups was assessed using the

MannWhitney U-test (npo0.05).

Fig.6. Bar charts of the mean changes ( SD) in full-mouth probing depth, clinical attachment level and percentage of sites with bleeding onprobing between baseline and 3 months post-SRP in the two treatment groups. The whiskers represent the SD. The significance of differencebetween the two treatment groups for each clinical parameter was assessed using the MannWhitneyU-test (npo0.05; nnpo0.01). SRP,scaling and root planing; MTZ, metronidazole; AMX, amoxicillin.




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ment. In the present study, at 3 monthspost-SRP, the Test group showed a 79%reduction in the number of sites in needof further therapy, while the Controlgroup showed a reduction of 57%(Table 4). Overall, these findings agreewith and extend data from previousinvestigations that also suggested addi-

tional clinical benefits when MTZ andAMX are combined with SRP in thetreatment of GAgP. (Guerrero et al.2005, Xajigeorgiou et al. 2006, Kaneret al. 2007, Machtei & Younis 2008).

The clinical efficacy of adjunctivesystemic MTZ and AMX comparedwith SRP alone in GAgP subjects hasonly been investigated in two RCTs(Guerrero et al. 2005, Xajigeorgiou etal. 2006). In these two reports, at 6months post-SRP, the combination ofSRP plus AMX and MTZ resulted in amean full-mouth reduction of 1.2 and

Fig.7. Bar charts of the mean changes ( SD) in probing depth and clinical attachment level at sites with initial probing depths43, 46 and

X7 mm between baseline and 3 months post-SRP in the two treatment groups. The whiskers represent the SD. The significance of differencebetween the two treatment groups for each clinical parameter was assessed using the MannWhitneyU-test (npo0.05; nnnpo0.001). SRP,scaling and root planing; MTZ, metronidazole; AMX, amoxicillin.

Fig.8. Plots of the mean changes in individual full-mouth mean clinical attachment levelbetween baseline and 3 months post-SRP of subjects in the two treatment groups. The circlesrepresent the mean value of each subject. The dashed line represents the median of change ofthis clinical parameter in all 30 subjects. Positive values represent a gain in clinicalattachment level (CAL), while negative values represent a loss in CAL at 3 months post-SRP. SRP, scaling and root planing; MTZ, metronidazole; AMX, amoxicillin.

362 Mestnik et al.



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1.5 mm in PD, and a mean CAL gainof 0.8 and 0.9 mm, respectively. In thepresent study, the Test group showed a

reduction of 1.6 mm in PD and a CALgain of 1.3 mm. In addition, in initiallydeep sites (PDX7 mm), the mean CAL

gain at 3 months was 2.0 and 3.2 mm forthe Control and Test groups, respec-tively. Beneficial results were alsoobserved in the initially intermediateand shallow sites. Overall, these resultsare somewhat better than those reportedby Guerrero et al. (2005) and Xajigeor-

giou et al. (2006), even for the subjectsin the Control group. One possibleexplanation for these differences is thefact that the studies differ to some extentregarding the treatment protocols used.It should be highlighted that in thepresent study, both groups rinsed with0.12% CHX for 2 months. Indeed, pre-vious studies demonstrated the clinicaland microbiological benefits of the opti-mal supragingival plaque control usingCHX rinses during and after SRP insubjects with chronic periodontitis(Faveri et al. 2006, Feres et al. 2009).

In addition to the beneficial clinicaland microbiological results observed inthe present study, it was also interestingto observe that only two subjects (6.6%,one from the Control and one from theTest group) presented adverse events.This result is in accordance with aprevious study from our group thatused the same antibiotic protocol in thetreatment of smokers with chronicperiodontitis (Matarazzo et al. 2008).

One limitation of the current study isthe short-term evaluation period.Indeed, longitudinal monitoring of these

subjects will be important in order todetermine whether this combination oftherapies would produce sustained ben-eficial changes in the subgingival micro-bial profile and periodontal clinicalparameters over time. Nevertheless, ithas been suggested that the short-termchanges in the microbial profile maydetermine long-term periodontal clinicalstability (Winkel et al. 2001, Haffajee2003, Matarazzo et al. 2008). Becausethe effects of this antibiotic protocol onthe subgingival microbial profile are notyet known, the 3-month data presented in

this manuscript provide important infor-mation for the periodontal literature.

In conclusion, the use of MTZ andAMX in combination with SRP yieldsshort-term additional clinical and micro-biological advantages in the treatmentof GAgP.

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Putative periodontal pathogens in subgingival

Table 2. Frequency of subjects colonized by Aggregatibacter actinomycetemcomitans at baseline

and 3 months post-SRP in the two treatment groups

Number of sites

colonized

Number of subjects colonized by A. actinomycetemcomitans

control test control test

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24 3 5 7 3

X5 11 9 4 0

Control, SRP; Test, SRP1MTZ1AMX.

Table 3. Demographic characteristics and mean ( SD) full-mouth clinical parameters at base-line and 3 months post-therapy in the two treatment groups

Variable Time point Treatment groups

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Gender (male/female) Baseline 4/11 6/9

Age (years) Baseline 27.6 3.5 26.8 3.9

% sites withPD43 mm Baseline 47.8 17.3 51.7 11.7PD 46 mm Baseline 37.5 16.8 31.9 10.9

PDX7 mm Baseline 14.7 8.3 16.4 12.3

PD (mm) Baseline 4.1 0.6a 4.3 0.7a

3 monthsn 3.2 0.6b 2.7 0.5b

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% of sites with

Plaque accumulation Baseline 62.7 22.4a 61.3 19.8a

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small letters indicate po0.05). Significance of the difference between groups was assessed using the

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small letters indicate po0.05). Significance of the difference between groups was assessed using the

MannWhitney U-test (npo0.05). SRP, scaling and root planing; MTZ, metronidazole; AMX,

amoxicillin; PD, probing depth.




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Address:

Marcelo Faveri

Centro de Pos-Gr aduaca o e Pesquisa-CEPPEUniversidade Guarulhos

Praca Tereza Cristina, 58 Centro

07023-070 Guarulhos, SP

Brazil

E-mail: [email protected]

Clinical Relevance

Scientific rationale for the study: It isgenerally accepted that the associa-tion of MTZ plus AMX with SRPbenefits the treatment of GAgP sub-jects. However, only a few controlledclinical trials to date have addressed

this topic, and the microbial effectsof this treatment have not yet beeninvestigated.Principal findings: Subjects receivingsystemic antibiotics showed additionalbeneficial changes in the compositionof the subgingival microbiota and in

the clinical parameters in comparisonwith those receiving SRP only.Practical implications: The morestriking effects of MTZ plus AMXin the subgingival microbial profileleads the short-term clinical advan-tages in the treatment of GAgP.


mailto:[email protected]:[email protected]

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