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Antimicrobial therapy inperiodontitis: the use of systemicantimicrobials against the

subgingival biofilm

Herrera D, Alonso B, Leo n R, Roldan S, Sanz M. Antimicrobial therapy in

periodontitis: the use of systemic antimicrobials against the subgingival biofilm. J ClinPeriodontol 2008; 35 (Suppl. 8): 4566. doi: 10.1111/j.1600-051X.2008.01260.x.

Abstract

Objectives: The aim was to answer three relevant questions: can systemic

antimicrobials be efficacious if the biofilm is not disrupted? Can the type ofdebridement of the subgingival biofilm impact upon the clinical outcomes of theadjunctive antimicrobial therapy? Is the efficacy of the adjunctive systemicantimicrobial therapy dependent on the quality of the debridement of the subgingival

biofilm and the sequence debridementantibiotic usage?

Material and Methods: Relevant papers were searched, critically analysed and theirdata were extracted.

Results: For the first question, studies assessing susceptibility of bacteria in biofilms,and clinical studies evaluating systemic antimicrobials as monotherapy, were

reviewed. For the second question, clinical studies comparing systemic antimicrobialsas adjuncts to non-surgical debridement or to periodontal surgery and clinical trialsusing systemic antibiotics with periodontal surgery were evaluated. For the thirdquestion, a previous systematic review was updated.

Conclusion: If systemic antimicrobials are indicated in periodontal therapy, theyshould be adjunctive to mechanical debridement. There is not enough evidence tosupport their use with periodontal surgery. Indirect evidence suggests that antibioticintake should start on the day of debridement completion, debridement should be

completed within a short time (preferably o1 week) and with an adequate quality,to optimize the results.

Key words: biofilm; non-surgical; periodontitis;surgical therapy; systemic antimicrobials

Accepted for publication 20 May 2008

David Herrera1

, Bettina Alonso1

,Ruben Leon2, Silvia Roldan1 and

Mariano Sanz1

1ETEP Research Group, Faculty of

Odontology, University Complutense of

Madrid, Madrid, Spain; 2Faculty of

Odontology, University of Chile, Santiago de

Chile, Chile

Periodontal diseases, specifically perio-

dontitis, are caused by pathogenic bac-terial species located in the subgingivalniche. These bacterial species adhere to

the tooth surfaces and are organized in a

complex structure, the dental plaque,which has been considered recently asan example of a biofilm (Marsh 2005).The presence of these pathogenic bac-teria within complex bacterial commu-nities may have important implicationsin the use of antimicrobial therapiesaimed to fight against them. In fact, atthe 5th European Workshop of Perio-dontology, it was concluded that dentalplaque displays properties that are typi-cal of biofilms and microbial commu-nities in general, a clinical consequenceof which is a reduced susceptibility to

antimicrobial agents as well as patho-

genic synergism (Marsh 2005).The use of systemic antimicrobials as

part of the therapy in the management of

periodontal diseases has been debatedfor decades. The adjunctive benefits ofusing systemic antimicrobials in thetreatment of periodontitis have beenreported in two systematic reviews pre-sented at European (Herrera et al. 2002)and World (Haffajee et al. 2003)Workshops. At the European Workshop,Herrera et al. (2002) concluded that inspecific clinical situations, such as withpatients with deep pockets, patients with

Conflict of interest and source of

funding statement

The authors declare that they have no

conflict of interests.

The 6th European Workshop on Perio-dontology was supported by an unrest-

ricted educational grant from StraumannAG.

No funding was provided for this paper.

J Clin Periodontol 2008; 35 (Suppl. 8): 4566 doi: 10.1111/j.1600-051X.2008.01260.x

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progressive or active disease, or withspecific microbiological profiles, thisantimicrobial therapy adjunctive toscaling and root planing (SRP) couldbe clinically relevant. However, Haffajeeet al. (2003) concluded that, althoughthere are sufficient data to suggest that

antibiotics might help in the treatmentof periodontitis, the optimum protocolof use has not been clearly defined.This lack of clear protocols of use maybe due in part to the specific propertiesof biofilms, which make subgingivalperiodontal pathogens more difficult totarget, and, therefore, the developmentof strategies specifically designed totreat the subgingival microflora, as abiofilm, is highly desirable. In themean time, treatment strategies basedon conventional therapies should beadapted to the present knowledge on

biofilms.Among the factors related to systemicantimicrobial usage in the treatment ofperiodontal diseases, adverse effectsshould be taken into account: in parti-cular, side effects for individualpatients, as well as the increase inbacterial resistance, which is a majorglobal public health problem. Thesefactors should be considered when pre-scribing systemic antimicrobials, andthey should not be used routinely butrather in certain patients and underdefined periodontal conditions (Herrera

et al. 2002, Lindhe & Palmer 2002).One of the key issues related to the

use of systemic antimicrobials in thetreatment of periodontitis has been theimportance of biofilm disruption. Speci-fically, three questions can be raised,which are very relevant clinically andstill somehow controversial:

1. Can systemic antimicrobials be effi-cacious if the biofilm is not dis-rupted? This question may also beformulated at a more clinician level:if a systemic antimicrobial will be

prescribed for the treatment of perio-dontitis, is there a need for adjunctiveroot debridement or will it be effi-cient as sole therapy?

2. Can the type of debridement (non-surgical versus surgical) of the sub-gingival biofilm impact upon theclinical outcomes of the adjunctiveantimicrobial therapy? This questionmay also be formulated at a moreclinician level: if a systemic antimi-crobial is prescribed as an adjunctiveto the treatment of severe perio-dontitis, should it be used as an

adjunctive to SRP or to surgicaldebridement?

3. Is the efficacy of the adjunctive sys-temic antimicrobial therapy depen-dent on the quality of thedebridement of the subgingival bio-film and the sequence debridement

antibiotic usage? This question mayalso be formulated at a more clini-cian level: if a systemic antimicrobialis going to be used as an adjunctivetherapy to debridement, at whichmoment of the treatment shouldthe antimicrobial be prescribed andhow that debridement should be per-formed (chronology, sessions, qual-ity, etc.)?

In addition, the reported adverseeffects of the adjunctive use of sys-temic antimicrobials were assessed.

The aim of the present review is tocarry out a critical evaluation of theavailable literature with the objectiveof defining the best therapeutic protocolof systemic antimicrobial use in thetreatment of periodontitis, by answeringthe three questions raised above.

Can Systemic Antimicrobials be

Efficacious if the Biofilm is Not

Disrupted?

Methods

Two different aspects were assessed toanswer this question: the biofilm char-

acteristics that prove that bacteriaarranged in organized communitiesdemonstrate a higher level of resistanceagainst antimicrobials, and clinical stu-dies evaluating the outcomes of the useof systemic antimicrobials as monother-apy, both compared with the use ofantimicrobials plus debridement, debri-dement alone and no therapy.

Biofilm resistance against antimicrobials

Different explanations have been sug-gested to explain the resistance of bio-films against antimicrobial agents:

The biofilm extra-cellular matrix(Mah & OToole 2001).

Different physiological phases ofthe microorganisms within a biofilm(Dibdin et al. 1996, Anderl et al.2003, Walters et al. 2003).

Horizontal gene transfer (Robertset al. 1999, Roberts & Stewart 2004).

Molecular mechanism of commu-nication among bacterial cells,

Quorum Sensing (Roberts & Mul-lany 2000).

Biofilm resistance against antimicrobials

in dental biofilms

The dental biofilm share most of the

features of other currently known bio-films (Costerton & Lewandowski 1997,Darveau et al. 2000, Bjarnsholt et al.2005), with antimicrobial resistancebeing of special relevance (Haffajee &Socransky 2000). A number of publica-tions have studied dental biofilms invitro, showing an increase in resistanceagainst amoxicillin, metronidazole anddoxycycline (Larsen 2002), in Porphyr-omonas gingivalis biofilms, and also for

Streptococcus constellatus, Aggregati-bacter actinomycetemcomitans andP. gingivalis, always as single-species

biofilms, for antibiotics such as clinda-mycin, doxycycline, metronidazole andmoxifloxacin (Noiri et al. 2003). Withmore complex biofilms (higher numberof species), using saliva samples fromdifferent patients, most of the bacterialspecies growing in a biofilm, demon-strated high levels of resistance againsttetracycline, minocycline, amoxicillin,doxycycline and amoxicillin/clavula-nate. Moreover, mature biofilms showeda higher degree of tolerance for antimi-crobial agents (Eick et al. 2004).

Because of this, different authors

have suggested that minimum inhibitoryconcentration (MIC) profiles should bedetermined for bacteria as part of abiofilm and not in the planktonic state.We currently lack, however, a standar-dized method to perform this type oftest. Although considerable efforts havebeen made to assess bacterial resistancein biofilms, many different methodolo-gies have been used, which makes itdifficult to effectively compare theresults among studies and thus provideguidelines of therapeutic value (Domingueet al. 1994, Sedlacek & Walker 2007).

Very recently, the first description ofresistance in the oral biofilm, due tohorizontal gene transference, wasreported in vivo, when Streptococcuscristaceus acquired a transposon thatconferred doxycyline resistance from astrain of Streptococcus oralis. Bothstrains were isolated from the subgingi-val biofilm in patients undergoing dox-ycycline therapy as part of theirperiodontal treatment (Warburton et al.2007). This transfer had been observedpreviously in non-oral strains, such astwo strains of Staphylococcus aureus

46 Herrera et al.

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that acquired an operon associated withvancomycin resistance (vanA operon)from Enterococcus faecalis strains(Weigel et al. 2003).

Clinical and microbiological outcomes of

the use of systemic antimicrobials as

monotherapy in the treatment ofperiodontitis

Two systematic reviews have recentlyaddressed the question of the efficacy ofusing systemic antimicrobials in thetreatment of periodontitis. One of thesereviews focused on the use of systemicantimicrobials as an adjunctive to SRPtherapy (Herrera et al. 2002); the otherreview assessed its adjunctive use both

to SRP and to periodontal surgery andwhen used as a monotherapy (Haffajeeet al. 2003). As monotherapy, four stu-

dies were included evaluating eithermetronidazole alone (Clark et al. 1983,Lindhe et al. 1983a) or metronizadolecombined with amoxicillin (Lopez et al.2000, Winkel et al. 2001). From thethree meta-analyses performed (one foradjunctive therapy to SRP, other tosurgery and as monotherapy), the useas monotherapy was the only one notreaching significant results (mean effectof 0.849mm, p5 0.083) and, therefore,the conclusion in the consensus reportwas that there was insufficient evi-dence to support the use of systemic

antibiotics as a monotherapy in perio-dontitis patients.

When reviewing the studies selectedin the systematic review presented at thefourth European Workshop (Herreraet al. 2002), some of the studies hadsplit-mouth design (see Table 1), andtherefore in these studies half of themouth was not scaled, and their resultscould also be assessed comparing theuse of the antibiotic as monotherapywith either no treatment, SRP alone orSRP plus adjunctive antimicrobial. Theadministration of tetracycline as mono-

therapy (Hellden et al. 1979) had only aminor effect on the clinical and micro-biological parameters examined, andthis effect was transient, being notice-able at the 8-week interval, but not after25 weeks. This was especially clear forthe microbiological outcomes (Listgartenet al. 1978). In another study usingtetracycline for 50 weeks (Lindhe et al.1983b), the clinical effect in a group ofpatients with excellent plaque con-trol was similar to that obtained withSRP in the control group, although arebound to a more pathogenic micro-

flora was observed after the end of theantibiotic therapy. When doxycyclinewas studied (Ng & Bissada 1998), andalthough a statistical analysis betweenscaled and non-scaled sites was onlyprovided for the placebo group, thefigures showed a limited or null impact

when doxycycline was used as mono-therapy. With metronidazole (Lindheet al. 1983a), the repeated subgingivaldebridement in the SRP and SRP plusantimicrobial groups resulted in morepronounced reduction of the inflamma-tory infiltrates than in the monotherapygroup. Finally, the combination ofmetronidazole and amoxicillin has alsobeen evaluated in a split-mouth design(Berglundh et al. 1998), concluding thatthe antibiotic regimen alone was lesseffective than mechanical therapy in thereduction of sites with bleeding on prob-

ing (BOP), probing pocket depth (PPD)and gain in clinical attachment levels(CALs). However, in the monotherapygroup there was a microbiologicalimpact observed at 2 months that lastedfor at least 12 months, when combinedwith a meticulous supragingival plaquecontrol.

These split-mouth studies were notdesigned to evaluate systemic antimi-crobials as monotherapy, but there isanother group of split-mouth and paral-lel studies specifically designed to eval-uate this issue. These studies are not

very numerous and most of the availableliterature has evaluated metronidazole.When a single dose of 2 g of metroni-dazole was compared with SRP andno treatment in a parallel study of 3months, a similar clinical and microbio-logical outcome was observed in bothmetronidazole and in SRP groups at 1month. These benefits, however, wereonly maintained at 3 months in the SRPgroup (Walsh et al. 1986). This positiveclinical and microbiological outcome ona short-term basis (4 weeks) was alsoobserved in a split-mouth study in

women using metronidazole 250 mg,q.i.d., for 7 days (Lekovic et al. 1983).In another split-mouth study, SRP plusmetronidazole demonstrated a signifi-cant clinical benefit in terms of PPDand BOP reductions at 3 months, whilemetronidazole alone showed only minorimprovements (van Oosten et al. 1987).No improvements were observed, after 3months, in a study with a similar design,for SRP plus metronidazole or metroni-dazole alone, in patients with inadequateoral hygiene and previous SRP 3 monthsearlier (Jenkins et al. 1989). When the

effect of metronidazole was comparedwith a placebo in a double-blind design,differences between groups were evi-dent, but the impact of the monotherapywas very limited, leading the authors torecommend adjunctive therapy (Wattset al. 1986). In summary, monotherapy

with metronidazole can result in PPDreductions ranging 02.4 mm, but withlimited CAL gain and reduction inbleeding. The results are inferior orequivalent at most, in a short-term basis,to the results achieved by SRP. Whencompared with the results obtained withthe use of adjunctive metronidazole,monotherapy results are significantlylower (Greenstein 1993).

Recently, two studies from the sameresearch group have reported on the useof antimicrobials as monotherapy inmoderate to advanced periodontitis

(Lopez & Gamonal 1998, Lopez et al.2006). The first is a double-blind clin-ical study comparing amoxicillin plusmetronidazole versus placebo during4 months. The authors concluded thatantibiotics were able to change theproportions of periodontal pathogens inthe subgingival flora and to significantlyimprove the clinical outcomes assessed.In the second publication, also reportingon a double-blind study, comparingamoxicillin plus metronidazole andsupragingival scaling versus SRP andtwo placebos for 12 months, similar

clinical results were observed in bothgroups, and the microbiological resultswere maintained for up to 12 months.

With the exception of these two stu-dies (Lopez & Gamonal 1998, Lopezet al. 2006), the rest of the reviewedliterature does not support the use ofsystemic antimicrobials as monotherapyin periodontitis. This conclusion wasalready published in 1993 when Greenstein(1993) reviewed the role of metronida-zole in the treatment of periodontaldiseases and concluded that its usageas sole therapy should not be recom-

mended, because only its adjunctive useto SRP had demonstrated clinical effi-cacy. Later, the 1996 position paper onsystemic antibiotics by the AmericanAcademy of Periodontology also sug-gested that systemic drugs should onlybe used as adjunctive therapy, based onthe concept of good medical practice(debridement should precede medica-tion), and the results of the reviewedstudies (AAP 1996). This conclusionwas later confirmed by Slots (2004),and the results of a systematic reviewand the following consensus report

Systemic antimicrobial therapy against the biofilm 47



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(Haffajee et al. 2003). However, themethodology of the reviewed paperson monotherapy was, in most cases, oflow quality. This should be taken intoaccount when interpreting the data.

Can the Type of Debridement (Non-Surgical versus Surgical) of the

Subgingival Biofilm Impact Upon the

Clinical Outcomes of the Adjunctive

Antimicrobial Therapy?

As discussed previously, the use ofsystemic antimicrobials can improvethe clinical and microbiological out-comes of periodontal mechanical ther-apy. Systemic antimicrobials have beenused mainly as an adjunct to basicperiodontal therapy (SRP) and enoughevidence exists to support this combinedtherapy (Herrera et al. 2002, Haffajee et

al. 2003). However, in certain situations,periodontal surgery may be necessaryand in these cases there is controversywith regard to when it is more effectiveto prescribe the systemic antimicrobial:either in conjunction with basic perio-dontal therapy or together with thesurgical phase.

In order to answer this question, wehave reviewed the efficacy of theadjunctive systemic antimicrobial useto periodontal surgery.

Methods

A search was performed in PubMed,with the following strategy: (perio-dontitis OR periodontal) AND (surgeryOR surgical) AND (antibiotic OR anti-microbial). The search was restricted topapers published in English language, inhumans, clinical trials, randomized clin-ical trials (RCT), meta-analysis andreviews.

In addition, we carried out a handsearch of the most relevant scientific

journals in Periodontology, such as

Journal of Clinical Periodontology and Journal of Periodontology, togetherwith the evaluation of secondary refer-ences from relevant papers and reviewarticles in order to supplement thesearch. Most of the included paperswere obtained by hand search.

Results

In the literature, there are many studiesdescribing the added effect of adminis-tering systemically antibiotics as anadjunct to periodontal surgery, ranging

from case reports to RCT. The numberof RCTs available is, however, limited.Therefore, we have also considered casereports and cohort studies in the evalua-tion. The available literature was classi-fied into three levels, according to thelevel of evidence provided to answer the

proposed question.

Comparative studies between SRP plus

antibiotics versus periodontal surgery

plus antibiotics

There is not one single clinical trial inthe searched literature with this design.Only a study by Palmer et al. (1996)may provide some evidence to answer

this question. This study was an RCTthat evaluated the efficacy of adjunctivesystemic tetracycline in the non-surgical

and surgical management of 38 patientswith aggressive periodontitis (early-onset periodontitis, as defined in thepaper), and they concluded that tetracy-cline was a useful adjunct, especially tonon-surgical treatment. Firstly, patientswere instructed in oral hygiene, fol-lowed by SRP and the prescription ofeither tetracycline 250 mg, q.i.d., for 14days, or a placebo, in a randomized,double-blind basis. After 3 months, amodified Widman flap was recom-mended at teeth with PPDX5 mm andBOP. The same course of tetracycline or

placebo was repeated, with an adjunc-tive 0.12% chlorhexidine mouthwash.Clinical evaluations were performed atbaseline, 3, 6 and 12 months, and so3-month results were available after boththe non-surgical and the surgical phase.Thirty-eight patients completed the non-surgical phase and 26 completed thesurgical phase. There was a reductionin PPD at 3 months, which was signifi-cantly greater in the test group. Bothgroups demonstrated CAL gains, withslightly more in the antibiotic group(statistically significant). There were

further reductions in mean PPD aftersurgery, which were maintained at12 months. No further statistically sig-nificant gain in CAL was observed fol-lowing surgery. The differences betweengroups (tetracycline versus placebo)were not statistically significant. Thecomparison of mean PDD and CALchanges following surgery suggests thatno further advantage was obtained by theantibiotic in the surgical phase, althoughthis may also be a result of the smallernumber of subjects and fewer sites trea-ted in the surgical phase.

RCTs comparing periodontal surgery plus antibiotic versus periodontal

surgery plus placebo

This group of studies has evaluatedantimicrobials as adjuncts to the surgicaltreatment of periodontitis, aiming toenhance both clinical and microbiologi-

cal outcomes (see Table 2).A meta-analysis by Haffajee et al.

(2003) reviewed three studies andincluded four comparisons (Kunihiraet al. 1985, Haffajee et al. 1995, Palmeret al. 1996). They reported that systemi-cally administered antimicrobial agentsprovide a significant clinical benefit interms of mean CAL gain (weightedmean 0.609, p50.007). Individually,the included comparisons suggestedbenefits of the adjunctive antimicrobial,although often not statistically signifi-cant. In addition, different drugs (peni-

cillin, tetracycline, amoxicillin plusclavulanate) were pooled in the meta-analyses.

Another group of RCTs has evaluatedthe adjunctive effect of selected antimi-crobial agents, such as ofloxacin(Kleinfelder et al. 2000) or azithromycin(Dastoor et al. 2007), combinedwith periodontal surgery, in the treat-ment of chronic periodontitis in A. acti-nomycetemcomitans-positive patients(Kleinfelder et al. 2000) or in chronicperiodontitis in smokers (Dastoor et al.2007). Ofloxacin plus surgery resultedin a significant CAL gain and in thesuppression of A. actinomycetemcomi-tans below detectable levels for at least12 months (Kleinfelder et al. 2000).Conversely, in heavy smokers, adjunc-tive azithromycin with periodontal sur-gery in one quadrant did notsignificantly enhance PDD reduction orCAL gain, although they observed fasterwound healing, and less gingival inflam-mation at the short-term evaluation(Dastoor et al. 2007).

Case reports, cohorts studies and other

clinical trials

The rationale of using systemic antibio-tics as part of a surgical protocol mayalso be based on other reasons, such as:

As an adjunct in the treatment ofspecific disease profiles (activeor refractory diseases, severe dis-eases, smokers, etc.), with perio-dontitis that could require a moreaggressive treatment.




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To prevent post-surgical complica-tions, including infection.

In periodontal surgery aiming forperiodontal regeneration.

Specific disease profiles

Because of the concept of specificinfection and the key role that A. actino-

mycetemcomitans may play, particularlyin localized aggressive periodontitis(described in the papers as localized

juvenile periodontitis), the adjunctiveuse of systemic antimicrobials withperiodontal treatment has received con-siderable attention, both clinically andscientifically. The reported results, how-

ever, do not demonstrate consistent find-ings. Although systemic antimicrobialscombined with non-surgical mechani-cal debridement were able to improvetreatment outcomes in many studies,this therapy often failed to eliminate

A. actinomycetemcomitans from subgin-gival areas. One hypothesis to explain

Table 2. Study design, patients and treatment features of selected papers assessing systemic antimicrobials as adjuncts to periodontal surgery

Author and year AB Country Study design Groups Follow-

up

Patients Age Disease description

Palmer et al. (1996) TET, placebo UK RCT 2 12 m 38 1224 EOP (30 L./8 G.)

Kunihira et al. (1985) PEN, placebo USA RCT 2 62 m 16 o30y L.JPHaffajee et al. (1995) TET, AUG,

placebo

USA RCT 4 10 m 40 48 12 Active, pockets 44 mm

Kleinfelder et al. (2000) OFLO Germany CCT 2 12 m 35 Aa-adv. P.Dastoor et al. (2007) AZI, placebo USA RCT (pilot

study)

2 6 m 30 ne modadv Ch.P, heavy smokers

Lindhe & Liljenberg (1984) TET Sweden Cohort study 2 5 y 28 1418/ 3948

JP versus adult P.

Kornman & Robertson

(1985)

TET USA Case series 1 Staged 8 1223 JP

Mandell et al. (1984) DOX, TET local USA Case series 1 264 d 4 1318 Active JP

Jaffin et al. (1984) TET USA Case series 1 4 y 4 JP

Mahmood & Dolby (1987) MET, placebo UK RCT (cross-

over)

2 6 m 15 2952 modadv P.

Soder et al. (1999) MET, placebo Sweden RCT 8 5 y 98 36.5 2.8 Ch.P. (smokers versus non-

smokers)

Haffajee et al. (1988) TET USA Case series 2 6 m 33 1742 Active PD.

Muller et al. (1993b) MIN Germany Case series 1 24 m 33 1363 Aa-P.

Muller et al. (1993a) MIN Germany Case series 1 24 m 33 Aa-P.

Author and year Treatment sequence Type of SURG AB dosage

Palmer et al. (1996) OHI1SRP1(TET versus placebo) followed bySURG1CHX1(TET versus placebo)

Modified Widman flap TET 250, 4 , 14 d

Kunihira et al. (1985) OHI1SRP followed by SURG1(PEN versus placebo)

then SPT

Open curettage PEN 250, 4 , 10d

Haffajee et al. (1995) SRP1SURG1CHX1(TET versus AUG versusplacebo versus IBU) then SPT

Modified Widman flap TET 250, 3 , 30d;AUG 375/125, 3 , 30d

Kleinfelder et al. (2000) OHI1supra1SURG1(OFLO versus nothing) then

SPT

Open flap surgery OFLO 200, 2 , 5 d

Dastoor et al. (2007) SRP followed by SURG1CHX1Ibuprofen1(AZI

versus placebo)

Apically positioned flap AZI 500, 1 , 3 d

Lindhe & Liljenberg (1984) SUR1CHX1TET then SPT Modified Widman flap TET 250, 4 , 14d

Kornman & Robertson (1985) SRP followed by (TET1SRP versus SPT) followedby SURG1TET

Modified Widman flap TET 250, 4 , 28d

Mandell et al. (1984) Local TET followed by DOX1(SURG versusnothing)

Flap without osseous re-countouring

DOX 100, 1 , 14 d

Jaffin et al. (1984) OHI1TET followed by SURG1TET Prichards technique TET 250, 4 , 28d

Mahmood & Dolby (1987) OHI1SRP followed by SURG1CHX1(MET versus

placebo)

Modified Widman flap MET 200, 3 , 7 d

Soder et al. (1999) SRP1(MET versus placebo) followed by SURG

followed by SPT

Modified Widman flap MET 400, 3 , 7 d

Haffajee et al. (1988) SURG1TET Modified Widman flap TET 250, 4 , 21d

Muller et al. (1993b) OHI1supra followed by SRP1CHX1MIN followedby SURG1MIN1CHX then SPT

Modified Widman flap MIN 200, 1 , 3 w

Muller et al. (1993a) OHI1supra followed by SRP1CHX1MIN followed

by SURG1MIN1CHX then SPT

Modified Widman flap MIN 200, 1 , 3 w

PEN, phenoxymethyl penicillin; TET, tetracycline; AUG, amoxicillin/clavulanate; OFLO, ofloxacin; AZI, azithromycin; DOX, doxycycline; MET,

metronidazole; MIN, minocycline; ORNI, ornidazole; CIP, ciprofloxacin; EOP, early onset periodontitis; JP, juvenile periodontitis; P, periodontitis; L.,localized; G., generalized; mod, moderate; adv, advanced; Ch., chronic; PD, periodontal disease; Aa, A. actinomyctemcomitans; OHI, oral hygiene

instruction; SRP, scaling and root planing; SURG, surgery; supra, supragingival prophylaxis; SPT, supportive periodontal therapy; w, weeks; d, days; m,

months; y, years.

50 Herrera et al.



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this failure was the possibility that A. actinomycetemcomitans may invadethe periodontal tissues, and, therefore,different studies were designed to evalu-ate whether periodontal surgery togetherwith systemic antimicrobials could over-come this problem and significantly

improve the results.Early studies assessing this hypoth-esis suggested that a more predictableresult was achieved with the combina-tion of SRP, surgery and systemicallyadministered tetracycline (Lindhe &Liljenberg 1984, Kornman & Robertson1985) or doxycycline (Mandell et al.1984). These favourable results wereattributed to the suppression of subgin-gival A. actinomycetemcomitans, or, atleast, its eradication in a large percen-tage of sites (Lindhe & Liljenberg 1984,Kornman & Robertson 1985). In some

studies, microbiological assessmentswere also performed, but plaque sam-ples were usually taken from a limitednumber of sites. These studies, in gen-eral, should be interpreted with caution,because some of them demonstrated anadded beneficial effect provided by theantibiotics, but this effect was not neces-sarily consistent from one study toanother. In addition, some of these stu-

dies included small samples: from fourpatients (Jaffin et al. 1984, Mandellet al. 1984) to eight patients (Kornman& Robertson 1985). Moreover, studydesigns also showed important limita-tions such as: split-mouth designs(Mandell et al. 1984), clinical protocols

of sequential stages of treatment(Kornman & Robertson 1985), casereports (Jaffin et al. 1984) or lack of aproper control group (Jaffin et al. 1984,Lindhe & Liljenberg 1984). Morerecently, despite clinical improvements(mean CAL gain of at least 2 mm andmean residual PPDo4 mm), A. actino-mycetemcomitans was not eliminatedfrom pooled subgingival samples inany of the patients treated with adjunc-tive minocycline to modified Widmanflap. Therefore, the authors concludedthat the evaluated protocol would be

appropriate in localized forms of perio-dontitis in A. actinomycetemcomitans-positive patients, but inappropriate inmore severe and generalized forms(Muller et al. 1993a, b).

Additional studies have evaluated theadjunctive effect of selected antimicro-bial agents, such as metronidazole(Mahmood & Dolby 1987, Soder et al.1999) or tetracycline (Haffajee et al.

1988), combined with periodontal sur-gery in the treatment of other perio-dontal conditions. In the treatment ofmoderate to severe periodontitis,adjunctive metronidazole to surgery(Mahmood & Dolby 1987) did not sig-nificantly improve the effects of surgery

and placebo, although a positive benefitin the group using metronidazole couldbe observed. In subjects showing currentdisease progression, adjunctive tetracy-cline (Haffajee et al. 1988) improved theresults in CAL gain and decreased thelevels of some suspected periodontalpathogens while increasing the levelsof certain beneficial species. In smo-kers, who tend to have a less favourableresponse to periodontal therapy, the useof antimicrobials, such as metronidazolein combination with surgery, had alimited additional effect (Soder et al.

1999).

To prevent post-surgical complica-tions, including infection (Table 3).

Periodontal surgery, as any othersurgery in the oral cavity, may beassociated with the risk of developing

post-operative complications, such asinfection (suppuration, pain, swelling,

Table 3. Study design, patients and treatment description of selected papers assessing post-surgical infection

Author and year AB Country Design Patients Surgeries,

n

Treatment plan Periodontal surgery

Pack & Haber(1983)

PEN,ERY USA Retrospective 218 927 SURG1(PEN or ERY) Different periodontal,osseous and mucogingival

SURG

Powell et al.

(2005)

Not

defined

USA Retrospective 395 1.053 SURG1AB Different periodontal,

osseous and mucogingivalSURG

Checchi et al.

(1992)

TET Italy Retrospective 231 498 OHI1SRP then SURG1TET(53/

498)1CHX

360 osseous contouring, 138

mucogingival SURGAppleman et al.

(1982)

CEP,

placebo

USA CCT 31 SURG1(CEP versus placebo) Apically positioned flap

Kidd & Wade

(1974)

PEN,

placebo

UK RCT 17 SURG1(PEN versus placebo) Curettage1osseous

re-contouring

Author and year AB dosage AB-moment Rate of infection With AB Without AB

Pack & Haber (1983) PEN 250, 4 , 7 d or

ERY 250, 4 , 7 d

Day of surgery 9/927 (1%) 1/43 (2%) 8/884 (o1%)

Powell et al. (2005) Not defined Pre- and/or post-surgery 22/1053 (2.09%) Pre- and post-surgery

8/281 (2.85%),

pre-surgery 1/29 (3.45%)

14/772 (1.81%)

Checchi et al. (1992) TET 250, 4 , 7d Immediately after surgery 21/498 (4.20%) 2/53 (3.80%) 19/445 (4.40%)Other variables

Appleman et al. (1982) CEP 500, 4, 3 d 1 h before Bacteremia, pain, swelling,

antibiotic susceptibility

Kidd & Wade (1974) PEN 250, 4 , 5 d Immediately before surgery Pain, swelling, healing,number of aspirins

AB, antibiotics; PEN, penicillin; ERY, erythromycin; TET, tetracycline hydrochloride; CEP, cephalexin; SURG, surgery; CHX, chlorhexidine; RCT or

CCT, randomized or controlled clinical trial; d, days.




8/22

redness, bacteraemia). However,whether the administration of systemicantimicrobials diminishes this risk isstill a matter of controversy and thisadjunctive use of systemic antibioticswith different surgical procedures isbased more on empiricism than on

scientific data.The main argument for the contro-versy is the low incidence of infectionsreported after periodontal surgery, ran-ging from 1% for all procedures (Pack& Haber 1983), 2.09% (Powell et al.2005) or 4.2% (Checchi et al. 1992). Itshould be pointed out that most of thesestudies are retrospective, with a limitedsample size, ranging from 218 patientsand 927 surgical procedures (Pack &Haber 1983), to 231 patients and 498surgical procedures (Checchi et al.1992). Only one large-scale, retrospec-

tive study (Powell et al. 2005), of multi-ple surgical modalities in differentperiodontal practices, included 395patients and 1053 surgical procedures.Perhaps it is necessary to design and

conduct comprehensive and accuratesurveys to further explore the preva-lence of clinical infections post-surgically, and thus being able to assesswhat risk factors are relevant in theirdevelopment and which treatment pro-tocols are able to significantly reduce its

occurrence.Although some studies have reportedthat adjunctive use of antibiotics canreduce pain and swelling, and canimprove wound healing and treatmentoutcomes, when compared with a pla-cebo, no statistically significant differ-ences were found. Some reports (Kidd& Wade 1974) support the concept thathealing is more rapid and the discomfortis smaller under antibiotic (penicillin)coverage during periodontal surgery.However, other studies (Pack & Haber1983, Checchi et al. 1992, Powell et al.

2005) do not support the routine use ofprophylactic antibiotics, such as tetra-cyclines (Checchi et al. 1992), penicillinor erythromycin (Pack & Haber 1983)and cephalexin (Appleman et al. 1982),

because these regimens were ineffectivein preventing post-operative infection.They concluded that unless there is amedical indication, there is no justifica-tion for using prophylactic antibiotic inperiodontal surgery. Even in somereports, an indiscriminate and prolonged

use of antibiotics may result in a higherrate of infection. In addition, the risksinvolved with the use of systemic anti-biotics (adverse events, etc.) mustalways be considered against the limitedbenefits.

In conjunction with periodontal sur-gery aiming for periodontal regen-eration (Table 4).

Studies evaluating regenerative pro-cedures with barrier membranes show awide variability and lack of predictable

results. Negative outcomes after thesesurgical procedures have been asso-ciated with membrane exposure andsubsequent membrane infection andcontamination of the healing wound

Table 4. Study design, patients and treatment features of selected papers assessing systemic antimicrobials as adjuncts to regenerative surgery

Author and year AB Country Design Groups Length Patients Age Indication

Nowzari et al. (1996) AMO1CLAV USA Cohorts 2 6 m 42 2969 23 wall defects

Mombelli et al. (1996) ORNI, placebo Switzerland RCT (split mouth) 2 2 50 w 10 3565 Class II furcation

Demolon et al. (1994) AMO1CLAV USA CCT 2 1 y 15 3670 Class II furcation

Demolon et al. (1993) AMO1CLAV USA CCT 2 4 w 15 3670 Class II furcationNowzari et al. (1995) AMO1CLAV USA RCT 2 24 w 18 3771 23 wall defects

Loos et al. (2002) AMO1

MET The Netherlands RCT (split mouth) 2

2 12 m 25 2 proximal defects X6 mmSculean et al. (2001) AMO1MET Germany RCT 2 1 y 34 1 intra-bony defect

Vest et al. (1999) MET1CIP1DOX USA RCT 2 9 m 24 Class II furcation

Author and year Treatment sequence Regenerative

technology

Dosage (mg) Sequence

AB-surgery

Nowzari et al. (1996) (SRP versus SURG) followed by

GTR1IBU1CHX1AUG followed by SPT

ePTFE AMOX1CLAV 5001125, 3 , 8d 1h prior

membrane

Mombelli et al. (1996) OHI1SRP1(GTR versus non GTR & ORNIversus placebo) followed by SPT

ePTFE ORNI 1000, 1 , 10 d 2 w after firstsurgery

Demolon et al. (1994) SRP1GTR1CHX1(AUG versus nothing) ePTFE AMOX1CLAV 2501125, 3 , 10d 1 h beforesurgery

Demolon et al. (1993) SRP1GTR1CHX1(AUG versus nothing)

followed by SPT

ePTFE AMOX1CLAV 2501125, 3 , 10d 1 h before

surgery

Nowzari et al. (1995) OHI1

SRP followed byGTR1IBU1CHX1(AUG versus nothing)

followed by SPT

ePTFE AMOX1

CLAV 5001

125, 3

, 8d 1h priormembrane

Loos et al. (2002) OHI1supra1SRP1SURG1CHX followed byCHX1(AMOX1MET versus nothing & GTR

versus non)

Polylactic acid AMOX1MET 3751250, 3 , 7 d 4 d beforeSURG

Sculean et al. (2001) OHI1supra1SRP followed by

EMD1CHX1(AMOX1MET versus nothing)followed by SPT

Enamel matrix

proteins

AMOX1MET 3751250, 3 , 7d First day of

surgery

Vest et al. (1999) GTR1CHX1(MET1CIP1DOX versus

nothing)

Polylactic

acid1DFDBA

MET (250, 3 ), CIP (250, 2 );

DOXY (50, 1 ); 7d

First day of

surgery

PEN, phenoxymethyl penicillin; AMO, amoxicillin; CLAV, clavulanate; CIP, ciprofloxacin; DOX, doxycycline; MET, metronidazole; MIN,

minocycline; ORNI, ornidazole; IBU, ibuprofen; OHI, oral hygiene instruction; SRP, scaling and root planing; SURG, surgery; supra, supragingival

prophylaxis; SPT, supportive periodontal therapy; DFDBA, demineralized freeze-dried bone allograft; GTR, guided tissue regeneration; ePTFE,

expanded polytetrafluoroethylene; RCT or CCT, randomized or controlled clinical trial; w, weeks; d, days; m, months; y, years.

52 Herrera et al.



9/22

(Murphy 1995, Nowzari et al. 1996),which result in reduced regeneration.Because of this, most researches inves-tigating regenerative procedures haveused adjunctive systemic antibiotics aspart of the surgical protocol (Cortellini& Bowers 1995, Machtei & Schallhorn

1995, Cortellini & Tonetti 2000, Korn-man & Robertson 2000, Sanz & Gio-vannoli 2000). However, the study ofPowell et al. (2005), which evaluatedthe prevalence of post-surgical infec-tions after various periodontal surgicalprocedures, concluded that the use ofregenerative membranes did not signifi-cantly increase infection rates (3.00%)compared with the non-use of membranes (1.88%).

The rationale for using antibiotics inthese procedures is to try to increase thepredictability of the results by control-

ling the subgingival microflora in theearly healing phase, in order to reducethe risk of post-operative infection andthus reduce the chance of bacterial con-tamination of the exposed membranes.However, the clinical utility and thelong-term efficacy of the use of systemicantibiotics during regenerative surgicalprocedures can be questioned.

The most relevant study design toassess the value of systemic antimicro-bials in regenerative procedures is theone including a group with surgery plusantibiotic and another group with sur-

gery plus placebo or nothing. Some ofthese studies have shown an additionalbenefit in the regenerative outcomes inthe test group, either with amoxicillinplus clavulanate (Nowzari et al. 1995)or ornidazole (Mombelli et al. 1996).Other reports, however, indicate that thegroup with adjunctive antibioticsshowed significant improvements inthe evaluated clinical parameters, butdid not have any significant effect onosseous healing in class II furcationdefects (Vest et al. 1999). Demolonet al. (1993, 1994) found large differ-

ences among individuals and lack ofsufficient bone formation to fill any ofthe furcation defects, indicating a lowpredictability of the procedure. In addi-tion, they observed, at the 1-year re-entry surgery, that bone filling waslimited and not consistent with theobserved clinical improvements. Theyconcluded that the use of antibiotic mayhave helped to control initial inflamma-tion (Demolon et al. 1993), but it had nodirect effects of clinical significance onbone regeneration or soft tissue attach-ment at 12 months (Demolon et al.

1994). Other authors question this addedclinical benefit of applying barrier mem-branes and systemic antibiotics, becausenone of them were relevant factors, andonly smoking has a strong impact on thetherapeutical outcomes in intra-osseousdefects (Loos et al. 2002).

Studies of guided tissue regenerationwith and without antibiotics have useddifferent regimens (Table 4). Currently,there are no studies that have comparedthe effects of different antibiotic regi-mens, or the best time to prescribe them,but it is important to consider that themicrobial colonization of the mem-branes begins within 3 min. after theirinsertion into the mouth (Nowzari et al.1996). The wide variation in the regi-mens used demonstrates that there is nogeneral agreement among clinicians onwhich is the most appropriate antibiotic,

its dose, duration of therapy or the timeto begin its administration.In most of the published studies eval-

uating the efficacy of the application ofenamel matrix derivatives (EMD) inregenerative periodontal surgery, apost-operative antibiotic regimen wasused. Very few studies have comparedthis surgical approach with and withoutthe systemic administration of antibio-tics. Sculean and colleagues have per-formed one such study and theyobserved no differences between treat-ments, indicating that the positive heal-

ing can be in great part be attributed tothe use of EMD. This study shows thatcareful patient selection, a meticuloussurgical technique and close post-opera-tive plaque control are more importantfactors for the outcome of the therapythan the routine administration of anti-biotics. It should be emphasized that theapplication of EMD in periodontalregenerative surgery leads to fewerpost-surgical complications than forother regenerative approaches, such asthe use of barrier membranes or graftmaterials and, consequently, the possi-

bility of a post-operative infection islower (Sculean et al. 2001).

Is the Efficacy of the Adjunctive

Systemic Antimicrobial Therapy

Dependent on the Quality of the

Debridement of the Subgingival

Biofilm and the Sequence

DebridementAntibiotic Usage?

Because subgingival bacteria are orga-nized in biofilms, in principle, they are

less susceptible to antimicrobials, unlessthere is a previous disruption bymechanical debridement and in thismanner the antimicrobial results shouldbe improved.

Following this rationale, threehypotheses can be proposed:

The better the quality of the debri-dement, the better the results.

Debridement should precede anti-biotic intake.

The time elapsed between the debri-dement and the antibiotic intakeshould be reduced to a minimum, inorder to avoid biofilm re-organization.

Methods

Search and selection of relevant papers

In order to evaluate these hypotheses,the previous systematic search carriedout 5 years ago was extended (Herreraet al. 2002). Briefly, studies wereselected if they were designed as RCTor controlled clinical trials (CCT) inwhich systemically healthy patientswith either aggressive periodontitis(Ag.P.) or chronic periodontitis (Ch.P.)were treated with SRP plus systemicantimicrobials in comparison with SRPalone or with placebo, and followed for

a minimum of 6 months. The mainoutcome measures that were consideredin these trials were changes in CALand PPD.

The extended search was performedin PubMed, with the following strategy:

(periodontitis OR periodontal dis-eases) AND (antibiotic OR antimicro-bial OR metronidazole ORciprofloxacin).

The search was restricted to RCT,CCT, systematic reviews and guide-lines, from 2001 to October 2007, andpapers published in English.

A total of 202 references wereretrieved. After screening of the titlesand abstracts by two independent

reviewers (D. H. and S. R.), 22 paperswere considered as suitable and full-length papers were obtained.

The full-length paper revealed thattwo papers did not fulfil the inclusionexclusion criteria (Purucker et al. 2001,Loesche et al. 2005), with regard toreported study design and outcome vari-ables, and to the use of local antibiotictherapy, respectively, and two morewere already present in the papers




10/22

selected for the previous systematicreview (Golub et al. 2001, Siguschet al. 2001).

Finally, 18 papers were selected, andtheir data were analysed and extracted.During data extraction, an additionalpaper (Giannopoulou et al. 2006) was

excluded, because the sample was thesame as in another included paper(Mombelli et al. 2005) and the outcomevariables were just related to gingivalcrevicular fluid.

After data extraction, the appropriate-ness of including papers evaluating theefficacy of low-dose doxycycline (LDD)was considered. This drug was includedin the previous systematic review(Herrera et al. 2002), due to the anti-microbial nature of the molecule,although it was not used for its antimi-crobial activity. In this review, because

this drug is used on a long-term basis,and its mode of action will not provideany information with respect to the pro-posed questions, we decided not toinclude the data from the selected papers,or from the LDD papers selected in 2002(Caton et al. 2000, Golub et al. 2001).

From the 17 newly selected papers,eight dealt with LDD (Caton et al. 2001,Novak et al. 2002, Emingil et al.2004a,b, Lee et al. 2004, Preshawet al. 2004, Mohammad et al. 2005,Needleman et al. 2007) and were notconsidered for the data analysis. There-

fore, nine additional papers (Rooneyet al. 2002, Smith et al. 2002, Ehmkeet al. 2005, Guerrero et al. 2005, Mas-carenhas et al. 2005, Mombelli et al.2005, Xajigeorgiou et al. 2006, Gomiet al. 2007, Haffajee et al. 2007) wereidentified together with the 23 studiesselected in 2002, after excluding theother referred studies assessing LDD(Caton et al. 2000, Golub et al. 2001).

Data from 32 papers were analysed,including 45 test groups comparing 10different systemic antimicrobials(amoxicillin, metronidazole, spiramy-

cin, azithromycin, tetracycline, doxycy-cline, clindamycin) or combinations(amoxicillin plus metronidazole, spira-mycin plus metronidazole, amoxillinplus clavulanate), in populations from10 different countries (Japan; the UnitedStates and Canada; Finland, Sweden, theNetherlands, the United Kingdom,Germany, Greece and Switzerland) inthree continents.

Five pairs of papers reported resultsfrom the same sample material: Listgar-ten et al. (1978) reported site-basedresults from the same sample from

which Hellden et al. (1979) describedfull-mouth results; Joyston-Bechal et al.(1984) described 22-week results fromthe same population that Joyston-Bechalet al. (1986) reported 3-year results;similarly, Ehmke et al. (2005) described24-month results from the same study as

the 12-month report of Flemmig et al.(1998); Palmer et al. (1998) first pre-sented the results for the whole popula-tion and later compared the results ofsmokers and non-smokers (Palmer et al.1999); and finally, McCulloch et al.(1990) and Kulkarni et al. (1991) alsodescribed results from the same patientsample.

The study design, characteristics ofthe patient sample and description ofperiodontitis of the 32 papers are sum-marized in Table 1.

Data extraction and evaluation

A number of factors were considered toevaluate the quality of debridement:

Operator (dentist, hygienist or dentalstudent).

Use of local anaesthesia (yes or no). Total time spent in debridement (in

hours).

Number of days of active (debride-ment) treatment.

Chronology of debridement (debri-

dement only once as initial therapy,or subsequent debridement sessionsat later stages).

The drug dosage was evaluated bycalculating the total dosage, also takinginto account the duration of the prescrip-tion and the number of cycles.

The relation between the debridementand the antibiotic usage was evaluatedas follows:

With debridement (coincidence of

both antibiotic and debridement,both starting the same day and last-ing equally).

With debridement plus additionaltime of drug intake (similar to theprevious, but the antibiotic lastedlonger than debridement).

Immediately after debridement(antibiotic intake starts after thelast session of debridement).

With new debridement (antibioticwas given when a subsequent debri-dement was performed, not afterinitial debridement).

Mostly before debridement (most ofthe antibiotic was taken before thedebridement was completed).

Delayed.

In addition, data on adverse eventswere also extracted and evaluated.

To assess the clinical efficacy of the

adjunctive therapy, three outcome vari-ables were compared between the testand placebo groups: changes in PPD, inCAL and in BOP. If multiple variablesfor the same measurement were avail-able, the one with significant results wasselected.

Results

Amoxicillin plus metronidazole (Tables

5a and 5b)

Seven comparisons were available, two

of them belonging to the same patientsample at two different time periods: 12(Flemmig et al. 1998) and 24 months(Ehmke et al. 2005). All comparisonsshowed an advantage in clinical out-comes for the test groups, most ofthem statistically significant. One studyin advanced periodontitis (Rooney et al.2002) and another in generalized Ag.P.(Guerrero et al. 2005) demonstratedstatistically significant improvementsover SRP alone in the three selectedoutcome variables (PPD, CAL andBOP). In these two studies, the debride-

ment was performed by periodontists,anaesthesia was used (if needed) and 34 h were spent. Most of the antibioticwas taken after debridement. In contrast,in the studies reporting less beneficialresults, debridement was performed byless experienced clinicians, and in thestudy that did not find significant differ-ences (Flemmig et al. 1998), debride-ment was performed by dental students.

Metronidazole (Tables 5a and 5b)

Data from 14 comparisons were avail-

able. Two sets of three comparisonsreported results from the same patientsample: one study reported results after22 weeks for all patients (Joyston-Bechal et al. 1984), or 22 weeks and 3years for the patients who finished thestudy (Joyston-Bechal et al. 1986);another study reported first results forthe whole sample (Palmer et al. 1998)and then stratified by smoking status(Palmer et al. 1999).

Three of the studies described verypositive results for the adjunctive treat-ment, and five positive results. Conversely,

54 Herrera et al.



11/22

Table5a.Factorsaffectingdebridementandantibioticintakeinstudiesevaluatingamoxicillinplusmetronidazoleormetronidazole

Authorandyear

Operator/s

Anaesthesia

Sessions

Tim

espent

(h)

PeriodofDB

ABuse

PreviousordelayedDBDays

mgper

dose

In

takes/

day

Totaldosage

Amoxicillin1metronidazole

Berglundhetal.

1998)

Notstated

Yes

35

NA

Not

described

WithDB(all?)

No

143751250

3

15,7

50110,5

00

Flemmigetal.

(1998)

Dentalstudent

Yes

4

8

Not

described

ImmediatelyafterDB

No

83751250

3

900016000

Rooneyetal.

(2002)

Periodontist

Yes

NA

3

712d

ImmediatelyafterDB

No

72501200

3

525014200

Guerreroetal.

(2005)

Periodontist

Asneeded

1

4

1d

WithDB16d

No

75001500

3

10,5

00110,5

00

Mombellietal.

(2005)

Oneclinician

Notexplained

24

NA

1w

WithnewDB(local)

PreviousDB

73751250

3

787515250

Ehmkeetal.

(2005)

Dentalstudent

Yes

4

8

Not

described

ImmediatelyafterDB

No

83751250

3

900016000

Xajigeorgiouetal.

(2006)

Oneclinician

Yes

4and1

NA

2wandNA

WithnewDB

PreviousDB6wbefore

75001500

3

10,500110,5

00

Metronidazole

Lindheetal.

(1983b)

Notstated

Notexplained

4

NA

2w

WithDB

NewABcycles(two)

14n

200

4

33,6

00

Joyston-Bechaletal.

(1984)

Hygienist

Notexplained

2

NA

1w

ImmediatelyafterDB

NewAB(1)1DB(2)

cycles

5w

200

3

6000

Loescheetal.

(1984)

Notstated

Notexplained

NA

NA

Not

described

WithDB(all?)

No

7

250

3

5250

Joyston-Bechaletal.

(1986)

Hygienist

Notexplained

2

NA

1w

ImmediatelyafterDB

NewAB(1)1DB(2)

cycles

5w

200

3

6000

Joyston-Bechaletal.

(1986)

Hygienist

Notexplained

2

NA

1w

ImmediatelyafterDB

NewAB(1)1DB(2)

cycles

5w

200

3

6000

Soderetal.

(1990)

Hygienist

Notexplained

NA

25

Not

described

1mafter

No

7

400

3

8400

Saxen&Asikainen(1993)

Dentalstudent

Notexplained

NA

NA

Not

described

Unclear

NewDBevery3months

10

200

3

6000

Palmeretal.

(1998)

Hygienist

Yes

2

3

1w

ImmediatelyafterDB

No

7

200

3

4200

Palmeretal.

(1999)

Hygienist

Yes

2

3

1w

ImmediatelyafterDB

No

7

200

3

4200

Palmeretal.

(1999)

Hygienist

Yes

2

4

1w

ImmediatelyafterDB

No

7

200

3

4200

Siguschetal.

(2001)

Hygienistand

not

stated

Notexplainedand

yes

45and1

2

NA

and24NAand2dImmediatelyafterDB

PreviousDB

8

500

2

8000

Rooneyetal.

(2002)

Periodontist

Yes

NA

4

712d

ImmediatelyafterDB

No

7

200

3

4200

Xajigeorgiouetal.

(2006)

Oneclinician

Yes

4and1

NA

2wandNA

WithnewDB

PreviousDB6wbefore

7

500

3

10,5

00

Haffajeeetal.

(2007)

Dentists

Yes

4

NA

3w

With1stand2ndq

DB

No

14

250

3

10,5

00

wTwocyclesofdrug.

DB,debridement;AB,antibiotic;NA,nota

vailable;w,weeks;m,months.




12/22

Table5b.

Clinicaloutcomesofstudiesevaluatingamoxicillinplusmetronidazoleorm

etronidazole

Authorandyear

Variable

SRPSRP1AB

SRPversus

SRP1AB

Variable

SRP

SRP1AB

SRPversus

SRP1AB

Variable

SRPSRP1AB

SRPversus

SRP1AB

PPD

changechange

interStats

CAL

change

change

interStats

BOP

changechange

interStats


Berglundhetal.

(1998)

%45(012mm)

23%

36%

NS

X6

1.5

2.1

o0.0

5

4s/t(024

months)

49%

58

%

NS

Flemmigetal.

(1998)

X7mm

1.0

32

1.4

05

NS

6s/t(base4

6mm)

26.8

%

33.0

3%

NS

Rooneyetal.

(2002)

%45mm

6.90%

14.6

0%

o0.0

01

4s/t(%sites

CAL45mm)

6.1

0

10.6

0

o0.0

5

4s/t;%BOP

20.7

0%

39.8

0%

o0.

001

Guerreroetal.

(2005)

%46mm

5.30%

10.8

0%

o0.0

5

X7

1.3

2.3

o0.0

01

6s/t

21%

32

%

0.

02

Mombellietal.

(2005)

2s/p(44m

m)

1.6

2.6

SS(at6m)

2s/p(44mm)

0.4

2.3

0.0

2

2s/p(44mm)20.0

%

30.0%

NS

Ehmkeetal.

(2005)

X7mm

0.3

1.7

o0.0

5

Xajigeorgiouetal.

(2006)

nsites46m

m

58%

80%

o0.0

5

6s/t,allsites

0.4

8

0.9

2

NS

6s/t,allsites

63.0

%

72.0%

NS

Metronidazole

Lindheetal.

(1983b)

4s/p(X6mm)%

46mm

72%

66%

NoStat

4s/pX6mm

1.6

1.8

NoStat

BOPis

Gi5213

89%

84

%

NoStat

Joyston-Bechaletal.

(1984)

Allteeth,4

s/t

0.93

1.18

o0.0

5(at22w)

Loescheetal.

(1984)

Allteeth(baselineX6mm)1.55

3.19

0.0

3

X6

0.2

3

1.4

2

0.0

5

Joyston-Bechaletal.

(1986)

Allteeth,4

s/t

0.62

1.03

NS

Joyston-Bechaletal.

(1986)

Allteeth,4

s/t

0.9

1.28

NS

Soderetal.

(1990)

4s/t(deeperofm

esialand

distal)

0.41

0.46

NS

NS

Saxen&Asikainen

(1993)

4s/t;only43(

%43)

7.30%

16.0

0%

NoStat

4s/t;

only43mm

12.4

%

21.5%

NoStat

Palmeretal.

(1998)

6s/tonly44.5mm

1.7

1.5

NS

6s/tonly44.5mm

0.5

1

0.6

7

NS

6s/t

Only44.5mm

7.2%

11.9%

NS

Palmeretal.

(1999)

6s/tonly44.5mm

1.98

1.83

NS

6s/tonly44.5mm

0.5

3

0.7

9

NS

6s/t

Only44.5mm

28.2

%

44.0%

NS

Palmeretal.

(1999)

6s/tonly44.5mm

1.12

1.2

NS

6s/tonly44.5mm

0.4

7

0.4

3

NS

6s/t

Only44.5mm

47.4

%

46.6%

NS

Siguschetal.

(2001)

6s/t,

baseline3

w;X6

1.1

4.3

SS

6s/t,

baseline3w

(X6)

0.1

2.8

SS

Rooneyetal.

(2002)

4s/t,

%45mm

6.90%

10.8

0%

o0.0

50.0

01

4s/t(%sites

CAL45mm)

6.1%

9.4%

NS

4s/t;%BOP

20.7

0%

29.3

0%

NS

Xajigeorgiouetal.

(2006)

6s/t,

%4

6

58%

87.8

0%

o0.0

5

6s/t,allsites

0.4

8

1.2

4

NS

6s/t,allsites

63.0

%

59.0%

NS

Haffajeeetal.

(2007)

6s/t,46

1.66

2.96

o0.0

1

6s/t,46mm

1.2

6

2.4

5

po0.0

5

Inbold,inter-groupstatisticallysignificantdifferencesinchangesbaselinefinalevaluatio

n;inboldplusitalics,inter-groupstatistically

significantdifferencesatafollow-upvisit.

SRP,scalingandrootplaning;AB,antibiotic;NA,notavailable;Stats,statisticalanalys

es;inter,inter-group;intra,intra-group;s,site;p,patient;t,tooth;NS,notstatisticallysignificant;SS,statistically

significant;PPD,probingpocketdepth;CAL,clinicalattachmentlevel;BOP,bleedingonprobing;w,weeks;d,days;m,months.

56 Herrera et al.



13/22

six studies were not able to detectstatistically significant differences.

From these studies, no clear trend wasfound, although it seems that dosagewas more relevant in the results thanfactors related to debridement. Morerecent studies, prescribing higher

dosages and including patients withmore aggressive forms of periodontitis,tended to report better results.

Doxycycline (Tables 6a and 6b)

Five comparisons were selected, two ofthem from the same patient sample(McCulloch et al. 1990, Kulkarni et al.1991). One of the studies showed verygood results, with statistically significantinter-group differences. Two additionalstudies found significant differences, butonly intra-group (Kulkarni et al. 1991) or

at a specific visit (Ng & Bissada 1998).The other two studies did not reportsignificant benefits in aggressive perio-dontitis patients, and the results for dox-ycycline were poor in comparison withthose using other antimicrobial agentsevaluated (Sigusch et al. 2001, Xajigeor-gion et al. 2006).

No clear trend could be observedregarding quality of debridement,because the beneficial effects wereobserved only in one report in activesites in refractory cases.

Tetracycline (Tables 6a and 6b)

Data were available from five compar-isons, although two of them belonged tothe same patient sample (Listgartenet al. 1978, Hellden et al. 1979).

None of them demonstrated addi-tional benefits. The drug prescriptionwas made in coincidence with thedebridement period, as most classicalstudies did. The most recent study asses-sing tetracycline was published in 1993.

Amoxicillin and amoxicillin plusclavulanate (Tables 6a and 6b)

Only one study assessed amoxicillinalone, and showed additional benefitsin terms of PPD reductions. In thisstudy, debridement was performed by aperiodontist within 712 days, and thedrug was prescribed after the last ses-sion of SRP. In contrast, no statisticallysignificant advantage was observed bythe three studies evaluating amoxicillinplus clavulanate. Although informationon the quality of debridement was not

clear, the drug was given 6 weeksafter SRP in one study (Winkel et al.1999), another did not provide statisticaldata (Walker et al. 1993) and twostudies only reported results fromselected active sites in refractorypatients (Walker et al. 1993, Magnusson

et al. 1994).

Azithromycin (Tables 6a and 6b)

Four studies were available, all of thempublished since 2002. Two of themdemonstrated statistically significantbenefits in PPD, and in either CAL(Mascarenhas et al. 2005) or BOP(Gomi et al. 2007). In both studies,Ch.P. patients were included. In theother studies (Smith et al. 2002, Haffa-

jee et al. 2007), no additional significantimprovements were found. In these two

studies the patient sample includedpatients with either Ag.P. or Ch.P.,although the age range of both fourstudies coincided.

The most relevant difference whencomparing these studies that obtainedpositive results and the ones that did notwas the period of active debridementtreatment, being 1 day (Gomi et al.2007) or a maximum of 1 week (Mascarenhas et al. 2005) for the posi-tive studies and 2 (Smith et al. 2002) or3 weeks (Haffajee et al. 2007) for thenegative.

In two studies, antibiotic intakestarted immediately after finishing deb-ridement, but in one case, without posi-tive results, this debridement wasperformed within 2 weeks (Smith et al.2002), while in the other, with positiveresults, within a maximum of 1 week(Mascarenhas et al. 2005).

In the other two studies, the prescrip-tion regime was different: in one, itstarted after the first session of SRP,which lasted 3 weeks (one session perweek) and no positive results werereported (Haffajee et al. 2007); in the

other, antibiotic intake started 3 daysbefore SRP, which was performed in 1day (Gomi et al. 2007). It should be

pointed out that azithromycin maintainsrelevant serum and tissue levels for upto 6 days (Malizia et al. 1997).

Clindamycin (Tables 6a and 6b)

Three studies were available: two inrefractory patients (Walker et al. 1993,Magnusson et al. 1994) and another inAg.P. (Sigusch et al. 2001). One of thestudies did not include a statistical eva-

luation (Walker et al. 1993), while theother two reported statistically signifi-cant benefits for the adjunctive therapy,in both cases with debridement underlocal anaesthesia.

Spiramycin and spiramycin plus

metronidazole (Tables 6a and 6b)

Two studies for spiramycin alone (AlJoburi et al. 1989, Bain et al. 1994) andone for the combination with metroni-dazole (Chin et al. 1988) were evalu-ated. Statistically significant benefitswere only seen when the comparisonwere performed at intermediate visits(Chin et al. 1988, Bain et al. 1994).The studies used the antibiotic togetherwith debridement, with additional daysfor the drug if necessary, as is commonin classical studies (the more recent of

these series of studies was published in1994).

Adverse effects (Table 7)

Adverse events were more frequent intest than in control groups. This wasespecially evident when two antibioticswere combined, mainly for the combi-nation of amoxicillin and metronida-zole. However, most adverse effectswere related to gastrointestinal problemsand were considered minor by thepatients. Few adverse effects led to

dropout from the studies. No properevaluation of adverse microbiologicaleffects was reported.

Discussion

Can systemic antimicrobials be

efficacious if the biofilm is not disrupted?

The evaluated studies (both on biofilmproperties and the clinical studies), theclassical review published in 1993(Greenstein 1993), the Position Papersby the American Academy of Perio-

dontology (AAP 1996, Slots 2004) anda systematic review and a consensusreport (Haffajee et al. 2003) clearly

suggest that the use of systemic anti-microbials as monotherapy in thetreatment of periodontitis is not recom-mended. However, the publication ofthe study performed by Lopez et al.(2006) raised controversy on the use ofantimicrobials for the treatment ofperiodontitis, and in particular, used asmonotherapy (Feres-Filho et al. 2006,Mombelli 2006, Walter & Weiger2006), which was already initiated after




14/22

Table6a.

Factorsaffectingdebridementandantibioticintakeinstudiesevaluatingtetr

acyclines,macrolides,penicillinsandclindamycin

Authorandyear

DB-relatedfactors

AB

andDB

ABdosage

operator/s

anaesthesia

sessions

timesp

ent(h)

periodofDB

antibiotic

use

previousor

delayedDB

days

mgper

dose

intakes/

day

total

dosage

Doxycycline

McCullochetal.

(1990)

Notstated

Notexplained

24

24

Notdescribed

Withnew

DB120d

NewDBat

1,3,7m

21

200(1d)

then100

1

2200

Kulkarnietal.

(1991)

Notstated

Notexplained

24

24

Notdescribed

Withnew

DB120d

NewDBat

1,3,7m

21

200(1d)

then100

1

2200

Ng&Bissada(1998)

Notstated

Yes

1

N

A

1day

With

DB141d

No

42

200(1d)

then100

1

4300

Siguschetal.

(2001)

Hygienistand

notstated

Notexplained

andyes

45and

12

NAan

d24

NAand2days

Immediately

afterDB

Previous

DB

8

200

1

1600

Xajigeorgiouetal.

(2006)

Oneclinician

Yes

4and1

N

A

2wandNA

Withnew

DB

PreviousDB

6wbefore

14

200(1stday)

and100

1

1500

Tetracycline

Listgartenetal.

(1978)

Notstated

Notexplained

24

N

A

2w

WithDB

NewABcycle

after4w

14n

250

4

28,0

00

Helldenetal.

(1979)

Notstated

Notexplained

24

N

A

2w

WithDB

NewABcycle

after4w

14n

250

4

28,0

00

Lindheetal.

(1983a)

Notstated

Yes

24

N

A

1w

WithDB

Lowerdose

for1y

350

250

4

(2w),

then1

87,5

00

AlJoburietal.

(1989)

Notstated

Notexplained

2

6

1w

With

DB17d

No

14

250

4

14,0

00

Saxen&Asikainen(1993)

Dentalstudent

Notexplained

NA

N

A

Notdescribed

Unclear

NewDB

every3m

12

250

4

12,0

00

Amoxicillin

Rooneyetal.

(2002)

Periodontist

Yes

NA

5

712days

Immediately

afterDB

No

7

250

3

5250

Augmentin

Walkeretal.

(1993)

Notstated

Notexplained

1

N

A

1day

WithDB1

13d

No

14

2501125

3

10,5

0015250

Magnussonetal.

(1994)

Notstated

Yes

NA

N

A

Notdescribed

Unclear

NewDB

every3m

14

2501125

3

10,5

0015250

Winkeletal.

(1999)

Notstated

Yes

36and

NA

N

A

Notdescribed

Withnew

DB19d

PreviousDB

6wbefore

10

5001125

3

15,0

0013750

Azithromycin

Smithetal.

(2002)

Hygienist

Notexplained

3

N

A

2w

Immediately

afterDB

No

3

500

1

1500

Mascarenhasetal.

(2005)

Notstated

Notexplained

2

N

A

1w(maximum)

Immediately

afterDB

No

5

500(1d),

250(4d)

1

1500

Haffajeeetal.

(2007)

Dentists

Yes

4

N

A

3w

With1st

qDB

No

3

500

1

1500

Gomietal.

(2007)

Notstated

Yes

1(test)and

46

1.5(test)andNA

1d(test)and5w

Before

subDB

Previous

supraDB

3

500

1

1500

58 Herrera et al.



15/22

Table6b.Clinicaloutcomesofstudiesevaluatingtetracyclines,macrolides,penicillins

andclindamycin

Authorandyear

Variable

SRPSRP1AB

SRPversus

SRP1AB

Variable

SRPSRP1AB

SRPversus

SRP1AB

Variable

SRPSRP1AB

SRPversus

SRP1AB

PPD

changechange

interStats

CAL

changechange

interStats

BOP

changechan

ge

interStats

Doxycycline

McCullochetal.

(1990)

1s/pactive

1.3

0.8

NS

Additional

loss(42mm)

79%

45%

o0.0

5

Kulkarnietal.

(1991)

NA

1s/pactive

0.78

4.10

Onlyintra

Ng&Bissada(1998)

6s/t,allsites

0.3

0.3

NS

6s/tallsites

0.9

0.4

SS(at24w)

Siguschetal.

(2001)

6s/t,X6

1.1

1.2

NS

6s/t,X6

0.1

0.9

NS

Xajigeorgiouetal.

(2006)

6s/t,allsites

0.69

0.8

9

NA

6s/tallsites

0.48

0.81

NS

6s/t,allsites63.0

%

67,0

%

NS

Tetracycline

Listgartenetal.

(1978)

1s/p

2.2

2.4

NS

1s/p

0

0

NS

Helldenetal.

(1979)

allsites43mm;

6s/t

1.8

2.2

NS

Sites43mm;3s/t

(buccal)

0.30

0.49

NS

BOPisGi4059.0

%

65.2

%

NS

Lindheetal.

(1983a)

4s/p(incisor1p

re-

molar)

2.3

3.1

NS

4s/p(incisor1pre-

molar)

1.4

1.7

NS

4s/p

85%

100%

NS

AlJoburietal.

(1989)

2s/p,

4loc/s;initialX7

2.85

3.0

4

NS

2s/p,

4loc/s;initialX7

1.54

1.79

NS

Saxen&Asikainen

(1993)

4s/t,

%43mm(base-

6m)

7.30%

11.4

0%

NoStats

4s/t;

only43mm

12.4

%

28.0

%

NoStats

Amoxicillin

Rooneyetal.

(2002)

4s/t;%45mm

6.9

10.8

o0.0

50.0

01

4s/t(%sites

CAL45mm)

6.10

8.70

NS

4s/t;%yes/no

20.7

27.9

NS

Augmentin

Walkeretal.

(1993)

1s/pactive;N

A

1s/pactive;9m

0.85

2.18

Magnussonetal.

(1994)

1s/pactive

0.7

3

1.5

5

NS

1s/pactive

0.84

1

NS

1s/pactive

25%

8%

NS

Winkeletal.

(1999)

6s/t;X6

2.7

2.4

NS

6s/t;X6

1.7

1.1

NS

4s/t;yes/no

30.0

%

40.0

%

NS

Clindamycin

Walkeretal.

(1993)

Notstated

Notexplained

1

N

A

1day

WithDB19d

No

10

150

4

6000

Magnussonetal.

(1994)

Notstated

Yes

NA

N

A

Notdescribed

Unclear

NewDB

every3m

10

NA

4

NA

Siguschetal.

(2001)

Hygienistand

notstated

Notexplained

andyes

45and12

NAand24

NAand2days

Immediately

afterDB

PreviousDB

8

150

4

4800

Spiramycin1metro

Chinetal.

(1988)

Notstated

Notexplained

2

6

1w

WithDB17d

No

14

2.25UI1375

2

63UI110,5

00

Spiramycin

AlJoburietal.

(1989)

Notstated

Notexplained

2

6

1w

WithDB17d

No

14

1.5UI

2

42UI

Bainetal.

(1994)

Notstated

Notexplained

NA

35

2w

WithDB

No

14

1.5UI

2

42UI

DB,debridement;AB,antibiotic;NA,nota

vailable;w,weeks;d,days;m,months;y,ye

ars.




16/22

the publication of the excellent resultsof the paper by Guerrero et al. (2005),and the evaluation of antimicrobial sus-ceptibilities by van Winkelhoff et al.(2005), with different letters to the edi-tor or editorials (Mombelli 2005, vanWinkelhoff 2005, Haffajee 2006, Nee-

dleman & Wisson 2006). All commentsstated that the risk of using antimicro-bials (systemic side effects, increase inantimicrobial resistance) should lead torestriction in their use in periodontitis incertain patients and certain conditions.In addition, their use should be com-bined with debridement, based on theknowledge of the biofilm characteristicsand the evidence available from clinicalstudies. The results provided by Lopezet al. (2006) have not been substantiatedby other authors and in fact, althoughin the title the antimicrobial systemic

therapy was considered as the onlytherapy, supragingival professionaldebridement was provided (by a perio-dontist and totalling 90 min. of treat-ment) and, secondly, although theperiodontitis was defined as moderateto severe, the proportions of moderateand deep PPD and mean CAL weremore close to initial disease (Armitage1999) (percentage of 46 mm sites atbaseline 6.31 6.17 and 15.27 9.73,for control and test groups, respectively;percentage of46 mm sites at baseline0.88 1.88 and 3.11 5.00, respec-

tively; and mean CAL at baseline3.73 0.82 and 3.84 0.56), beingpossible that for this severity, that supra-gingival debridement may have apowerful subgingival impact. All thesefactors make it reasonable to interprettheir results with caution, and thusmaintain the previous conclusions,already published by Greenstein (1993)and agreed upon by the position papersof the American Academy of Perio-dontology (AAP 1996, Slots 2004).

Can the type of debridement (non-surgical

versussurgical) of the subgingival biofilm

impact upon the clinical outcomes of the

adjunctive antimicrobial therapy?

Although the scientific literatureincludes numerous studies that havedescribed the effects of the administra-tion of systemic antimicrobials in com-bination with different periodontaltreatments, there is limited evidence tosupport its use as an adjunct to perio-dontal surgery (Ciancio 2002, Haffajeeet al. 2003).T

able6b.

(Contd.)

Authorandyear

Variable

SRPSRP1AB

SRPversus

SRP1AB

Variable

SRPSRP1AB

SRPversus

SRP1AB

Variable

SRPSRP1AB

SRPversus

SRP1AB

PPD

changechange

interStats

CAL

changechange

interStats

BOP

changechan

ge

interStats

Azithromycin

Smithetal.

(2002)

4s/t,45mm

2.22

3.09

NA

NA

NA

NA

NA

4s/t;%yes/no

16.6

23.4

NS

Mascarenhasetal.

(2005)

6s/t,46mm

1.98

3.52

o0.0

5

6s/t;X6

1.32

3.52

o0.0

5

6s/t%BOP

17.7

%

18.6

%

NS

Haffajeeetal.

((2007)

6s/t,46mm

1.66

2.35

NS

6s/t,46

1.26

1.7

NS

Gomietal.

(2007)

Mean

0.75

1.62

o0.0

01

Mean

1.47

2.62

NS

Mean%BOP

18.5

26.0

o0.0

1

Clindamycin

Walkeretal.

(1993)

1s/pactive;N

A

1s/pactive;9m

0.85

2

NoStats

Magnussonetal.

(1994)

1s/pactive

0.73

0.93

NS

1s/pactive

0.84

0.15

0.0

05n

1s/pactive

25%

25%

NS

Siguschetal.

(2001)

6s/t,X6

1.1

4.4

SS

6s/t;baseline3w;X6

0.1

2.4

SS

Spiramycin1metro

Chinetal.

(1988)

2site/p,4loc/s

ite

2s/p;4loc/s

0.60

0.60

po0.0

5(at6m)

Spiramycin

AlJoburietal.

(1989)

2s/p,4loc/s;initialX72,85

2,5

7

NS

2s/p;4loc/s;initialX7

1.54

1.46

NS

Bainetal.

(1994)

2s/p;proximal;

X6

2,4

2,8

7

0.0

07(at24w)

2s/p;46mm(prox)

1.58

1.87

NS

Inbold,inter-groupstatisticallysignificantdifferencesinchangesbaseline-finalevaluatio

n,andinboldplusitalics,atafollow-upvisit.

SRP,scalingandrootplaning;AB,antibiotic;NA,notavailable;Stats,statisticalanalyses;inter,inter-group;intra,intra-group;s,site;p,patient;loc,location;t,tooth;NS,notsta

tisticallysignificant;SS,

statisticallysignificant;PPD,probingpocke

tdepth;CAL,clinicalattachmentlevel;BOP,bleedingonprobing;w,weeks;m,months;y,years.

60 Herrera et al.



17/22

An initial overview of the selectedpapers revealed that the use of antibio-tics as part of a surgical protocol mayhave two distinct objectives: to prevent

possible complications, including infec-tion, and as an adjunct in the treatmentof periodontitis, trying to enhance theclinical or microbiological outcomes.

The use of systemic antimicrobials inregenerative periodontal surgeries hasusually combined both aims: on theone hand, to prevent post-operative com-plications when a foreign body is placedinside the periodontium; on the other, toimprove the regenerative outcomes by

reducing bacterial contamination.The prevention of post-surgical infec-tions through the routine use of perio-perative antibiotics appears for the mostpart to be based on empiricism, and thisantibiotic prophylaxis has not beenshown to offer an advantage in prevent-ing infections (Pack & Haber 1983,Checchi et al. 1992, Powell et al.2005). Additional indications of theprophylactic use of antibiotics, includ-ing the prevention of bacterial endocar-ditis (Wilson et al. 2007), or inmedically compromised patients

(Pallasch & Slots 1996, Powell et al.2005), should be considered followingupdated guidelines.

There have been relatively few con-trolled trials assessing the additionaleffect on periodontal outcomes ofadjunctive antimicrobials used in con-

junction with periodontal surgeries(Kunihira et al. 1985, Haffajee et al.1995, Palmer et al. 1996, Kleinfelderet al. 2000, Dastoor et al. 2007). Somestudies suggest that there might be abeneficial effect with antimicrobial use,although often these benefits were not

clearly better than those of the controlgroups, either because the differencesdid not reach the level of statisticalsignificance or the magnitudes were oflittle clinical relevance (Kunihira et al.1985, Mahmood & Dolby 1987, Palmeret al. 1996, Dastoor et al. 2007).

Different reviews investigatingregenerative procedures in periodontaltreatment have recommended the use ofsystemic antibiotic therapy, as part ofthe treatment protocol (Cortellini &Bowers 1995, Machtei & Schallhorn1995, Cortellini & Tonetti 2000,

Kornman & Robertson 2000, Sanz &Giovannoli 2000), with the aim ofcontrolling the subgingival microflorain the early healing phase and to reducecomplications, such as the infectionfrom exposed membranes, and in thismanner trying to increase the predict-ability of results. However, the clinicalneed and the long-term efficacy of theadjunctive use of systemic antibioticsin periodontal regenerative surgical pro-cedures can be questioned, becausethere are few controlled trials assessingthis use (Demolon et al. 1993, 1994,

Table 7. Percentage of patients affected of adverse effects associated with the use of systemic

antimicrobials

% patients % patients Adverse effects

SRP SRP1AB description


Berglundh et al. (1998) NA NA NA

Flemmig et al. (1998) 0% 30% Diarrhoea and 2 excluded

Rooney et al. (2002) 0% 0% NoGuerrero et al. (2005) 19% 55% Diarrhoea, taste, stomach,

unwellness

Mombelli et al. (2005) NA NA NAEhmke et al. (2005) 0% 30% Diarrhoea and 2 excluded

Xajigeorgiou et al. (2006) 0% 20.0% Gastrointestinal

Metronidazole

Lindhe et al. (1983b) NA NA NA

Joyston-Bechal et al. (1984) NA NA NA

Loesche et al. (1984) NA NA Metalic taste

Joyston-Bechal et al. (1986) NA NA NAJoyston-Bechal et al. (1986) NA NA NA

Soder et al. (1990) 19% 30% Diarrhoea, taste

Saxen & Asikainen (1993) NA NA NA

Palmer et al. (1998) NA NA NA

Palmer et al. (1999) NA NA NAPalmer et al. (1999) NA NA NA(Sigusch et al. (2001) NA NA NA

(Rooney et al. (2002) 0% 0% No

(Xajigeorgiou et al. (2006) 0% 8.3% Metallic taste

Haffajee et al. (2007) 0% 8.3% Dizziness, diarrhoeaDoxycycline

McCulloch et al. (1990) 0.0% 10.3% Gastrointestinal-mild

Kulkarni et al. (1991) 0.0% 0.0% No effectsNg & Bissada (1998) 0.0% 0.0% No effects

Sigusch et al. (2001) NA NA NA

Xajigeorgiou et al. (2006) 0.0% 0.0%

Tetracycline

Listgarten et al. (1978) NA NA NA

Hellden et al. (1979) NA NA NA

Lindhe et al. (1983a) NA NA NA

Al Joburi et al. (1989) 0.0% 3.7% DiarrhoeaSaxen & Asikainen (1993) NA NA NA

Amoxicillin

Rooney et al. (2002) 0.0% 0.0% No

Amoxicillin and clavulanate

Walker et al. (1993) NA NA NA

Magnusson et al. (1994) NA NA NAWinkel et al. (1999) 20.0% 20.0% Mild diarrhoea

Azithromycin

Smith et al. (2002) 0.0% 0.0% NoMascarenhas et al. (2005) 0.0% 0.0% No

Haffajee et al. (2007)

antibióticos no biofilme subgengival-2008

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