non‐surgical periodontal therapy with systemic … aggressive...aggressive periodontitis are...

Review Article

Non-surgical periodontaltherapy with systemicantibiotics in patients withuntreated aggressiveperiodontitis: a systematicreview and meta-analysis

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

periodontal therapy with systemic antibiotics in untreated aggressive periodontitis

patients: a systematic review and meta-analysis. J Periodont Res 2014;

doi: 10.1111/jre.12252 . © 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) compared to SRP alone in patients with untreated aggressive periodonti-

tis.

Background: In patients with aggressive periodontitis, SRP is often combined

with the use of systemic antibiotics. However, the effectiveness of these anti-

biotics over time and differences in effectiveness between different antibiotics

are hardly known.

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

their earliest records until January 20, 2014. Several journals were hand

searched and some authors were contacted for additional information. The fol-

lowing outcome measures were analysed: mean probing pocket depth reduction,

mean clinical attachment level gain and mean bleeding on probing change.

Extracted data were pooled using a random effect model. Weighted mean differ-

ences were calculated and heterogeneity was assessed.

Results: The search yielded 296 abstracts. Ultimately, 101 articles were selected of

which 14 articles met the eligibility criteria. Systemic antibiotics showed a signifi-

cant (p < 0.05) additional pocket depth reduction for moderate (0.36 � 0.22 mm

at 3 mo, 6 mo 0.42 � 0.22 mm and 12 mo 0.88 � 0.27 mm) and deep pockets

(0.74 � 0.36 mm at 3 mo, 6 mo 0.85 � 0.55 mm and 12 mo 1.26 � 0.81 mm)

and a significant clinical attachment gain for moderate (0.26 � 0.18 at 3 mo,

6 mo 0.52 � 0.15 and 12 mo 0.83 � 0.38) and deep pockets (0.59 � 0.18 at

3 mo, 0.96 � 0.21 at 6 mo and 1.00 � 0.80 at 12 mo).

Conclusion: For the treatment of patients with aggressive periodontitis, sys-

temic antibiotics combined with non-surgical periodontal therapy resulted in

J. A. J. Keestra1,2, I. Grosjean1,2,

W. Coucke3, M. Quirynen1,2

W. Teughels1,2,41Department 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 4Fund for Scientific

Research Flanders (FWO), Egermontstraat,

Brussels, Belgium

Johan Anton Jochum Keestra, DDS,

Department of Oral Health Sciences,

Periodontology, KU Leuven – University of

Leuven and Department of Periodontology,

University Hospitals Leuven Kapucijnenvoer 33,

B-3000 Leuven, Belgium

Tel: +(32) 16 332485

Fax: +(32) 16 332484

e-mail: [email protected]

Key words: aggressive periodontitis; non-

surgical periodontal therapy; systemic

antibiotics

Accepted for publication November 01, 2014

J Periodont Res 2014All rights reserved

© 2014 John Wiley & Sons A/S.

Published by John Wiley & Sons Ltd

JOURNAL OF PERIODONTAL RESEARCH

doi:10.1111/jre.12252

a significant additional effect compared to non-surgical therapy alone. There

is a visible trend that showed metronidazole + amoxicillin is the most potent

antibiotic combination.

Introduction

Periodontitis is an inflammatory dis-

order that leads to the destruction of

the tooth supporting structures. This

destruction is caused by an imbalance

between a wide range of microorgan-

isms, host response and essential

modifying factors (1). Inflammation,

loss of connective tissue attachment

and loss of alveolar bone support are

the clinical signs. Periodontitis is

divided into aggressive periodontitis

(characterized by a rapid loss of clini-

cal attachment and alveolar bone)

and chronic periodontitis (character-

ized by a progressive loss of clinical

attachment and alveolar bone) (2).

Today the treatment goals are to

resolve inflammation and reduce the

infection so that a clinical condition is

created, which is compatible with

periodontal health (3).

Aggressive periodontitis is charac-

terized by a rapid loss of clinical

attachment and alveolar bone affect-

ing adolescents and young adults (4).

It is subclassified as localized or gen-

eralized in relation to the extent of

the periodontal destruction. In a

recent article, Albandar proposed a

new case definition for patients with

aggressive periodontitis (5). The fol-

lowing distinctive criteria are recom-

mended:

1 An early age onset, usually before

25 years of age. The age of onset

might be a predictor of the disease’s

severity.

2 Loss of periodontal tissue occurs at

multiple permanent teeth. The tis-

sue loss occurs because of a micro-

bial infection.

3 The periodontal destruction is

detectable clinically and radio-

graphically. Typically, the lesions

are depicted radiographically as

vertical bone loss at the proximal

surfaces of posterior teeth. The pat-

tern of bone loss is usually similar

bilaterally. In advanced cases, the

lesions may be depicted radiograph-

ically as a horizontal loss of the

alveolar bone.

4 There is a relatively high progres-

sion rate of periodontal tissue loss.

5 The primary teeth may also be

affected.

6 Clinically healthy except for the

presence of periodontitis.

The major differences with respect

to the classification of Armitage (2)

are that some primary and secondary

features, such as familial aggregation,

elevated proportions of Aggregatibact-

er actinomycetemcomitans or Por-

phyromonas gingivalis, hyper-

responsive macrophage phenotypes

and phagocyte abnormalities, are not

considered anymore.

The treatment and maintenance for

aggressive periodontitis are challeng-

ing for periodontists. There are still

no established protocols and guide-

lines (6). The first step in the treat-

ment of aggressive periodontitis is a

non-surgical periodontal therapy. This

therapy consists of scaling and root

planing (SRP) and oral hygiene

instructions combined with the

adjunctive use of systemic antibiotics.

This SRP can be done within 24 h or

within 1 wk, which is called full

mouth disinfection. The SRP can also

be done over a longer period, which

is called staged SRP. Systemic antibi-

otics help the immune system by sup-

pressing the target microbial species.

It is currently well established that

systemic antibiotics should not be

administered without previous disrup-

tion of the biofilm (7). The possible

antibiotic regimens for aggressive

periodontitis that have been reported

in the literature are penicillins (amoxi-

cillin, AMOX), tetracyclines (doxycy-

cline [DOX], tetracycline, TET),

macrolides (azithromycin, AZI) and

nitroimidazole (metronidazole, MET).

Evidently, the ultimate goal in the

treatment of aggressive periodontitis

is to create a clinical condition, which

is necessary to save and maintain as

many teeth as possible (6).

The reason why systemic antibiotics

are given in combination with the ini-

tial non-surgical periodontal therapy

is to suppress pathogenic bacteria and

create a health-associated biofilm. If

the use of systemic antibiotics is con-

sidered, the clinician needs to take

into account the patient’s compliance,

adverse effects and bacterial resistance

(8–11). The EU (12,13) and WHO

(14) have made some recommenda-

tions to prevent bacterial resistance

worldwide. The key points are, avoid

antibiotics whenever possible and use

narrow-spectrum antibiotics if possi-

ble (11). It is highly necessary to

develop evidence-based clinical proto-

cols that will help and guide the clini-

cian in his decision when and what

kind of systemic antibiotic regimen

should be used. As a step towards this

protocol, this meta-analysis evaluates

if there are differences between the

effectiveness of the different types of

systemic antibiotics in combination

with SRP vs. SRP alone in patients

with untreated aggressive periodonti-

tis and whether the effect is consistent

over time.

Material and methods

The following systematic review was

conducted in agreement with the rec-

ommendations of the Cochrane Col-

laboration (15) and the principles of

the PRISMA (Preferred Reporting

Items for Systemic Reviews and

Meta-Analyses) statement (16).

Focused question (PICO)

The focused question that has been

used was: “Do systemic antibiotics

combined with SRP vs. SRP alone in

untreated aggressive periodontitis

patients have an additional effect on

the clinical outcomes”.

2 Keestra et al.

Search strategy

The MEDLINE-PubMed database

was searched from their earliest

records until January 20, 2014. 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 of

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 (I.G. and

J.K.). The studies were analysed

according to inclusion criteria:

1 Studies were limited to randomized

controlled clinical trials of at least

more than 1 mo duration.

2 The population was limited to sub-

jects with aggressive periodontitis

(2).

3 The interventions of interest were

full mouth SRP (SRP within 1 wk)

or staged SRP (SRP more than a

week apart) 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 (PPD) reduction and

clinical attachment level change. Clin-

ical attachment level change and PPD

reduction were if possible divided into

moderate (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 (I.G. and

J.K.). 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 (I.G.

and J.K.). 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 out-

come 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, the CON-

SORT guidelines (17), the Delphi list

(18) and the checklist as proposed by

Van der Weijden et al. (19). The fol-

lowing seven criteria were used: selec-

tion 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 to have a moder-

ate 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 (I.G. and J.K.).

If there was any disagreement, it was

resolved by discussion.

Statistical analyses

Data of the included studies were

extracted and entered into a data-

base. Mean values and SDs were

extracted from the data. If no SD

was available it was recalculated by

the formula (SE = SD/√n) with n the

sample size. When intermediate

assessments were performed, the 3, 6,

9 or 12 mo data were considered. If

there were insufficient data available,

the corresponding authors were con-

tacted for additional data. The avail-

able data were recalculated to present

data such as mean BOP change,

mean clinical attachment level gain

and mean PPD reduction. Clinical

attachment level gain and PPD

reduction were also presented for

moderate (4–6 mm) and deep pockets

(> 6 mm). The I2 statistic was used

to assess the heterogeneity between

the studies. Because of observed het-

erogeneity mean differences were

combined for continuous data using

random effects models meta-analysis.

Study weights were determined by the

sample size (20).

Results

The initial search resulted in a total

of 6738 articles (Fig. 1). After screen-

ing the titles, 296 abstracts were

included for further analysis. Analysis

of the abstracts resulted in 101 poten-

tial articles. In the third phase, the

full text articles of the remaining 101

articles were evaluated, of which 44

articles (21–64) did not pass the inclu-

sion criteria (Table 1). Another 43

articles (65–107) were excluded

because they were about patients with

chronic periodontitis. Screening of the

reference lists of full text articles did

not result in any additional articles.

In Table 2 the main characteristics of

the 14 included articles (108–121) are

summarized. Four authors have pro-

vided additional results, which were

Non-surgical periodontal therapy with systemic antibiotics 3

not present in the articles (111,117–119). These 14 included articles repre-

sent 13 studies. These studies were

divided in to the following groups: az-

ithromycin (AZI; two studies), DOX

(two studies), MET (one study),

MET+AMOX (10 studies) and TET

one study. The quality evaluation was

based on seven criteria (17–19). The

potential risk of bias in the 13 studies

included was low in eight, moderate

in two and high in four studies

(Table 2).

Probing pocket depth reduction

At 3 mo, 386 patients out of 13 stud-

ies could be analysed (Fig. 2 and

Table S1). A statistically significant

mean difference of 0.34 � 0.11 mm

and heterogeneity I2 = 26%, in favour

of the use of a systemic antibiotic was

observed. AZI (0.36 � 0.33 mm, one

study, 32 patients and I2 = NA) and

MET+AMOX (0.39 � 0.16 mm, eight

studies, 248 patients and I2 = 38%)

showed a statistically significant mean

difference when compared to the con-

trol group. DOX, MET and TET did

not show a statistically significant

mean difference when compared to

the control group. However, it should

be noted that for AZI, MET and

TET only one study was available.

At 6 mo, 290 patients out of 10 stud-

ies could be analysed. A statistically

significant mean difference of

0.51 � 0.11 mm and heterogeneity

I2 = 28%, in favour of the use of a sys-

temic antibiotic was observed. MET

(1.16 � 0.56 mm, one study, 23

patients and I2 = NA) and MET+A-

MOX (0.51 � 0.09 mm, seven studies,

214 patients and I2 = 0%) showed a

statistically significant mean difference

when compared to the control group.

DOX and AZI did not show a statisti-

cally significant mean difference when

compared to the control group. How-

ever, it should be noted that for DOX,

AZI and MET only one study was

available. At 9 mo, no studies could be

analysed.

At 12 mo, 65 patients out of two

studies could be analysed. A statisti-

cally significant mean difference of


I2 = 42%, in favour of the use of a

systemic antibiotic was observed. At

12 mo, only results for MET+AMOX

were available.


moderate pockets

At 3 mo, 191 patients out of six

studies could be analysed (Fig. 3 and



and heterogeneity I2 = 81%, in

favour of the use of a systemic anti-

biotic was observed. MET+AMOX

(0.43 � 0.22 mm, four studies, 135

patients and I2 = 76%) showed a

statistically significant mean differ-

ence when compared to the control

group. AZI did not show a statisti-

cally significant mean difference

when compared to the control

group.






systemic antibiotic was observed.

MET+AMOX (0.50 � 0.21 mm, four




trol group. AZI did not show a statis-

tically significant mean difference


At 9 mo, 24 patients out of one

study could be analysed. No statisti-


(0.65 � 0.94 mm, one study, 24

patients and I2 = NA), in favour of

the use of a systemic antibiotic (AZI)

was observed.

At 12 mo 54 patients out of two





temic antibiotic was observed.

MET+AMOX (0.89 � 0.28 mm, one

study, 30 patients and I2 = NA)






However, it should be noted that for

both antibiotics only one study was

available.


deep pockets

At 3 mo, 191 patients out of six stud-

ies could be analysed (Fig. 4 and




of the use of a systemic antibiotic

was observed. MET+AMOX (0.88 �0.27 mm, four studies, 135 patients

and I2 = 42%) showed a statistically

significant mean difference when com-

Electronic search:

Periodontal diseases [MESH] AND Anti-Infective Agents [MESH]Metronidazole [MESH] AND Periodontal diseases [MESH]

6738 articles

Screening titles:

296 abstracts

Screening abstracts:

Screening full text:

101 full text articles

Total 14 articles included

6442 titles excluded

195 abstracts excluded

44 full text articles excluded

43 chronic periodontitis articles excluded

Fig. 1. Search strategy.

4 Keestra et al.

pared to the control group. AZI did



the control group.

















(0.62 � 1.65 mm, one study, 24



was observed.


could be analysed. A statistically sig-

nificant mean difference of 1.26 �0.81 mm and heterogeneity I2 = 0%,

in favour of the use of a systemic anti-

biotic was observed. MET+AMOX

(1.40 � 0.91 mm, one study, 30

patients and I2 = NA) showed a statis-

tically significant mean difference when

compared to the control group. AZI

did not show a statistically significant

mean difference when compared to the

control group. However, it should be

noted that for both antibiotics only

one study was available.

Table 1. Characteristics of the 44 excluded articles

Study Reason for exclusion

Preus et al. (2013) (21) Two different control groups

Rodrigues et al. (2012) (22) No control group

Haas et al. (2012) (23) Only radiographic results

Haas et al. (2012) (24) Only microbiological results

Basegmez et al. (2011) (25) Useful clinical results, more information needed. Could not contact the author

Schmidt et al. (2011) (26) No control group

Varela et al. (2011) (27) The same patients – Heller et al. (116)

Serrano et al. (2011) (28) Using different types of antibiotic regimens (amoxicillin/doxycycline)

T€uter et al. (2010) (29) Useful clinical results, more information needed. Could not contact the author

Mestnik et al. (2010) (30) Mestnik et al. (111) – long-term results

Cionca et al. (2010) (31) The same patients – Cionca et al. (77)

Valenza et al. (2009) (32) No control group

Machtei et al. (2008) (33) Differences between two antibiotic regimens, no control group

Akincibay et al. (2008) (34) Differences between two antibiotic regimens, no control group

Novak et al. (2008) (35) Combination systemic and local antibiotics

Moreira et al. (2007) (36) Comparing two different SRP protocols

Kaner et al. (2007) (37) Using different timing moments of antibiotic regimen

Moeintaghavi et al. (2007) (38) Clinical results based on pockets ≥ 5 mm, author could not give extra information

Emingil et al. (2006) (39) Same clinical results – Emingil et al. (72)

Guerrero et al. (2005) (40) The same patients – Griffiths et al. (117)

Vergani et al. (2004) (41) Useful clinical results, more information needed. Could not contact the author

Blandino et al. (2004) (42) Useful clinical results, more information needed. Could not contact the author

Emingil et al. (2004) (91) The same patients – Emingil et al. (43)

Kamma et al. (2000) (44) No control group

Palmer et al. (1999) (45) The same patients – Palmer et al. (104)

Tinoco et al. (1998) (46) SRP in combination with modified Widman flap surgery

Flemmig et al. (1998) (47) Clinical result with/without AA/PG, could not contact the author for more information

Noyan et al. (1997) (48) No control group with SRP

Sefton et al. (1996) (49) The same patients – Smith et al. (98)

Yilmaz et al. (1996) (50) No control group with SRP

Haffajee et al. (1995) (51) Antibiotics in combination with modified Widman flap surgery

Sax�en et al. (1993) (52) Useful clinical results, more information needed. Could not contact the author

Loesche et al. (1992) (53) Clinical outcome: periodontal surgery yes/no

Loesche et al. (1991) (54) Clinical outcome: periodontal surgery yes/no

Chin et al. (1988) (55) The same patients – Al-Joburi et al. (107)

Quee et al. (1987) (56) Useful clinical results, more information needed. Could not contact the author

Joyston-Bechal et al. (1986) (57) Useful clinical results, more information needed. Could not contact the author

Loesche et al. (1984) (58) Control group not comparable with test group

Joyston-Bechal et al. (1984) (59) Useful clinical results, more information needed. Could not contact the author

Lindhe et al. (1983) (60) Three antibiotic periods during treatment

Lindhe et al. (1983) (61) Two antibiotic periods during treatment

Loesche et al. (1981) (62) Control group not comparable with test group

Helld�en et al. (1979) (63) Two antibiotic periods during treatment

Listgarten et al. (1978) (64) Two antibiotic periods during treatment

AA, Actinobacillus actinomycetemcomitans; PG, Porphyromonas gingivalis.


Table

2.Characteristics

ofthe14included

articles

6 Keestra et al.

Clinical attachment level gain

At 3 mo, 386 patients out of 13 studies

could be analysed (Fig. 5 and Table

S4). A statistically significant mean dif-

ference of 0.40 � 0.30 mm and hetero-

geneity I2 = 85%, in favour of the use

of a systemic antibiotic was observed.

MET+AMOX (0.50 � 0.40 mm, eight




trol group. AZI, DOX, MET and TET

did not show a statistically significant

mean difference when compared to the

control group. However, it should be

noted that for AZI, MET and TET

only one study was available.

At 6 mo, 290 patients out of 10






MET+AMOX (0.36 � 0.10 mm,

seven studies, 214 patients and

I2 = 0%) showed a statistically signifi-

cant mean difference when compared

to the control group. AZI, DOX and

MET did not show a statistically sig-

nificant mean difference when com-

pared to the control group. However,

it should be noted that for AZI, DOX

and MET only one study was avail-

able. At 9 mo, no studies could be

analysed.







Study or Subgroup1 Azithromycin

Emingil et al. 2012Subtotal (95% CI)

2 Doxycycline

Baltacioglu et al. 2011Xajigeorgiou et al. 2006Subtotal (95% CI)

3 Metronidazole

Xajigeorgiou et al. 2006Subtotal (95% CI)

4 Metronidazole + Amoxicillin

Silva-senem et al. 2013 & Heller et al. 2011Beliveau et al. 2012Mestnik et al. 2012Aimetti et al. 2012Oliveira et al. 2012Griffiths et al. 2011Baltacioglu et al. 2011Yek et al. 2010Xajigeorgiou et al. 2006Subtotal (95% CI)

5 Tetracycline

Palmer et al. 1996Subtotal (95% CI)

Total (95% CI)

Mean differenceIV, Random, 95% CI

–1 –0.5 0 0.5 1

Test 3 mo control


–1 –0.5 0 0.5 1


–1 –0.5 0 0.5 1


–1 –0.5 0 0.5 1

Test 6 mo control Test 9 mo control Test 12 mo control

Fig. 2. Probing pocket depth reduction.


Emingil et al. 2012Haas et al. 2008Subtotal (95% CI)


Casarin et al. 2012Mestnik et al. 2012Aimetti et al. 2012Griffiths et al. 2011Subtotal (95% CI)

Total (95% CI)


–1 –0.5 0 0.5 1

Test 3 mo control


–1 –0.5 0 0.5 1


–1 –0.5 0 0.5 1


–1 –0.5 0 0.5 1


Fig. 3. Probing pocket depth reduction moderate pockets.

8 Keestra et al.


were available.

Clinical attachment level gain

moderate pockets

At 3 mo, 159 patients out of five





of the use of a systemic antibiotic was

observed. MET+AMOX (0.27 �0.19

mm, four studies, 135 patients and

I2 = 57%) showed a statistically sig-






be noted that for AZI only one study

was available.









showed a statistically significant


the control group. AZI did not show

a statistically significant mean differ-


group. However, it should be noted

that for AZI only one study was

available.




(0.41 � 1.75 mm, one study, 24



was observed.


Emingil et al. 2012Haas et al. 2008Subtotal (95% CI)


Casarin et al. 2012Mestnik et al. 2012Aimetti et al. 2012Griffiths et al. 2011Subtotal (95% CI)

Total (95% CI)


–1 –0.5 0 0.5 1

Test 3 mo control


–1 –0.5 0 0.5 1


–1 –0.5 0 0.5 1


–1 –0.5 0 0.5 1


Fig. 4. Probing pocket depth reduction deep pockets.


Emingil et al. 2012Subtotal (95% CI)

2 Doxycycline

Baltacioglu et al. 2011Xajigeorgiou et al. 2006Subtotal (95% CI)

3 Metronidazole



Silva-senem et al. 2013 & Heller et al. 2011Aimetti et al. 2012Mestnik et al. 2012Beliveau et al. 2012Oliveira et al. 2012Griffiths et al. 2011Baltacioglu et al. 2011Yek et al. 2010Xajigeorgiou et al. 2006Subtotal (95% CI)

5 Tetracycline


Total (95% CI)


–1 –0.5 0 0.5 1

Test 3 mo control


–1 –0.5 0 0.5 1


–1 –0.5 0 0.5 1


–1 –0.5 0 0.5 1


Fig. 5. Clinical attachment level gain.







temic antibiotic was observed.










available.

Clinical attachment level gain deep

pockets






of the use of a systemic antibiotic

was observed. MET+AMOX (0.63 �

0.25 mm, four studies, 135 patients

and I2 = 34%) showed a statistically

significant mean difference when com-





be noted that for AZI only one study

was available.









showed a statistically significant


the control group. AZI did not show




that for AZI only one study was

available.




(0.52 � 2.71 mm, one study, 24



was observed.
















available.

Bleeding on probing change

At 3 mo, 333 patients out of 11

studies could be analysed (Fig. 8

and Table S7). A statistically signifi-


Haas et al. 2008Subtotal (95% CI)


Aimetti et al. 2012Casarin et al. 2012Mestnik et al. 2012Griffiths et al. 2011Subtotal (95% CI)

Total (95% CI)


–1 –0.5 0 0.5 1

Test 3 mo control


–1 –0.5 0 0.5 1


–1 –0.5 0 0.5 1


–1 –0.5 0 0.5 1


Fig. 6. Clinical attachment level gain moderate pockets.


Haas et al. 2008Subtotal (95% CI)


Aimetti et al. 2012Casarin et al. 2012Mestnik et al. 2012Griffiths et al. 2011Subtotal (95% CI)

Total (95% CI)


–1 –0.5 0 0.5 1

Test 3 mo control


–1 –0.5 0 0.5 1


–1 –0.5 0 0.5 1


–1 –0.5 0 0.5 1


Fig. 7. Clinical attachment level gain deep pockets.

10 Keestra et al.

cant mean difference of

9.38 � 4.70% and heterogeneity



MET+AMOX (10.07 � 5.85%,

seven studies, 219 patients and

I2 = 89%) showed a statistically sig-


pared to the control group. AZI,

DOX, MET and TET did not show




that for AZI, DOX, MET and TET

only one study was available.

At 6 mo, 266 patients out of nine






MET+AMOX (8.85 � 5.51 mm, six




trol group. AZI, DOX and MET did




be noted that for AZI, DOX and

MET only one study was available.

At 9 mo, no studies could be analy-

sed.








were available.

Discussion

In the literature, evidence is available

about the additional effect of sys-

temic antibiotics in combination with

SRP for the treatment of patients

with aggressive periodontitis when

compared to only SRP. This review

has tried to evaluate systematically

the current available evidence and

has tried to compare the effectiveness

of different types of systemic antibi-

otics as well as their long-term

effects (up to 1 year). Thirteen clini-

cal studies could be included from

which the data were obtained and

used to calculate the mean difference

in clinical improvement for PPD,

clinical attachment level and BOP

change. PPD and clinical attachment

level difference were additionally

analysed for initially moderate pock-

ets (4–6 mm) and deep pockets

(> 6 mm).

The meta-analysis for the mean

PPD difference showed statistically

significant differences when compared

to SRP at 3, 6 and 12 mo in favour

of the adjunctive use of systemic

antibiotics (0.34 � 0.11, 0.51 � 0.11

and 0.51 � 0.38 mm). The analysis

was hampered by the fact that the

follow-up period from most of the

studies was only 3–6 mo. When anal-

ysing only the studies that had

results at 3, 6 and 12 mo

(108,111,116), the clinical additional

difference of these studies was similar

at 3 mo (0.33 � 0.33 mm), higher at

6 mo (0.63 � 0.27 mm) and similar

at 12 mo (0.51 � 0.38 mm) when

compared to the overall effect. Over-

all, it seems that the initial effect of

the adjunctive systemic antibiotics on

the mean PPD difference remains

stable for at least 1 year. Addition-

ally only two studies of MET+A-

MOX were available at 12 mo and

unfortunately no other systemic anti-

biotic regimen was available. It

became clear that only for MET+A-

Study or Subgroup

1 AzithromycinEmingil et al. 2012Subtotal (95% CI)

2 Doxycycline


3 Metronidazole



Silva-senem et al. 2013 & Heller et al. 2011Oliveira et al. 2012Casarin et al. 2012Aimetti et al. 2012Beliveau et al. 2012Mestnik et al. 2012Griffiths et al. 2011Xajigeorgiou et al. 2006Subtotal (95% CI)

5 Tetracycline


Total (95% CI)


–20 –10 0 10 20

Test 3 mo control


–20 –10 0 10 20


–20 –10 0 10 20


–20 –10 0 10 20


Fig. 8. Bleeding on probing change.


MOX there is evidence that the mean

PPD difference when compared to

SRP could be obtained for up to

1 year.


PPD difference in moderate and deep

pockets showed a similar outcome as

for mean whole mouth PPD reduction

albeit more pronounced. When analy-

sing only the studies that had results

at 3, 6 and 12 mo (111,119), the clini-

cal additional difference for the mod-

erate pockets in these studies was

higher at 3 mo (0.73 � 0.32 mm) and

6 mo (0.74 � 0.28 mm) and similar at

12 mo (0.88 � 0.27 mm), for the deep

pockets in these studies was higher at

3 mo (1.28 � 0.90 mm) and 6 mo

(1.35 � 0.71 mm) and similar at

12 mo (1.26 � 0.81 mm) when com-

pared to the overall effect. Based on

these studies, it seems that the initial

effect of the systemic antibiotics on

the mean PPD difference of moderate

and deep pockets remains stable for

at least 1 year. Additionally only one

study using AZI (119) and one using

MET+AMOX (111) were available at

12 mo. It became clear that only for

MET+AMOX the mean PPD differ-

ence when compared to SRP could be

obtained for up to 1 year.


clinical attachment level difference

showed statistically significant differ-

ences when compared to SRP at 3, 6

and 12 mo in favour of the use of

antibiotics (0.41 � 0.32, 0.36 � 0.11

and 0.46 � 0.37 mm). The analysis

was also hampered by the fact that

the follow-up period from most of

the studies was only 3–6 mo. When

analysing only the studies that had

results at 3, 6 and 12 mo (108,111),

the clinical additional difference of

these studies was higher at 3 mo

(0.63 � 0.35 mm) and 6 mo

(0.49 � 0.27 mm), and similar at

12 mo (0.46 � 0.37 mm) when com-

pared to the overall effect. Overall, it

seems that the initial effect of the sys-

temic antibiotics on the mean clinical

attachment level difference remains

stable for at least 1 year. Addition-

ally, only two studies using MET+A-

MOX were available at 12 mo and

unfortunately no other antibiotics

were available. It became clear that

for MET+AMOX the mean clinical

attachment level difference when com-

pared to SRP could be obtained for

up to 1 year.


clinical attachment level difference in

moderate and deep pockets showed a

similar outcome as for mean whole

mouth clinical attachment level differ-

ence albeit more pronounced. When

analysing only the studies that had

results at 3, 6 and 12 mo (111,119),

the clinical additional difference for

the moderate pockets in these studies

was higher at 3 mo (0.61 � 0.36 mm)

and 6 mo (0.58 � 0.32 mm) and simi-

lar at 12 mo (0.83 � 0.38 mm), for

the deep pockets in these studies was

higher at 3 mo (1.09 � 0.66 mm) and

6 mo (1.05 � 0.69 mm) and similar at

12 mo (1.00 � 0.80 mm) when com-

pared to the overall effect. Based on

these studies, it seems that the initial

effect of the systemic antibiotics on

the mean clinical attachment level dif-

ference of moderate and deep pockets

remains stable for at least 1 year.

Additionally only one study using

AZI (119) and one using MET+A-

MOX (111) were available at 12 mo.

It became clear that only for

MET+AMOX the mean clinical

attachment level difference when com-

pared to SRP could be obtained for

up to 1 year.


BOP difference showed statistically

significant differences when compared

to SRP at 3, 6 and 12 mo in favour

of the use of antibiotics (9.38 �4.70%, 6.84 � 3.81% and 12.76 �10.35%). The analysis was ham-

pered by the fact that the follow-up

period from most of the studies was

only 3–6 mo. When analysing only

the studies that had results at 3, 6

and 12 mo (108,111), the clinical

additional difference of these studies

was higher at 3 mo (12.38 � 8.76%)

and 6 mo (15.16 � 9.01%) and

similar at 12 mo (12.76 � 10.35%)

when compared to the overall effect.

Overall, it seems that the initial

effect of systemic antibiotics on the

mean BOP difference remains stable

for at least 1 year. Additionally only

two studies of MET+AMOX were

available at 12 mo and unfortunately

no other antibiotics were available.

It became clear that for MET+A-

MOX the mean clinical attachment

level difference when compared to

SRP could be obtained for up to

1 year.

The 13 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 (110,114,115,121) had

some impact on the final outcomes,

the meta-analysis for the clinical out-

comes: overall PPD difference, overall

clinical attachment level difference

and overall BOP difference were recal-

culated. This having done resulted in

an overall PPD difference at 3 mo

(0.29 � 0.09 mm), 6 mo (0.49 � 0.14

mm) and 12 mo (0.51 � 0.38 mm),

overall clinical attachment level differ-

ence at 3 mo (0.25 � 0.11 mm), 6 mo

(0.35 � 0.11 mm) and 12 mo (0.46

� 0.37 mm) and overall BOP differ-

ence at 3 mo (10.30 � 6.98%), 6 mo

(7.30 � 4.23%) and 12 mo (12.76 �10.35%). For the overall PPD differ-

ence, clinical attachment level differ-

ence 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. How-

ever, more studies will give more con-

clusive results.

The findings of this meta-analysis

should be interpreted with caution

because the meta-analysis had some

limitations. There were no restrictions

for the study population made. In

addition, there was only a limited

amount of data (13 studies) available.

In the 13 studies there were only four

different antibiotics used. For AZI

(109,119), DOX (115,120), MET (120)

and TET (121) just one or two studies

were available compared with 10 stud-

ies (108,110–118,120) for the combi-

nation MET+AMOX. As yet there is

no general consensus on which spe-

cific systemic antibiotic should be

used. Nearly all the studies had a fol-

low-up period of 6 mo. Unfortu-

12 Keestra et al.

nately, just three studies

(108,111,116,119) showed the results

at 12 mo. As only three studies had a

12 mo follow-up period and because

of the previous discussed limited

availability of data it is dangerous to

give long-term conclusions about the

effect of antibiotics.

Since the data of our previous

study Keestra et al. (122) were avail-

able it was possible to compare the

effectiveness of MET+AMOX in

chronic vs. patients with aggressive

periodontitis. When analysing the

data, the PPD difference for moderate

pockets in patients with chronic peri-

odontitis was 0.60 � 0.15 mm at

3 mo, 0.50 � 0.23 mm at 6 mo and

0.60 � 0.24 mm at 12 mo. While in

patients with aggressive periodontitis,

it was 0.43 � 0.22 mm at 3 mo, 0.50

� 0.21 mm at 6 mo and 0.89 �0.28 mm at 12 mo. The PPD differ-

ence for deep pockets in patients with

chronic periodontitis was 0.92 �0.49 mm at 3 mo, 0.79 � 0.27 mm at

6 mo and 1.00 � 0.53 mm at 12 mo.

In patients with aggressive periodonti-

tis, the results were 0.88 � 0.27 mm

at 3 mo, 1.09 � 0.39 mm at 6 mo

and 1.40 � 0.91 mm at 12 mo. The

clinical attachment level difference for

moderate pockets in patients with

chronic periodontitis was 0.42 �0.18 mm at 3 mo, 0.33 � 0.14 mm at

6 mo and 0.40 � 0.22 mm at 12 mo.

While in patients with aggressive peri-

odontitis, it was 0.27 � 0.19 mm at

3 mo, 0.52 � 0.15 mm at 6 mo and

0.85 � 0.39 mm at 12 mo. The clini-

cal attachment level difference for

deep pockets in patients with

chronic periodontitis was 0.67 �0.55 mm at 3 mo, 0.48 � 0.53 mm

at 6 mo and 0.80 � 0.48 mm at

12 mo. In patients with aggressive

periodontitis the results were 0.63 �0.25 mm at 3 mo, 0.94 � 0.28 mm

at 6 mo and 1.03 � 0.84 mm at

12 mo. The number of studies on

which these data are based was simi-

lar for both periodontal conditions.

Based on these data it seems that

the effect of MET+AMOX in

patients with aggressive periodontitis

is lower at 3 mo compared to the

effect in patients with chronic peri-

odontitis. However, the effect of

MET+AMOX is higher at 6 and

12 mo in patients with aggressive

periodontitis than in patients with

chronic periodontitis.

In the past 3 years, four systematic

reviews have been published about

systemic antibiotics in combination

with SRP for the treatment of

patients with periodontitis. The sys-

tematic review from Zandbergen et al.

(123) focused on the effect of

MET+AMOX in combination with

SRP without making the distinction

between patients with aggressive peri-

odontitis and patients with chronic

periodontitis. Two other reviews from

Sgolastra et al. (124) deal with DOX

and MET+AMOX (125) in combina-

tion with SRP for the treatment of

patients with chronic periodontitis.

Only one other review, also from Sgo-

lastra et al. (10), focused on systemic

antibiotics in combination with SRP

for the treatment of patients with

aggressive periodontitis. However,

only MET+AMOX was included in

the meta-analysis. A disadvantage of

the latter meta-analysis is that for cal-

culating the PPD, clinical attachment

level and BOP, 3 and 6 mo follow-up

data were pooled and used for the

meta-analysis. As far as the data of

the current meta-analysis can be com-

pared to this meta-analysis, the data

appear similar.

In 2014 Preus et al. (11) emphasized

that extreme care should be taken

when the usage of systemic antibiotics

in patients with periodontitis is con-

sidered. These authors addressed four

items that might be potential caveats

in recent reviews (10,123–125). One of

these was the overall treatment strat-

egy. In the literature, many different

non-surgical periodontal treatment

options are available. In Table 2 a

subdivision has been made between

studies using a full mouth SRP and

staged SRP approach. A subanalysis

was tried to see if there is a difference

in outcome depending on the SRP

approach. Regrettably, too few studies

were available to make a reasonable

conclusion. Additionally, there are no

studies available that compared a full

mouth SRP and systemic antibiotics

to staged SRP and systemic antibiot-

ics. Perhaps further research should

focus on the most effective non-surgi-

cal periodontal therapy instead of the

most effective systemic antibiotic regi-

men.

The results of this meta-analysis

support the additional effect of the

usage of systemic antibiotics in

patients with aggressive periodontitis.

These systemic antibiotics support the

immune system by suppressing the

target microbial species and causes a

delayed microbial infection, better

infection control and, in the end, an

improved periodontal healing. The

widespread usage of systemic antibiot-

ics in the dental practice is not some-

thing that should be promoted.

Therefore, the clinical additional ben-

efit should be balanced against the

side effects such as bacterial resis-

tance, nausea, thrush, gastrointestinal

intolerance, antibiotic hypersensitivity,

vomiting and diarrhoea. As men-

tioned in the introduction the WHO

(14) and EU (12,13) made some rec-

ommendations to prevent bacterial

resistance. The bacterial resistance

may be a neglected problem, which

was already proven in 2005 by Van

Winkelhoff. The study showed a

major susceptibility difference profile

between periodontal pathogens iso-

lated from patients with periodontitis

in Spain and the Netherlands (126).

Currently it is impossible to define

which microbiological profiles would

necessitate the use of adjunctive sys-

temic antimicrobials. At the fourth

European Workshop on Periodontol-

ogy, Herrera et al. in 2002 defined

these specific clinical situations, as

patients with deep pockets, patients

with progressive or “active” disease,

or with specific microbiological pro-

files (127). In the consensus statement

of the sixth European Workshop on

Periodontology, it was posed that the

use of systemic antibiotics in peri-

odontitis should be restricted to cer-

tain patients and certain periodontal

conditions such as in aggressive peri-

odontitis or in severe and progressing

forms of periodontitis (9).

Based on the findings of this meta-

analysis, systemic antibiotics com-

bined with non-surgical periodontal

therapy resulted in a significant addi-

tional effect for the treatment of


patients with aggressive periodontitis.

Because of the limited availability of

different antibiotic regimens with an

adequate quantity of studies, there

remains only one antibiotic regimen,

MET+AMOX. Therefore, it is not

possible to draw the conclusion that

MET+AMOX is the best performing,

but there is a visible trend. The anti-

biotic regimens AZI, DOX, MET,

TET did not show any significant

additional effect. The effect of

MET+AMOX on patients with

aggressive periodontitis is lower at

3 mo but higher at 6 and 12 mo com-

pared to the patients with chronic

periodontitis. For long-term stability,

more long-term studies are needed to

prove the firmness of the additional

effect. However, based on currently

available data, the clinical benefit of

MET+AMOX is not lost over a per-

iod of 1 year and even seems to

increase. Their prescription, however,

should be considered on a case-by-

case basis and limited as much as pos-

sible, considering the risks of indis-

criminate use of systemic antibiotics

in the world.

Acknowledgements

This paper has been prepared without

any sources of institutional, private

or corporate financial support, and

there are no potential conflicts of

interest.

Supporting Information

Additional Supporting Information

may be found in the online version of

this article:

Table S1 PPD reduction.

Table S2 PPD reduction moderate

pockets.

Table S3 PPD reduction deep pock-

ets.

Table S4 CAL gain.

Table S5 CAL gain moderate pock-

ets.

Table S6 CAL gain deep pockets.

Table S7 BOP change.

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