Non-surgical periodontal therapy with systemic antibiotics in patients with untreated chronic
periodontitis: a systematic review and meta-analysis
For figures, tables and references we refer the reader to the original paper.
The goals of today's treatment of periodontitis are to reduce infection, resolve inflammation and
create a clinical condition, which is compatible with periodontal health [1]. Periodontitis is typically
treated initially in a non-surgical way. Non-surgical periodontal therapy consists of scaling and root
planing (SRP) combined with oral hygiene instructions. Typically, this results in gain in attachment
and recession of the gingival margin due to resolution of the inflammation. Now and then, even
though the expected effect has been achieved, some residual pockets remain after therapy [2].
Additional periodontal surgery is needed to resolve these residual pockets. When the expected effect
of non-surgical periodontal therapy is not achieved, the treatment needs to be adjusted and hereby
systemic antibiotics could be a good alternative. Systemic antibiotics help the immune system by
suppressing the target microbial species. The literature [3-5] shows that systemic antibiotics in
combination with non-surgical periodontal therapy might improve the clinical results. These
improved clinical results are positive side effects of systemic antibiotic usage and therefore induce a
better treatment outcome. In 2002 Herrera concluded that in specific clinical situations such as
patients with deep pockets, patients with progressive or “active” disease, or patients with specific
microbiological profiles systemic antibiotics usage in combination with non-surgical periodontal
therapy could be clinically relevant [5]. Systemic antibiotic usage has also been used as a
monotherapy. However, for the best clinical outcomes the combination with non-surgical
periodontal therapy is highly recommended [6]. Additionally, the American Academy of
Periodontology suggested that systemic antibiotics should only be used as an adjunctive therapy,
based on the concept of “good medical practice” [7].
Many different systemic antibiotic regimens have been used. The most common are penicillins
(amoxicillin, cefuroximaxetil), tetracyclines (doxycycline, minocycline, tetracycline), macrolides
(azithromycin, flurithromycin, spiramycin, clindamycin), quinolones (moxifloxacin, ciprofloxacin) and
nitroimidazole (metronidazole, ornidazole). Amoxicillin is commonly used in combination with
metronidazole. Local applications of most of these antibiotics have also been used primarily in
combination with non-surgical periodontal therapy [8, 9].
The rationale for the use of systemic antibiotics in combination with non-surgical periodontal therapy
is to suppress pathogenic bacteria and create a healthy biofilm. If the use of systemic antibiotics is
considered, the clinician needs to decide at which point of the treatment the systemic antibiotics will
be used. One has to take into account the patient's compliance, adverse effects and bacterial
resistance [4, 5]. The most recent meta-analyses focused on the effectiveness of one systemic
antibiotic regimen and none of them compared the effects of the different types of systemic
antibiotics that the clinician is using today [8-13]. However, it becomes necessary to develop an
evidence-based clinical protocol to help to decide if, when, how and what kind of systemic antibiotic
regimen should be used. As a first step towards such protocol, this meta-analysis evaluates if there
are differences between the effectiveness of the different types of systemic antibiotics in
combination with SRP vs. SRP alone in patients with untreated chronic periodontitis and whether the
effect is consistent over time.
Material and methods
The following systematic review was conducted in agreement with recommendations of the
Cochrane Collaboration [14] and the principles of the PRISMA (Preferred Reporting Items for
Systemic Reviews and Meta-Analyses) statement [15].
The focused question that has been used was: “Do systemic antibiotics combined with SRP vs. SRP
alone in untreated chronic periodontitis patients have an additional effect on the clinical outcomes.”
Search strategy
The MEDLINE-PubMed database was searched from their earliest records until May 16, 2013. The
following search terms were used: Periodontal diseases [MESH] AND Anti-Infective Agents [MESH]
and Metronidazole [MESH] AND Periodontal diseases [MESH]. In addition, a manual search was
performed on issues from the past 10 years of the Journal of Clinical Periodontology, Journal of
Periodontal Research and Journal of Periodontology.
Study inclusion and exclusion criteria
The selection process was performed by two masked reviewers (IG and JK). The studies were
analysed according to inclusion criteria:
1.Studies were limited to randomized controlled clinical trials of at least more than 1 month of
duration.
2.The population was limited to subjects with chronic periodontitis [16].
3.The interventions of interest were full mouth SRP (scaling and root planing within one week,
FMSRP) or staged SRP (scaling and root planing more than a week apart, SSRP) with or without the
use of systematic antibiotics.
4.No specific systemic antibiotics were excluded.
5.Only papers in the English language were included.
Only studies that met all inclusion criteria were analysed according to the exclusion criteria:
1.History of refractory periodontitis.
2.Combination of local and systemic antibiotics.
3.Primary outcome of interest were not analysed.
4.Duplicated studies.
Outcome variables
The primary outcomes were probing pocket depth reduction and clinical attachment level change.
clinical attachment level change and probing pocket depth reduction were, if possible, divided into
moderate pockets (4–6 mm) and deep pockets (> 6 mm). The secondary outcome was bleeding on
probing (BOP) change.
Data extraction
The title and abstract of studies of possible relevance for the review were obtained and screened
independently by two masked reviewers (IG and JK). Papers without abstracts but with titles
suggesting relevance to the subject of the review were selected for full text screening. The selected
full text papers were independently read in detail to check whether they passed the
inclusion/exclusion criteria. The references of full text articles were screened for any relevant
additional articles. The papers that fulfilled all the selection criteria were processed for data
extraction. Discrepancies with regard to the inclusion or exclusion of studies were resolved by
discussion between the reviewers (IG and JK). The extracted data included year of publication, design
of the study, number of patients per study arm, length of follow-up, type of antibiotic, dosage of the
antibiotic, duration of the antibiotic regimen, timing of the antibiotic in relation to SRP and primary
and secondary outcome measures at 3, 6, 9 and 12 mo.
Quality assessment
A quality assessment of the methodologies of all included studies was conducted. It was based on the
randomized controlled trial checklist of the Cochrane Center, CONSORT guidelines [17], Delphi list
[18] and checklist as proposed by Van der Weijden et al. [19]. The following seven criteria were used;
selection bias, allocation bias, performance bias, detection bias, defined inclusion/exclusion criteria,
attrition bias and reporting bias. When all these criteria were fulfilled, the article was classified as a
low risk of bias (L). When one or two of these criteria were assessed as high risk of bias or unclear,
the study was regarded as a moderate potential risk of bias (M). The risk of potential bias was high,
when three or more criteria had a high or unclear risk of bias (H). The risk of bias was evaluated
independently by two masked reviewers (IG and JK). If there was any disagreement, it was resolved
by discussion.
Statistical analyses
Data of the included studies were extracted and entered into a database. Mean values and standard
deviations were extracted from the data. If no standard deviation was available it was recalculated
by the formula (SE = SD/√n) with n as the sample size. When intermediate assessments were
performed, the 3, 6, 9 or 12 mo data were considered. If there was insufficient data available, the
corresponding authors were contacted for additional data. The available data were recalculated to
present the data such as mean BOP change, mean clinical attachment level gain and mean probing
pocket depth reduction. Clinical attachment level gain and probing pocket depth reduction were also
presented for moderate pockets (4–6 mm) and deep pockets (> 6 mm). The I2 statistic was used to
assess the heterogeneity between the studies. Because of observed heterogeneity mean differences
were combined for continuous data using random effects models meta-analysis [20]. Study weights
were determined by the sample size.
Results
The initial search resulted in a total of 6422 articles (Fig. 1). After screening the titles, 281 abstracts
were included for further analysis. Analysis of the abstracts resulted in 95 potential articles. In the
third phase, the full text articles of the remaining 95 articles were evaluated, of which 40 [21-60] did
not pass the inclusion criteria (Table 1). Another 12 articles [61-72] were excluded because they were
about patients with aggressive periodontitis. Screening of the reference lists of the full text articles
did not result in any additional articles. In Table 2 the main characteristics of the 43 included studies
[73-115] are summarized. Eight authors have provided additional results that were not present in the
articles [82, 83, 86, 87, 91, 95, 100, 105]. These studies were divided in to the following groups:
amoxicillin (AMOX, one study); amoxicillin + clavulanic acid (AMOX + CLAV, one); azithromycin (AZI,
eight); clarithromycin (CLA, one); low-dose doxycycline (DOXL, 14); high-dose doxycycline (DOXH,
four); metronidazole (MET, seven); metronidazole + amoxicillin (MET + AMOX, 10); moxifloxacin
(MOX, one); ornidazole (ORN, one); spiramycin (SPI, two); and tetracycline (TET, two). The quality
evaluation was based on seven criteria [17-19]. The potential risk of bias in the 43 studies included
was low in 15, moderate in four and high in 24 (Table 2).
Probing pocket depth reduction
At 3 mo, 1506 patients out of 35 studies could be analysed (Fig. 2 and Table S1). A statistically
significant mean difference of 0.28 mm ± 0.09 and heterogeneity I2 = 69%, in favour of the use of a
systemic antibiotic was observed. AZI (0.39 mm ± 0.27, six studies, 185 patients, I2 = 74%), CLA (0.88
mm ± 0.23, one study, 37 patients, I2 = NA), MET (0.15 mm ± 0.10, five studies, 111 patients, I2 =
0%), MET + AMOX (0.29 mm ± 0.20, seven studies, 275 patients, I2 = 58%), MOX (0.65 mm 0.44, one
study, 65 patients, I2 = NA), ORN (1.64 mm ± 0.81, one study, 50 patients, I2 = NA) and SPI (0.50 mm
± 0.29, one study, 193 patients, I2 = NA) showed a statistically significant mean difference when
compared to the control group. However, it should be noted that for CLA, MOX, ORN and SPI only
one study was available. For CLA and ORN there was a statistically significant larger difference when
compared to AZI, MET and MET + AMOX. DOXL and DOXH did not show a statistically significant
mean difference when compared to the control group.
At 6 mo, 1272 patients out of 28 studies could be analysed. A statistically significant mean difference
of 0.37 mm ± 0.05 and heterogeneity I2 = 77%, in favour of the use of a systemic antibiotic was
observed. AZI (0.32 mm ± 0.21, seven studies, 128 patients, I2 = 44%), CLA (1.00 mm ± 0.22, one
study, 37 patients, I2 = NA), DOXL (0.28 mm ± 0.17, nine studies, 269 patients, I2 = 66%), MET +
AMOX (0.39 mm ± 0.34, four studies, 221 patients, I2 = 80%), MOX (0.70 mm ± 0.43, one study, 65
patients, I2 = NA), ORN (1.92 mm ± 0.82, one study, 50 patients, I2 = NA) and SPI (0.47 mm ± 0.29,
one study, 193 patients, I2 = NA) showed a statistically significant mean difference when compared
to the control group. However, it should be noted that for CLA, MOX, ORN and SPI only one study
was available. For CLA and ORN there was a statistically significant larger mean difference when
compared to AZI, DOXL and MET + AMOX. AMOX + CLAV, DOXH and MET did not show a statistically
significant mean difference when compared to the control group.
At 9 mo, 164 patients out of five studies could be analysed. A statistically significant mean difference
of 0.49 mm ± 0.42 and heterogeneity I2 = 89%, in favour of the use of a systemic antibiotic was
observed. CLA (1.18 mm ± 0.23, one study, 37 patients, I2 = NA) and DOXL (0.39 mm ± 0.16, three
studies, 107 patients, I2 = 0%) showed a statistically significant mean difference when compared to
the control group. However, it should be noted that for CLA only one study was available. For CLA
there was a statistically significant larger difference when compared to DOXL. AZI did not show a
statistically significant mean difference when compared to the control group.
At 12 mo, 702 patients out of 15 studies could be analysed. A statistically significant mean difference
of 0.26 mm ± 0.13 and heterogeneity I2 = 50%, in favour of the use of a systemic antibiotic was
observed. MET (0.18 mm ± 0.17, two studies, 114 patients, I2 = 0%), MET + AMOX (0.55 mm ± 0.37,
three studies, 133 patients, I2 = 41%) and MOX (0.99 mm ± 0.53, one study, 65 patients, I2 = NA)
showed a statistically significant mean difference when compared to the control group. However, it
should be noted that for MOX only one study was available. For MOX there was a statistically significant larger difference when compa-red to MET. AMOX + CLAV, AZI, DOXL, DOXH and TET did not
show a statistically significant mean differ-ence when compared to the control group.
Probing pocket depth reduction: moderate pockets
At 3 mo, 1358 patients out of 21 studies could be analysed (Fig. 3 and Table S2). A statistically
significant mean difference of 0.27 mm ± 0.09 and heterogeneity I2 = 58%, in favour of the use of a
systemic antibiotic was observed. DOXL (0.21 mm ± 0.08, five studies, 664 patients, I2 = 0%), MET
(0.33 mm ± 0.15, four studies, 164 patients, I2 = 0%), MET + AMOX (0.60 mm ± 0.15, four studies, 167
patients, I2 = 0%) and MOX (0.27 mm ± 0.24, one study, 65 patients, I2 = NA) showed a statistically
significant mean difference when compared to the control group. However, it should be noted that
for MOX only one study was available. Between MET + AMOX and DOXL there was a statistically
significant difference in favour of MET + AMOX. No statistically significant differences between MET +
AMOX and MET or MOX were noted. AZI, DOXH, SPI and TET did not show a statistically significant
mean difference when compared to the control group.
At 6 mo, 1293 patients out of 18 studies could be analysed. A statistically significant mean difference
of 0.23 mm ± 0.10 and heterogeneity I2 = 63%, in favour of the use of a systemic antibiotic was
observed. DOXL (0.22 mm ± 0.09, five studies, 664 patients, I2 = 0%), MET (0.30 mm ± 0.25, one
study, 76 patients, I2 = NA), MET + AMOX (0.50 mm ± 0.23, three studies, 150 patients, I2 = 50%) and
MOX (0.29 mm ± 0.21, one study, 65 patients, I2 = NA) showed a statistically significant mean
difference when compared to the control group. However, it should be noted that for MET and MOX
only one study was available. No statistically significant differences for DOXL, MET, MET + AMOX and
MOX were noted. AZI, DXOH, SPI and TET did not show a statistically significant mean difference
when compared to the control group.
At 9 mo, 638 patients out of four studies could be analysed. A statistically significant mean difference
of 0.29 mm ± 0.10 and heterogeneity I2 = 0%, in favour of the use of a systemic antibiotic was
observed. Only results for DOXL were available at 9 mo.
At 12 mo, 305 patients out of five studies could be analysed. A statistically significant mean
difference of 0.25 mm ± 0.27 and heterogeneity I2 = 76%, in favour of the use of a systemic antibiotic
was observed. MET (0.40 mm ± 0.24, one study, 67 patients, I2 = NA), MET + AMOX (0.60 mm ± 0.24,
one study, 68 patients, I2 = NA) and MOX (0.31 mm ± 0.28, one study, 65 patients, I2 = NA) showed a
statistically significant mean difference when compared to the control group. However, it should be
noted that for all of these antibiotics, only one study was available. No statistically significant
differences between these three antibiotics were noted. AZI and DOXH did not show a statistically
significant mean difference when compared to the control group.
Probing pocket depth reduction: deep pockets
At 3 mo, 1462 patients out of 24 studies could be analysed (Fig. 4 and Table S3). A statistically
significant mean difference of 0.62 mm ± 0.17 and heterogeneity I2 = 50%, in favour of the use of a
systemic antibiotic was observed. AZI (0.52 mm ± 0.28, five studies, 169 patients, I2 = 0%), DOXL
(0.41 mm ± 0.23, six studies, 682 patients, I2 = 26%), DOXH (0.91 mm ± 0.64, one study, 65 patients,
I2 = NA), MET (0.83 mm ± 0.28, five studies, 211 patients, I2 = 0%), MET + AMOX (0.92 mm ± 0.49,
four studies, 167 patients, I2 = 62%) and MOX (1.03 mm ± 0.61, one study, 65 patients, I2 = NA)
showed a statistically significant mean difference when compared to the control group. However, it
should be noted that for DOXH and MOX only one study was available. No statistically significant
differences between these six antibiotics were noted. SPI and TET did not show a statistically
significant mean difference when compared to the control group.
At 6 mo, 1397 patients out of 21 studies could be analysed. A statistically significant mean difference
of 0.58 mm ± 0.16 and heterogeneity I2 = 33%, in favour of the use of a systemic antibiotic was
observed. AZI (0.52 mm ± 0.34, six studies, 209 patients, I2 = 27%), DOXL (0.62 mm ± 0.22, six
studies, 682 patients, I2 = 0%), DOXH (0.74 mm ± 0.63, one study, 65 patients, I2 = NA), MET (0.78
mm ± 0.45, two studies, 123 patients, I2 = 0%), MET + AMOX (0.79 mm ± 0.27, three studies, 150
patients, I2 = 30%) and MOX (0.87 mm ± 0.61, one study, 65 patients, I2 = NA) showed a statistically
significant mean difference when compared to the control group. However, it should be noted that
for DOXH and MOX only one study was available. No statistically significant differences between
these six antibiotics were noted. SPI and TET did not show a statistically significant mean difference
when compared to the control group.
At 9 mo, 613 patients out of four studies could be analysed. A statistically significant mean difference
of 0.52 mm ± 0.23 and heterogeneity I2 = 0%, in favour of the use of a systemic antibiotic was
observed. Only results for DOXL were available at 9 mo.
At 12 mo, 453 patients out of eight studies could be analysed. A statistically significant mean
difference of 0.74 mm ± 0.30 and heterogeneity I2 = 29%, in favour of the use of a systemic antibiotic
was observed. DOXH (0.65 mm ± 0.62, one study, 65 patients, I2 = NA), MET (0.92 mm ± 0.48, two
studies, 114 patients, I2 = 0%), MET + AMOX (1.00 mm ± 0.53, one studies, 68 patients, I2 = NA) and
MOX (1.03 mm ± 0.55, one study, 65 patients, I2 = NA) showed a statistically significant mean
difference when compared to the control group. However, it should be noted that for DOXL, DOXH,
MET + AMOX and MOX only one study was available. No statistically significant differences between
these four antibiotics were noted. AZI and DOXL did not show a statistically significant mean
difference when compared to the control group.
Clinical attachment level gain
At 3 mo, 1506 patients out of 35 studies could be analysed (Fig. 5 and Table S4). A statistically
significant mean difference of 0.20 mm ± 0.11 and heterogeneity I2 = 69%, in favour of the use of a
systemic antibiotic was observed. CLA (0.92 mm ± 0.19, one study, 37 patients, I2 = NA), DOXL (0.31
mm ± 0.12, 10 studies, 315 patients, I2 = 0%) and ORN (1.68 mm ± 0.93, one study, 50 patients, I2 =
NA) showed a statistically significant mean difference when compared to the control group.
However, it should be noted that for CLA and ORN only one study was available. CLA and ORN
showed a significantly more pronounced difference compared to DOXL. AMOX + CLAV, AZI, DOXH,
MET, MET + AMOX, MOX and SPI did not show a statistically significant mean difference when
compared to the control group.
At 6 mo, 1272 patients out of 28 studies could be analysed. A statistically significant mean difference
of 0.31 mm ± 0.17 and heterogeneity I2 = 83%, in favour of the use of a systemic antibiotic was
observed. CLA (0.95 mm ± 0.20, one study, 37 patients, I2 = NA), DOXL (0.38 mm ± 0.27, nine studies,
269 patients, I2 = 79%), MET (0.18 mm ± 0.17, two studies, 123 patients, I2 = 0%), MOX (0.35 mm ±
0.34, one study, 65 patients, I2 = NA) and ORN (2.00 mm ± 0.95, one study, 50 patients, I2 = NA)
showed a statistically significant mean difference when compared to the control group. However, it
should be noted that for CLA, MOX and ORN only one study was available. CLA and ORN showed a
significantly more pronounced difference when compared to DOXL, MET and MOX. AMOX + CLAV,
AZI, DOXH, MET + AMOX and SPI did not show a statistically significant mean difference when
compared to the control group.
At 9 mo, 164 patients out of five studies could be analysed. A statistically significant mean difference
of 0.45 mm ± 0.55 and heterogeneity I2 = 96%, in favour of the use of a systemic antibiotic was
observed. CLA (1.07 mm ± 0.20, one study, 37 patients, I2 = NA) and DOXL (0.55 ± 0.38, three studies,
107 patients, I2 = 47%) showed a statistically significant mean difference when compared to the
control group. However, it should be noted that for CLA only one study was available. CLA showed a
significantly more pronounced difference compared to DOXL. AZI did not show a statistically
significant mean difference when compared to the control group.
At 12 mo, 702 patients out of 15 studies could be analysed. A statistically significant mean difference
of 0.10 mm ± 0.11 and heterogeneity I2 = 36%, in favour of the use of a systemic antibiotic was
observed. MET (0.21 mm ± 0.20, two studies, 114 patients, I2 = 0%), MOX (0.31 ± 0.26, one study, 65
patients, I2 = NA) and TET (0.31 mm ± 0.26, one study, 89 patients, I2 = NA) showed a statistically
significant mean difference when compared to the control group. However, it should be noted that
for MOX and TET only one study was available. No statistically significant differences between these
three antibiotics were noted. AMOX + CLAV, AZI, DOXL, DOXH and MET + AMOX did not show a
statistically significant mean difference when compared to the control group.
Clinical attachment level gain: moderate pockets
At 3 mo, 1164 patients out of 17 studies could be analysed (Fig. 6 and Table S5). A statistically
significant mean difference of 0.18 mm ± 0.06 and heterogeneity I2 = 0%, in favour of the use of a
systemic antibiotic was observed. DOXL (0.15 mm ± 0.09, four studies, 644 patients, I2 = 0%), MET
(0.25 mm ± 0.18, four studies, 164 patients, I2 = 0%) and MET + AMOX (0.42 mm ± 0.18, four studies,
167 patients, I2 = 0%) showed a statistically significant mean difference when compared to the
control group. MET + AMOX showed a significantly more pronounced difference compared to DOXL.
AZI, SPI and TET did not show a statistically significant mean difference when compared to the
control group.
At 6 mo, 1099 patients out of 14 studies could be analysed. A statistically significant mean difference
of 0.17 mm ± 0.08 and heterogeneity I2 = 24%, in favour of the use of a systemic antibiotic was
observed. DOXL (0.12 mm ± 0.09, four studies, 644 patients, I2 = 0%), MET (0.30 mm ± 0.20, one
study, 76 patients, I2 = NA) and MET + AMOX (0.33 mm ± 0.14, three studies, 150 patients, I2 = 0%)
showed a statistically significant mean difference when compared to the control group. However, it
should be noted that for MET only one study was available. No statistically significant differences
between these three antibiotics were noted. AZI, SPI and TET did not show a statistically significant
mean difference when compared to the control group.
At 9 mo, 618 patients out of three studies could be analysed. A statistically significant mean
difference of 0.25 mm ± 0.11 and heterogeneity I2 = 25%, in favour of the use of a systemic antibiotic
was observed. Only results for DOXL were available at 9 mo.
At 12 mo, 175 patients out of three studies could be analysed. A statistically significant mean
difference of 0.29 mm ± 0.17 and heterogeneity I2 = 6%, in favour of the use of a systemic antibiotic
was observed. MET + AMOX (0.40 mm ± 0.22, one study, 68 patients, I2 = NA) showed a statistically
significant mean difference when compared to the control group. However, it should be noted that
for MET + AMOX only one study was available. AZI and MET did not show a statistically significant
mean difference when compared to the control group.
Clinical attachment level gain: deep pockets
At 3 mo, 1268 patients out of 14 studies could be analysed (Fig. 7 and Table S6). A statistically
significant mean difference of 0.49 mm ± 0.17 and heterogeneity I2 = 38%, in favour of the use of a
systemic antibiotic was observed. AZI (0.43 mm ± 0.40, four studies, 125 patients, I2 = 0%), DOXL
(0.31 mm ± 0.20, five studies, 662 patients, I2 = 0%), MET (0.66 mm ± 0.28, five studies, 211 patients,
I2 = 0%) and MET + AMOX (0.67 mm ± 0.55 four studies, 167 patients, I2 = 76%) showed a statistically
significant mean difference when compared to the control group. No statistically significant
differences between these four antibiotics were noted. SPI and TET did not show a statistically
significant mean difference when compared to the control group.
At 6 mo, 1111 patients out of 17 studies could be analysed. A statistically significant mean difference
of 0.42 mm ± 0.18 and heterogeneity I2 = 18%, in favour of the use of a systemic antibiotic was
observed. DOXL (0.39 mm ± 0.28, five studies, 570 patients, I2 = 0%) and MET (0.64 mm ± 0.38, two
studies, 123 patients, I2 = 0%) showed a statistically significant mean difference when compared to
the control group. No statistically significant differences between these two antibiotics were noted.
AZI, MET + AMOX, SPI and TET did not show a statistically significant mean difference when
compared to the control group.
At 9 mo, 593 patients out of three studies could be analysed. A statistically significant mean
difference of 0.43 mm ± 0.25 and heterogeneity I2 = 0%, in favour of the use of a systemic antibiotic
was observed. Only results for DOXL were available at 9 mo.
At 12 mo, 313 patients out of three studies could be analysed. A statistically significant mean
difference of 0.61 mm ± 0.29 and heterogeneity I2 = 0%, in favour of the use of a systemic antibiotic
was observed. MET (0.73 mm ± 0.61, three studies, 114 patients I2 = 32%) and MET + AMOX (0.80
mm ± 0.48, one study, 68 patients, I2 = NA) showed a statistically significant mean difference when
compared to the control group. No statistically significant differences between these two antibiotics
were noted. AZI and DOXL did not show a statistically significant mean difference when compared to
the control group.
Bleeding on probing change
At 3 mo, 1168 patients out of 30 studies could be analysed (Fig. 8 and Table S7). A statistically
significant mean difference of 5.39% ± 3.07 and heterogeneity I2 = 65%, in favour of the use of a
systemic antibiotic was observed. AMOX + CLAV (20.00% ± 8.56, one study, 21 patients, I2 = NA),
MET + AMOX (7.90% ± 5.39, eight studies, 292 patients, I2 = 62%) and MOX (12.90% ± 9.56, one
study, 65 patients, I2 = NA) showed a statistically significant mean difference when compared to the
control group. However, it should be noted that for AMOX + CLAV and MOX only one study was
available. No statistically significant differences between these three antibiotics were noted. AMOX,
AZI, DOXL, DOXH and MET did not show a statistically significant mean difference when compared to
the control group.
At 6 mo, 959 patients out of 23 studies could be analysed. A statistically significant mean difference
of 5.18% ± 3.37 and heterogeneity I2 = 67%, in favour of the use of a systemic antibiotic was
observed. AMOX + CLAV (20.00% ± 8.56, one study, 21 patients, I2 = NA) and MET + AMOX (9.88% ±
6.94, six studies, 262 patients, I2 = 77%) showed a statistically significant mean difference when
compared to the control group. However, it should be noted that for AMOX + CLAV only one study
was available. No statistically significant differences between these two antibiotics were noted.
AMOX, AZI, DOXL, DOXH, MET and MOX did not show a statistically significant mean difference when
compared to the control group.
At 9 mo, 55 patients out of two studies could be analysed. Owing to the scarcity of the studies, the
results were not considered for analysis.
At 12 mo, 622 patients out of 13 studies could be analysed. A statistically significant mean difference
of 3.80% ± 2.97 and heterogeneity I2 = 29%, in favour of the use of a systemic antibiotic was
observed. AMOX + CLAV (10.00% ± 8.56, one study, 21 patients, I2 = NA) and MET (6.90% ± 6.43, two
studies, 114 patients, I2 = 17%) showed a statistically significant mean difference when compared to
the control group. However, it should be noted that for AMOX + CLAV only one study was available.
No statistically significant differences between these two antibiotics were noted. AZI, DOXL, DOXH,
MET + AMOX, MOX and TET did not show a statistically significant mean difference when compared
to the control group.
Discussion
In the literature, a lot of evidence is available, which suggests that systemic antibiotics in
combination with SRP result in additional clinical benefits compared to only SRP. This review has
systematically evaluated the current available evidence and has compared the effectiveness of the
different types of systemic antibiotics as well as their long-term effects (up to 1 year). Forty-five
clinical studies were included, from which data were obtained and used to calculate the mean
difference in clinical improvement for BOP, clinical attachment level and probing pocket depth
change. Clinical attachment level and probing pocket depth difference were additionally analysed for
initially moderate pockets (4–6 mm) and deep pockets (> 6 mm).
The meta-analysis for the mean probing pocket depth difference showed statistically significant
differences when compared to SRP at 3, 6 and 12 mo in favour of the use of antibiotics (0.28 mm ±
0.09, 0.37 mm ± 0.05 and 0.26 mm ± 0.13). The analysis was hampered by the fact that the follow-up
period from most of the studies was only 3–6 mo. When analysing only studies that had results at 3,
6 and 12 mo [73, 75, 80, 83, 86, 92, 99], the clinical additional difference of these studies was lower
at 3 mo (0.20 mm ± 0.11) and 6 mo (0.26 mm ± 0.15) and higher at 12 mo (0.30 mm ± 0.16) when
compared to the overall effect. Overall, it seems that the initial effect of the systemic antibiotics on
the mean probing pocket depth difference remains stable for at least 1 year. Additionally, when
disregarding the antibiotics with only one study in the analysis [AMOX + CLAV [111], CLA [79], MOX
[86], ORN [73], SPI [114] and TET [107]], it became clear that only for MET + AMOX the mean probing
pocket depth difference when compared to SRP could be obtained for up to 1 year.
The meta-analysis for the mean probing pocket depth difference in moderate pockets showed a
similar outcome as for mean whole mouth probing pocket depth reduction, albeit more pronounced.
When analysing only studies that had results at 3, 6 and 12 mo [74, 86], the clinical additional
difference of these studies was higher at 3 mo (0.33 mm ± 0.12), 6 mo (0.33 mm ± 0.12) and 12 mo
(0.35 mm ± 0.22) when compared to the overall effect. Based on these studies, it seems that the
initial effect of the systemic antibiotics on the mean probing pocket depth difference of moderate
pockets remains stable for at least 1 year. Additionally, when disregarding the antibiotics with only
one study in the analysis [DOXH [86], MOX [86], SPI [115] and TET [115]], there seemed to be a trend
that for MET + AMOX and MET the mean probing pocket depth difference for moderate pockets
when compared to SRP could be obtained for up to 1 year.
The meta-analysis for the mean probing pocket depth difference in deep pockets also showed a
similar outcome as for mean whole mouth probing pocket depth reduction, albeit more pronounced.
When analysing only studies that had results at 3, 6 and 12 mo [74, 86, 92], the clinical additional
difference of these studies was higher at 3 mo (0.90 mm ± 0.22), 6 mo (0.82 mm ± 0.24) and 12 mo
(0.83 mm ± 0.25) when compared to the overall effect. Based on these studies, it seems that the
initial effect of the systemic antibiotics on the mean probing pocket depth difference of deep pockets
remains stable for at least 1 year. Additionally, when disregarding the antibiotics with only one study
in the analysis [DOXH [86], MOX [86], SPI [115] and TET [115]], there seemed to be a trend that for
MET + AMOX and MET the mean probing pocket depth difference of deep pockets when compared
to SRP could be obtained for up to 1 year.
The meta-analysis for the mean clinical attachment level difference showed statistically significant
differences when compared to SRP at 3, 6 and 12 mo in favour of the use of antibiotics (0.20 mm ±
0.11, 0.31 mm ± 0.17 and 0.10 mm ± 0.11). The analysis was hampered by the fact that the follow-up
period from most of the studies was only 3–6 mo. When analysing only studies that had results at 3,
6 and 12 mo [74, 75, 80, 83, 86, 92, 99, 111], the clinical additional difference of these studies was
lower at 3 mo (0.09 mm ± 0.09), 6 mo (0.11 mm ± 0.10) and 12 mo (0.08 mm ± 0.12) when compared
to the overall effect. Based on these studies, it seems that the effect of the systemic antibiotics on
the mean clinical attachment level difference was relatively low and was almost lost over a 1 year
period. Additionally, when disregarding the antibiotics with only one study in the analysis [AMOX +
CLAV [111], CLA [79], MOX [86], ORN [73], SPI [114] and TET [107]], it became clear that none of the
used systemic antibiotics had a superior additional effect.
The meta-analysis for the mean clinical attachment level difference in moderate pockets showed a
similar outcome as for mean whole mouth clinical attachment level gain, albeit more pronounced.
When analysing only one study that had results at 3, 6 and 12 mo [74], the clinical additional
difference of this study was higher at 3 mo (0.35 mm ± 0.16), 6 mo (0.36 mm ± 0.13) and 12 mo (0.31
mm ± 0.19) when compared to the overall effect. Additionally, when disregarding the antibiotics with
only one study in the analysis [SPI [115] and TET [115]], it seems that the initial effect of systemic
antibiotics on the mean clinical attachment level difference of moderate pockets remain stable over
at least 6 mo. There are insufficient data to draw firm conclusions on the effect at 1 year for this
parameter, but there is at least one study that showed that MET + AMOX was able to maintain its
initial effect.
The meta-analysis for the mean clinical attachment level difference in deep pockets showed a similar
outcome as for mean whole mouth clinical attachment level gain, albeit more pronounced. When
analysing only one study that had results at 3, 6 and 12 mo [74, 92], the clinical additional difference
of this study was higher at 3 mo (0.77 mm ± 0.22), 6 mo (0.65 mm ± 0.26) and 12 mo (0.63 mm ±
0.30) when compared to the overall effect. Additionally, when disregarding the antibiotics with only
one study in the analysis [SPI [115] and TET [115]], there seemed to be a trend that for MET + AMOX
and MET the mean clinical attachment level difference of deep pockets when compared to SRP could
be obtained for up to 1 year.
The meta-analysis for the mean BOP difference showed statistically significant differences when
compared to SRP at 3, 6 and 12 mo in favour of the use of antibiotics (5.39% ± 3.07, 5.18% ± 3.37 and
3.80% ± 2.97). When analysing only the studies that had results at 3, 6 and 12 mo [74, 83, 86, 92, 95,
111], the clinical additional difference of these studies was lower at 3 mo (3.19% ± 5.42) and 6 mo
(3.41 ± 4.73) and higher at 12 mo (3.93% ± 2.82) when compared to the overall effect. Overall, it
seems that the initial effect of systemic antibiotics on the mean BOP difference was relatively low but
remained stable over a 1 year period. Additionally, when disregarding the antibiotics with only one
study in the analysis [AMOX [105], AMOX + CLAV [111], MOX [86] and TET [107]], there seemed to be
a trend that MET + AMOX resulted in the most pronounced BOP difference when compared to SRP,
at least for up to 6 mo.
The overall findings of this review should be interpreted with caution because the meta-analysis had
some limitations. This review had no restrictions for the study population. There were also no
specific demands of what type of antibiotic, antibiotic dosage or antibiotic regimen was used in this
review. Any type of antibiotic, dosage and regimen was accepted. Up to now, there is no consensus
on the optimal dosage for the usage of systemic antibiotics. There was a considerable difference
between the follow-up period and various studies used. Only a few studies showed the results at 12
mo. The results of the meta-analysis could be biased because there is no clear distinction between
these variables and because fewer results at 12 mo are available.
The 45 studies included in this review represent a large amount of data that could be of high value.
The quality of the articles were analysed based on seven criteria [17-19]. Overall, the studies with a
high risk of bias were also accepted for the meta-analysis. To check if the studies with a high risk of
bias [79, 82, 83, 86, 90, 93, 95, 96, 98, 100-104, 106-115] had some impact on final outcomes, the
meta-analysis for the clinical outcomes: overall probing pocket depth difference, overall clinical
attachment level difference and overall BOP difference were recalculated. This resulted in: an overall
probing pocket depth difference at 3 mo (0.20 mm ± 0.09), at 6 mo (0.26 mm ± 0.14) and at 12 mo
(0.22 mm ± 0.16); overall clinical attachment level difference at 3 mo (0.15 mm ± 0.09), at 6 mo (0.17
mm ±0.13) and at 12 mo (0.11 mm ± 0.12); and overall BOP difference at 3 mo (5.18% ± 4.14), at 6
mo (3.88% ± 4.18) and at 12 mo (2.17% ± 4.70). For the overall probing pocket depth difference,
clinical attachment level difference and BOP difference, the difference was initially less, but at 12 mo,
almost the same as the results with none of the studies excluded. Overall, the studies with a high risk
of bias could bias the results. However, more studies will give a more conclusive result.
The results of this meta-analysis support the additional effect of the usage of systemic antibiotics for
patients with untreated chronic periodontitis. This additional effect can be explained by delayed
microbial infection, better infection control and improved periodontal healing because these
antibiotics support the immune system by suppressing the target microbial species. However, one
should take into account that the widespread use of systemic antibiotics in periodontology might
lead to bacterial resistance in the long term. In 2005, van Winkelhoff showed a major susceptibility
difference profile between periodontal pathogens isolated from patients with periodontitis in Spain
and the Netherlands [116]. This difference can be explained by the usage or misuse of higher dose of
antibiotics in the Mediterranean countries. When a biofilm is not mechanically disrupted, subgingival
bacteria become more resistant to systemic antibiotics and this could lead to bacterial resistance [6].
Resistance and other unwanted side effects of antibiotics such as diarrhoea, nausea, vomiting,
thrush, gastrointestinal intolerance and antibiotic hypersensitivity should be balanced against the
positive effects of antibiotics. Therefore, systemic antibiotics should only be added to the normal
non-surgical periodontal therapy in specific clinical situations. At the 4th European Workshop on
Periodontology, Herrera et al. [5] defined these specific clinical situations, as patients with deep
pockets, patients with progressive or “active” disease, or with specific microbiological profiles.
Currently it is impossible to define which microbiological profiles would necessitate the use of
adjunctive systemic antimicrobials. Therefore, in the consensus statement of the 6th European
Workshop on Periodontology, it was posed that the use of systemic antibiotics in periodontitis
should be restricted to certain patients and certain periodontal conditions such as in aggressive
periodontitis or in severe and progressing forms of periodontitis [117]. Their prescription, however,
should be considered on a case-by-case basis and limited as much as possible.
Based on our previous findings, it is hard to state which systemic antibiotic is the best to use.
However, when only taking into account those antibiotics for which multiple studies exist and looking
at probing pocket depth and clinical attachment level in moderate and deep pockets and BOP, there
seems to be a trend that MET + AMOX is more effective than MET and that MET is more effective
than AZI. Based upon the majority of data DOXL seems to position itself in terms of efficiency
between MET and AZI on the short term but over a period of 1 year this effect seems gone. However,
further research is necessary to clarify this finding. More studies are necessary that follow the longterm results of the different antibiotics to ascertain if the effect of systemic antibiotics is stable over
time.
Acknowledgements
This paper has been prepared without any sources of institutional, private or corporate financial
support, and there are no potential conflicts of interest.