Antibioterapia en Periodoncia

2014 John Wiley & Sons A/S.
Published by John Wiley & Sons Ltd
J Periodont Res 2014

All rights reserved
JOURNAL OF PERIODONTAL RESEARCH

doi:10.1111/jre.12221
Review Article
Non-surgical periodontal
therapy with systemic
antibiotics in patients with
untreated chronic
periodontitis: a systematic
review and meta-analysis
J. A. J. Keestra1,2, I. Grosjean1,2,
W. Coucke3, M. Quirynen1,2,
W. Teughels1,2,4
1
Department of Oral Health Sciences,

Periodontology, KU Leuven & University of
Leuven, Leuven, Belgium, 2Department of
Periodontology, University Hospitals Leuven,
Leuven, Belgium, 3Department of Clinical
Biology, Scientific Institute of Public Health,
Brussels, Belgium and 4FWO, Fund for
Scientific Research Flanders, Brussels,
Belgium
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 eectiveness of
dierent 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 attachment level gain and mean probing pocket depth reduction. Extracted data were
pooled using a random eect model. Weighted mean dierences were calculated
and heterogeneity was assessed.
Results: The search yielded 281 abstracts. Ultimately, 95 studies were selected,
describing 43 studies meeting the eligibility criteria. Systemic antibiotics showed
a significant (p < 0.05) additional pocket depth reduction for moderate (at 3 mo
0.27 mm ! 0.09, at 6 mo 0.23 mm ! 0.10 and at 12 mo 0.25 mm ! 0.27) and
deep pockets (at 3 mo 0.62 mm ! 0.17, at 6 mo 0.58 mm ! 0.16 and at 12 mo
0.74 mm ! 0.30). Statistically, no specific type of antibiotic was superior over
another. However, when analysing the clinical data for initially moderate pockets or deep pockets, some trends became apparent.
Johan Anton Jochum Keestra, DDS,

Department of Periodontology, School of
Dentistry, Oral Pathology & Maxillo-Facial
Surgery, Faculty of Medicine, Catholic
University Leuven, Kapucijnenvoer 33, Leuven
B-3000, Belgium
Tel: (32)-16-332485
Fax: (32)-16-332484
e-mail: hanskeestra@gmail.com
Key words: chronic periodontitis; non-surgical
Conclusion: Systemic antibiotics combined with SRP oer additional clinical

improvements compared to SRP alone. Although there were no statistically
periodontal therapy; systemic antibiotics

Accepted for publication July 7, 2014
Keestra et al.
significant dierences, 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 azithromycin. Additionally, there was a trend that the magnitude of the clinical benefit
became smaller over time (1 year).
The goals of todays 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 eect has been achieved,
some residual pockets remain after
therapy (2). Additional periodontal
surgery is needed to resolve these
residual pockets. When the expected
eect 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 (35) shows that systemic antibiotics in combination with nonsurgical periodontal therapy might
improve the clinical results. These
improved clinical results are positive
side eects 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 dierent 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 nonsurgical 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 patients compliance, adverse eects and bacterial
resistance (4,5). The most recent metaanalyses focused on the eectiveness
of one systemic antibiotic regimen and
none of them compared the eects of
the dierent types of systemic antibiotics that the clinician is using today
(813). 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 metaanalysis evaluates if there are dierences between the eectiveness of the
dierent types of systemic antibiotics
in combination with SRP vs. SRP
alone in patients with untreated
chronic periodontitis and whether the
eect 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 MetaAnalyses) 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 eect 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).
Antibiotics in chronic periodontitis

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
(46 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
insucient 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 pre-
sented for moderate pockets (46 mm)

and deep pockets (> 6 mm). The I2
statistic was used to assess the heterogeneity between the studies. Because
of observed heterogeneity mean dierences were combined for continuous
data using random eects 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 (2160)
did not pass the inclusion criteria
(Table 1). Another 12 articles (6172)
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 (73115) 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 (1719). 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 dierence of 0.28 mm ! 0.09
and heterogeneity I2 = 69%, in favour
Keestra et al.
Electronic search:
Periodontal diseases [MESH] AND Anti-Infective Agents [MESH]
Metronidazole [MESH] AND Periodontal diseases [MESH]
6422 articles
Screening titles:
6141
6
titles excluded
281 abstracts
Screening abstracts:
186
6 abstracts excluded
Screening full text:
95 full text articles
40
6 full text articles excluded
Total 43 articles included
12
6 aggressive periodontitis
articles excluded
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 statistically significant mean dierence 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 dierence when compared
to AZI, MET and MET + AMOX.
DOXL and DOXH did not show a
statistically significant mean dierence when compared to the control
group.
At 6 mo, 1272 patients out of 28
studies could be analysed. A statistically significant mean dierence 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 dierence
when compared to the control group.
CLA, MOX, ORN and SPI only one
study was available. For CLA and
ORN there was a statistically significant larger mean dierence when
compared to AZI, DOXL and
MET + AMOX.
AMOX + CLAV,
DOXH and MET did not show a statistically significant mean dierence
At 9 mo, 164 patients out of five
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 dierence 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 dierence when compared
to DOXL. AZI did not show a statistically significant mean dierence

studies could be analysed. A statistically
significant mean dierence 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
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 dierence when compared to MET. AMOX + CLAV, AZI,
DOXL, DOXH and TET did not show
a statistically significant mean dierence when compared to the control
group.
Probing pocket depth reduction:
moderate pockets

studies could be analysed (Fig. 3 and
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
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 dierences
between MET + AMOX and MET or
MOX were noted. AZI, DOXH, SPI
and TET did not show a statistically
significant mean dierence when compared to the control group.

Table 1. Characteristics of the 40 excluded studies
Study
Reason for exclusion
Preus et al. (2013)

Haas et al. (2012) (1)
Haas et al. (2012) (2)
Basegmez et al. (2011)
Two dierent 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 dierent types of antibiotic regimens (amoxicillin/
doxycycline)
Mestnik et al. (63); long-term results
The same patients; Cionca et al. (85)
Dierences between two antibiotic regimens, no control
group
Dierences 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; Griths et al. (68)
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
Clinical outcome: periodontal surgery yes/no
Clinical outcome: periodontal surgery yes/no
The same patients; Al-Joburi et al. (115)
Control group not comparable with test group
Three antibiotic periods during treatment
Two antibiotic periods during treatment
Control group not comparable with test group
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)
Haajee et al. (1995)
Sax"en et al. (1993)
Loesche et
Loesche et
Chin Quee
Chin Quee
al. (1992)
al. (1991)
et al. (1988)
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)
Helld"en et al. (1979)
Listgarten et al. (1978)
AA, Aggregatibacter actinomycetemcomitans; PG, Porphyromonas gingivalis.
significant
mean
dierence
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
(0.50 mm ! 0.23, three studies, 150

patients,
I2 = 50%)
and
MOX
(0.29 mm ! 0.21, one study, 65
compared to the control group. However, it should be noted that for MET
and MOX only one study was available. No statistically significant dierences for DOXL, MET, MET +
AMOX and MOX were noted. AZI,
DXOH, SPI and TET did not show a
statistically significant mean dierence
At 9 mo, 638 patients out of four
I2 = 0%, in favour of the use of a systemic antibiotic was observed. Only
results for DOXL were available at
9 mo.
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 dierence 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 dierences between these three antibiotics
were noted. AZI and DOXH did not
show a statistically significant mean
dierence when compared to the control group.
Probing pocket depth reduction:
deep pockets

mean dierence 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%),
G"
orska
et al. (93)
Llamb"es
et al. (94)
Ehmke
et al. (95)
Mascarenhas
et al. (96)
Needleman
et al. (91)
Haajee
et al. (92)
Yashima
et al. (83)
Ribeiro
et al. (84)
Cionca
et al. (85)
Guentsch
et al. (86)
Matarazzo
et al. (87)
Emingil
et al. (88)
Preshaw
et al. (89)
Gomi et al. (90)
Deo et al. (82)
Blinding?
University
Double-blind
University
Blinding?
University
Single-blind
University
Double-blind
University
Double-blind
University
Single-blind
University
Double-blind
University
Double-blind
University
Double-blind
University
Blinding?
University
Double-blind
University
Double-blind
University
Blinding?
University
Blinding?
University
Double-blind
University
Double-blind
University
Double-blind
Multi-centre
Double-blind
University
Double-blind
University
Double-blind
Multi-centre
Blinding?
Multicenter
Double-blind
University
Single-blind
University
Pradeep
et al. (73)
Feres
et al. (74)
Goodson
et al. (75)
Han et al. (76)
Sampaio
et al. (77)
Silva
et al. (78)
Pradeep
et al. (79)
Emingil
et al. (80)
Oteo et al. (81)
Study design
Reference
No placebo vs.
antibiotics
No placebo vs.
antibiotics
No placebo vs.
antibiotics
No placebo vs.
antibiotics
Placebo vs.
antibiotics
Placebo vs.
antibiotics
No placebo vs.
antibiotics
Placebo vs.
antibiotics
Placebo vs.
antibiotics
Placebo vs.
antibiotics
Placebo vs.
antibiotics
Placebo vs.
antibiotics
Placebo vs.
antibiotics
Placebo vs.
antibiotics
No placebo vs.
antibiotics
Placebo vs.
antibiotics
Placebo vs.
antibiotics
No placebo vs.
antibiotics
Placebo vs.
antibiotics
Placebo vs.
antibiotics
Placebo vs.
antibiotics
No placebo vs.
antibiotics
Placebo vs.
antibiotics
No placebo vs.
antibiotics
Comparison
SSRP
FMSRP
12 mo
6 mo
SSRP
SSRP
FMSRP
FMSRP
3 mo
6 mo
9 mo
6 mo
SSRP
FMSRP
FMSRP
SSRP
3 mo
3 mo
24 mo
6 mo
SSRP
FMSRP
12 mo
12 mo
FMSRP
6 mo
SSRP
FMSRP
6 mo
6 mo
FMSRP
12 mo
FMSRP
SSRP
9 mo
6 mo
SSRP
SSRP
6 mo
3 mo
SSRP
24 mo
SSRP
SSRP
12 mo
12 mo
SSRP
Treatment
6 mo
Follow-up
Table 2. Characteristics of the 43 included studies
After SSRP
After FMSRP
After 1st FMSRP
After 1st SSRP
After 1st SSRP
3 d before
FMSRP
After 1st SSRP
After 1st FMSRP
After 1st SSRP
After 1st SSRP
After 1st FMSRP
After FMSRP
3 d before
FMSRP
After FMSRP
After FMSRP
After FMSRP
After 1st SSRP
After SSRP
After 1st SSRP
After SSRP
After SSRP
After 1st SRP
After 1st SSRP
After SSRP
Timing
antibiotics
Detection
bias
Inclusion/
exclusion
Attrition
bias
Reporting
Bias
Amoxicillin 375 mg 3 9 for 8 d

Metronidazole 250 mg 3 9 for 8 d
Azithromycin 500 mg + 250 1 9 for 4 d
Conclusion
Performance
bias
Doxycycline 200 mg + 100 mg 1 9 for 15 d
Allocation
bias
Selection
bias
Azithromycin 500 mg 1 9 for 3 d

Doxycycline 20 mg 2 9 for 90 d

Moxifloxacin 400 mg 1 9 for 7 d

Clarithromycin 500 mg 2 9 for 3 d

Ornidazole 500 mg 2 9 for 7 d
Antibiotics
Quality assessment
6
Keestra et al.
Double-blind
University
Double-blind
University
Double-blind
University
Blinding?
University
Double-blind
Multi-centre
Blinding?
University
Blinding?
University
Double-blind
University
Double-blind
University
Double-blind
University
Blinding?
University
Double-blind
University
Double-blind
Multi-centre
Single-blind
University
Double-blind
University
Single-blind
University
Blinding??
University
Double-blind
Multi-centre
Double-blind
University
G
urkan
et al. (97)
Lee et al. (98)
Placebo vs.
antibiotics
Placebo vs.
antibiotics
Placebo vs.
antibiotics
Placebo vs.
antibiotics
Placebo vs.
antibiotics
No placebo vs.
antibiotics
Placebo vs.
antibiotics
Placebo vs.
antibiotics
Placebo vs.
antibiotics
Placebo vs.
antibiotics
No placebo vs.
antibiotics
Placebo vs.
antibiotics
Placebo vs.
antibiotics
No placebo vs.
antibiotics
Placebo vs.
antibiotics
No placebo vs.
antibiotics
Placebo vs.
antibiotics
Placebo vs.
antibiotics
Placebo vs.
antibiotics
Comparison
SSRP
SSRP
FMSRP
SSRP
SSRP
SSRP
SSRP
SSRP
SSRP
FMSRP
SSRP
FMSRP
SSRP
SSRP
9 mo
2 mo
6 mo
9 mo
6 mo
5 mo
13 year
6 mo
9 mo
3 mo
12 mo
6 mo
24 mo
6 mo
FMSRP
SSRP
3 mo
6 mo
SSRP
SSRP
9 mo
12 mo
SSRP
Treatment
6 mo
Follow-up
After 1st FMSRP
After 1st SSRP
After 1st SSRP
After FMSRP
After SSRP
After 1st FMSRP
After SSRP
After SSRP
Before SSRP
After SSRP
After SSRP
After 1st SSRP
After FMSRP
Before SSRP
After 1st SSRP
After SSRP
After 1st SSRP
After SSRP
After 1st SSRP
Timing
antibiotics
( ), Low risk of bias; ( ) unclear risk of bias; ( ) high risk of bias.
Al-Joburi
et al. (115)
Emingil
et al. (99) (1)
Carvalho
et al. (100)
Preshaw
et al. (101)
Akalin
et al. (102)
Alptekin
et al. (103)
Novak
et al. (104)
Rooney
et al. (105)
Smith
et al. (106)
Ramberg
et al. (107)
Winkel
et al. (108)
Caton
et al. (109)
Feres
et al. (110)
Winkel
et al. (111)
Palmer
et al. (112)
Berglundh
et al. (113)
Bain et al. (114)
Study design
Reference
Table 2. (continued)
Detection
bias
Inclusion/
exclusion
Attrition
bias
Reporting
Bias
Conclusion
Spiramycin 500 mg 2 9 for 14 d

Tetracycline 250 mg 4 9 for 14 d

Spiramycin 500 mg 2 9 for 14 d

Clavulanic acid 3 9 for 10 d

Tetracycline 250 mg 4 9 for 21 d

Performance
bias
Allocation
bias
Selection
bias
Antibiotics
Quality assessment
Keestra et al.
Mean difference
IV, Random, 95% CI
Study or subgroup
1 Amoxicillin + Clavulanic acid
Winkel et al. 1999
Subtotal (95% CI)
Mean difference
IV, Random, 95% CI
Mean difference
IV, Random, 95% CI
Mean difference
IV, Random, 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
Needleman et al. 2007
Grska et al. 2006
Grkan 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
Llambs 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
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
Winkel et al. 2001
Berglundh et al. 1998
Subtotal (95% CI)
8 Moxifloxacin
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
Test control
0.5
0
0.5
Test control
0.5
0
0.5
Test control
1 1
0.5
0
0.5
Test control
Fig. 2. Probing pocket depth reduction.
DOXH
(0.91 mm !
0.64,
one
study, 65 patients, I2 = NA), MET
(0.83 mm ! 0.28, five studies, 211

(0.92 mm ! 0.49, four studies, 167
patients,
I2 = 62%)
and
MOX
(1.03 mm ! 0.61, one study, 65


Mean difference
IV, Random, 95% CI
Mean difference
IV, Random, 95% CI
Study or subgroup
1 Azithromycin
Han et al. 2012
Sampaio et al. 2011
Oteo et al. 2010
Smith et al. 2002
Subtotal (95% CI)
Mean difference
IV, Random, 95% CI
Mean difference
IV, Random, 95% CI
Preshaw et al. 2008
Grkan et al. 2005
Preshaw et al. 2004
Novak et al. 2002
Caton et al. 2000
Subtotal (95% CI)
Subtotal (95% CI)
4 Metronidazole
Feres et al. 2012
Silva et al. 2011
Subtotal (95% CI)
Feres et al. 2012
Silva et al. 2011
Ribeiro et al. 2009
Winkel et al. 2001
Subtotal (95% CI)
6 Moxifloxacin
Subtotal (95% CI)
7 Spiramycin
Al-Joburi et al. 1989
Subtotal (95% CI)
8 Tetracycline
Subtotal (95% CI)
Total (95% CI)
1
0.5
0
0.5
Test control
1 1
0.5
0
0.5
Test control
1 1
0.5
0
0.5
Test control
1 1
0.5
0.5
0
Test control
Fig. 3. Probing pocket depth reduction: moderate pockets.

DOXH and MOX only one study was
available. No statistically significant
dierences between these six antibiotics were noted. SPI and TET did not
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
DOXH and MOX only one study was
dierences between these six antibiotics were noted. SPI and TET did not
At 9 mo, 613 patients out of four

9 mo.
At 12 mo, 453 patients out of
eight studies could be analysed. A
of 0.74 mm ! 0.30 and heterogeneity
DOXH (0.65 mm ! 0.62, one study,
65
patients,
I2 = NA),
MET
(0.92 mm ! 0.48, two studies, 114
10
Keestra et al.
Mean difference
IV, Random, 95% CI
Study or subgroup
1 Azithromycin
Han et al. 2012
Sampaio et al. 2011
Oteo et al. 2010
Smith et al. 2002
Subtotal (95% CI)
Mean difference
IV, Random, 95% CI
Mean difference
IV, Random, 95% CI
Mean difference
IV, Random, 95% CI
Preshaw et al. 2008
Grkan et al. 2005
Preshaw et al. 2004
Novak et al. 2002
Caton et al. 2000
Subtotal (95% CI)
Subtotal (95% CI)
4 Metronidazole
Feres et al. 2012
Silva et al. 2011
Subtotal (95% CI)
Feres et al. 2012
Silva et al. 2011
Ribeiro et al. 2009
Winkel et al. 2001
Subtotal (95% CI)
6 Moxifloxacin
Subtotal (95% CI)
7 Spiramycin
Subtotal (95% CI)
8 Tetracycline
Subtotal (95% CI)
Total (95% CI)
1
0.5
0
0.5
Test control
1 1
0.5
0
0.5
Test control
0
0.5
0.5
Test control
1 0.5
0
0.5
Test control
Fig. 4. Probing pocket depth reduction: deep pockets.
(1.00 mm ! 0.53, one studies, 68

patients,
I2 = NA)
and
MOX
(1.03 mm ! 0.55, one study, 65
DOXL, DOXH, MET + AMOX and
MOX only one study was available.
between these four antibiotics were
noted. AZI and DOXL did not show
a statistically significant mean dierence when compared to the control
group.
Clinical attachment level gain

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

CLA and ORN only one study was
available. CLA and ORN showed a
significantly more pronounced dierence compared to DOXL. AMOX +
CLAV,
AZI,
DOXH,
MET,
MET + AMOX, MOX and SPI did
not show a statistically significant
mean dierence when compared to
the control group.
significant mean dierence of 0.31 mm !
0.17 and heterogeneity I2 = 83%, in

Study or ubgroupz
Winkel et al. 1999
Subtotal (95% CI)
Mean difference
IV, Random, 95% CI
Mean difference
IV, Random, 95% CI
Mean difference
IV, Random, 95% CI
Mean difference
IV, Random, 95% CI
2 Azithromycin
Han et al. 2012
Sampaio et al. 2011
Oteo et al. 2010
Yashima et al. 2009
Gomi et al. 2007
Subtotal (95% CI)
3 Clarithromycin
Pradeep et al. 2011
Subtotal (95% CI)
Emingil et al. 2011
Deo et al. 2010
Emingil et al. 2008
Grska et al. 2006
Grkan et al. 2005
Emingil et al. 2004 (1)
Lee et al. 2004
Alptekin et al. 2000
Subtotal (95% CI)
Llambs et al. 2005
Akalin et al. 2004
Feres et al. 1999
Subtotal (95% CI)
6 Metronidazole
Feres et al. 2012
Silva et al. 2011
Subtotal (95% CI)
Goodson et al. 2012
Feres et al. 2012
Silva et al. 2011
Cionca et al. 2009
Winkel et al. 2001
Subtotal (95% CI)
8 Moxifloxacin
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
Test control
Fig. 5. Clinical attachment level gain.
1 0.5 0 0.5 1
Test control
1 0.5 0 0.5 1
Test control
1 0.5 0 0.5 1
Test control
11
12
Keestra et al.
favour of the use of a systemic antibiotic was observed. CLA (0.95 mm !

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
CLA, MOX and ORN only one study
was available. CLA and ORN showed
a significantly more pronounced dierence when compared to DOXL, MET
and MOX. AMOX + CLAV, AZI,
DOXH, MET + AMOX and SPI did
mean dierence when compared to the
control group.
CLA (1.07 mm ! 0.20, one study, 37
patients, I2 = NA) and DOXL
(0.55 ! 0.38, three studies, 107
compared to the control group. However, it should be noted that for CLA
only one study was available. CLA
showed a significantly more pronounced dierence compared to
DOXL. AZI did not show a statistically significant mean dierence when
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
dierence when compared to the control group. However, it should be
noted that for MOX and TET only
one study was available. No statistically significant dierences between
these three antibiotics were noted.

AMOX + CLAV,
AZI,
DOXL,
DOXH and MET + AMOX did not
Clinical attachment level gain:
moderate pockets

observed. DOXL (0.15 mm ! 0.09,
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 dierence when compared to
the control group. MET + AMOX
showed a significantly more pronounced dierence compared to
DOXL. AZI, SPI and TET did not
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
MET only one study was available.
between these three antibiotics were
noted. AZI, SPI and TET did not
At 9 mo, 618 patients out of three

Only results for DOXL were available
at 9 mo.
MET + AMOX
(0.40 mm ! 0.22,
one study, 68 patients, I2 = NA)
noted that for MET + AMOX only
one study was available. AZI and
MET did not show a statistically significant mean dierence when compared to the control group.
Clinical attachment level gain: deep
pockets

of the use of a systemic antibiotic
was observed. AZI (0.43 mm ! 0.40,
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
compared to the control group. No
statistically
significant
dierences
between these four antibiotics were
noted. SPI and TET did not show a
At 6 mo, 1111 patients out of
17 studies could be analysed. A
of 0.42 mm ! 0.18 and heterogeneity
570 patients, I2 = 0%) and MET
(0.64 mm ! 0.38, two studies, 123
compared to the control group. No
statistically
significant
dierences
between these two antibiotics were

Mean difference
IV, Random, 95% CI
Mean difference
IV, Random, 95% CI
Study or subgroup
1 Azithromycin
13
Mean difference
IV, Random, 95% CI
Mean difference
IV, Random, 95% CI
Han et al. 2012

Sampaio et al. 2011
Oteo et al. 2010
Subtotal (95% CI)
Preshaw et al. 2008
Grkan et al. 2005
Preshaw et al. 2004
Caton et al. 2000
Subtotal (95% CI)
3 Metronidazole
Feres et al. 2012
Silva et al. 2011
Subtotal (95% CI)
Feres et al. 2012
Silva et al. 2011
Ribeiro et al. 2009
Winkel et al. 2001
Subtotal (95% CI)
5 Spiramycin
Subtotal (95% CI)
6 Tetracycline
Subtotal (95% CI)
Total (95% CI)
1
0.5
0
0.5
Test control
0.5
0.5
0
Test control
1 1
0.5
0
0.5
Test control
1 1
0.5
0
0.5
Test control
Fig. 6. Clinical attachment level gain: moderate pockets.
noted. AZI, MET + AMOX, SPI and

TET did not show a statistically significant mean dierence when compared to the control group.
9 mo.
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 dierence

between these two antibiotics were
noted. AZI and DOXL did not show a
Bleeding on probing change

mean dierence of 5.39% ! 3.07 and
heterogeneity I2 = 65%, in favour of
the use of a systemic antibiotic was
observed. AMOX + CLAV (20.00% !
MET + AMOX (7.90% ! 5.39, eight
studies, 292 patients, I2 = 62%) and
MOX (12.90% ! 9.56, one study, 65
AMOX + CLAV and MOX only one
study was available. No statistically

significant dierences between these
three antibiotics were noted. AMOX,
AZI, DOXL, DOXH and MET did
mean dierence when compared to the
control group.
5.18% ! 3.37
and
heterogeneity
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%)
noted that for AMOX + CLAV only
one study was available. No statistically significant dierences between
these two antibiotics were noted.
14
Keestra et al.
Mean difference
IV, Random, 95% CI
Study or subgroup
1 Azithromycin
Han et al. 2012
Sampaio et al. 2011
Oteo et al. 2010
Subtotal (95% CI)
Mean difference
IV, Random, 95% CI
Mean difference
IV, Random, 95% CI
Mean difference
IV, Random, 95% CI
Preshaw et al. 2008
Grkan et al. 2005
Preshaw et al. 2004
Caton et al. 2000
Subtotal (95% CI)
3 Metronidazole
Feres et al. 2012
Silva et al. 2011
Subtotal (95% CI)
Feres et al. 2012
Silva et al. 2011
Ribeiro et al. 2009
Winkel et al. 2001
Subtotal (95% CI)
5 Spiramycin
Subtotal (95% CI)
6 Tetracycline
Subtotal (95% CI)
Total (95% CI)
1
0.5
0
0.5
Test control
0.5
0
0.5
Test control
0.5
0
0.5
Test control
1 1
0.5
0
0.5
Test control
Fig. 7. Clinical attachment level gain: deep pockets.
AMOX, AZI, DOXL, DOXH, MET

and MOX did not show a statistically
significant mean dierence 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.
3.80% ! 2.97
and
heterogeneity
AMOX + CLAV
(10.00% ! 8.56,
one study, 21 patients, I2 = NA) and
MET (6.90% ! 6.43, two studies, 114
AMOX + CLAV only one study was

dierences between these two antibiotics were noted. AZI, DOXL,
DOXH, MET + AMOX, MOX and
TET did not show a statistically significant mean dierence 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 eectiveness of the dierent
types of systemic antibiotics as well as
their long-term eects (up to 1 year).
Forty-five
clinical
studies
were
included, from which data were
obtained and used to calculate the

mean dierence in clinical improvement for BOP, clinical attachment
level and probing pocket depth
change. Clinical attachment level and
probing pocket depth dierence were
additionally analysed for initially
moderate pockets (46 mm) and deep
pockets (> 6 mm).
The meta-analysis for the mean
probing pocket depth dierence
showed statistically significant dierences 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 36 mo. When analysing only studies that had results at 3,
6 and 12 mo (73,75,80,83,86,92,99),
the clinical additional dierence of

Mean difference
IV, Random, 95% CI
Study or subgroup
1 Amoxicillin
Mean difference
IV, Random, 95% CI
Mean difference
IV, Random, 95% CI
15
Mean difference
IV, Random, 95% CI
Rooney et al. 2002

Subtotal (95% CI)
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
Gomi et al. 2007
Subtotal (95% CI)
Grska et al. 2006
Subtotal (95% CI)
Llambs et al. 2005
Feres et al. 1999
Subtotal (95% CI)
6 Metronidazole
Feres et al. 2012
Silva et al. 2011
Rooney et al. 2002
Palmer et al. 1998
Subtotal (95% CI)
Feres et al. 2012
Silva et al. 2011
Cionca et al. 2009
Ribeiro et al. 2009
Ehmke et al. 2005
Rooney et al. 2002
Winkel et al. 2001
Subtotal (95% CI)
8 Moxifloxacin
Subtotal (95% CI)
9 Tetracycline
Ramberg et al. 2001
Subtotal (95% CI)
Total (95% CI)
20
10
0
10
Test control
20 20
10
0
10
Test control
20 20
10
0
10
Test control
20
20
10
0
10
Test control
20
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 compared to the overall eect. Overall, it
seems that the initial eect of the
systemic antibiotics on the mean probing pocket depth dierence 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 dierence when compared to SRP could be obtained for
up to 1 year.
probing pocket depth dierence 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 dierence 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 eect. Based on these studies, it seems that the initial eect of
the systemic antibiotics on the mean
probing pocket depth dierence 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 dierence
for moderate pockets when compared
to SRP could be obtained for up to
1 year.
probing pocket depth dierence in
deep pockets also showed a similar
probing pocket depth reduction, albeit
and 12 mo (74,86,92), the clinical
additional dierence of these studies
was higher at 3 mo (0.90 mm ! 0.22),
6 mo (0.82 mm ! 0.24) and 12 mo
the overall eect. Based on these
studies, it seems that the initial eect
of the systemic antibiotics on the
mean probing pocket depth dierence
of deep pockets remains stable for at
least 1 year. Additionally, when
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 dierence of
deep pockets when compared to SRP
could be obtained for up to 1 year.
The meta-analysis for the mean clinical attachment level dierence showed
statistically
significant
dierences
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 36 mo. When analysing
and 12 mo (74,75,80,83,86,92,99,111),
the clinical additional dierence 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 eect.
Based on these studies, it seems that

the eect 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 eect.
The meta-analysis for the mean clinical attachment level dierence in moderate pockets showed a similar
clinical attachment level gain, albeit
only one study that had results at 3, 6
and 12 mo (74), the clinical additional
dierence of this study was higher
at 3 mo (0.35 mm ! 0.16), 6 mo
(0.36 mm !
0.13)
and
12 mo
the overall eect. Additionally, when
one study in the analysis [SPI (115)
and TET (115)], it seems that the initial
eect of systemic antibiotics on the
mean clinical attachment level dierence of moderate pockets remain stable
over at least 6 mo. There are insucient data to draw firm conclusions on
the eect at 1 year for this parameter,
but there is at least one study that
showed that MET + AMOX was able
to maintain its initial eect.
clinical attachment level dierence in
deep pockets showed a similar
clinical attachment level gain, albeit
only one study that had results at 3, 6
and 12 mo (74,92), the clinical additional dierence of this study was
higher at 3 mo (0.77 mm ! 0.22),
6 mo (0.65 mm ! 0.26) and 12 mo
the overall eect. Additionally, when
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 dierence of deep pockets when
compared to SRP could be obtained
for up to 1 year.

BOP dierence showed statistically
significant dierences 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 dierence 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 eect. Overall, it
seems that the initial eect of systemic
antibiotics on the mean BOP dierence 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 dierence 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 dierence 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 (1719). 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,
96,98,100104,106115) had some

impact on final outcomes, the metaanalysis for the clinical outcomes:
overall probing pocket depth dierence, overall clinical attachment level
dierence and overall BOP dierence
were recalculated. This resulted in: an
overall
probing
pocket
depth
dierence 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 dierence 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
dierence 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 dierence, clinical
attachment level dierence and BOP
dierence, the dierence 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 eect of the
usage of systemic antibiotics for
patients with untreated chronic periodontitis. This additional eect 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 Winkelho showed a major
susceptibility
dierence
profile
between periodontal pathogens isolated from patients with periodontitis
in Spain and the Netherlands (116).
This dierence 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 eects of antibiotics such as diarrhoea, nausea,
vomiting,
thrush,
gastrointestinal
intolerance and antibiotic hypersensi-
tivity should be balanced against the

positive eects 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 eective
than MET and that MET is more
eective than AZI. Based upon the
majority of data DOXL seems to
position itself in terms of eciency
between MET and AZI on the short
term but over a period of 1 year this
eect seems gone. However, further
research is necessary to clarify this
finding. More studies are necessary
that follow the long-term results of
the dierent antibiotics to ascertain if
the eect 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.
17
Supporting Information
Additional Supporting Information
may be found in the online version of
this article:
Table S1 Probing pocket depth
reduction.
reduction: moderate pockets.
reduction: deep pockets.
Table S4 Clinical attachment level
gain.
gain: moderate pockets.
gain: deep pockets.
Table S7 BOP change.
References
1. Lang NP, Tonetti MS. Periodontal risk
assessment (PRA) for patients in supportive periodontal therapy (SPT). Oral
Health Prev Dent 2003;1:716.
2. Badersten A, Nilveus R, Egelberg J.
Eect of nonsurgical periodontal therapy. I. Moderately advanced periodontitis. J Clin Periodontol 1981;8:5772.
3. Mombelli A, Schmid B, Rutar A et al.
Persistence patterns of Porphyromonas
gingivalis, Prevotella intermedia/nigrescens, and Actinobacillus actinomyetemcomitans after mechanical therapy of
periodontal disease. J Periodontol
2000;71:1421.
4. Haajee AD, Socransky SS, Gunsolley
JC. Systemic anti-infective periodontal
therapy. A systematic review. Ann Periodontol 2003;8:115181.
5. Herrera D, Sanz M, Jepsen S et al. A
systematic review on the eect of systemic antimicrobials as an adjunct to
scaling and root planing in periodontitis
patients. J Clin Periodontol 2002;29:
136159.
6. Herrera D, Alonso B, Le"
on R et al.
Antimicrobial therapy in periodontitis:
the use of systemic antimicrobials
against the subgingival biofilm. J Clin
Periodontol 2008;35:4566.
7. AAP. Systemic antibiotics in periodontics. J Periodontol 1996;67:831838.
8. Bonito AJ, Lux L, Lohr KN. Impact of
local adjuncts to scaling and root planing in periodontal disease therapy: a
systematic
review.
J
Periodontol
2005;76:12271236.
9. Herrera D, Matesanz P, Bascones-Martinez A et al. Local and systemic
antimicrobial therapy in periodontitics.
J Evid Based Dent Pract 2012;12:5060.
10. Angaji M, Gelskey S, Nogueira-Filho G
et al. A systematic review of clinical
18
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Keestra et al.
ecacy of adjunctive antibiotics in the
treatment of smokers with periodontitis.
J Periodontol 2010;81:15181528.
Sgolastra F, Petrucci A, Gatto R et al.
Long-term ecacy of subantimicrobialdose doxycycline as an adjunctive treatment to scaling and root planing: a systematic review and meta-analysis. J
Periodontol 2011;82:15701581.
Sgolastra F, Gatto R, Petrucci A et al.
Eectiveness of systemic amoxicillin/
metronidazole as adjunctive therapy to
scaling and root planing in the treatment of chronic periodontitis: a systematic review and meta-analysis. J
Periodontol 2012;83:12571269.
Zandbergen D, Slot DE, Cobb CM
et al. The clinical eect of scaling and
root planing and the concomitant
administration of systemic amoxicillin
and metronidazole: a systematic review.
J Periodontol 2013;84:332351.
Higgins JPT, Green S, eds. Cochrane
Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March
2011]. The Cochrane Collaboration, 2011.
Available from http://www.cochrane.org/
handbook. Accessed November 4, 2012.
Moher D, Liberati A, Tetzla J et al.
Preferred reporting items for systematic
reviews and meta-analyses: The PRISMA statement. J Clin Epidemiol
2009;62:10061012.
Armitage GC. Development of a classification system for periodontal diseases
and
conditions.
Ann
Periodontol
1999;4:16.
Schulz KF, Altman DG, Moher D
et al. CONSORT 2010 Statement:
updated guidelines for reporting parallel
group randomised trials. J Clin Epidemiol 2010;63:834840.
Verhagen AP, de Vet HC, de Bie RA
et al. The Delphi list: a criteria list for
quality assessment of randomized clinical trials for conducting systematic
reviews developed by Delphi consensus.
J Clin Epidemiol 1998;51:12351241.
Van der Weijden F, DellAcqua F, Slot
DE. Alveolar bone dimensional changes
of post-extraction sockets in humans: a
systematic review. J Clin Periodontol
2009;36:10481058.
The Cochrane Collaboration. Review
Manager (RevMan) [Computer program]. Version 5.2. Copenhagen: The
Nordic Cochrane Centre, The Cochrane
Collaboration, 2012.
Preus HR, Gunleiksrud TM, Sandvik L
et al. A randomized, double-masked
clinical trial comparing four periodontitis treatment strategies: 1-year clinical
results. J Periodontol 2013;84:2075
2086.
Haas AN, Silva-Boghossian CM, Colombo AP et al. Adjunctive azithromy-
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
cin in the treatment of aggressive

periodontitis: microbiological findings
of a 12-month randomized clinical trial.
J Dent 2012;40:556563.
Haas AN, Seleme F, Segatto P et al.
Azithromycin as an adjunctive treatment of aggressive periodontitis: radiographic findings of a 12-month
randomized clinical trial. Am J Dent
2012;25:215219.
Basegmez C, Berber L, Yalcin F.
Clinical and biochemical ecacy of minocycline in nonsurgical periodontal
therapy: a randomized controlled pilot
study. J Clin Pharmacol 2011;51:915
922.
Schmidt E, Kaciroti N, Loesche W.
Benefits of additional courses of systemic azithromycin in periodontal therapy. Gen Dent 2011;59:180187.
Varela VM, Heller D, Silva-Senem MX
et al. Systemic antimicrobials adjunctive
to a repeated mechanical and antiseptic
therapy for aggressive periodontitis: a 6month randomized controlled trial. J
Periodontol 2011;82:11211130.
Serrano C, Torres N, Bejarano A et al.
Clinical and microbiological comparison
of three non-surgical protocols for the
initial treatment of chronic periodontitis.
J Int Acad Periodontol 2011;13:1726.
T
uter G, Serdar M, Kurtis B et al.
Eects of scaling and root planing and
subantimicrobial dose doxycycline on
gingival crevicular fluid levels of matrix
metalloproteinase-8, -13 and serum levels
of HsCRP in patients with chronic periodontitis. J Periodontol 2010;81:1132
1139.
Mestnik MJ, Feres M, Figueiredo LC
et al. Short-term benefits of the adjunctive use of metronidazole plus amoxicillin in the microbial profile and in the
clinical parameters of subjects with generalized aggressive periodontitis. J Clin
Cionca N, Giannopoulou C, Ugolotti G
et al. Microbiologic testing and outcomes of full-mouth scaling and root
planing with or without amoxicillin/
metronidazole in chronic periodontitis.
Machtei EE, Younis MN. The use of 2
antibiotic regimens in aggressive periodontitis: comparison of changes in
clinical parameters and gingival crevicular fluid biomarkers. Quintessence Int
2008;39:811819.
Akincibay H, Orsal SO, Sengun D et al.
Systemic administration of doxycycline
versus metronidazole plus amoxicillin in
the treatment of localized aggressive periodontitis: a clinical and microbiologic
study. Quintessence Int 2008;39:e33e39.
Novak MJ, Dawson DR 3rd, Magnusson I et al. Combining host modulation
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
and topical antimicrobial therapy in the

management of moderate to severe periodontitis: a randomized multicenter
trial. J Periodontol 2008;79:3341.
Moeintaghavi A, Talebi-Ardakani MR,
Haerian-Ardakani A et al. Adjunctive
eects of systemic amoxicillin and metronidazole with scaling and root planing: a randomized, placebo controlled
clinical trial. J Contemp Dent Pract
2007;8:5159.
Emingil G, Gurkan A, Atilla G et al.
Adjunctive low-dose doxycycline therapy eect on clinical parameters and
gingival crevicular fluid tissue plasminogen activator levels in chronic periodontitis. Inflamm Res 2006;55:550558.
Guerrero A, Griths GS, Nibali L
et al. Adjunctive benefits of systemic
amoxicillin and metronidazole in nonsurgical treatment of generalized aggressive periodontitis: a randomized placebo-controlled clinical trial. J Clin
Periodontol 2005;32:10961107.
Vergani SA, Silva EB, Vinholis AH
et al. Systemic use of metronidazole in
the treatment of chronic periodontitis: a
pilot study using clinical, microbiological, and enzymatic evaluation. Braz
Oral Res 2004;18:121127.
Blandino G, Lo Bue AM, Milazzo I
et al. Comparison of systemic flurithromycin therapy and clinical procedures
in the treatment of periodontal diseases.
J Chemother 2004;16:151155.
Emingil G, Atilla G, Sorsa T et al.
The eect of adjunctive low-dose doxycycline therapy on clinical parameters
and gingival crevicular fluid matrix
metalloproteinase-8 levels in chronic
periodontitis. J Periodontol 2004;75:
106115.
Kamma JJ, Nakou M, Mitsis FJ. The
clinical and microbiological eects of
systemic ornidazole in sites with and
without subgingival debridement in
early-onset periodontitis patients. J Periodontol 2000;71:18621873.
Palmer RM, Matthews JP, Wilson RF.
Non-surgical periodontal treatment with
and without adjunctive metronidazole
in smokers and non-smokers. J Clin Periodontol 1999;26:158163.
Tinoco EM, Beldi MI, Campedelli F
et al. Clinical and microbiological
eects of adjunctive antibiotics in treatment of localized juvenile periodontitis.
A controlled clinical trial. J Periodontol
1998;69:13551363.
Flemmig TF, Milian E, Karch H et al.
Dierential clinical treatment outcome
after systemic metronidazole and amoxicillin in patients harboring Actinobacillus
actinomycetemcomitans
and/or
Porphyromonas gingivalis. J Clin Periodontol 1998;25:380387.

44. Noyan U, Yilmaz S, Kuru B et al. A
clinical and microbiological evaluation
of systemic and local metronidazole
delivery in adult periodontitis patients.
J Clin Periodontol 1997;24:158165.
45. Sefton AM, Maskell JP, Beighton D et al.
Azithromycin in the treatment of periodontal disease. Eect on microbial flora.
46. Yilmaz S, Kuru B, Noyan U et al. A
clinical and microbiological evaluation
of systemic and local metronidazole
delivery in early onset periodontitis
patients. J Marmara Univ Dent Fac
1996;2:500509.
47. Haajee AD, Dibart S, Kent RL Jr et al.
Clinical and microbiological changes
associated with the use of 4 adjunctive
systemically administered agents in
the treatment of periodontal infections.
48. Saxen L, Asikainen S. Metronidazole in
the treatment of localized juvenile
periodontitis.
J
Clin
Periodontol
1993;20:166171.
49. Loesche WJ, Giordano JR, Hujoel P
et al. Metronidazole in periodontitis:
reduced need for surgery. J Clin Periodontol 1992;19:103112.
50. Loesche WJ, Schmidt E, Smith BA
et al. Eects of metronidazole on periodontal treatment needs. J Periodontol
1991;62:247257.
51. Chin QT, Al-Joburi W, Lautar-Lemay
C et al. Comparison of spiramycin and
tetracycline used adjunctively in the
treatment of advanced chronic periodontitis. J Antimicrob Chemother
1988;22:171177.
52. Quee TC, Chan EC, Clark C et al. The
role of adjunctive Rodogyl therapy in
the treatment of advanced periodontal
disease. A longitudinal clinical and microbiologic
study.
J
Periodontol
1987;58:594601.
53. Joyston-Bechal S, Smales FC, Duckworth R. A follow-up study 3 years
after metronidazole therapy for chronic
periodontal disease. J Clin Periodontol
1986;13:944949.
54. Loesche WJ, Syed SA, Morrison EC
et al. Metronidazole in periodontitis. I.
Clinical and bacteriological results after
15
to
30 weeks.
J
Periodontol
1984;55:325335.
55. Joyston-Bechal S, Smales FC, Duckworth R. Eect of metronidazole on
chronic periodontal disease in subjects
using a topically applied chlorhexidine
gel. J Clin Periodontol 1984;11:5362.
56. Lindhe J, Liljenberg B, Adielson B et al.
Use of metronidazole as a probe in the
study of human periodontal disease.
57. Lindhe J, Liljenberg B, Adielsson B.
Eect of long-term tetracycline therapy
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
on human periodontal disease. J Clin

Loesche WJ, Syed SA, Morrison EC
et al. Treatment of periodontal infections due to anaerobic bacteria with
short-term treatment with metronidazole. J Clin Periodontol 1981;8:2944.
Hellden LB, Listgarten MA, Lindhe J.
The eect of tetracycline and/or scaling
on human periodontal disease. J Clin
Listgarten MA, Lindhe J, Hellden L.
Eect of tetracycline and/or scaling on
human periodontal disease. Clinical,
microbiological, and histological observations. J Clin Periodontol 1978;5:246
271.
Emingil G, Han B, Ozdemir G et al.
Eect of azithromycin, as an adjunct to
nonsurgical periodontal treatment, on
microbiological parameters and gingival
crevicular fluid biomarkers in generalized aggressive periodontitis. J Periodontal Res 2012;47:729739.
Beliveau D, Magnusson I, Bidwell JA
et al. Benefits of early systemic antibiotics in localized aggressive periodontitis:
a retrospective study. J Clin Periodontol
2012;39:10751081.
Mestnik MJ, Feres M, Figueiredo LC
et al. The eects of adjunctive metronidazole plus amoxicillin in the treatment
of generalized aggressive periodontitis: a
1-year double-blinded, placebo-controlled, randomized clinical trial. J Clin
Casarin RC, Peloso Ribeiro ED, Sallum
EA et al. The combination of amoxicillin and metronidazole improves clinical
and microbiologic results of one-stage,
full-mouth, ultrasonic debridement in
aggressive periodontitis treatment. J Periodontol 2012;83:988998.
Aimetti M, Romano F, Guzzi N et al.
Full-mouth disinfection and systemic
antimicrobial therapy in generalized
aggressive periodontitis: a randomized,
placebo-controlled trial. J Clin Periodontol 2012;39:284294.
Baltacioglu E, Aslan M, Sarac O et al.
Analysis of clinical results of systemic
antimicrobials combined with nonsurgical periodontal treatment for generalized aggressive periodontitis: a pilot
study. J Can Dent Assoc 2011;77:b97.
Heller D, Varela VM, Silva-Senem MX
et al. Impact of systemic antimicrobials
combined with anti-infective mechanical
debridement on the microbiota of generalized aggressive periodontitis: a 6month RCT. J Clin Periodontol
2011;38:355364.
Griths GS, Ayob R, Guerrero A et al.
Amoxicillin and metronidazole as an
adjunctive treatment in generalized
aggressive periodontitis at initial ther-
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
19
apy or re-treatment: a randomized controlled clinical trial. J Clin Periodontol

2011;38:4349.
Yek EC, Cintan S, Topcuoglu N et al.
Ecacy of amoxicillin and metronidazole combination for the management
of generalized aggressive periodontitis.
Haas AN, de Castro GD, Moreno T
et al. Azithromycin as an adjunctive
treatment of aggressive periodontitis:
12-months randomized clinical trial.
Xajigeorgiou C, Sakellari D, Slini T
eects of dierent antimicrobials on
generalized aggressive periodontitis.
Palmer RM, Watts TL, Wilson RF. A
double-blind trial of tetracycline in the
management of early onset periodontitis. J Clin Periodontol 1996;23:670674.
Pradeep AR, Kalra N, Priyanka N
et al. Systemic ornidazole as an adjunct
to non-surgical periodontal therapy in
the treatment of chronic periodontitis: a
randomized, double-masked, placebocontrolled clinical trial. J Periodontol
2012;83:11491154.
Feres M, Soares GM, Mendes JA et al.
Metronidazole alone or with amoxicillin
as adjuncts to non-surgical treatment of
chronic periodontitis: a 1-year doubleblinded, placebo-controlled, randomized
clinical trial. J Clin Periodontol
2012;39:11491158.
Goodson JM, Haajee AD, Socransky
SS et al. Control of periodontal infections: a randomized controlled trial I.
The primary outcome attachment gain
and pocket depth reduction at treated
sites. J Clin Periodontol 2012;39:526
536.
Han B, Emingil G, Ozdemir G et al.
Azithromycin as an adjunctive treatment of generalized severe chronic periodontitis: clinical, microbiologic, and
biochemical parameters. J Periodontol
2012;83:14801491.
Sampaio E, Rocha M, Figueiredo LC
eects of azithromycin in the treatment
of generalized chronic periodontitis: a
randomized placebo-controlled clinical
trial. J Clin Periodontol 2011;38:838
846.
Silva MP, Feres M, Sirotto TA et al.
Clinical and microbiological benefits of
metronidazole alone or with amoxicillin
as adjuncts in the treatment of chronic
periodontitis: a randomized placebocontrolled clinical trial. J Clin Periodontol 2011;38:828837.
Pradeep AR, Kathariya R. Clarithromycin, as an adjunct to non surgical
periodontal therapy for chronic peri-
20
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
Keestra et al.
odontitis: a double blinded, placebo
controlled, randomized clinical trial.
Arch Oral Biol 2011;56:11121119.
Emingil G, Gurkan A, Atilla G et al.
Subantimicrobial-dose doxycycline and
cytokine-chemokine levels in gingival
crevicular fluid. J Periodontol 2011;
82:452461.
Oteo A, Herrera D, Figuero E et al.
Azithromycin as an adjunct to scaling
and root planing in the treatment of
Porphyromonas
gingivalis-associated
periodontitis: a pilot study. J Clin Periodontol 2010;37:10051015.
Deo V, Gupta S, Bhongade ML et al.
Evaluation of subantimicrobial dose
doxycycline as an adjunct to scaling and
root planing in chronic periodontitis
patients with diabetes: a randomized,
placebo-controlled clinical trial. J Contemp Dent Pract 2010;11:009016.
Yashima A, Gomi K, Maeda N et al.
One-stage full-mouth versus partialmouth scaling and root planing during
the eective half-life of systemically
administered azithromycin. J Periodontol 2009;80:14061413.
Ribeiro EP, Bittencourt S, Zanin IC
et al. Full-mouth ultrasonic debridement associated with amoxicillin and
metronidazole in the treatment of severe
chronic periodontitis. J Periodontol
2009;80:12541264.
Cionca N, Giannopoulou C, Ugolotti G
et al. Amoxicillin and metronidazole as
an adjunct to full-mouth scaling and
root planing of chronic periodontitis. J
Guentsch A, Jentsch H, Pfister W et al.
Moxifloxacin as an adjunctive antibiotic
in the treatment of severe chronic periodontitis. J Periodontol 2008;79:1894
1903.
Matarazzo F, Figueiredo LC, Cruz SE
et al. Clinical and microbiological benefits of systemic metronidazole and
amoxicillin in the treatment of smokers
with chronic periodontitis: a randomized placebo-controlled study. J Clin
Emingil G, Atilla G, Sorsa T et al. The
eect of adjunctive subantimicrobial
dose doxycycline therapy on GCF
EMMPRIN levels in chronic periodontitis. J Periodontol 2008;79:469476.
Preshaw PM, Novak MJ, Mellonig J
et al. Modified-release subantimicrobial
dose doxycycline enhances scaling and
root planing in subjects with periodontal
disease. J Periodontol 2008;79:440452.
Gomi K, Yashima A, Nagano T et al.
Eects of full-mouth scaling and root
planing in conjunction with systemically
administered azithromycin. J Periodontol 2007;78:422429.
91. Needleman I, Suvan J, Gilthorpe MS

et al. A randomized-controlled trial of
low-dose doxycycline for periodontitis
in smokers. J Clin Periodontol 2007;
34:325333.
92. Haajee AD, Torresyap G, Socransky
SS. Clinical changes following four different periodontal therapies for the
treatment of chronic periodontitis: 1year results. J Clin Periodontol 2007;
34:243253.
93. Gorska R, Nedzi-Gora M. The eects
of the initial treatment phase and of
adjunctive low-dose doxycycline therapy
on clinical parameters and MMP-8,
MMP-9, and TIMP-1 levels in the saliva and peripheral blood of patients
with chronic periodontitis. Arch Immunol Ther Exp (Warsz) 2006;54:419426.
94. Llambes F, Silvestre FJ, HernandezMijares A et al. Eect of non-surgical
periodontal treatment with or without
doxycycline on the periodontium of
type 1 diabetic patients. J Clin Periodontol 2005;32:915920.
95. Ehmke B, Moter A, Beikler T et al.
Adjunctive antimicrobial therapy of
periodontitis: long-term eects on disease progression and oral colonization.
96. Mascarenhas P, Gapski R, Al-Shammari K et al. Clinical response of azithromycin as an adjunct to non-surgical
periodontal therapy in smokers. J Periodontol 2005;76:426436.
97. Gurkan A, Cinarcik S, Huseyinov A.
Adjunctive subantimicrobial dose doxycycline: eect on clinical parameters and
gingival crevicular fluid transforming
growth factor-beta levels in severe, generalized chronic periodontitis. J Clin
98. Lee JY, Lee YM, Shin SY et al. Eect
of subantimicrobial dose doxycycline as
an eective adjunct to scaling and root
planing. J Periodontol 2004;75:1500
1508.
99. Emingil G, Atilla G, Sorsa T et al.
Eectiveness of adjunctive low-dose
doxycycline therapy on clinical parameters and gingival crevicular fluid laminin-5 gamma2 chain levels in chronic
periodontitis.
J
Periodontol
2004;75:13871396.
100. Carvalho LH, DAvila GB, Leao A
et al. Scaling and root planing, systemic
metronidazole and professional plaque
removal in the treatment of chronic
periodontitis in a Brazilian population.
I. Clinical results. J Clin Periodontol
2004;31:10701076.
101. Preshaw PM, Hefti AF, Novak MJ
et al. Subantimicrobial dose doxycycline
enhances the ecacy of scaling and root
planing in chronic periodontitis: a mul-
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
ticenter trial. J Periodontol 2004;

75:10681076.
Akalin FA, Baltacioglu E, Sengun D
et al. A comparative evaluation of the
clinical eects of systemic and local
doxycycline in the treatment of chronic
periodontitis. J Oral Sci 2004;46:2535.
Alptekin NO, Kurtoglu F, Serpek B
et al. Eects on the clinical indices and
gingival crevicular fluid enzyme activities of the cyclical regimen of low-dose
doxycycline therapy for adult periodontitis. J Int Acad Periodontol 2000;2:38.
Novak MJ, Johns LP, Miller RC et al.
Adjunctive benefits of subantimicrobial
dose doxycycline in the management of
severe, generalized, chronic periodontitis. J Periodontol 2002;73:762769.
Rooney J, Wade WG, Sprague SV et al.
Adjunctive eects to non-surgical periodontal therapy of systemic metronidazole and amoxycillin alone and
combined. A placebo controlled study.
Smith SR, Foyle DM, Daniels J et al.
A double-blind placebo-controlled trial
of azithromycin as an adjunct to nonsurgical treatment of periodontitis in
adults: clinical results. J Clin Periodontol 2002;29:5461.
Ramberg P, Rosling B, Serino G et al.
The long-term eect of systemic tetracycline used as an adjunct to non-surgical
treatment of advanced periodontitis. J
Clin Periodontol 2001;28:446452.
Winkel EG, van Winkelho AJ, Timmerman MF et al. Amoxicillin plus metronidazole in the treatment of adult
periodontitis patients. A double-blind
placebo-controlled study. J Clin Periodontol 2001;28:296305.
Caton JG, Ciancio SG, Blieden TM
et al. Treatment with subantimicrobial
dose doxycycline improves the ecacy
of scaling and root planing in patients
with adult periodontitis. J Periodontol
2000;71:521532.
Feres M, Haajee AD, Goncalves C et al.
Systemic doxycycline administration in
the treatment of periodontal infections
(I). Eect on the subgingival microbiota.
Winkel EG, van Winkelho AJ,
Barendregt DS et al. Clinical and microbiological eects of initial periodontal
therapy in conjunction with amoxicillin
and clavulanic acid in patients with adult
periodontitis. A randomised doubleblind, placebo-controlled study. J Clin
Palmer RM, Matthews JP, Wilson RF.
Adjunctive systemic and locally delivered metronidazole in the treatment of
periodontitis: a controlled clinical study.
Br Dent J 1998;184:548552.

113. Berglundh T, Krok L, Liljenberg B
et al. The use of metronidazole and
amoxicillin in the treatment of advanced
periodontal disease. A prospective, controlled clinical trial. J Clin Periodontol
1998;25:354362.
114. Bain CA, Beagrie GS, Bourgoin J et al.
The eects of spiramycin and/or scaling
on advanced periodontitis in humans.
J Can Dent Assoc 1994;60:209, 212

217.
115. Al-Joburi W, Quee TC, Lautar C et al.
Eects of adjunctive treatment of periodontitis with tetracycline and spiramycin. J Periodontol 1989;60:533539.
116. van Winkelho AJ, Herrera D, Oteo A
et al.
Antimicrobial
profiles
of
periodontal pathogens isolated from
21
periodontitis patients in The Netherlands and Spain. J Clin Periodontol

2005;32:893898.
117. Sanz M, Teughels W. Innovations in
non-surgical periodontal therapy: consensus Report of the Sixth European
Workshop on Periodontology. J Clin

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2014 John Wiley & Sons A/S.

Published by John Wiley & Sons Ltd

J Periodont Res 2014

JOURNAL OF PERIODONTAL RESEARCH

Department of Oral Health Sciences,

Keestra JAJ, Grosjean I, Coucke W, Quirynen M, Teughels W. Non-surgical

Johan Anton Jochum Keestra, DDS,

Conclusion: Systemic antibiotics combined with SRP oer additional clinical

periodontal therapy; systemic antibiotics

The goals of todays treatment of

systemic antibiotics should only be

Material and methods

The focused question that has been

The MEDLINE-PubMed database

Study inclusion and exclusion

The selection process was performed

Antibiotics in chronic periodontitis

The primary outcomes were probing

The title and abstract of studies of

study, number of patients per study

Data of the included studies were

sented for moderate pockets (46 mm)

At 3 mo, 1506 patients out of 35 studies could be analysed (Fig. 2 and

Total 43 articles included

Fig. 1. Search strategy.

of the use of a systemic antibiotic

nine studies, 269 patients, I2 = 66%),

to DOXL. AZI did not show a statistically significant mean dierence

At 3 mo, 1358 patients out of 21

Antibiotics in chronic periodontitis

Reason for exclusion

Preus et al. (2013)

Two dierent control groups

Schmidt et al. (2011)

Joyston-Bechal et al. (1986)

AA, Aggregatibacter actinomycetemcomitans; PG, Porphyromonas gingivalis.

DOXL (0.22 mm ! 0.09, five studies,

(0.50 mm ! 0.23, three studies, 150

At 3 mo, 1462 patients out of 24

Deo et al. (82)

Table 2. Characteristics of the 43 included studies

After 1st FMSRP

After 1st SSRP

After 1st SSRP

After 1st FMSRP

After 1st SSRP

After 1st SSRP

After 1st FMSRP

After 1st SSRP

After 1st SSRP

After 1st SRP

After 1st SSRP

Amoxicillin 375 mg 3 9 for 8 d

Doxycycline 200 mg + 100 mg 1 9 for 15 d

Azithromycin 500 mg 1 9 for 3 d

Azithromycin 500 mg 1 9 for 3 d

Doxycycline 40 mg 1 9 for 270 d

Amoxicillin 375 mg 3 9 for 7 d

Azithromycin 500 mg 1 9 for 3 d