J Clin Periodontol 2012; 39: 955961 doi: 10.1111/j.1600-051X.2012.01932.

The effects of adjunctive

metronidazole plus amoxicillin in
the treatment of generalized
aggressive periodontitis:
a 1-year double-blinded,
placebo-controlled, randomized
clinical trial

Maria J. Mestnik1, Magda Feres1,

Luciene C. Figueiredo1, Geisla
Soares1, Ricardo P. Teles2, Daiane
Fermiano1, Poliana M. Duarte1 and
Marcelo Faveri1
1

Department of Periodontology, Dental

Research Division, Guarulhos University,
Guarulhos, Sao Paulo, Brazil; 2Department
of Periodontology, The Forsyth Institute,
Cambridge, MA, USA

Mestnik MJ, Feres M, Figueiredo LC, Soares G, Teles RP, Fermiano D,

Duarte PM, Faveri M. 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 Periodontol 2012; 39: 955961.
doi: 10.1111/j.1600-051X.2012.01932.x.

Abstract
Aim: To evaluate the clinical eects of the adjunctive use of metronidazole
(MTZ) and amoxicillin (AMX) in the treatment of generalized aggressive periodontitis (GAgP).
Methods: Thirty subjects were randomly assigned to receive scaling and root
planing (SRP) alone or combined with MTZ (400 mg/TID) and AMX (500 mg/
TID) for 14 days. Subjects were clinically monitored at baseline, 6 months and
1 year post-therapies.
Results: Both therapies led to a statistically signicant improvement in all clinical
parameters at 1 year post-therapy (p < 0.05). Subjects receiving MTZ plus AMX
exhibited the deepest reductions in mean probing depth (PD) and gain in clinical
attachment between baseline and 1 year post-therapy in the full-mouth analysis
and in initially intermediate (PD 46 mm) and deep (PD  7 mm) sites (p < 0.01).
In addition, the antibiotic group presented lower mean number of residual sites
with PD  5 or 6 mm as well as fewer subjects still presenting nine or more sites
with PD  5 mm or three or more sites with PD  6 mm at the end of the study
period.
Conclusion: The non-surgical treatment of GAgP is markedly improved by the
adjunctive use of MTZ+AMX, up to 1 year post-treatment.

Key words: Amoxicillin; generalized

aggressive periodontitis; metronidazole;
periodontal disease; periodontal treatment;
scaling and root planing
Accepted for publication 19 June 2012

Conflict of interest and source of funding statement

The authors declare that they have no conict of interests. This study was supported by Research Grant #2007/55291-9 from Fundacao de Amparo a` Pesquisa
do Estado de Sao Paulo (FAPESP, Brazil).
2012 John Wiley & Sons A/S

Amoxicillin (AMX) and metronidazole (MTZ) adjunctive to scaling

and root planing (SRP) has been
originally suggested as a promising

955

956

Mestnik et al.

treatment for subjects with periodontitis colonized by Aggregatibacter

actinomycetemcomitans (Winkelho
et al. 1989, Pavicic et al. 1992, 1994,
Winkel et al. 2001), mainly due to a
possible synergistic eect of this
combination of drugs in inhibiting
this pathogen. However, randomized
controlled clinical trials (RCT) demonstrated that this treatment protocol improves the clinical and
microbiological eects of SRP, even
when prescribed without prior diagnostic of A. actinomycetemcomitans
in subjects exhibiting chronic (Berglundh et al. 1998, Winkel et al. 2001,
Matarazzo et al. 2008, Cionca et al.
2010, Silva et al. 2011, Goodson
et al. 2012) or GAgP (Guerrero
et al. 2005, Xajigeorgiou et al. 2006,
Kaner et al. 2007, Machtei & Younis
2008, Yek et al. 2010, Mestnik et al.
2010, Baltacioglu et al. 2011, Aimetti
et al. 2012, Lima Oliveira et al.
2012.
Guerrero et al. (2005) published
the rst RCT evaluating the clinical
eects of MTZ+AMX in the treatment of GAgP up to 6 months posttreatment. The authors showed that
the use of adjunctive antibiotics led
to a better clinical response than
that observed with SRP alone. Afterwards, the clinical benets of this
combination of drugs in the clinical
parameters of subjects with GAgP
were corroborated by other studies
(Kaner et al. 2007, Machtei & Younis 2008, Yek et al. 2010, Baltacioglu
et al. 2011, Aimetti et al. 2012).
However, double-blinded, placebocontrolled RCTs beyond 6 months
of follow-up for this therapy in subjects with GAgP are still missing in
the literature.
We have recently evaluated the
short-term clinical and microbiological outcomes of the adjunctive use
of AMX+MTZ in 30 subjects with
GAgP. Subjects taking adjunctive
antibiotics showed greater improvements in the mean full-mouth
probing depth (PD) and clinical
attachment level (CAL), as well as in
initially intermediate and deep sites in
comparison with SRP alone. Furthermore, these subjects presented fewer
sites with PD  5 mm than those
treated with SRP alone at 3 months
post-therapy. In addition to these
favourable clinical results, the antibiotics led to a more benecial change
in the subgingival microbial prole

(Mestnik et al. 2010). The present

study is a longitudinal clinical evaluation of this investigation. The microbiological data will be presented in a
companion study (manuscript in
preparation).
Therefore, the purpose of this
study was to evaluate the clinical
eects of the adjunctive use of MTZ
+AMX by directly comparing the
clinical outcomes of this treatment
protocol with those obtained with
SRP alone, at 6 months and 1 year
post-therapy.
Materials and Methods
Sample size calculation

This study is a longitudinal analysis

of a RCT (Mestnik et al. 2010)
designed and powered to compare
the eects of SRP alone or with
MTZ+AMX on the subgingival
microbial prole of subjects with
GAgP. The ideal sample size to
assure adequate power for that RCT
was calculated considering dierences in at least 6.6 percentage
points between groups for the proportion of the red complex species
and a standard deviation of 5. It was
determined that 13 subjects per
group would be necessary to provide
80% power with an a of 0.05.
Subject population, inclusion and
exclusion criteria

Subjects were selected from the population referred to the Periodontal

Clinic of Guarulhos University
(Guarulhos, SP, Brazil) according to
the criteria previously described
(Mestnik et al. 2010). In brief, the 30
eligible subjects were thoroughly
informed of the nature, potential
risks and benets of their participation in the study and signed a Term
of Informed Consent. They were in
good general health, had at least 20
teeth excluding third molars and
teeth indicated for extraction and
were diagnosed with GAgP based on
the current classication of the
American Academy of Periodontology (Armitage 1999). The inclusion
criteria were as follows:

 30 years of age;
minimum of six permanent teeth,
including incisors and/or rst
molars, with at least one site each

with PD and CAL  5 mm and

a minimum of six teeth other
than rst molars and incisors
with at least one site each with
PD and CAL  5 mm;
familial aggregation (during the
anamneses, the subjects were
asked if they had at least one
other member of the family presenting or with history of periodontal disease).

The exclusion criteria were as follows: previous subgingival scaling

and root planing, allergy to amoxicillin and metronidazole, smoking,
pregnancy and systemic diseases that
could aect the progression of periodontal disease (e.g. diabetes and
immunological disorders), long-term
administration of anti-inammatory
medication, need of antibiotic coverage for routine dental therapy, antibiotic therapy in the previous
6 months and allergy to chlorhexidine (CHX).
Experimental design, allocation
concealment and treatment protocol

In this double-blinded, randomized,

placebo-controlled clinical trial, subjects were randomly assigned using a
computer-generated table to one of
the following treatment groups:
Control: SRP+Placebo; and Test:
SRP+systemic MTZ (400 mg) and
AMX (500 mg). Subjects in the
Control group received MTZ and
AMX placebos. Both antibiotics and
placebos were administered TID for
14 days. Supragingival biolm control in both groups was achieved by
rinsing with 0.12% CHX solution.
All subjects were instructed to gargle
with 15 ml of CHX twice a day for
60 days for 1 min. in the morning
(30 min. after breakfast and tooth
brushing) and at night (before going
to sleep).
Before the study began, all subjects received full-mouth supragingival scaling and instruction on proper
home-care techniques. They were
also given the same dentifrice to use
during the period of the study (Colgate Total; Anakol Ind. Com.
Ltda- Kolynos do Brasil Colgate
Palmolive Co, Sao Bernardo do
Campo, SP, Brazil). All subjects
received full-mouth SRP performed under local anaesthesia from
four to six appointments lasting
2012 John Wiley & Sons A/S

MTZ plus AMX in the treatment of GAgP

approximately 1 h each. Treatment
of the entire oral cavity was completed from 10 to 14 days. SRP was
performed by one trained periodontist using manual instruments. The
antibiotic or placebo therapies and
the CHX rinses started immediately
after the rst session of mechanical
instrumentation.
Guarulhos University Pharmacy
prepared the CHX rinses and the
antibiotics/placebos pills and sent
them to the study coordinator
(M.Fa.), who marked the code number of each subject on a set of two
packs, according to the therapy
assigned, and gave them to the examiner (M.J.M.). All study personnel,
including the examiner, biostatisticians and participants were kept
blinded as to patient assignment to
treatment. All subjects received clinical monitoring at baseline and at 6
and 12 months post-therapy. Periodontal maintenance was conducted
at 3, 6 and 12 months post-therapy
and included oral hygiene instructions,
supragingival plaque control and SRP
on residual sites with PD  5 mm.
This study protocol was approved by
the Guarulhos University Clinical
Research Ethics Committee.
Monitoring of compliance and adverse
events

The subjects were asked to bring the

packs containing the medication once
a week when compliance was
checked. The packs contained 21 capsules of each placebo or antibiotic,
enough for 1 week of medication.
During these visits, subjects returned
the old pack containing the placebo
or antibiotic and received a new pack
of medication/placebo. They also
answered a questionaire about any
self-perceived side-eects of the medication/placebo. Two study assistants
conducted this enquiry, and were also
responsible for calling the subjects
every 2 days to monitor compliance.
Clinical monitoring

Clinical monitoring was performed

by one calibrated examiner and the
treatment was carried out by another
clinician. Thus, the examiner and the
clinician were masked as to the
nature of the treatment groups. Visible plaque (presence or absence),
gingival bleeding (presence or
2012 John Wiley & Sons A/S

absence), bleeding on probing (BOP;

presence or absence), suppuration
(presence or absence), PD (mm) and
CAL (mm) were measured at six
sites per tooth (mesiobuccal, buccal,
distobuccal, distolingual, lingual and
mesiolingual) in all teeth, excluding
third molars. The PD and CAL
measurements were recorded to the
nearest millimetre using a North
Carolina periodontal probe (Hu-Friedy, Chicago, IL, USA).
Investigator calibration

The examiner participated in a calibration exercise that was performed

in 10 non-study subjects with periodontitis. The calibration exercise
was previously described in Mestnik
et al. (2010). In brief, the standard
error of measurement was calculated
and the intra-examiner variability
was 0.15 mm for PD and 0.19 mm
for CAL.
Primary and secondary outcome variables

It was dened that the primary outcome variable to determine the superiority of one treatment over the
other would be dierences between
groups for mean CAL changes at
12 months post-treatment in sites
with baseline PD  7 mm. The
secondary
outcome
variables
were dierences between groups
for the following parameters: mean
PD change in sites with baseline PD
 7 mm, mean CAL and PD
changes in the full-mouth as well as
in sites with baseline PD between 4
and 6 mm, mean changes in individual full-mouth mean CAL, dierence
in the number of sites with PD
 5 mm or PD  5 and  6 mm, as
well as the prevalence of subjects
with low, moderate or higher risk of
disease progression.
Statistical analysis

Each individual clinical parameter

was computed per subject and then
across subjects in both groups.
Changes in PD and CAL in sites
with initial PD 46 and  7 mm or
the mean number/percentage of sites
with PD  5mm and  6mm, were
averaged separately within the PD
categories per subject and then
across subjects in each group. The
signicance of dierences within

957

each group (over the course of the

study) was sought using Friedman
and Dunns multiple comparison
tests, and between groups (at each
time point) using the MannWhitney
test. Chi-square test was used to
compare the dierences in the frequency of gender, of subjects exhibiting dierent categories of residual
sites at 1 year of follow-up and of
self-perceived adverse eects. The
data were evaluated using intentionto-treat analysis with last observation carried forward. The level of
signicance was set at 5%.
Results

To validate the clinical comparisons

conducted in this manuscript, we
performed a post hoc power calculation based on the observed changes
in CAL in initially deep sites (PD
 7 mm) between the control and
test groups (1.03 mm) at 1 year
post-treatment, considering the mean
observed SDs of 1.17 mm (Table 2).
Therefore, it was determined that 17
subjects per group would be necessary to provide 80% power, and 14
to provide 75% power, with an a of
0.05.
Subject retention, compliance and
adverse eects

The study was conducted between

July 2007 and December 2010.
Figure 1 presents the ow chart of
the study design. Two subjects per
group did not return for the 12month follow-up visit. Adverse events
were reported previously by Mestnik
et al. (2010). No statistically signicant dierences were observed
between groups for the number of
subjects reporting adverse events. All
subjects reported that they would
start the treatment again if necessary.
All subjects reported that they completed the course of the antibiotics,
and this information was conrmed
by pill counts.
Clinical findings

Table 1 presents demographic characteristics and full-mouth mean data

for the clinical parameters evaluated
at baseline, and at 6 months and
1 year post-therapies. The baseline
and 3-month data were reported
previously (Mestnik et al. 2010).

958

Mestnik et al.
200 subjects assessed for
eligibility
170 excluded. Reason:
Not meeting inclusion
criteria

Screening

30 subjects randomized

SRP
n=15

SRP+MTZ+AMX
n=15

Lost to follow up: n=0

Lost to follow up: n=0

n=15 with complete data

n=15 analyzed

n=15 with complete data

n=15 analyzed

Lost to follow up: n=2

Reason: could not be
contacted

Lost to follow up: n=2

Reason: could not be
contacted

n=13 with complete data

n=15 analyzed

n=13 with complete data

n=15 analyzed

Allocation

6 months

1 year

Fig. 1. Flow chart of the study design.

Table 1. Demographic characteristics and mean ( standard deviation) full-mouth clinical
parameters at baseline and at follow-up visits
Variable

Time-point

Treatment groups
SRP
(n = 15)

Gender (male/female)*
Age (years)
PD (mm)

CAL (mm)

% Sites with
Plaque accumulation

Gingival bleeding

Bleeding on probing

Suppuration

MW
(p-value)

SRP+MTZ+AMX
(n = 15)

Baseline
Baseline
Baseline
6 months
1 year
Baseline
6 months
1 year

4/11
27.6
4.09
3.16
3.17
4.23
3.50
3.63

3.5
0.62a
0.52b
0.46b
0.50a
0.63b
0.58b

6/9
26.8
4.27
2.64
2.64
4.47
3.23
3.32

3.9
0.71a
0.35b
0.42b
0.84a
0.54b
0.74b

0.56711
0.23423
0.66311
0.00246
0.00264
0.39516
0.19136
0.14089

Baseline
6 months
1 year
Baseline
6 months
1 year
Baseline
6 months
1 year
Baseline
6 months
1 year

62.7
34.0
33.3
23.7
7.5
7.9
63.8
16.4
13.7
3.8
0.3
0.4

22.4a
14.0b
13.2b
20.4a
9.1b
7.5b
21.3a
13.5b
10.3b
9.3a
0.8b
0.9b

61.3
35.9
35.9
37.3
3.4
9.3
77.7
10.7
10.0
1.8
0.5
0.3

19.8a
13.7b
13.6b
27.2a
3.8b
8.7b
19.7a
8.8b
7.1b
3 .8a
1.1b
0.6b

0.93389
0.70889
0.77153
0.64817
0.21281
0.69310
0.17093
0.30947
0.35058
0.11869
0.63186
0.78988

The signicance of dierences between baseline and the follow-up visits was assessed using
Friedman and Dunns multiple comparison tests (dierent letters indicate signicant dierences between time points).
The signicance of dierences between groups at each time point was assessed using the
MannWhitney (MW) and Chi-square Test (*). Values in bold indicate p < 0.05.
SRP, scaling and root planing; MTZ, metronidazole; AMX, amoxicillin; PD, probing depth;
CAL, clinical attachment level; SD, standard deviation.

There were no statistically signicant

dierences between groups for any
parameter at baseline (p > 0.05). All
therapies led to a statistically signicant decrease in mean PD, CAL and
in the percentage of sites with visible
plaque, gingival bleeding, BOP and
suppuration. At 6 months and
1 year, the full-mouth mean PD was
statistically signicantly lower in the
test group in comparison with the
control group. The mean PD reduction and clinical attachment (CA)
gain between baseline and 6 months
or 1 year post-therapy are presented
in Table 2. Subjects taking MTZ
+AMX exhibited a greater reduction
in PD and gain in CA in comparison
with those receiving SRP-only; in the
full-mouth analysis and in initially
intermediate (PD 46 mm) and
deep (PD  7 mm) sites (p < 0.01).
Figure 2 presents changes in mean
full-mouth CAL for individual subjects at 1 year post-SRP. The median
of CAL change for the 30 subjects
of the study was 0.93 mm. The
number of subjects showing CAL
gain within or above this value (0.93
2.30) was 10 and 6 in the Test and
Control
groups,
respectively.
Conversely, the number of subjects
presenting CAL change below 0.93
(0.93 to 0.45) was 5 and 9, for test
and control groups respectively.
Table 3 shows the mean number
and percentage of sites with PD  5
and  6 mm over the course of the
study. Both treatments were eective
in reducing the number/percentage
of deep sites (PD  5 and  6mm)
during the course of the study
(p < 0.05). At 6 months and 1-year
post-treatment, the test group had
less sites with PD  5 mm and
 6 mm in comparison with the control group (p < 0.001). Data for
residual sites at subject level are presented in Table 4. The upper panel
of Table 4 was organized according
to the individual risk prole for periodontal disease progression proposed by Lang & Tonetti (2003), as
follows: low risk:  4 sites with PD
 5 mm; moderate risk: 58 sites
with PD  5 mm and high risk:  9
sites with PD  5 mm. Fewer subjects in the test group (n = 4) still
had high risk for disease progression
at 1 year (  9 sites with PD
 5 mm), in comparison with the
control group (n = 12). Conversely,
eight subjects in the test group and
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MTZ plus AMX in the treatment of GAgP

Table 2. Mean probing depth reduction and clinical attachment gain between baseline and
6 months and 1 year post-therapy
Baseline
PD

Variable

Time-point

Treatment groups
SRP
(n = 15)

Full-mouth

PD reduction
CA gain

46 mm

PD reduction
CA gain

 7 mm

PD reduction
CA gain

06
01
06
01
06
01
06
01
06
01
06
01

months
year
months
year
months
year
months
year
months
year
months
year

0.94
0.92
0.78
0.93
1.33
1.41
1.12
1.11
2.79
2.78
2.34
2.32

0.38
0.47
0.41
0.47
0.41
0.47
0.50
0.63
0.74
1.09
0.81
1.11

MW
(p-value)

SRP+MTZ+AMX
(n = 15)
1.58
1.61
1.23
1.61
2.09
2.30
1.72
1.96
4.27
4.18
3.43
3.35

0.51
0.60
0.41
0.60
0.40
0.29
0.41
0.44
1.34
1.42
1.14
1.23

0.00084
0.00230
0.01074
0.00230
0.00021
0.00002
0.00302
0.00072
0.00017
0.00139
0.00024
0.00227

The signicance of dierences between groups at each time point was assessed using the
MannWhitney test (MW). Values in bold indicate p < 0.05.
SRP, scaling and root planing; MTZ, metronidazole; AMX, amoxicillin; PD, probing depth;
CA, clinical attachment; SD, standard deviation.

Fig. 2. Plots of the mean changes in individual full-mouth mean clinical attachment
level between baseline and 1 year post-scaling and root planing of subjects in the two
treatment groups. The circles represent the mean value of each subject. The line represents the median of change in this clinical parameter in all 30 subjects. Positive values
represent a gain in clinical attachment level (CAL), whereas negative values represent
a loss in CAL at 1 year post-SRP. SRP, scaling and root planing; MTZ, metronidazole; AMX, amoxicillin.

only one in the SRP group showed

low risk for disease progression (  4
sites with PD  5 mm) at the end of
the study period. This same trend
was observed for PD  6 mm. At
12 months
post-treatment,
six
subjects in the MTZ+AMX group
had  3 sites with PD  6 mm, as
opposed to 13 subjects in the control
group.
Discussion

To our knowledge, this was the rst

double-blinded
placebo-controlled
2012 John Wiley & Sons A/S

RCT to provide data up to 1 year of

the adjunctive use of MTZ+AMX in
the treatment of GAgP. The results
indicated that the clinical benets
observed with the use of this therapeutic protocol in the short-term
analysis (Mestnik et al. 2010) were
maintained and even extended at
6 months and 1 year post-treatment.
Subjects
taking
MTZ+AMX
exhibited signicantly greater reductions in PD and gain in CA than
those receiving SRP alone, in the
full-mouth analysis as well as in initially intermediate or deep sites. All

959

these dierences were statistically

signicant at 6 months and 1 year
post-therapies (Table 2). Interesting
information was also provided by
the results of gain in CA at the
subject level (Fig. 2). From the 15
subjects taking antibiotics, nine were
among those who have gained more
CA at 1 year, a totally inverse trend
seen in the SRP group, which had
nine subjects among those who
gained less CA. These added benet
of MTZ+AMX in improving mean
PD and CA agree and extend data
from previous RCTs (Guerrero et al.
2005, Xajigeorgiou et al. 2006, Yek
et al. 2010, Aimetti et al. 2012).
Although the mean changes in
PD and CA were overall maintained
from the 3 months to 1 year of
follow-up, some important clinical
dierences were observed between
the short-term and the long-term
analysis on the number of sites with
PD  5 mm (Tables 3 and 4). At
3 months post-treatment, the dierence in mean number of these residual sites between control and test
groups was 6.8 (18.2 and 11.4
respectively; p < 0.05) (Mestnik et al.
2010), whereas at 1 year, this dierence was greatly accentuated to 16.9
sites (23.3 and 6.4 respectively;
p < 0.00). This is probably the most
striking nding of this study, as the
presence of sites with PD  5 mm
after treatment has been indicated as
one of the most important parameters to evaluate treatment success
and to predict disease recurrence and
the need of further treatment (Renvert & Persson 2002, Lang & Tonetti
2003, Matuliene et al. 2008, 2010).
Curiously, the frequency of these
residual sites decreased in the test
group from 3 months (Mestnik et al.
2010) to 1 year, whereas an increase
was detected in the control group.
One plausible explanation of this
opposite clinical trend may be dierences on the eect of the two treatments in changing the subgingival
microbial prole. As clearly demonstrated in the short-term analysis
(Mestnik et al. 2010), at 3 months
post-treatment, the group receiving
adjunctive MTZ+AMX had signicantly lower levels and proportions
of all pathogens from the red
complex
and
some
putative
periodontal pathogens from the
orange complex in comparison with
those receiving SRP alone. The

960

Mestnik et al.

Table 3. Mean number and (mean percentage) standard deviation of sites with probing
depth  5 mm and probing depth  6 mm at baseline and at follow-up visits
Variable

Time-point

Treatment groups
SRP
(n = 15)

PD  5 mm

Baseline
6 months
1 year

PD  6 mm

Baseline
6 months
1 year

42.7
(30.9
19.0
(12.9
23.1
(16.0
25.5
(17.0
8.7
(5.9
9.9
(6.7

MW
(p-value)

SRP+MTZ+AMX
(n = 15)

15.4a
11.1)
16.0b
10.6)
13.4b
8.8)
17.5a
11.1)
13.3b
8.3)
11.9b
7.9)

54.3
(37.7
7.6
(5.8
6.4
(5.2
33.5
(24.3
3.7
(2.8
3.3
(2.7

17.3a
12.5)
8.9b
6.8)
7.2b
6.1)
18.4a
13.2)
6.5b
4.5)
5.1b
4.4)

0.98348
0.00606
0.00028
0.22861
0.01637
0.00338

The signicance of dierences between baseline and the follow-up visits was assessed using
Friedman and Dunns multiple comparison tests (dierent letters indicate signicant dierences between time points). The signicance of dierences between groups at each time
point was assessed using the MannWhitney test (MW). Values in bold indicate p < 0.05
SRP, scaling and root planing; MTZ, metronidazole; AMX, amoxicillin; PD, probing
depth.
Table 4. Number and percentage of subjects presenting low (  4 sites with probing depth
 5 mm), moderate (58 sites with probing depth  5 mm) or high (  9 sites with probing
depth  5 mm) risk for disease progression according to Lang & Tonetti (2003) as well as
presenting 0, 12 or  3 sites with probing depth  6 mm at 1 year post-treatment
Variable

Categories

Treatment groups
SRP
(%)

Risk for disease

progression
Number of
PD  6 mm

Low risk
Moderate risk
High risk
0
12
3

1
02
12
0
2
13

(6.6)
(13.4)
(80.0)
(0.0)
(13.4)
(86.6)

Chi-square
p-value

SRP+MTZ+AMX
(%)
8
3
4
5
4
6

(53.3)
(20.0)
(26.7)
(33.3)
(26.7)
(40.0)

0.008

0.031

The signicance of dierences between groups was assessed using Chi-Square Test.
SRP, scaling and root planing; MTZ, metronidazole; AMX, amoxicillin; PD, probing
depth.

remaining presence of high proportion of pathogens at the end of the

periodontal therapy may increase the
risk of future disease progression
(Teles et al. 2008, Kinney et al.
2011). The longitudinal microbiological eects of these treatments will
be presented in a second study and
will certainly contribute to the better
understanding of this and other
clinical trends.
The data for remaining deep sites
at the subject level were also rather
enlightening (Table 4). At the end of
the study period, 12 subjects (86.6%)
from the control group against only
4 (26.7%) from the test group
presented high risk for future disease
recurrence according to Lang &

Tonetti (2003), i.e. nine or more sites

with PD  5 mm. The only study
that did not found added benets
for the adjunctive use of MTZ
+AMX in reducing the frequency of
residual pockets used a lower dose
of MTZ, 250 mg (Varela et al.
2011), as opposed to 400500 mg
applied in all other investigations
(Guerrero et al. 2005, Xajigeorgiou
et al. 2006, Yek et al. 2010, Aimetti
et al. 2012). However, the impact of
dierent doses and durations of this
antibiotic protocol still needs to be
further explored.
One limitation of this investigation was the low number of subjects
in each group, which conferred a
power of 75% to this study, below

80% that, by convention, is a more

acceptable level of power. This
occurred because this RCT was originally designed and powered to
compare the eects of SRP alone or
with MTZ+AMX in the subgingival
microbial prole. Hence, 15 subjects
per group would be enough to
provide 80% of power using the
microbiological primary outcome
variable (dierences between groups
for proportion of red complex), but
not for the clinical outcome variable
used in this study. The main problem of low powered RCTs is the
increased probability of type II error
(false negative) that is the study
might have been too small to detect
actual dierences between groups.
This was clearly not a problem in
this study, as the majority of the
clinical results and the primary
outcome variable evaluated were
statistically signicantly dierent
between the two groups, always in
favour of the antibiotic treatment.
Apparently, this combination of
therapies is so potent in comparison
with the mechanical treatment alone
that its benets are evident even in
a trial with 75% of chances of
detecting them.
The longitudinal results presented
in this manuscript, together with
those reported in previous RCTs of
3- and 6-month (Guerrero et al.
2005, Mestnik et al. 2010, Yek et al.
2010, Baltacioglu et al. 2011, Aimetti
et al. 2012) demonstrated that this
treatment
protocol
(SRP+MTZ
+AMX) is of great benet for subjects with GAgP. In addition, none
of these studies reported the occurrence of serious adverse events with
the use of this combination of drugs.
In conclusion, the results of this
study indicate that the non-surgical
treatment of GAgP is markedly
improved
by
the
adjunctive
use of MTZ+AMX, up to 1 year
post-treatment.

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blinded, placebo-controlled randomized controlled clinical trials (RCTs)

beyond 6 months of follow-up for
this therapy in subjects with GAgP
are still missing in the literature.
Principal ndings: The antibiotic
therapy was signicantly better than
SRP alone in improving all clinical
parameters evaluated, including the

reduction in the mean number of

residual pockets up to 1-year
post-treatment.
Practical implications: The adjunctive use of MTZ+AMX oers additional clinical benet for the
treatment of subjects with GAgP.

Address:
Marcelo Faveri
Centro de Pos-Graduacao e PesquisaCEPPE
Universidade Guarulhos
Praca Tereza Cristina, 229 Centro
07023-070 Guarulhos, SP
Brazil
E-mail: mfaveri@prof.ung.br