10.59987/ads/2018.3.111-122
Periodontitis is a chronic inflammatory disease that results from a complex polymicrobial infection. The purpose of this review was to assess the efficacy of systemic administered antibiotics as an adjuvant to full mouth scaling and root planing with antiseptics (full mouth disinfection) and without the use of antiseptics in conjunction with systemic antibiotics in the treatment of chronic periodontitis. The following systemic review was conducted in agreement with the recommendations of the Cochrane Collaboration and the principles of the PRISMA (Preferred Reporting Items for the Systemic Reviews and Meta Analyses statement). The search resulted in 31 studies. Only 6 studies fulfilled the inclusion criteria and were eligible to be included in this systemic review. Further, long term randomised control trials with careful case selection of specific treatment protocols as well as standardised regimens for antibiotic use is required to obtain sufficient scientific evidence based treatment clinical guidelines for adjuvant use of systemic antibiotics with full mouth scaling and root planing and full mouth disinfection in treatment of chronic periodontitis.
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Annali di stomatologia
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Clinical efficacy of systemic antibiotics as an adjunctive therapy to one stage full mouth disinfection (OSFMD) and full-mouth scaling and root planning in the treatment of chronic periodontitis: a systematic review of randomised clinical trials
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Clinical efficacy of systemic antibiotics as an adjunctive therapy to one stage full mouth disinfection (OSFMD) and full-mouth scaling and root planning in the treatment of chronic periodontitis: a systematic review of randomised clinical trials
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                                                                                                 Review article



    Clinical efficacy of systemic antibiotics as an
    adjunctive therapy to one stage full mouth
    disinfection (OSFMD) and full-mouth scaling and




                                                                                              li
    root planning in the treatment of chronic




                                                                                            na
    periodontitis: a systematic review of randomised
    clinical trials




                                                                                          io
    Eman Elhassan1 DDS                                     disinfection in treatment of chronic periodontitis.




                                                                     az
    Iole Vozza2 DDS, PhD
    Alessandro Quaranta3 DDS, PhD                          Key Words: antibiotics, randomised clinical trials,
                                                           disinfection, periodontitis.




                                                                   rn
    1 Faculty of Health and Medical Sciences, The
    University of Western Australia, Perth, Australia      Introduction
    2 Department of Oral and Maxillo-facial Sciences,

    “Sapienza” University of Rome, Rome, Italy             Periodontitis is a chronic inflammatory disease that




                                                       te
    3 Griffith Health Centre, Griffith University,         results from a complex polymicrobial infection, lead-
    Gold Coast Campus, Australia                           ing to tissue destruction as a consequence of the per-
                                                           turbation of the homeostasis between the subgingival
                                                     In    microbiota and the host defenses in susceptible indi-
    Corresponding Author:                                  viduals (1). Initial phase of treatment should aim to
    Iole Vozza                                             reduce or eliminate the pathogenic microorganisms
    Department of Oral and Maxillo-facial Sciences         associated with disease. Treatment strategies involve
                               ni
    “Sapienza” University of Rome                          scaling and root planing. This can be achieved in var-
    Via Caserta 6                                          ious visits or as full mouth scaling and root planing
    00161 Rome, Italy                                      within 48 hours. Full mouth scaling and root planing
    E-mail: iole.vozza@uniroma1.it                         has been associated with additional clinical and mi-
                             io


                                                           crobiological benefits (2, 3). Full mouth disinfection
                                                           as suggested by Quirynen et al. (4) differs from the
    Summary                                                full mouth scaling and root planing. It is a protocol
                           iz



                                                           that involves full mouth scaling and root planing with-
    Periodontitis is a chronic inflammatory disease        in 24 hours, subgingival irrigation of all pockets with a
    that results from a complex polymicrobial infec-       1% chlorhexidine gel in order to kill remaining subgin-
           Ed




    tion. The purpose of this review was to assess the     gival bacteria, tongue brushing with the chlorohexi-
    efficacy of systemic administered antibiotics as       dine 1% gel for 1 min, mouth rinsing with a 0.2%
    an adjuvant to full mouth scaling and root planing     chlorhexidine solution for 2 min to reduce the flora in
    with antiseptics (full mouth disinfection) and         the saliva and on the tonsils before and after scaling
    without the use of antiseptics in conjunction with     and root planing and optimal oral hygiene, supported
    systemic antibiotics in the treatment of chronic       for the first 2 weeks by mouth rinsing with 0.2%
 IC




    periodontitis. The following systemic review was       chlorhexidine solution. The conventional form of
    conducted in agreement with the recommenda-            staged nonsurgical periodontal therapy involves scal-
    tions of the Cochrane Collaboration and the prin-      ing and root planing (SRP) has been shown to result
    ciples of the PRISMA (Preferred Reporting Items        in clinical improvements of periodontal health (5, 6). It
C




    for the Systemic Reviews and Meta Analyses             has been suggested that it carries the risk for recont-
    statement). The search resulted in 31 studies. On-     amination of already-treated areas from untreated
    ly 6 studies fulfilled the inclusion criteria and      sites still harbouring large amounts of periodontal
    were eligible to be included in this systemic re-      pathogens (7). Based on this hypothesis, Quirynen
©




    view. Further, long term randomised control trials     introduced the protocol of one-stage full mouth disin-
    with careful case selection of specific treatment      fection (OSFMD) in order to reduce the bacterial load
    protocols as well as standardised regimens for         in pockets and intraoral niches, prevent the intra-oral
    antibiotic use is required to obtain sufficient sci-   transmission of periodontal pathogens from periodon-
    entific evidence based treatment clinical guide-       tal pockets to recently instrumented and healing peri-
    lines for adjuvant use of systemic antibiotics with    odontal sites and therefore produce a less pathogenic
    full mouth scaling and root planing and full mouth     subgingival environment (4).

    Annali di Stomatologia 2018;IX (3):111-122                                                                  111
    E. Elhassan et al.


    Systemic antibiotics have been used as an adjuvant           findings in patients with advanced chronic periodonti-
    to full mouth scaling and root planning to achieve fur-      tis. They compared the OSFMD protocol using
    ther clinical improvements. Different antibiotic regi-       chlorhexidine for 2 months against conventional SRP.
    mens have been indicated in the treatment of moder-          There was a significant reduction in bleeding scores,
    ate to advanced chronic periodontitis including peni-        plaque, a probing depth reduction in probing depths




                                                                                                    li
    cillins (amoxicillin), tetracyclines (doxycycline,           especially in deep pockets (>7 mm) in the test group.
    minocycline, tetracycline), macrolides (azithromycin,        Microbiologically, there was reduction in the putative




                                                                                                  na
    clarithromycin, spiramycin, clindamycin), quinolones         periodontal pathogens in both groups however the full
    (moxifloxacin, ciprofloxacin) and nitroimidazole             mouth disinfection group was always significantly
    (metronidazole, ornidazole) (8, 9). The rationale for        higher. It was concluded that OSFMD was effective
    the use of systemic antibiotics in combination with          on medium term at improving the clinical outcomes
    non-surgical periodontal therapy is to suppress path-        associated with periodontal health (3). Mongardini et




                                                                                                io
    ogenic bacteria to levels that are associated with           al. (15) investigated the clinical results of OSFMD in
    health (9). The purpose of this review was to assess         comparison to scaling and root planning per quadrant
    the efficacy of systemic administered antibiotics as         at 2-week intervals, in the control of severe periodon-




                                                                           az
    an adjuvant to full mouth scaling and root planing           titis over an 8-month period in 40 subjects using a
    with antiseptics (full mouth disinfection) and without       randomised control trial. Significant additional im-
    the use of antiseptics in conjunction with systemic an-      provements were reported in the OSFMD group in
    tibiotics in the treatment of chronic periodontitis.         terms of plaque, bleeding scores, and probing depth




                                                                         rn
                                                                 reduction (1.2 mm for single-rooted and 0.9 mm for
    One-stage full mouth disinfection (OSFMD)                    multi-rooted teeth, with corresponding additional
    The various steps in the original protocol for OSFMD         gains in attachment of 1.0 mm and 0.8) in patients
    of the oral cavity propagated by the Leuven group (4)        with advanced chronic periodontitis. The Authors con-




                                                          te
    included full-mouth scaling and root planing within 24       cluded that OSFMD results in significant clinical im-
    hours; in order to reduce the total number of subgin-        provements over conventional periodontal therapy for
    gival pathogenic bacteria (10, 11); subgingival irriga-      an 8-month period in the treatment of severe adult
                                                        In
    tion of the pockets with chlorhexidine gel to further        and/or generalized early onset periodontitis, especial-
    eliminate bacteria (12); tongue brushing with                ly when treating deep pockets. Many theories were
    chlorhexidine and mouth rinsing & gargling with              proposed for the reported success of the OSFMD in
    chlorhexidine mouthwash to reduce the bacterial load         these studies through the reduction of the transloca-
                             ni
    in saliva and tonsils. The protocol also included oral       tion of periodontopathogens. The exact mechanism
    rinses twice daily for 1 min with chlorhexidine for 2        however was unknown. It was hypothesized that it
    weeks, during the initial healing phase to deplete the       could be due to the reduction of the bacterial over-
    supragingival plaque deposits and prevent biofilm for-       load in a short period and prevention of re-infection. It
                           io


    mation (13). The research group at the Catholic Uni-         could be due to the indirect impact of change in the
    versity at Leuven, Belgium conducted a series of clin-       supra gingival plaque which may extend sub gingival-
    ical trials to explore the effectiveness of one stage full   ly as suggested by several studies (10, 18). The role
                         iz



    mouth disinfection protocol, (3, 7, 14, 15), and they        of antiseptics in OSFMD was explored in 2006 by
    consistently demonstrated a superior clinical out-           Quirynen (19). He compared the effects of full mouth
    come. This was in contrast with other groups findings        disinfection, with and without concomitant use of dif-
           Ed




    which didn’t report any difference using this protocol       ferent types and durations of antiseptics in compari-
    (16). In 1995, Quirynen et al. (4) compared full-mouth       son with quadrant scaling and root planning in chron-
    disinfection with quadrant wise periodontal therapy in       ic periodontitis, over 8 months. Again, he demonstrat-
    10 patients with advanced periodontal disease. Re-           ed superior clinical outcomes for the OSFMD group.
    duction of plaque and probing depths, as well as             In subsequent study (20), use of a strong antiseptic in
    pathogenic species, was significantly greater at 1           the OSFMD was found to play a significant role com-
 IC




    month for the OSFMD group. The deep pockets (7 - 8           pared to full mouth scaling and root planning. These
    mm) exhibited a better response than the moderate            results were inconsistent with findings from other re-
    pockets (5 to 6 mm). Culture analyses showed that            search groups which conducted research involving
    samples from the test group harboured significantly          the full mouth disinfection concept (2, 16, 21-23).
C




    fewer pathogenic species at 1 month and significantly        These researchers were able to observe some statis-
    more beneficial bacteria at 2 months post-treatment.         tically significant improvements in some outcome
    P gingivalis was eliminated from the test group. Long-       variables; however concluded that these improve-
    term results of this pilot study were reported later (17)    ments, whilst statistically significant; were not of a
©




    which demonstrated statistically significant greater re-     significant amount to be of clinical relevance (2).
    duction of probing depth in full mouth disinfection up       They considered the Leuven studies “proof of princi-
    to 1 mm. Therefore, they concluded that one-stage            ple “experiments which provoked the recolonization in
    full-mouth disinfection demonstrated significant clini-      the control group. They argued that they had long
    cal and microbiological advantages over conventional         time intervals before completion of debridement (6
    treatment on a short-term basis. Bollen et al. con-          weeks), no oral hygiene instructions were advised for
    ducted a randomised clinical trial with microbiological      the untreated quadrants and only 7 patients with ad-

    112                                                                            Annali di Stomatologia 2018;IX (3):111-122
    Clinical efficacy of systemic antibiotics as an adjunctive therapy to one stage full mouth disinfection (OSFMD) and full-
    mouth scaling and root planning in the treatment of chronic periodontitis: a systematic review of randomised clinical trials

    vanced periodontal disease and significant calculus             are all possible hypothesizes. OSFMD requires less
    deposits were selected for the studies. This generat-           time to complete the treatment than multiple visits
    ed an ongoing debate as to whether full-mouth disin-            without any disadvantages to the patient which is also
    fection should be the treatment of choice. It must be           an important factor. More research is needed to fur-
    noted that none of these studies followed the original          ther explore the scientific concepts related to it as




                                                                                                         li
    protocol of full mouth disinfection, originally suggest-        well as the use of other adjuvants such as antibiotics
    ed by Quirynen (4) concerning the use of antiseptics            with the full mouth disinfection protocol in treatment




                                                                                                       na
    in the Full Mouth Disinfection protocol. Some studies,          of chronic periodontitis.
    (21, 22) employed antiseptics, but they used less po-
    tent povidone iodine. Systematic reviews published in
    2008 (22,23), substantiated that OSFMD with and                 Materials and methods
    without antiseptics found only minor differences be-




                                                                                                     io
    tween the treatment strategies for adults with chronic          The following systemic review was conducted in
    periodontitis. The studies compared for the OSFMD               agreement with the recommendations of the
    with antiseptics did not consider the different proto-          Cochrane Collaboration (27) and the principles of the




                                                                               az
    cols and different types of antiseptics used in the             PRISMA (Preferred Reporting Items for the Systemic
    OSFMD protocols. In 2009, (24) Swierkot reviewed                Reviews and Meta Analyses statement) (28).
    the OSFMD concept by conducting a study to com-
    pare clinical and microbiological effects of the original       Focused question (PICO)




                                                                             rn
    OSFMD protocol, full mouth scaling and root planning            The focused question that has been used was: “Do
    as well as conventional quadrant scaling and root               systemic antibiotics combined with full mouth scaling
    planning in 28 patients with chronic periodontitis at 1,        and root planing vs full mouth scaling and root plan-
    2, 4 and 8 months. It concluded that all the different          ing alone in treatment of chronic periodontitis have an




                                                           te
    modalities resulted in significant clinical effects at any      additional effect on the clinical outcomes”?
    time. OSFMD displayed higher reduction in probing
    depths and bleeding on probing sites after 1 and 2              PICO Criteria
    months. However, a major limitation in the study was
                                                         In         Participants: participants of any age with chronic peri-
    the reduced number of probing depths >7 mm in this              odontitis receiving full mouth scaling and root planing
    study which could lead to incomparable results to the           or full mouth disinfection protocol (within 48 hours).
    Leuven group studies that noticed statistical differ-           Intervention: the intervention evaluated the use of
                               ni
    ences mainly in moderate to deep probing depths.                systemic antibiotics with or without chlorohexidine
    Considering the advantages of OSFMD technique,                  (antiseptics).
    patient and operator comfort, systemic effects and its          Comparison: comparison of results with or without
    cost-effectiveness, the use of this technique in peri-          use of systemic antibiotics.
                             io


    odontitis patients is recommended. The most recent              Outcomes: primary outcomes is PD (probing depth)
    meta-analysis by Fang (25) showed that even though              reduction, CAL (clinical attachment level) gain. Sec-
    OSFMD had modest statistically insignificant addi-              ondary outcomes included reduction in full mouth
                           iz



    tional clinical benefits over quadrant scaling and root         bleeding scores, plaque scores and microbiological
    planing in pocket depth reduction and clinical attach-          changes.
    ment level gain, they recommend OSFMD as the first
           Ed




    choice for the treatment of adult chronic periodontitis.        Search strategy
    A recent comprehensive study published in by Fonse-             The PubMed database was searched from their earli-
    ca (26), which also compared different treatment                est records until January 2019. The following search
    modalities for chronic periodontitis, compared                  terms were used: Periodontal diseases [MESH]/
    OSFMD, Quadrant conventional therapy, and Full                  (TEXT)OR chronic Periodontitis AND Full mouth scal-
    mouth scaling and root planning with and without use            ing and root planing [MESH]/(TEXT) OR Full mouth
 IC




    of systemic azithromycin. It reported a significant re-         disinfection [MESH] /(TEXT) AND Antibiotics
    duction in all clinical parameters in all treatment             [MESH](TEXT) AND Prospective Clinical trial. In ad-
    modalities however the OSFMD group with chloro-                 dition, a manual search was performed on issues
    hexidine showed higher reductions in probing depths,            from the past 10 years of the Journal of Clinical Peri-
C




    percentage of diseased sites as well as lower bacteri-          odontology and Journal of Periodontology and bibli-
    al counts than all the other groups at a 180 days               ographies of all the retrieved papers.
    which again reenforces the superiority of the OSFMD
    protocol with concomitant use of chlorhexidine. The             Study inclusion and exclusion criteria
©




    OSFMD protocol results in significant additional clini-         The following eligibility criteria were imposed for in-
    cal and microbiological improvements with nonsurgi-             clusion in the systemic review: 1. Studies were limit-
    cal periodontal therapy. The scientific basis of the im-        ed to randomised controlled clinical trials, sample
    proved results with this protocol are yet to be com-            size of at least 20 patients, with follow-up of at least
    pletely understood. Reduction in the probability of             more than three months duration; 2. The population
    bacterial cross contamination, combination of anti-             was limited to subjects in good general health with
    septics (chlorhexidine) and or Schwartzman reaction             chronic periodontitis; 3. The interventions of interest

    Annali di Stomatologia 2018;IX (3):111-122                                                                              113
    E. Elhassan et al.


    were full mouth disinfection (SRP within 24 hours,          quence generation; II. Allocation concealment; III.
    FMSRP with use of chlorohexidine) or full mouth scal-       Blinding of personnel and outcome assessors; IV.
    ing and root planning (SRP within 48 hours) with or         Handling of incomplete outcome data. Assessment of
    without the use of systemic antibiotics; 4. No specific     methodological study quality was performed by the
    systemic antibiotics were excluded; 5. Clinical para-       reviewer using the criteria proposed by the Cochrane




                                                                                                   li
    meters of interest of PD and CAL as primary outcome         Reviewer’s Handbook (Higgins and Green 2009) (27).
    parameters, with BOP and FMPS as secondary out-             Included articles were evaluated through methodolog-




                                                                                                 na
    come parameters, data presented by means of pre-            ical RCT aspects into “Low risk”, “High risk”, or “Un-
    and post-treatment data, incremental data or both; 6.       clear” (27). These included a. Selection bias (Ran-
    Only papers in the English language were included.          dom sequence generation, Allocation concealment);
    Only studies that met all the inclusion criteria were       b. Performance bias (Blinding of the participants and
    analysed.                                                   personnel); c. Detection bias (Blinding of the outcome




                                                                                               io
    Exclusion criteria:                                         assessment); d. Attrition bias (Incomplete outcome
    1) History of refractory periodontitis                      data); e. Reporting bias (Selective reporting); f. Other
    2) Combination of local and systemic antibiotics            bias (Other sources of bias). To be included articles




                                                                          az
    3) Primary outcome of interest was not analysed             had to be considered adequate in all six aspects.
    4) Duplicated studies.
                                                                Characteristics of the study design
    Outcome variables                                           All selected studies were randomised controlled clini-




                                                                        rn
    The primary outcome variables in the studies were           cal trials. The evaluation period varied between the
    reduction in probing depth, changes in clinical attach-     studies from 6 months to 5 years. A considerable het-
    ment level. Secondary outcomes included differences         erogeneity in the design, duration (evaluation period),
    in bleeding on probing (BOP). Other outcome vari-           and regimen of SRP was present in the studies. The




                                                         te
    ables included were microbiological changes due to          number, sex, and age of the participants and the peri-
    treatment.                                                  odontal diagnosis also varied among the studies.
                                                                Risk of bias: Risk of bias was evaluated through qual-
    Selection strategy
                                                       In       ity analysis performed by the reviewers. Quality
    Eligibility assessment was performed through titles         analysis of the RCT was done according to the
    and analysis of the abstracts and full text. If the         Cochrane Handbook risk assessment. Four included
    search key words and the relevant information to the        studies estimated risk of bias is “Low Risk” according
    eligibility criteria were present in the title, the ab-
                             ni
                                                                to the Cochrane Handbook criteria for judging risk of
    stract, or both, the study was selected for full-text       bias assessment tool. This includes assessment if six
    reading. Titles and abstracts of the search results 10      RCT issues: randomisation, concealment, incomplete
    were screened independently by two reviewers (AQ,           outcome data, selective reporting, other bias. All the
                           io


    EE, IV), for possible inclusion in the literature review.   size criteria were assessed as adequate, inadequate
    Studies without abstracts but with titles suggesting        or unclear.
    they were related to the objectives of this review were
                         iz



    also selected for full-text screening to avoid excluding
    potentially relevant articles. A hand search of the ref-    Results
    erence lists of all selected studies for additional rele-
           Ed




    vant articles was completed. The full text articles of      Search and selection
    all the selected studies were included in the full text     The search resulted in 31 studies. Only 6 studies ful-
    analysis. The full text of all the studies with possible    filled the inclusion criteria and were eligible to be in-
    relevance was assessed by two reviewers (EE, AQ).           cluded in this systemic review. Most of the studies
    After selection, full-text studies were read in detail by   were excluded because the completion of SRP oc-
    reviewer. Those studies that fulfilled all the selection    curred in a period greater than 48 hours or because
 IC




    criteria were processed for data extraction. Data of        many studies reported on cases of aggressive peri-
    the included articles were extrapolated. The full texts     odontitis (Fig. 1). All five studies included in the sys-
    of all studies of possible relevance were obtained for      tematic review were randomised clinical control trials
    independent assessment by the reviewers. Any dis-           that assessed clinical parameters before and after in-
C




    agreement was resolved by discussion. Data were             tervention at different time points after treatment. All
    extracted independently by the reviewers using a da-        the studies assessed the clinical parameters for 6
    ta extraction form. Disagreement regarding data ex-         months, except one study that extended the results to
    traction was resolved by consensus.                         1-year post treatment. The length of follow-up ranged
©




                                                                from 6 months to 5 years in the studies included. De-
    Quality assessment                                          tailed information regarding the selected study char-
    Assessment of methodological study quality was per-         acteristics and the Authors’ conclusions are present-
    formed combining the proposed criteria by the               ed in Table 1. Two studies had a high risk of bias due
    Cochrane hand book for systemic reviews for inter-          to the inclusion of patients in the analysis despite the
    ventions (27). It compromises evaluating quality            discontinuation of the intervention. Detailed analysis
    through four methodological RCT aspects: I. Se-             is presented in Table 2.

    114                                                                           Annali di Stomatologia 2018;IX (3):111-122
    Clinical efficacy of systemic antibiotics as an adjunctive therapy to one stage full mouth disinfection (OSFMD) and full-
    mouth scaling and root planning in the treatment of chronic periodontitis: a systematic review of randomised clinical trials

                                                                    Outcomes: In the present review, the reduction in
                                                                    mean pocket depth after intervention ranged from 2-
                                                                    3 mm in all the studies. The length of follow-up was 6
                                                                    months in all studies except one study that reported
                                                                    up to 5 years post intervention.




                                                                                                         li
                                                                    Results of individual studies: The comparison of the




                                                                                                       na
                                                                    findings in the selected studies is difficult due to the
                                                                    heterogeneity of the data, different protocols followed in
                                                                    each study therefore it was decided to report the type
                                                                    of intervention of each study and specific methodology
                                                                    used. The articles are reported in chronological order.




                                                                                                     io
                                                                    Primary outcomes
                                                                    Ribeiro (29). Reported results at 6 months showed an




                                                                               az
                                                                    additional reduction in PD depth was noted in the test
                                                                    group (0.83 mm) in PD [P2 mm at 43.52% of sites
                                                                    (control) compared to 53.03% (test)]. However, both
                                                                    groups had similar RAL gain [1.68 (control) and 1.88




                                                                             rn
                                                                    mm (test) group]. It was therefore concluded by the
                                                                    group that both treatments resulted in significant clini-
                                                                    cal improvements.




                                                                te
                                                                    Cionca (30). Clinical results obtained at 3 months
                                                                    were maintained at 6 months, the mean PD reduction
                                                                    in test group was 3.0 mm in test group, and 3.1 in
    Figure 1. Flowchart of literature search and inclusion.
                                                              In    placebo group. Sites presenting with pockets initially
                                                                    >6 mm showed a mean decrease in mean PD from
    Intervention                                                    7.3 -+0.3 mm at baseline to 3.6+-0.8 mm at 3 months
    All six studies compared full mouth scaling and root            and 3.7+- 0.6 mm at 6 months in the test group unlike
    planning and/or full mouth disinfection with or without
                               ni
                                                                    the placebo group that showed a decrease from 7.2+-
    the use of systemic antibiotics. Different regimes of an-       0.7 mm to 5.2+- 1.1 mm at 3 months and 4.9 mm +-
    tibiotics were used in each study (Tab. 1). Data from           1.4 mm at 6 months, which shows a clear 16 advan-
    each article were collected, and a descriptive report was       tage of use of systemic antibiotics in these sites. The
                             io


    generated about the type of study, number of patients,          results of the study show a significant improvement in
    mean follow-up period (Tab. 1), and clinical parameters:        the clinical outcomes of full mouth nonsurgical peri-
    bleeding on probing, pocketing depth, clinical attach-          odontal debridement with antibiotics and significantly
                           iz



    ment level and microbiological assessment. Data from            reduced need for additional therapy.
    each study was analysed and information about the type
    of study, number of participants, Mean PD (pocket               Preus (31). No statistically significant differences were
           Ed




    depth) reduction, Mean CAL (clinical attachment level)          noted between the different groups at baseline, 3 and
    gain, changes in BOP in each group after intervention,          12 months. All the groups displayed significant im-
    and length of follow-up, is recorded in Table 1.                provements in all the analysed parameters. Mean
                                                                    Clinical attachment level (CAL) ranged 1.06 to 1.29
                                                                    mm at 3 and 12 months, mean PD was around 2.20 to
    Characteristics of included studies                             2.28 mm at 3 and 12 months in all four groups. The
 IC




                                                                    mean gain in CAL from baseline to 1 year was slightly
    Participants                                                    more in groups with antibiotics {0.72, (0.60 to 0.85)
    The included studies involved a total of 440 partici-
                                                                    and 0.81 (0.67 to 0.96) compared to 0.61 (0.51 to
    pants (Tab. 1).
                                                                    0.72) and 0.64 (0.52 to 0.76) in groups with no antibi-
C




                                                                    otics. Metronidazole treatment was significantly influ-
    Quality analysis: Quality analysis was completed util-
                                                                    ential of the mean probing depth (PD) reduction which
    ising the GRADE approach outlined in the Cochrane
                                                                    ranged from 0.81 to 1.03 mm. Metronidazole was
    hand book, which specifies four levels of quality. All
                                                                    found to exert an adjunctive effect on the mechanical
©




    studies included in the review were randomised trials
                                                                    periodontal therapy for <= 12 months after treatment.
    with a high-quality rating. Limitations in the imple-
                                                                    It resulted in additional gain of CAL, reduction in PDs
    mentation of the study design in two studies which
                                                                    and more frequent eradication of the pockets >=5 mm,
    have the same design as one reported 12 months
                                                                    [Absence of pockets >= 5 mm at 1 year was found to
    while the other reported 5 years had a high risk of
                                                                    be 72.7% (FDIS group +met) and 62.2% (SRP + met)
    bias, this eventually reduced the quality of the body
                                                                    compared to 42.2% (Displace) and 39.1% (SRP+
    of evidence from high to moderate quality evidence.
                                                                    placebo) in groups without metronidazole]}.

    Annali di Stomatologia 2018;IX (3):111-122                                                                              115
                                                             ©
                                             Table 1. Characteristics of included studies in literature review.




   116
                                             Study
                                                                        C
                                                               Design and            Diagnosis, No of             Regimen as         Regimen             Follow-up     Conclusion of the Authors          Bias Assessment
                                                               Evaluation            Subjects (end), Age          Adjunct to SRP     for Antiseptics use                                                  Bias (Cochrane “Risk of
                                                               period                                                                                                                                     bias” assessment tool) (29)
                                                                                                                                                                                                                                           E. Elhassan et al.




                                                                         IC
                                             Ribeiro, et al.   RCT Parallel          Ch P 25 patients, 12         Amoxicillin        Nil                    6 months   Both groups showed a reduction Low risk
                                                               Double masked         =c, 13 = T                   375 mg,                                              in PD, and gain in RAL.
                                                                                     Mean age= 46                 metronidazole                                        Mean Decrease in PD 2.45
                                                                                                                  250 mg 3 times                                       mm+- 0.5 mm in control group
                                                                                                                  daily for 7 days                                     and 3.28+-0.41 mm in test
                                                                                                                                                                       group
                                                                                                  Ed
                                                                                                                                                                       At 6 m, lower Bo P and
                                                                                                                                                                       additional reduction (0.83 mm)
                                                                                                                   iz                                                  in PD Similar RAL Gain in
                                                                                                                                                                       Antibiotics group
                                                                                                                     io
                                             Cionca, et al.    RCT Single centre Ch P 47 patients 24=C,           Metronidazole      Subgingival            6 months   Systemic metronidazole +
                                                               Double masked,     23=T Mean Age 50.5              500 mg,            irrigation with 0.1%              amoxicillin improved 6 month
                                                               Placebo controlled                                 amoxicillin 375    chlorhexidine                     clinical outcomes of full mouth
                                                               RCT                                                mg 3 times daily   solution rinse
                                                                                                                                               Rinse with              non-surgical periodontal
                                                                                                                       ni
                                                                                                                  for 7 days         0.25 CHX twice                    debridement
                                                                                                                                     daily (10 days)                   .0.4 ± 0.8 persisting pockets
                                                                                                                                                                       were still present in test group
                                                                                                                                                  In
                                                                                                                                                                       compared to 3.0 +-4.3 in control


                                             Preus, et al.     RCT Four arm          Ch P 180 patients    Metronidazole              Subgingival          12 months    Metronidazole has a significant    High risk (Patients
                                                                                                                                                    te
                                                               parallel group,       G1=44 (FDIS+ Met)    400 mg, 3 times            irrigation with 1%                adjunctive effect on clinical      discontinued intervention in
                                                               double masked         G2= 45 (FDIS         daily for 10 days          CHX gel tongue                    parameters of CAL, PD and          all groups were still included
                                                               clinical trial        +placebo) G3=45 (SRP                            brushing with CHX                 absence of pockets >=5 mm          in the analysis)
                                                                                                                                                                       rn
                                                                                     +Met) G4=46 (SRP +                              gel 1 minute every
                                                                                     placebo)                                        night (9 days) -0.2%
                                                                                                                                     CHX mouthwash
                                                                                                                                     every morning (9
                                                                                                                                                                         az
                                                                                                                                     days)
                                                                                                                                                                                                                        To be continued
                                                                                                                                                                                            io



Annali di Stomatologia 2018;IX (3):111-122
                                                                                                                                                                                              na
                                                                                                                                                                                                li
                                                              ©
                                             continue from Table 1    C
                                              Fonseca, et al. RCT Four arm       Ch P 186 participants      FAZ + QSAZ           FC=Subgingival        6 months   Adjuvant use of azithromycin did Low risk
                                                              parallel group,    (6 groups) G1=15           (Azithromycin        irrigation with 0.12%            not provide any significant
                                                              double masked      (FAZ) G2=15 (FC)           500 mg once          CHX gel for                      improvement on clinical and
                                                              clinical trial     G3=15 (FNC) G4=14          daily for 3 days)    1 minute                         microbiological parameters.
                                                                       IC
                                                                                 (QSAZ) G5=13 (QSC)                                                               The adjuvant use of CHX
                                                                                 G6= 13 (QSNC)                                   Mouthwash 0.12%                  especially in FMD protocol (FC)
                                                                                                                                 CHX for 30 secs at               followed by QS showed more
                                                                                                                                 beginning and end                significant improvement
                                                                                                                                 of each session +
                                                                                                                                 CHX 0.12%
                                                                                                                                 mouthwash twice
                                                                                              Ed




Annali di Stomatologia 2018;IX (3):111-122
                                                                                                                                 daily for 2 weeks
                                                                                                                                 QSC=daily used of
                                                                                                                                 CHX 0.12% for 60
                                                                                                             iz
                                                                                                                                 days

                                              Preus, et al.   RCT Four arm       Ch P 161 (7 lost at        Metronidazole        Subgingival irrigation 5 years   Metronidazole increased the             High risk (Patients
                                                                                                               io
                                                              parallel group,    initial treatment, 16 at   400 mg, 3 times      with 1% CHX gel                  highest CAL recording                   discontinued intervention in
                                                              double masked      5-year follow-up.          daily for 10 days    Tongue brushing                  statistically insignificantly by 0.17   all groups were still included
                                                              clinical trial     Patient G1 (FDIS+                               with CHX gel 1                   mm while FDIS decreased it by           in the analysis)
                                                                                 Met) G2 (FDIS +                                 minute every night               0.12 mm small statistically
                                                                                 placebo) G3 (SRP +                              (9 days)                         significant differences, too small
                                                                                                                 ni
                                                                                 Met) G4 (SRP +                                  0.2% CHX                         to recommend metronidazole
                                                                                 placebo)                                        mouthwash every                  treatment as an adjuvant
                                                                                                                                 morning (9 days)                 treatment
                                                                                                                                              In
                                              Cosgarea, et al. RCT Three arm     Ch P 102 patients (33      Amoxicillin +        All groups. PPDs>4 6 months      Patients with severe chronic            Low risk
                                                               parallel group,   groups), 91 patients       metronidazole        mm rinsed with                   periodontitis SRP in conjunction
                                                                                                                                                te
                                                               double masked     only completed. G1-        500 mg TID for 3     Chlorhexidine                    with amoxicillin and
                                                               clinical trial    =30 (SRP + placebo)        days amoxicillin +   digluconate solution.            metronidazole 500 mg lead to
                                                                                 G2=30 (SRP + AMX +         metronidazole        Chlorohexidine                   greater clinical improvements.
                                                                                                                                                                  rn
                                                                                 MET 3 days) G3=31          500 mg TID for 7     digluconate solution             No statistical difference between
                                                                                 (SRP + AMX + MET 7         day                  0.2% rinse twice                 3 and 5-day regimen
                                                                                 days)                                           daily for 14 days

                                             Legend of abbreviations: RCT, Randomised control trials; AZ, Azithromycin; FAZ, Full mouth SRP within 24 hrs with AZ; FC, FMD with CHX (FMD protocol + CHX 0.12% twice daily for
                                                                                                                                                                    az
                                             2 weeks); BOP, Bleeding on Probing; CHX, chlorhexidine; QSC, SRP per quadrant with CHX (daily 0.12% for 60 days); FNC, Full mouth SRP without CHX; PD, Pocket depth; SRP,
                                             Scaling and root planning; QSNC, SRP per quadrant without CHX; QSAZ, SRP per quadrant with AZ; CAL, Clinical attachment Level; Ch P, Chronic periodontitis; FMD, Full mouth
                                                                                                                                                                                                                                           Clinical efficacy of systemic antibiotics as an adjunctive therapy to one stage full mouth disinfection (OSFMD) and full-




                                             Disinfection (FMD protocol + CHX 0.12% twice daily for 2 weeks); RAL, Relative attachment level, measured from fixed point occlusal splint to base of pocket.
                                                                                                                                                                                         io
                                                                                                                                                                                                                                           mouth scaling and root planning in the treatment of chronic periodontitis: a systematic review of randomised clinical trials




   117
                                                                                                                                                                                           na
                                                                                                                                                                                             li
    E. Elhassan et al.


    Table 2. Risk of bias assessment according to Cochrane Handbook Risk of Bias Assessment (27) (H= HIGH, L=LOW).

                                   Ribeiro,       Cionca ,
                                                  Cionca,            Preus,
                                                                   Preus,            Fonseca,
                                                                                    Fonseca,          Preus,
                                                                                                       Preus,et al.     Cosagrea,
                                                                                                                        Cosagrea,
                                  et al. (29)    et al.
                                                 et al. (30)
                                                         (30)    etetal.al.(31)
                                                                             (31)    et al. al.
                                                                                    (26)et  (26)    et al.(32-34)
                                                                                                           (32-34)       et al.
                                                                                                                        et  al. (33)
                                                                                                                                 (33)
     Random sequence                  L               L                L                L                 L                  L




                                                                                                             li
     generation (selection
     bias)




                                                                                                           na
     Allocation                       L               L                L                L                 L                  L
     concealment
     (selection bias)




                                                                                                         io
     Blinding of participants         L               L                L                L                 L                  L
     and personnel
     (performance bias)




                                                                                      az
     Blinding of outcome              L               L                L                L                 L                  L
     assessment
     (detection bias)

     Incomplete outcome               L               L                L                L                 L                  L




                                                                                    rn
     data (attrition bias)

     Selective reporting              L               L                L                L                 L                  L
     (reporting bias)




                                                            te
     Other bias                       L               L               H                 L                 H                  L
                                                          In
    Preus (32). This study is the follow treatment of the           regimen. CAL gain was statistically significantly in-
    previous study for 5 years, 161 patients only were              creased in the antibiotic groups (1.63+-0.5 mm) and
    available for the 5-year review. Statistically significant      (1.7+-0.53 mm) in the 3 and 7-day AB regimen com-
                                 ni
    additional changes in CAL with adjuvant metronida-              pared to 1.13+-0.74 mm in the placebo group.
    zole were found at 5 years of 0.40 mm in the SRP
    group and 0.06 mm in full mouth disinfection group.             Secondary outcomes
                               io


    However additional benefit with use of systemic                 Ribeiro (29). 6 months resulted in lower bleeding on
    metronidazole was small and doesn’t justify use of              probing (BOP) (7,755 at test sites, compared to
    antibiotics. No mention of.                                     21.11% at control sites). Real time PCR and Elisa
                             iz



                                                                    failed to identify any significant differences between
    Fonseca (26). All groups in this study presented sig-           the groups. However only the test treatments group
    nificant reduction in the percentage of periodontal             reduced the numbers of all microorganisms below the
           Ed




    diseases sites, gingival index, plaque score, and               levels of detection. Both groups presented statistical-
    CAL gain at 90 days, demonstrating all treatment                ly significant reduction of PG and Tf only.
    modalities were effective. However, the FC group
    [Full mouth disinfection (FMD) with chlorhexidine               Cionca (30). The number of persisting bleeding pock-
    (CHX) for 2 weeks] showed a higher reduction in                 ets was 7.5 times greater if the subjects had not re-
    probing depth reduction (from 2.10 +- 0.50 to 1.53              ceived the antibiotics after full mouth scaling and root
 IC




    +- 0.41 mm) and percentage of periodontal disease               planing. The mean PS, GI, REC, were not significant-
    sites (from 6.58+- 7.95 to 2.13+- 3.90) as well as              ly different.
    lower total bacterial counts at 90 and 180 days. The
    full mouth scaling and root planing group plus                  Preus (31). The distribution of sites with plaque at 12
C




    azithromycin in this study unlike other studies in the          months was like baseline, however the percentage of
    literature demonstrated less reduction in probing               sites with BOP reduced in all groups.
    depth compared to the full mouth disinfection group.
    Therefore, it was concluded that adjuvant used of               Preus (32). The 5-year results reported reduced
©




    azithromycin did not provide any significant benefit.           plaque score and BOP in all groups that was main-
                                                                    tained at 5 years.
    Cosgarea (33). All groups presented significant clini-
    cal improvement. Average pocket reduction at 6                  Fonseca (26). All groups in this study presented signifi-
    months in the placebo group (1.90 +-0.69 mm) was                cant reduction in the percentage of periodontal diseases
    significantly smaller compared to 3-day antibiotic              sites, gingival index, and plaque score at 90 days,
    (AB) (2.5+-0.62) and (2.76+-0.62) for the 7-day AB              demonstrating all treatment modalities were effective.

    118                                                                                     Annali di Stomatologia 2018;IX (3):111-122
    Clinical efficacy of systemic antibiotics as an adjunctive therapy to one stage full mouth disinfection (OSFMD) and full-
    mouth scaling and root planning in the treatment of chronic periodontitis: a systematic review of randomised clinical trials

    Cosgarea (33). All groups presented similar decrease            and microbiological changes. It must be noted that
    in BOP at 6 months, there was more reduction of                 the participants in this trial had moderately deep peri-
    BOP in AB groups (9.47+-5.34 and 7.75 +- 6.64)                  odontal probing depths, and results were diluted by
    compared to placebo group (13.07+-9.02). FMPS was               the mean value of the healthy sites. It was noted in 5
    similar in all treatment groups.                                studies that the probing depth reduction was more




                                                                                                         li
                                                                    noticeable in deep (PD >6 mm) and percentage of
                                                                    diseases sites which were sites with 4 mm and BOP




                                                                                                       na
    Discussion                                                      decreased significantly in all patients receiving sys-
                                                                    temic antibiotics, which decreased the need of further
    There is a lot of evidence in the literature which sug-         periodontal therapy, assumed to be surgery in these
    gests that systemic antibiotics in combination with             patients. Microbiological results were recorded in 2
    scaling and root planing result in additional clinical          studies only with conflicting results, as one study




                                                                                                     io
    benefits compared to scaling and root planing alone,            demonstrated significant reductions with the use of
    (29, 30) most of the studies compare the effect of              systemic antibiotics while the other showed no
    conventional scaling and root planing carried out in            changes with the use of antibiotics but significant re-




                                                                               az
    staged visits that could be weeks apart. Since the              duction with use of the full mouth disinfection proto-
    proposal of the full mouth disinfection protocol, by            col. No changes were found with regards to the in-
    Quirynen et al. (4) which suggest that additional clini-        flammatory markers in the one study that analysed
    cal benefits were compared to conventional scaling              them in GCF before and after intervention. All the




                                                                             rn
    and root planning, many studies have revealed better            studies reported on the 6 months, except two studies
    clinical and microbiological outcomes with this new             by Preus et al. which reported results up to 12
    protocol (3, 4, 15, 34). Other studies have failed to           months (31) and 5 years (32). They reported positive
    demonstrate such results (21-23). A review by Lang              outcomes with the use of systemic antibiotics which




                                                           te
    et al. (22) on the effects of full mouth scaling and root       was maintained up to 5 years in those studies, how-
    planing with or without chlorohexidine and conven-              ever it noted that the different was minimal despite
    tional scaling and root planing has shown statistically         being statistically significant.
    significant differences between the full mouth de-
                                                         In
    bridement with and without antiseptics and conven-
    tional scaling and root planing however, they were in-          Limitations
    consistent and small and therefore concluded both
                               ni
    treatment modalities were effective, it also delineated         Outcome level
    that full mouth scaling and root planning provided ad-          This present review only reported on the data pre-
    ditional benefits in terms of time as treatment is car-         sented by 6 studies (RCT Studies) to estimate the
    ried out in less time. The aim of this review is to             treatment effects of the use of systemic antibiotics
                             io


    analyse the additional effects provided by systemic             with full mouth scaling and root planing with or with-
    use of antibiotics in the non-surgical treatment of             out antibiotics. The excluded publications are listed in
    chronic periodontitis using full mouth scaling and root         Table 3 (35-46). The studies included used different
                           iz



    planing with or without use of antiseptics. Only 6              regimens of antibiotics for different duration. The out-
    studies fulfilled the criteria to be included in this re-       come of the review depending on the studies includ-
    view, which is a very limited number, most of these             ed was influenced by the patient population, the data
           Ed




    studies were randomised controlled trials with a low            collection, the type and regimen of the systemic an-
    risk of bias. Different systemic antibiotics 18 and regi-       tibiotic used and the analyses that differed between
    mens were used in each of the studies, which                    studies.
    ranged, from combination (amoxicillin and metronida-
    zole, metronidazole alone and azithromycin). It must            Study and review level
    be noted that in the literature there is no recommen-           The main limitation of the present systematic review
 IC




    dations for a specific antibiotic regimen to be used in         was the heterogeneity in the design, intervention, da-
    the treatment of chronic periodontitis. Probing reduc-          ta collection, and analyses. The limited number of
    tion, CAL changes were the primary outcome of all               studies that fulfilled the criteria also limited the
    the studies, 2 studies analysed the microbiological             amount of data to be analysed as well as the different
C




    outcomes after treatment as well and one study                  regimens of systemic antibiotics used and short fol-
    analysed the levels of inflammatory mediators                   low-up duration of only 6 months in most studies.
    (PGE2, IL and interferon) after treatment. 3 of the             Therefore, more well designed, multicentre studies
    studies demonstrated significant probing depth reduc-           with long follow-up are required to obtain evidence
©




    tion with relation of systemic antibiotics when com-            based guidelines.
    pared to full mouth scaling and root planing without
    antibiotics. One study reported no significant changes
    with the use of systemic antibiotics compared to full           Conclusions
    mouth scaling and root planing and reported more
    significant changes with the full mouth disinfection            Implications for practice
    protocol instead in terms of PD reduction, CAL gain             In the present systematic review, despite the limited

    Annali di Stomatologia 2018;IX (3):111-122                                                                              119
    E. Elhassan et al.


    Table 3. List of publications excluded in methodological assessment.

     Publication                   Ref no         Reason for exclusion
     Gomi, et al. 2007             (35)           SRP was completed within 7 days
     Pradeep, et al. 2012          (36)           SRP was not completed within 24 hours




                                                                                                                li
     Matarazzo, et al. 2008        (37)           Patient selection was smokers only (10 cigarettes per day for 5 years)




                                                                                                              na
     Smith, et al. 2012            (38)           SRP was carried out within 3 weeks
     Jentsch, et al. 2016          (39)           No control group. Both groups received different types of antibiotics
                                                  (azithromycin or amoxicillin + metronidazole)
     Haffajee, et al. 2004         (40)           Patients had previous periodontal therapy and only local antibiotics was used as




                                                                                                            io
                                                  well
     Winkel, et al. 2001           (41)           SRP was carried out in 3 to 6 sessions
     Silva, et al. 2011            (42)           Treatment was carried out in 4- 6 visits not within 24 hours




                                                                                    az
     Harks, et al. 2015            (43)           Aggressive periodontitis patients were included in the study
     Lopez, et al. 2006            (44)           SRP was completed in 2 sessions 3 days apart
     Faveri, et al. 2014           (45)           All patients received SRP+ systemic metronidazole and groups were categorised
                                                  according to smoking status




                                                                                  rn
     Haffajee, et al. 2007         (46)           SRP was completed quadrant wise in weeks




                                                              te
    number of studies reviewed, it was nevertheless pos-                2.  Apatzidou DA, Riggio MP, Kinane DF. Quadrant root plan-
    sible to conclude that the use of adjuvant antibiotics                  ing versus same-day full-mouth root planing - II. Microbio-
    with full mouth scaling and root planing and full                       logical findings. Journal of Clinical Periodontology.
                                                                            2004;31(2):141-148.
    mouth disinfection provided additional clinical bene-
    fits in terms of PD reduction, CAL gain especially in
                                                            In          3. Bollen CML, Mongardini C, Papaioannou W, Van Steen-
                                                                            berghe D, Quirynen M. The effect of a one-stage full-mouth
    PDs >6 mm. Even though one study did not demon-                         disinfection on different intra-oral niches - Clinical and mi-
    strate its superiority compared to other treatment pro-                 crobiological observations. Journal of Clinical Periodontol-
    tocols, it was an effective clinical modality of treat-                 ogy. 1998;25(1):56-66.
                                 ni
    ment (26). Use of antibiotics should be approached                  4. Quirynen M, Bollen CML, Vandekerckhove BNA, Dekeyser
    with caution as to prevent bacterial resistance to sys-                 C, Papaioannou W, Eyssen H. Full-vs partial-mouth disin-
    temic antibiotics. More research is required to further                 fection in the treatment of periodontal infections - short-term
                               io


    verify these results.                                                   clinical and microbiological observations. Journal of Dental
                                                                            Research. 1995;74(8):1459-1467.
                                                                        5. Badersten A, Nilvéus R, Egelberg J. Effect of nonsurgical pe-
    Implications for research                                               riodontal therapy. Journal of Clinical Periodontology.
                             iz



    Further, long term randomised control trials with care-                 1981;8(1):57-72.
    ful case selection of specific treatment protocols as               6. Cobb CM. Clinical significance of non-surgical periodontal
    well as standardised regimens for antibiotic use is re-                 therapy: an evidence-based perspective of scaling and root
            Ed




    quired to obtain sufficient scientific evidence based                   planing. J Clin Periodontol. 2002;29(Suppl2):6-16.
    on treatment clinical guidelines for adjuvant use of                7. Quirynen M, De Soete M, Dierickx K, van Steenberghe D.
    systemic antibiotics with full mouth scaling and root                   The intra-oral translocation of periodontopathogens jeop-
                                                                            ardises the outcome of periodontal therapy - A review of the
    planing and full mouth disinfection in treatment of
                                                                            literature. Journal of Clinical Periodontology. 2001;28(6):499-
    chronic periodontitis.                                                  507.
                                                                        8. Haffajee AD, Socransky SS, Gunsolley JC. Systemic anti-
 IC




                                                                            infective periodontal therapy. A systematic review. Annals
    Acknowledgement                                                         of periodontology / the American Academy of Periodontol-
                                                                            ogy. 2003;8(1):115.
    This review has been carried out as part of research                9. Herrera D, Sanz M, Jepsen S, Needleman I, Roldán S. A sys-
C




    requirements of the first Author as a requirement of                    tematic review on the effect of systemic antimicrobials as an
                                                                            adjunct to scaling and root planing in periodontitis patients.
    the first Author for the completion of the Doctor of
                                                                            Oxford, UK: Blackwell Science Ltd. 2002;136-159.
    Clinical Dentistry Program in Periodontics at the Uni-
                                                                        10. Listgarten MA. Structure of the microbial flora associated with
    versity of Western Australia.                                           periodontal health and disease in man. A light and electron
©




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