Supplementalfilesfor Online Publication

Non-surgicalperiodontaltherapysupplementedwithsystemicallyadministeredazithromycin - a systematicreviewofRCT’s

Supplementalfilesfor online publication

Sabrina L. Buset, Nicola U. Zitzmann, Roland Weiger, Clemens Walter

Department ofPeriodontology, EndodontologyandCariology, University of Basel, Basel, Switzerland

Runninghead: Azithromycin in non – surgicalperiodontalTherapy

Keywords [All MeSHHeadings]: PeriodontalDebridement, Azithromycin, Aggressive Periodontitis, Chronic Periodontitis

Conflictof Interest: The authorsstatethatthereisnoconflictofinterest.

Correspondingauthor:

Clemens Walter

Dept. ofPeriodontology, EndodontologyandCariology

University of Basel

Hebelstrasse 3,

CH-4056 Basel,

Switzerland

Tel.: +41 61 2672628

Fax: +41 61 2672659

Email:

Appendix 1PRISMA 2009 Checklist[1, 2].

Section/topic / # / Checklist item / Reported on page #
TITLE
Title / 1 / Identify the report as a systematic review, meta-analysis, or both. / 1
ABSTRACT
Structured summary / 2 / Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. / 2
INTRODUCTION
Rationale / 3 / Describe the rationale for the review in the context of what is already known. / 3-4
Objectives / 4 / Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). / 4
METHODS
Protocol and registration / 5 / Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. / n.r.
Eligibility criteria / 6 / Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. / 5
Information sources / 7 / Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. / 4
Search / 8 / Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. / 4
Study selection / 9 / State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). / 5
Data collection process / 10 / Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. / 5,6
Data items / 11 / List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. / 5,6
Risk of bias in individual studies / 12 / Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. / 6
Appendix 2
Summary measures / 13 / State the principal summary measures (e.g., risk ratio, difference in means). / 6
Synthesis of results / 14 / Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis. / n.r.
Section/topic / # / Checklist item / Reported on page #
Risk of bias across studies / 15 / Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies). / 6
Appendix 2
Additional analyses / 16 / Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified. / n.r.
RESULTS
Study selection / 17 / Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. / 6, Figure 1,
Appendix 4
Study characteristics / 18 / For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. / 6-8
Table 1a and b, Table 2
Risk of bias within studies / 19 / Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). / Appendix 2
Results of individual studies / 20 / For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. / n.r.
Synthesis of results / 21 / Present results of each meta-analysis done, including confidence intervals and measures of consistency. / n.r.
Risk of bias across studies / 22 / Present results of any assessment of risk of bias across studies (see Item 15). / Appendix 2
Additional analysis / 23 / Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). / n.r.
DISCUSSION
Summary of evidence / 24 / Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). / 9
Limitations / 25 / Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). / 9-11
Conclusions / 26 / Provide a general interpretation of the results in the context of other evidence, and implications for future research. / 11-12
FUNDING
Funding / 27 / Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. / n.r.

Appendix 2. Risk of bias of inlcuded studies according to Higgins et al. 2011 modified by Graziani et al. 2012 [3, 4].

author & years / sequence generation / allocation concealment / blinding / incomplete outcome data / selective outcome reporting / other sources of bias
Emingil et al. 2012[5] / + / + / + / + / + / − / 84%
Haas et al. 2008[6] / + / + / + / + / + / ? / 84%
Haffajee et al. 2007[7] / + / ? / + / ? / + / ? / 50%
Han et al. 2012[8] / + / + / + / + / + / ? / 84%
Gomi et al. 2007[9] / ? / ? / ? / + / + / ? / 34%
Mascarenhas et al. 2005[10] / + / ? / + / + / + / + / 84%
Oteo et al. 2010[11] / + / + / ? / + / + / + / 84%
Sampaio et al. 2011[12] / + / + / + / + / + / ? / 84%
Yashima et al. 2009[13] / ? / ? / + / + / + / ? / 50%

+ = low risk of bias

− = high risk of bias

? = unclear risk of bias

Appendix 3. Definition of periodontal disease, periodontal disease assessment and definition of smoking of included publications.

author & year / definition of periodontal disease / periodontal assessment / tobacco consumption
chronic periodontitis
Gomi et al. 2007[9] / ≥20 teeth, average PD4mm with BoP, radiographic bone loss in each quadrant / full-mouth clinical recording / n.r.
Haffajee et al. 2007[7] / ≥20 teeth, ≥1 molar per quadrant, ≥8 sites PD4mm / 6 sites per tooth on all teeth excluding 3rd molars / AZM = 3 current smoker1
SRP = 2 current smoker1
Han et al. 2012[8] / >30 sites ≥5mm CAL and ≥2 sites PD ≥6mm in each quadrant with BoP / 6 sites per tooth on all teeth / AZM = 42.8% smokers (exclusion criteria ≥10 cig/day; ø2.6±4.01 cig/day)
C = 50% smokers (exclusion criteria ≥10 cig/day; ø3.6±4.2 cig/day)
Mascarenhas et al. 20052[10] / ≥10 teeth (excluding 3rd molars), ≥6 teeth PD and CAL 5mm and BoP / 6 sites per tooth on all teeth excluding 3rd molars / ≥1 pack of cig/day for ≥5 years
Oteo et al. 2010[11] / radiographic evidence of generalized alveolar bone loss >30%, ≥1 pocket PD5mm per quadrant with BoP, ≥3 teeth per quadrant, presence of P. gingivalis / 6 sites per tooth on all teeth excluding 3rd molars / AZM = 8 smokers (>10 cig/day)
C = 6 smokers (>10 cig/day)
non-smokers = non-smokers, former smokers or <10 cig/day
Sampaio et al. 2011[12] / ≥15 teeth (excluding 3rd molars), ≥30% of sites with PD and CAL ≥5mm and BoP, ≥3 non-contiguous inter-proximal sites PD and CAL ≥7mm and 2 other non-contiguous sites PD and CAL ≥6mm / 6 sites per tooth on all teeth excluding 3rd molars / AZM = 5 smokers1
C = 5 smokers1
Yashima et al. 2009[13] / ≥20 remaining teeth, average PD ≥4mm with BoP and deepest PD ≥6mm, radiographic evidence of bone loss in each quadrant / 6 sites per tooth on all teeth excluding 3rd molars / no smokers included
aggressive periodontitis
Emingil et al. 2012[5] / ≥16 teeth, CAL ≥5mmPD ≥6mm on ≥8 teeth (≥3 other than central incisors or first molars), radiographic bone loss ≥30% of the root length of affected teeth / 6 sites on each tooth / self reported
≥10 cig/day excluded
AZM = 9 / 16 never smokers, 43.8% smokers (<10 cig/day)
C = 10 / 16 never smokers, 38.5% smokers (<10 cig/day)
Haas et al. 2008[6] / LAgP: CAL ≥4mm with BoP in ≥1 incisor or first molar and ≤2 teeth other than incisors or first molars
GAgP: CAL with BoP ≥4mm in ≥1 incisor or first molar and ≥3 teeth other than incisors or first molars / 6 sites per tooth on all teeth excluding 3rd molars / AZM = 3 smokers1
C = 2 smokers1

1smoking not further defined

2smokers

PD = probing depth, BoP = bleeding on probing, n.r. = not reported, SRP = scaling and rootplaning, CAL = clinical attachment level, C = control, AZM = azithromycin, cig = cigarettes

Appendix 4. Excludedstudiesandreasonforexclusion.

author & year / reason for exclusion
Ali et al. 2011[14] / poster abstract
Filatova et al. 1995[15] / Russian language
Shibukawa et al. 2003[16] / Japanese language
Schmidt et al. 2010[17] / no RCT, surgical treatment
Smith et al. 2002[18] / follow up < 6 months

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2.Moher D, Liberati A, Tetzlaff J and Altman DG (2009) Preferredreportingitemsforsystematicreviewsand meta-analyses: the PRISMA statement. BMJ339:b2535. doi: 10.1136/bmj.b2535

3.Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L and Sterne JA (2011) The CochraneCollaboration'stoolforassessingriskofbias in randomisedtrials. BMJ343:d5928. doi: 10.1136/bmj.d5928

4.Graziani F, Figuero E and Herrera D (2012) Systematicreviewofqualityofreporting, outcomemeasurementsandmethodstostudyefficacyofpreventiveandtherapeuticapproachestoperi-implantdiseases. J ClinPeriodontol39 Suppl 12:224-244. doi: 10.1111/j.1600-051X.2011.01832.x

5.Emingil G, Han B, Ozdemir G, Tervahartiala T, Vural C, Atilla G, Baylas H andSorsa T (2012) Effectofazithromycin, as an adjuncttononsurgicalperiodontaltreatment, on microbiologicalparametersandgingivalcrevicular fluid biomarkers in generalized aggressive periodontitis. J Periodontal Res 47:729-739. doi: 10.1111/j.1600-0765.2012.01488.x

6.Haas AN, de Castro GD, Moreno T, Susin C, AlbandarJM, Oppermann RVandRosingCK (2008) Azithromycinas an adjunctivetreatmentof aggressive periodontitis: 12-monthsrandomizedclinicaltrial. J ClinPeriodontol 35:696-704. doi: 10.1111/j.1600-051X.2008.01254.x

7.Haffajee AD, Torresyap G andSocransky SS (2007) Clinical changesfollowingfour different periodontaltherapiesforthetreatmentofchronicperiodontitis: 1-yearresults. JClinPeriodontol 34:243-253

8.Han B, Emingil G, Ozdemir G, Tervahartiala T, Vural C, Atilla G, Baylas H andSorsa T (2012) Azithromycinas an adjunctivetreatmentofgeneralizedseverechronicperiodontitis: clinical, microbiologic, andbiochemicalparameters. J Periodontol 83:1480-1491. doi: 10.1902/jop.2012.110519

9.Gomi K, Yashima A, Iino F, Kanazashi M, Nagano T, Shibukawa N, Ohshima T, Maeda N andArai T (2007) Drug concentration in inflamedperiodontaltissues after systemicallyadministeredazithromycin. J Periodontol 78:918-923

10.Mascarenhas P, Gapski R, Al-Shammari K, Hill R, Soehren S, FennoJC, GiannobileWVand Wang HL (2005) Clinical responseofazithromycinas an adjunctto non-surgicalperiodontaltherapy in smokers. J Periodontol 76:426-436. doi: 10.1902/jop.2005.76.3.426

11.Oteo A, Herrera D, Figuero E, O'Connor A, Gonzalez I and Sanz M (2010) Azithromycinas an adjuncttoscalingandrootplaning in thetreatmentofPorphyromonasgingivalis-associatedperiodontitis: a pilotstudy. JClinPeriodontol 37:1005-1015. doi: 10.1111/j.1600-051X.2010.01607.x

12.Sampaio E, Rocha M, FigueiredoLC, Faveri M, Duarte PM, Gomes Lira EAandFeres M (2011) Clinical andmicrobiologicaleffectsofazithromycin in thetreatmentofgeneralizedchronicperiodontitis: a randomizedplacebo-controlledclinicaltrial. JClinPeriodontol 38:838-846. doi: 10.1111/j.1600-051X.2011.01766.x

13.Yashima A, Gomi K, Maeda N andArai T (2009) One-stage full-mouth versus partial-mouthscalingandrootplaningduringtheeffective half-lifeofsystemicallyadministeredazithromycin. J Periodontol 80:1406-1413. doi: 10.1902/jop.2009.090067

14.Ali BRS, NesheliMHNand Ali F (2011) Effectofazithromycin, a chemicalmacrolide in reducingtissuedestructionofpatientswithchronicperiodontitis. Clinical BiochemistrySuppl44:S51

15.Filatova NA, KuznetsovEA, Dmitrieva LA, TsarevVNand Kalinin AI (1995) Prospects in theuseof a newmacrolideantibioticazitromicin (sumamed) in combinedtherapyofperiodontitis. Stomatologiia 74:12-15

16.Shibukawa N, Gomi K, Iino F, Kanazashi M, Suzuki J, Ohshima T, Maeda N andArai T (2003) Change ofsubgingivalbacterialfloraandlevelofdrugconcentration in gingivaofperiodontalpatientssystemicallyadministeredazithromycin. Oral TherapeuticsandPharmacology 22:83-90

17.Schmidt E, Kaciroti N andLoesche W (2011) Benefitsof additional coursesofsystemicazithromycin in periodontaltherapy. Gen Dent 59:180-7; quiz 188-189

18.Smith SR, Foyle DM, Daniels J, Joyston-Bechal S, Smales FC, Sefton A and Williams J (2002) A double-blind placebo-controlledtrialofazithromycinas an adjunctto non-surgicaltreatmentofperiodontitis in adults: clinicalresults. J ClinPeriodontol 29:54-61