J Periodont Res 2014 © 2014 John Wiley & Sons A/S.

All rights reserved Published by John Wiley & Sons Ltd

JOURNAL OF PERIODONTAL RESEARCH

doi:10.1111/jre.12221
Review Article
J. A. J. Keestra1,2, I. Grosjean1,2,
Non-surgical periodontal W. Coucke3, M. Quirynen1,2,
W. Teughels1,2,4

therapy with systemic

1
Department of Oral Health Sciences,
Periodontology, KU Leuven & University of
Leuven, Leuven, Belgium, 2Department of

antibiotics in patients with

Periodontology, University Hospitals Leuven,
Leuven, Belgium, 3Department of Clinical
Biology, Scientific Institute of Public Health,
Brussels, Belgium and 4FWO, Fund for

untreated chronic Scientific Research Flanders, Brussels,

Belgium

periodontitis: a systematic
review and meta-analysis
Keestra JAJ, Grosjean I, Coucke W, Quirynen M, Teughels W. Non-surgical
periodontal therapy with systemic antibiotics in patients with untreated chronic
periodontitis: a systematic review and meta-analysis. J Periodont Res 2014; doi:
10.1111/jre.12221. © 2014 John Wiley & Sons A/S. Published by John Wiley &
Sons Ltd

Objective: The purpose of this meta-analysis is to evaluate the effectiveness of

different systemic antibiotics in combination with scaling and root planing (SRP)
when compared to SRP alone in patients with untreated chronic periodontitis.

Background: Although chronic periodontitis is mostly treated without adjunctive

systemic antibiotics, some recent meta-analyses have shown clinical benefit for
some systemic antibiotics when used as an adjunct to SRP. However, there is a
wide variety of systemic antibiotic regimens used today. It remains unclear if the
selected type of systemic antibiotic influences the magnitude of clinical benefit.

Material and Methods: The MEDLINE-PubMed database was searched from

their earliest records through May 16, 2013. Several journals were hand
searched and some authors were contacted for additional information. Outcome
measures analysed were mean bleeding on probing change, mean clinical attach-
ment level gain and mean probing pocket depth reduction. Extracted data were
pooled using a random effect model. Weighted mean differences were calculated
and heterogeneity was assessed.

Results: The search yielded 281 abstracts. Ultimately, 95 studies were selected,
Johan Anton Jochum Keestra, DDS,
describing 43 studies meeting the eligibility criteria. Systemic antibiotics showed
Department of Periodontology, School of
a significant (p < 0.05) additional pocket depth reduction for moderate (at 3 mo Dentistry, Oral Pathology & Maxillo-Facial
0.27 mm  0.09, at 6 mo 0.23 mm  0.10 and at 12 mo 0.25 mm  0.27) and Surgery, Faculty of Medicine, Catholic
University Leuven, Kapucijnenvoer 33, Leuven
deep pockets (at 3 mo 0.62 mm  0.17, at 6 mo 0.58 mm  0.16 and at 12 mo
B-3000, Belgium
0.74 mm  0.30). Statistically, no specific type of antibiotic was superior over Tel: (32)-16-332485
another. However, when analysing the clinical data for initially moderate pock- Fax: (32)-16-332484
e-mail: hanskeestra@gmail.com
ets or deep pockets, some trends became apparent.
Key words: chronic periodontitis; non-surgical
Conclusion: Systemic antibiotics combined with SRP offer additional clinical periodontal therapy; systemic antibiotics
improvements compared to SRP alone. Although there were no statistically Accepted for publication July 7, 2014
2 Keestra et al.
significant differences, there was a trend that for initially moderate and deep
pockets, metronidazole or metronidazole combined with amoxicillin, resulted in
clinical improvements that were more pronounced over doxycycline or azithro-
mycin. Additionally, there was a trend that the magnitude of the clinical benefit
became smaller over time (1 year).
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). Periodon-
titis is typically treated initially in a
non-surgical way. Non-surgical perio-
dontal 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 sys-
temic antibiotics could be a good
alternative. Systemic antibiotics help
the immune system by suppressing
the target microbial species. The liter-
ature (3–5) shows that systemic anti-
biotics 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 situ-
ations such as patients with deep
pockets, patients with progressive or
“active” disease, or patients with spe-
cific microbiological profiles systemic
antibiotics usage in combination with
non-surgical periodontal therapy
could be clinically relevant (5). Sys-
temic antibiotic usage has also been
used as a monotherapy. However,
for the best clinical outcomes the
combination with non-surgical period-
ontal therapy is highly recommended
(6). Additionally, the American Acad-
emy 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 (doxy-
cycline, minocycline, tetracycline),
macrolides (azithromycin, flurithro-
mycin, spiramycin, clindamycin), qui-
nolones (moxifloxacin, ciprofloxacin)
and nitroimidazole (metronidazole,
ornidazole). Amoxicillin is commonly
used in combination with metronida-
zole. 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 sys-
temic antibiotics in combination with
non-surgical periodontal therapy is to
suppress pathogenic bacteria and cre-
ate a healthy biofilm. If the use of sys-
temic 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 compli-
ance, 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 antibi-
otics 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 antibi-
otic regimen should be used. As a first
step towards such protocol, this meta-
analysis evaluates if there are differ-
ences 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 recom-
mendations of the Cochrane Collabo-
ration (14) and the principles of the
PRISMA (Preferred Reporting Items
for Systemic Reviews and Meta-
Analyses) statement (15).
Focused question (PICO)
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 Peri-
odontal diseases [MESH]. In addition,
a manual search was performed on
issues from the past 10 years of the
Journal of Clinical Periodontology, Jour-
nal 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 lan-
guage 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 possi-
ble, 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 exclu-
sion of studies were resolved by dis-
cussion 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 anti-
biotic, dosage of the antibiotic, dura-
tion 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 methodol-
ogies of all included studies was con-
ducted. 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 We-
ijden et al. (19). The following seven
criteria were used; selection bias, allo-
cation bias, performance bias, detec-
tion bias, defined inclusion/exclusion
criteria, attrition bias and reporting
bias. When all these criteria were ful-
filled, 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 inde-
pendently by two masked reviewers
(IG and JK). If there was any dis-
agreement, it was resolved by discus-
sion.
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 corre-
sponding authors were contacted for
additional data. The available data
were recalculated to present the data
such as mean BOP change, mean clini-
cal attachment level gain and mean
probing pocket depth reduction. Clini-
cal attachment level gain and probing
pocket depth reduction were also pre-
Antibiotics in chronic periodontitis 3
sented for moderate pockets (4–6 mm)
and deep pockets (> 6 mm). The I2
statistic was used to assess the hetero-
geneity between the studies. Because
of observed heterogeneity mean differ-
ences 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 arti-
cles. 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 addi-
tional 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); clari-
thromycin (CLA, one); low-dose
doxycycline (DOXL, 14); high-dose
doxycycline (DOXH, four); metroni-
dazole (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 stud-
ies 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
4 Keestra et al.
Electronic search:
Periodontal diseases [MESH] AND Anti-Infective Agents [MESH]
Metronidazole [MESH] AND Periodontal diseases [MESH]
6422 articles
Screening titles:
281 abstracts
Screening abstracts:
Screening full text:
95 full text articles
Total 43 articles included
Fig. 1. Search strategy.
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 statisti-
cally 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 signifi-
cant larger difference when compared
to AZI, MET and MET + AMOX.
DOXL and DOXH did not show a
statistically significant mean differ-
ence when compared to the control
group.
At 6 mo, 1272 patients out of 28
studies could be analysed. A statisti-
cally 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,
6
6141 titles excluded
6 abstracts excluded
186
6 full text articles excluded
40
6 aggressive periodontitis
12
articles excluded
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 sta-
tistically 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 signifi-
cant larger mean difference when
compared to AZI, DOXL and
MET + AMOX. AMOX + CLAV,
DOXH and MET did not show a sta-
tistically significant mean difference
when compared to the control group.
At 9 mo, 164 patients out of five
studies could be analysed. A statisti-
cally 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 statisti-
cally significant mean difference when
compared to the control group. How-
ever, it should be noted that for CLA
only one study was available. For
CLA there was a statistically signifi-
cant larger difference when compared
to DOXL. AZI did not show a statis-
tically 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 antibi-
otic 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 statisti-
cally significant mean difference when
compared to the control group. How-
ever, it should be noted that for MOX
only one study was available. For
MOX there was a statistically signif-
icant 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 stud-
ies, 167 patients, I2 = 0%) and MOX
(0.27 mm  0.24, one study, 65
patients, I2 = NA) showed a statisti-
cally significant mean difference when
compared to the control group. How-
ever, it should be noted that for
MOX only one study was available.
Between MET + AMOX and DOXL
there was a statistically significant dif-
ference 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 com-
pared to the control group.
At 6 mo, 1293 patients out of 18
studies could be analysed. A statistically

Table 1. Characteristics of the 40 excluded studies
Study
Preus et al. (2013)
Haas et al. (2012) (1)
Haas et al. (2012) (2)
Basegmez et al. (2011)
Schmidt et al. (2011)
Varela et al. (2011)
Serrano et al. (2011)
T€
uter et al. (2010)
Mestnik et al. (2010)
Cionca et al. (2010)
Machtei et al. (2008)
Akincibay et al. (2008)
Novak et al. (2008)
Moeintaghavi et al. (2007)
Emingil et al. (2006)
Guerrero et al. (2005)
Vergani et al. (2004)
Blandino et al. (2004)
Emingil et al. (2004) (2)
Kamma et al. (2000)
Palmer et al. (1999)
Tinoco et al. (1998)
Flemmig et al. (1998)
Noyan et al. (1997)
Sefton et al. (1996)
Yilmaz et al. (1996)
Haffajee et al. (1995)
Saxen et al. (1993)
Loesche et al. (1992)
Loesche et al. (1991)
Chin Quee et al. (1988)
Chin Quee et al. (1987)
Joyston-Bechal et al. (1986)
Loesche et al. (1984)
Joyston-Bechal et al. (1984)
Lindhe et al. (1983) (1)
Lindhe et al. (1983) (2)
Loesche et al. (1981)
Hellden et al. (1979)
Listgarten et al. (1978)
AA, Aggregatibacter actinomycetemcomitans; PG, Porphyromonas gingivalis.
significant mean difference
0.23 mm  0.10 and heterogeneity
I2 = 63%, in favour of the use of a
systemic antibiotic was observed.
Reason for exclusion
Two different control groups
Only radiographic results
Only microbiological results
Useful clinical results, more information needed. Could
not contact the author
No control group
The same patients; Heller et al. (67)
Using different types of antibiotic regimens (amoxicillin/
doxycycline)
Useful clinical results, more information needed. Could
not contact the author
Mestnik et al. (63); long-term results
The same patients; Cionca et al. (85)
Differences between two antibiotic regimens, no control
group
Differences between two antibiotic regimens, no control
group
Combination systemic and local antibiotics
Clinical results based on pockets ≥ 5 mm, author could
not give extra information
Same clinical results; Emingil et al. (80)
The same patients; Griffiths et al. (68)
Useful clinical results, more information needed. Could
not contact the author
Useful clinical results, more information needed. Could
not contact the author
The same patients; Emingil et al. (39)
No control group
The same patients; Palmer et al. (112)
SRP in combination with modified Widman flap surgery
Clinical result with/without AA/PG, could not contact
the author for more information
No control group with SRP
The same patients; Smith et al. (106)
No control group with SRP
Antibiotics in combination with modified Widman flap
surgery
Useful clinical results, more information needed. Could
not contact the author
Clinical outcome: periodontal surgery yes/no
Clinical outcome: periodontal surgery yes/no
The same patients; Al-Joburi et al. (115)
Useful clinical results, more information needed. Could
not contact the author
Useful clinical results, more information needed. Could
not contact the author
Control group not comparable with test group
Useful clinical results, more information needed. Could
not contact the author
Three antibiotic periods during treatment
Two antibiotic periods during treatment
Control group not comparable with test group
Two antibiotic periods during treatment
Two antibiotic periods during treatment
of 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
Antibiotics in chronic periodontitis 5
(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 statisti-
cally significant mean difference when
compared to the control group. How-
ever, it should be noted that for MET
and MOX only one study was avail-
able. No statistically significant differ-
ences 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 statisti-
cally significant mean difference of
0.29 mm  0.10 and heterogeneity
I2 = 0%, in favour of the use of a sys-
temic 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 statisti-
cally 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 signifi-
cant mean difference when compared
to the control group. However, it
should be noted that for all of these
antibiotics, only one study was avail-
able. No statistically significant differ-
ences between these three antibiotics
were noted. AZI and DOXH did not
show a statistically significant mean
difference when compared to the con-
trol 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 antibi-
otic 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%),
 6

Table 2. Characteristics of the 43 included studies

Quality assessment

Timing Selection Allocation Performance Detection Inclusion/ Attrition Reporting

Reference Study design Comparison Follow-up Treatment antibiotics Antibiotics bias bias bias bias exclusion bias Bias Conclusion
Keestra et al.

Pradeep Double-blind Placebo vs. 6 mo SSRP After SSRP Ornidazole 500 mg 2 9 for 7 d L
et al. (73) University antibiotics
Feres Double-blind Placebo vs. 12 mo SSRP After 1st SSRP Amoxicillin 500 mg 3 9 for 14 d L
et al. (74) University antibiotics Metronidazole 400 mg 3 9 for 14 d
Goodson Single-blind No placebo vs. 24 mo SSRP After 1st SRP Amoxicillin 500 mg 2 9 for 14 d M
et al. (75) University antibiotics Metronidazole 250 mg 3 9 for 14 d
Han et al. (76) Double-blind Placebo vs. 6 mo SSRP After SSRP Azithromycin 500 mg 3 9 for 3 d L
University antibiotics
Sampaio Double-blind Placebo vs. 12 mo SSRP After SSRP Azithromycin 500 mg 1 9 for 5 d L
et al. (77) University antibiotics
Silva Double-blind Placebo vs. 3 mo SSRP After 1st SSRP Amoxicillin 500 mg 3 9 for 14 d L
et al. (78) University antibiotics Metronidazole 400 mg 3 9 for 14 d
Pradeep Blinding? Placebo vs. 9 mo SSRP After SSRP Clarithromycin 500 mg 2 9 for 3 d H
et al. (79) University antibiotics
Emingil Double-blind Placebo vs. 12 mo SSRP After 1st SSRP Doxycycline 20 mg 2 9 for 90 d L
et al. (80) University antibiotics
Oteo et al. (81) Double-blind Placebo vs. 6 mo FMSRP After FMSRP Azithromycin 500 mg 1 9 for 3 d L
University antibiotics
Deo et al. (82) Blinding? Placebo vs. 6 mo FMSRP After FMSRP Doxycycline 20 mg 2 9 for 180 d H
University antibiotics
Yashima Blinding? No placebo vs. 12 mo FMSRP 3 d before Azithromycin 500 mg 1 9 for 3 d H
et al. (83) University antibiotics FMSRP
Ribeiro Double-blind Placebo vs. 6 mo FMSRP After FMSRP Amoxicillin 375 mg 3 9 for 7 d L
et al. (84) University antibiotics Metronidazole 250 mg 3 9 for 7 d
Cionca Double-blind Placebo vs. 6 mo FMSRP After FMSRP Amoxicillin 375 mg 3 9 for 7 d L
et al. (85) University antibiotics Metronidazole 500 mg 3 9 for 7 d
Guentsch Double-blind No placebo vs. 12 mo FMSRP After 1st FMSRP Doxycycline 200 mg + 100 mg 1 9 for 9 d H
et al. (86) Multi-centre antibiotics Moxifloxacin 400 mg 1 9 for 7 d
Matarazzo Double-blind Placebo vs. 3 mo SSRP After 1st SSRP Amoxicillin 500 mg 3 9 for 14 d L
et al. (87) University antibiotics Metronidazole 400 mg 3 9 for 14 d
Emingil Double-blind Placebo vs. 6 mo SSRP After 1st SSRP Doxycycline 20 mg 2 9 for 90 d L
et al. (88) University antibiotics
Preshaw Double-blind Placebo vs. 9 mo FMSRP After 1st FMSRP Doxycycline 40 mg 1 9 for 270 d L
et al. (89) Multi-centre antibiotics
Gomi et al. (90) Blinding? No placebo vs. 6 mo FMSRP 3 d before Azithromycin 500 mg 1 9 for 3 d H
Multicenter antibiotics FMSRP
Needleman Double-blind Placebo vs. 6 mo SSRP After 1st SSRP Doxycycline 20 mg 2 9 for 90 d L
et al. (91) University antibiotics
Haffajee Single-blind No placebo vs. 12 mo SSRP After 1st SSRP Azithromycin 500 mg 1 9 for 3 d M
et al. (92) University antibiotics Metronidazole 250 mg 3 9 for 14 d
Doxycycline 20 mg 2 9 for 90 d
Gorska Blinding? No placebo vs. 3 mo SSRP After 1st SSRP Doxycycline 20 mg 2 9 for 90 d H
et al. (93) University antibiotics
Llambes Double-blind No placebo vs. 3 mo FMSRP After 1st FMSRP Doxycycline 200 mg + 100 mg 1 9 for 15 d M
et al. (94) University antibiotics
Ehmke Blinding? No placebo vs. 24 mo FMSRP After FMSRP Amoxicillin 375 mg 3 9 for 8 d H
et al. (95) University antibiotics Metronidazole 250 mg 3 9 for 8 d
Mascarenhas Single-blind No placebo vs. 6 mo SSRP After SSRP Azithromycin 500 mg + 250 1 9 for 4 d H
et al. (96) University antibiotics
Table 2. (continued)
Quality assessment

Timing Selection Allocation Performance Detection Inclusion/ Attrition Reporting

Reference Study design Comparison Follow-up Treatment antibiotics Antibiotics bias bias bias bias exclusion bias Bias Conclusion

G€
urkan Double-blind Placebo vs. 6 mo SSRP After 1st SSRP Doxycycline 20 mg 2 9 for 90 d L
et al. (97) University antibiotics
Lee et al. (98) Double-blind Placebo vs. 9 mo SSRP After SSRP Doxycycline 20 mg 2 9 for 270 d H
University antibiotics
Emingil Double-blind Placebo vs. 12 mo SSRP After 1st SSRP Doxycycline 20 mg 2 9 for 90 d M
et al. (99) (1) University antibiotics
Carvalho Blinding? Placebo vs. 3 mo SSRP After SSRP Metronidazole 400 mg 3 9 for 10 d H
et al. (100) University antibiotics
Preshaw Double-blind Placebo vs. 9 mo SSRP After 1st SSRP Doxycycline 20 mg 2 9 for 270 d H
et al. (101) Multi-centre antibiotics
Akalin Blinding? No placebo vs. 2 mo SSRP Before SSRP Doxycycline 200 mg + 100 mg 1 9 for 14 d H
et al. (102) University antibiotics
Alptekin Blinding? Placebo vs. 6 mo FMSRP After FMSRP Doxycycline 20 mg 2 9 for 120 d H
et al. (103) University antibiotics
Novak Double-blind Placebo vs. 9 mo SSRP After 1st SSRP Doxycycline 20 mg 2 9 for 180 d H
et al. (104) University antibiotics
Rooney Double-blind Placebo vs. 6 mo SSRP After SSRP Amoxicillin 250 mg 3 9 for 7 d L
et al. (105) University antibiotics Metronidazole 200 mg 3 9 for 7 d
Smith Double-blind Placebo vs. 5 mo SSRP After SSRP Azithromycin 500 mg 1 9 for 3 d H
et al. (106) University antibiotics
Ramberg Blinding? No placebo vs. 13 year SSRP Before SSRP Tetracycline 250 mg 4 9 for 21 d H
et al. (107) University antibiotics
Winkel Double-blind Placebo vs. 6 mo SSRP After SSRP Amoxicillin 375 mg 3 9 for 7 d H
et al. (108) University antibiotics Metronidazole 250 mg 3 9 for 7 d
Caton Double-blind Placebo vs. 9 mo SSRP After SSRP Doxycycline 20 mg 2 9 for 270 d H
et al. (109) Multi-centre antibiotics
Feres Single-blind No placebo vs. 3 mo FMSRP After 1st FMSRP Doxycycline 200 mg + 100 mg 1 9 for 14 d H
et al. (110) University antibiotics
Winkel Double-blind Placebo vs. 12 mo SSRP After SSRP Amoxicillin 500 mg 3 9 for 10 d H
et al. (111) University antibiotics Clavulanic acid 3 9 for 10 d
Palmer Single-blind No placebo vs. 6 mo FMSRP After FMSRP Metronidazole 200 mg 3 9 for 7 d H
et al. (112) University antibiotics
Berglundh Blinding?? Placebo vs. 24 mo SSRP After 1st SSRP Amoxicillin 375 mg 2 9 for 14 d H
et al. (113) University antibiotics Metronidazole 250 mg 3 9 for 14 d
Bain et al. (114) Double-blind Placebo vs. 6 mo SSRP After 1st SSRP Spiramycin 500 mg 2 9 for 14 d H
Multi-centre antibiotics
Al-Joburi Double-blind Placebo vs. 6 mo FMSRP After 1st FMSRP Spiramycin 500 mg 2 9 for 14 d H
et al. (115) University antibiotics Tetracycline 250 mg 4 9 for 14 d

( ), Low risk of bias; ( ) unclear risk of bias; ( ) high risk of bias.

Antibiotics in chronic periodontitis
7
8 Keestra et al.

Mean difference Mean difference Mean difference Mean difference

Study or subgroup IV, Random, 95% CI IV, Random, 95% CI IV, Random, 95% CI IV, Random, 95% CI
1 Amoxicillin + Clavulanic acid
Winkel et al. 1999
Subtotal (95% CI)
2 Azithromycin
Han et al. 2012
Sampaio et al. 2011
Oteo et al. 2010
Yashima et al. 2009
Haffajee et al. 2007
Gomi et al. 2007
Mascarenhas et al. 2005
Subtotal (95% CI)
3 Clarithromycin
Pradeep et al. 2011
Subtotal (95% CI)

4 Doxycycline low-dose
Emingil et al. 2011
Deo et al. 2010
Emingil et al. 2008
Haffajee et al. 2007
Needleman et al. 2007
Górska et al. 2006
Gürkan et al. 2005
Emingil et al. 2004 (1)
Lee et al. 2004
Alptekin et al. 2000
Subtotal (95% CI)

5 Doxycycline high-dose
Guentsch et al. 2008
Llambés et al. 2005
Akalin et al. 2004
Feres et al. 1999
Subtotal (95% CI)
6 Metronidazole
Feres et al. 2012
Silva et al. 2011
Matarazzo et al. 2008
Haffajee et al. 2007
Carvalho et al. 2004
Subtotal (95% CI)
7 Metronidazole + Amoxicillin
Feres et al. 2012
Goodson et al. 2012
Silva et al. 2011
Cionca et al. 2009
Matarazzo et al. 2008
Winkel et al. 2001
Berglundh et al. 1998
Subtotal (95% CI)
8 Moxifloxacin
Guentsch et al. 2008
Subtotal (95% CI)
9 Ornidazole
Pradeep et al. 2012
Subtotal (95% CI)
10 Spiramycin
Bain et al. 1994
Subtotal (95% CI)
11 Tetracycline
Ramberg et al. 2001
Subtotal (95% CI)

Total (95% CI)

–1 –0.5 0 0.5 1 –1 –0.5 0 0.5 1 –1 –0.5 0 0.5 1 –1 –0.5 0 0.5 1

Test control Test control Test control Test control

Fig. 2. Probing pocket depth reduction.

DOXH (0.91 mm  0.64, one patients, I2 = 0%), MET + AMOX (1.03 mm  0.61, one study, 65
study, 65 patients, I2 = NA), MET (0.92 mm  0.49, four studies, 167 patients, I2 = NA) showed a statisti-
(0.83 mm  0.28, five studies, 211 patients, I2 = 62%) and MOX cally significant mean difference when
 Antibiotics in chronic periodontitis 9

Mean difference Mean difference Mean difference Mean difference

Study or subgroup IV, Random, 95% CI IV, Random, 95% CI IV, Random, 95% CI IV, Random, 95% CI
1 Azithromycin
Han et al. 2012
Sampaio et al. 2011
Oteo et al. 2010
Mascarenhas et al. 2005
Smith et al. 2002
Subtotal (95% CI)
2 Doxycycline low-dose
Preshaw et al. 2008
Gürkan et al. 2005
Preshaw et al. 2004
Novak et al. 2002
Caton et al. 2000
Subtotal (95% CI)

3 Doxycycline high-dose
Guentsch et al. 2008
Subtotal (95% CI)
4 Metronidazole
Feres et al. 2012
Silva et al. 2011
Matarazzo et al. 2008
Carvalho et al. 2004
Subtotal (95% CI)

5 Metronidazole + Amoxicillin
Feres et al. 2012
Silva et al. 2011
Ribeiro et al. 2009
Matarazzo et al. 2008
Winkel et al. 2001
Subtotal (95% CI)

6 Moxifloxacin
Guentsch et al. 2008
Subtotal (95% CI)
7 Spiramycin
Al-Joburi et al. 1989
Subtotal (95% CI)
8 Tetracycline
Al-Joburi et al. 1989
Subtotal (95% CI)

Total (95% CI)

–1 –0.5 0 0.5 1 –1 –0.5 0 0.5 1 –1 –0.5 0 0.5 1 –1 –0.5 0 0.5 1

Test control Test control Test control Test control

Fig. 3. Probing pocket depth reduction: moderate pockets.

compared to the control group. How-
ever, it should be noted that for
DOXH and MOX only one study was
available. No statistically significant
differences between these six antibiot-
ics were noted. SPI and TET did not
show a statistically significant mean
difference when compared to the con-
trol group.
At 6 mo, 1397 patients out of 21
studies could be analysed. A statisti-
cally 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 stud-
ies, 150 patients, I2 = 30%) and
MOX (0.87 mm  0.61, one study, 65
patients, I2 = NA) showed a statisti-
cally 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 antibiot-
ics were noted. SPI and TET did not
show a statistically significant mean
difference when compared to the con-
trol group.
At 9 mo, 613 patients out of four
studies could be analysed. A statisti-
cally significant mean difference of
0.52 mm  0.23 and heterogeneity
I2 = 0%, in favour of the use of a sys-
temic 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
10 Keestra et al.

Mean difference Mean difference Mean difference Mean difference

Study or subgroup IV, Random, 95% CI IV, Random, 95% CI IV, Random, 95% CI IV, Random, 95% CI
1 Azithromycin
Han et al. 2012
Sampaio et al. 2011
Oteo et al. 2010
Haffajee et al. 2007
Mascarenhas et al. 2005
Smith et al. 2002
Subtotal (95% CI)

2 Doxycycline low-dose
Preshaw et al. 2008
Haffajee et al. 2007
Gürkan et al. 2005
Preshaw et al. 2004
Novak et al. 2002
Caton et al. 2000
Subtotal (95% CI)

3 Doxycycline high-dose
Guentsch et al. 2008
Subtotal (95% CI)

4 Metronidazole
Feres et al. 2012
Silva et al. 2011
Matarazzo et al. 2008
Haffajee et al. 2007
Carvalho et al. 2004
Subtotal (95% CI)

5 Metronidazole + Amoxicillin
Feres et al. 2012
Silva et al. 2011
Ribeiro et al. 2009
Matarazzo et al. 2008
Winkel et al. 2001
Subtotal (95% CI)
6 Moxifloxacin
Guentsch et al. 2008
Subtotal (95% CI)
7 Spiramycin
Al-Joburi et al. 1989
Subtotal (95% CI)
8 Tetracycline
Al-Joburi et al. 1989
Subtotal (95% CI)

Total (95% CI)

–1 –0.5 0 0.5 1 –1 –0.5 0 0.5 1 –1 –0.5 0 0.5 1 –1 –0.5 0 0.5 1

Test control Test control Test control Test control

Fig. 4. Probing pocket depth reduction: deep pockets.

(1.00 mm  0.53, one studies, 68 compared to the control group.

patients, I2 = NA) and MOX
(1.03 mm  0.55, one study, 65
patients, I2 = NA) showed a statisti-
cally significant mean difference when
compared to the control group. How-
ever, 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 differ-
ence 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 statisti-
cally significant mean difference when
However, it should be noted that for
CLA and ORN only one study was
available. CLA and ORN showed a
significantly more pronounced differ-
ence 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
 Antibiotics in chronic periodontitis 11

Mean difference Mean difference Mean difference Mean difference

Study or ubgroupz IV, Random, 95% CI IV, Random, 95% CI IV, Random, 95% CI IV, Random, 95% CI
1 Amoxicillin + Clavulanic acid
Winkel et al. 1999
Subtotal (95% CI)

2 Azithromycin
Han et al. 2012
Sampaio et al. 2011
Oteo et al. 2010
Yashima et al. 2009
Gomi et al. 2007
Haffajee et al. 2007
Mascarenhas et al. 2005
Subtotal (95% CI)

3 Clarithromycin
Pradeep et al. 2011
Subtotal (95% CI)

4 Doxycycline low-dose
Emingil et al. 2011
Deo et al. 2010
Emingil et al. 2008
Needleman et al. 2007
Haffajee et al. 2007
Górska et al. 2006
Gürkan et al. 2005
Emingil et al. 2004 (1)
Lee et al. 2004
Alptekin et al. 2000
Subtotal (95% CI)

5 Doxycycline high-dose
Guentsch et al. 2008
Llambés et al. 2005
Akalin et al. 2004
Feres et al. 1999
Subtotal (95% CI)

6 Metronidazole
Feres et al. 2012
Silva et al. 2011
Matarazzo et al. 2008
Haffajee et al. 2007
Carvalho et al. 2004
Subtotal (95% CI)

7 Metronidazole + Amoxicillin
Goodson et al. 2012
Feres et al. 2012
Silva et al. 2011
Cionca et al. 2009
Matarazzo et al. 2008
Winkel et al. 2001
Berglundh et al. 1998
Subtotal (95% CI)

8 Moxifloxacin
Guentsch et al. 2008
Subtotal (95% CI)

9 Ornidazole
Pradeep et al. 2012
Subtotal (95% CI)

10 Spiramycin
Bain et al. 1994
Subtotal (95% CI)

11 Tetracycline
Ramberg et al. 2001
Subtotal (95% CI)

Total (95% CI)

–1 –0.5 0 0.5 1 –1 –0.5 0 0.5 1 –1 –0.5 0 0.5 1 –1 –0.5 0 0.5 1

Test control Test control Test control Test control

Fig. 5. Clinical attachment level gain.

12 Keestra et al.
favour of the use of a systemic antibi-
otic 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 differ-
ence 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 statisti-
cally 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 statisti-
cally significant mean difference when
compared to the control group. How-
ever, it should be noted that for CLA
only one study was available. CLA
showed a significantly more pro-
nounced difference compared to
DOXL. AZI did not show a statisti-
cally significant mean difference when
compared to the control group.
At 12 mo, 702 patients out of 15
studies could be analysed. A statisti-
cally 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 con-
trol group. However, it should be
noted that for MOX and TET only
one study was available. No statisti-
cally 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 con-
trol 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 pro-
nounced difference compared to
DOXL. AZI, SPI and TET did not
show a statistically significant mean
difference when compared to the con-
trol group.
At 6 mo, 1099 patients out of 14
studies could be analysed. A statisti-
cally 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 stud-
ies, 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 con-
trol group.
At 9 mo, 618 patients out of three
studies could be analysed. A statisti-
cally 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 statisti-
cally 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 con-
trol group. However, it should be
noted that for MET + AMOX only
one study was available. AZI and
MET did not show a statistically sig-
nificant mean difference when com-
pared 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 statisti-
cally 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 statisti-
cally significant mean difference when
compared to the control group. No
statistically significant differences
between these two antibiotics were
 Antibiotics in chronic periodontitis 13

Mean difference Mean difference Mean difference Mean difference

Study or subgroup IV, Random, 95% CI IV, Random, 95% CI IV, Random, 95% CI IV, Random, 95% CI
1 Azithromycin
Han et al. 2012
Sampaio et al. 2011
Oteo et al. 2010
Mascarenhas et al. 2005
Subtotal (95% CI)
2 Doxycycline low-dose
Preshaw et al. 2008
Gürkan et al. 2005
Preshaw et al. 2004
Caton et al. 2000
Subtotal (95% CI)

3 Metronidazole
Feres et al. 2012
Silva et al. 2011
Matarazzo et al. 2008
Carvalho et al. 2004
Subtotal (95% CI)

4 Metronidazole + Amoxicillin
Feres et al. 2012
Silva et al. 2011
Ribeiro et al. 2009
Matarazzo et al. 2008
Winkel et al. 2001
Subtotal (95% CI)

5 Spiramycin
Al-Joburi et al. 1989
Subtotal (95% CI)
6 Tetracycline
Al-Joburi et al. 1989
Subtotal (95% CI)

Total (95% CI)

–1 –0.5 0 0.5 1 –1 –0.5 0 0.5 1 –1 –0.5 0 0.5 1 –1 –0.5 0 0.5 1

Test control Test control Test control Test control

Fig. 6. Clinical attachment level gain: moderate pockets.

noted. AZI, MET + AMOX, SPI and
TET did not show a statistically sig-
nificant mean difference when com-
pared to the control group.
At 9 mo, 593 patients out of three
studies could be analysed. A statisti-
cally significant mean difference of
0.43 mm  0.25 and heterogeneity
I2 = 0%, in favour of the use of a sys-
temic 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 statisti-
cally 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 statis-
tically 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 statisti-
cally significant mean difference when
compared to the control group. How-
ever, 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 statisti-
cally 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 con-
trol group. However, it should be
noted that for AMOX + CLAV only
one study was available. No statisti-
cally significant differences between
these two antibiotics were noted.
14 Keestra et al.

Mean difference Mean difference Mean difference Mean difference

Study or subgroup IV, Random, 95% CI IV, Random, 95% CI IV, Random, 95% CI IV, Random, 95% CI
1 Azithromycin
Han et al. 2012
Sampaio et al. 2011
Oteo et al. 2010
Haffajee et al. 2007
Mascarenhas et al. 2005
Subtotal (95% CI)

2 Doxycycline low-dose
Preshaw et al. 2008
Haffajee et al. 2007
Gürkan et al. 2005
Preshaw et al. 2004
Caton et al. 2000
Subtotal (95% CI)

3 Metronidazole
Feres et al. 2012
Silva et al. 2011
Matarazzo et al. 2008
Haffajee et al. 2007
Carvalho et al. 2004
Subtotal (95% CI)

4 Metronidazole + Amoxicillin
Feres et al. 2012
Silva et al. 2011
Ribeiro et al. 2009
Matarazzo et al. 2008
Winkel et al. 2001
Subtotal (95% CI)

5 Spiramycin
Al-Joburi et al. 1989
Subtotal (95% CI)

6 Tetracycline
Al-Joburi et al. 1989
Subtotal (95% CI)

Total (95% CI)

–1 –0.5 0 0.5 1 –1 –0.5 0 0.5 1 –1 –0.5 0 0.5 1 –1 –0.5 0 0.5 1

Test control Test control Test control Test control

Fig. 7. Clinical attachment level gain: deep pockets.

AMOX, AZI, DOXL, DOXH, MET
and MOX did not show a statistically
significant mean difference when com-
pared 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 statisti-
cally 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 statisti-
cally significant mean difference when
compared to the control group. How-
ever, it should be noted that for
AMOX + CLAV only one study was
available. No statistically significant
differences between these two antibi-
otics were noted. AZI, DOXL,
DOXH, MET + AMOX, MOX and
TET did not show a statistically sig-
nificant mean difference when com-
pared 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 cur-
rent available evidence and has com-
pared 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 improve-
ment 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 differ-
ences 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 analy-
sing only studies that had results at 3,
6 and 12 mo (73,75,80,83,86,92,99),
the clinical additional difference of
 Antibiotics in chronic periodontitis 15

Mean difference Mean difference Mean difference Mean difference

Study or subgroup IV, Random, 95% CI IV, Random, 95% CI IV, Random, 95% CI IV, Random, 95% CI
1 Amoxicillin
Rooney et al. 2002
Subtotal (95% CI)
2 Amoxicillin + Clavulanic acid
Winkel et al. 1999
Subtotal (95% CI)

3 Azithromycin
Han et al. 2012
Sampaio et al. 2011
Oteo et al. 2010
Yashima et al. 2009
Haffajee et al. 2007
Gomi et al. 2007
Mascarenhas et al. 2005
Subtotal (95% CI)

4 Doxycycline low-dose
Needleman et al. 2007
Haffajee et al. 2007
Górska et al. 2006
Subtotal (95% CI)
5 Doxycycline high-dose
Guentsch et al. 2008
Llambés et al. 2005
Feres et al. 1999
Subtotal (95% CI)

6 Metronidazole
Feres et al. 2012
Silva et al. 2011
Matarazzo et al. 2008
Haffajee et al. 2007
Carvalho et al. 2004
Rooney et al. 2002
Palmer et al. 1998
Subtotal (95% CI)

7 Metronidazole + Amoxicillin
Feres et al. 2012
Silva et al. 2011
Cionca et al. 2009
Ribeiro et al. 2009
Matarazzo et al. 2008
Ehmke et al. 2005
Rooney et al. 2002
Winkel et al. 2001
Berglundh et al. 1998
Subtotal (95% CI)

8 Moxifloxacin
Guentsch et al. 2008
Subtotal (95% CI)

9 Tetracycline
Ramberg et al. 2001
Subtotal (95% CI)

Total (95% CI)

–20 –10 0 10 20 –20 –10 0 10 20 –20 –10 0 10 20 –20 –10 0 10 20

Test control Test control Test control Test control

Fig. 8. Bleeding on probing change.

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 com-
pared to the overall effect. Overall, it
seems that the initial effect of the
systemic antibiotics on the mean prob-
ing 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 com-
pared 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 addi-
tional 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
16 Keestra et al.
the overall effect. Based on these stud-
ies, 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 clin-
ical attachment level difference showed
statistically significant differences
when compared to SRP at 3, 6 and
12 mo in favour of the use of antibiot-
ics (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 fol-
low-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 dif-
ference was relatively low and was
almost lost over a 1 year period. Addi-
tionally, when disregarding the antibi-
otics 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 clin-
ical attachment level difference in mod-
erate 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 differ-
ence of moderate pockets remain stable
over at least 6 mo. There are insuffi-
cient 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 addi-
tional 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 addi-
tional 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 com-
pared to the overall effect. Overall, it
seems that the initial effect of systemic
antibiotics on the mean BOP differ-
ence was relatively low but remained
stable over a 1 year period. Addition-
ally, 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 con-
siderable difference between the fol-
low-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). Over-
all, the studies with a high risk of bias
were also accepted for the meta-analy-
sis. 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 differ-
ence, 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 clin-
ical 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 prob-
ing 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 peri-
odontitis. 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 bac-
terial resistance in the long term. In
2005, van Winkelhoff showed a major
susceptibility difference profile
between periodontal pathogens iso-
lated 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 coun-
tries. When a biofilm is not mechani-
cally disrupted, subgingival bacteria
become more resistant to systemic
antibiotics and this could lead to bac-
terial resistance (6). Resistance and
other unwanted side effects of antibi-
otics such as diarrhoea, nausea,
vomiting, thrush, gastrointestinal
intolerance and antibiotic hypersensi-
tivity should be balanced against the
positive effects of antibiotics. There-
fore, systemic antibiotics should only
be added to the normal non-surgical
periodontal therapy in specific clinical
situations. At the 4th European
Workshop on Periodontology, Herre-
ra et al. (5) defined these specific clini-
cal situations, as patients with deep
pockets, patients with progressive or
“active” disease, or with specific
microbiological profiles. Currently it
is impossible to define which microbi-
ological profiles would necessitate the
use of adjunctive systemic antimicro-
bials. Therefore, in the consensus
statement of the 6th European Work-
shop on Periodontology, it was posed
that the use of systemic antibiotics in
periodontitis should be restricted to
certain patients and certain periodon-
tal conditions such as in aggressive
periodontitis or in severe and pro-
gressing 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 antibi-
otic 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 long-term results of
the different antibiotics to ascertain if
the effect of systemic antibiotics is
stable over time.
Acknowledgements
This paper has been prepared with-
out any sources of institutional, pri-
vate or corporate financial support,
and there are no potential conflicts
of interest.
Antibiotics in chronic periodontitis 17
Supporting Information
Additional Supporting Information
may be found in the online version of
this article:
Table S1 Probing pocket depth
reduction.
Table S2 Probing pocket depth
reduction: moderate pockets.
Table S3 Probing pocket depth
reduction: deep pockets.
Table S4 Clinical attachment level
gain.
Table S5 Clinical attachment level
gain: moderate pockets.
Table S6 Clinical attachment level
gain: deep pockets.
Table S7 BOP change.
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