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

The effects of adjunctive Maria J. Mestnik1, Magda Feres1,

Luciene C. Figueiredo1, Geisla
Soares1, Ricardo P. Teles2, Daiane

metronidazole plus amoxicillin in Fermiano1, Poliana M. Duarte1 and

Marcelo Faveri1
1
Department of Periodontology, Dental

the treatment of generalized Research Division, Guarulhos University,

Guarulhos, Sao Paulo, Brazil; 2Department
of Periodontology, The Forsyth Institute,

aggressive periodontitis: Cambridge, MA, USA

a 1-year double-blinded,
placebo-controlled, randomized
clinical trial
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 peri-
odontitis (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
Key words: Amoxicillin; generalized
with PD  5 or 6 mm as well as fewer subjects still presenting nine or more sites
aggressive periodontitis; metronidazole;
with PD  5 mm or three or more sites with PD  6 mm at the end of the study periodontal disease; periodontal treatment;
period. scaling and root planing
Conclusion: The non-surgical treatment of GAgP is markedly improved by the
adjunctive use of MTZ+AMX, up to 1 year post-treatment. Accepted for publication 19 June 2012

Conflict of interest and source of funding statement

Amoxicillin (AMX) and metronida-
The authors declare that they have no conict of interests. This study was sup-
zole (MTZ) adjunctive to scaling
ported by Research Grant #2007/55291-9 from Fundacao de Amparo a Pesquisa
do Estado de Sao Paulo (FAPESP, Brazil).
and root planing (SRP) has been
originally suggested as a promising
2012 John Wiley & Sons A/S 955
956 Mestnik et al.
treatment for subjects with periodon-
titis 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) dem-
onstrated that this treatment proto-
col improves the clinical and
microbiological eects of SRP, even
when prescribed without prior diag-
nostic of A. actinomycetemcomitans
in subjects exhibiting chronic (Bergl-
undh 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 treat-
ment of GAgP up to 6 months post-
treatment. The authors showed that
the use of adjunctive antibiotics led
to a better clinical response than
that observed with SRP alone. After-
wards, 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 & Youn-
is 2008, Yek et al. 2010, Baltacioglu
et al. 2011, Aimetti et al. 2012).
However, double-blinded, placebo-
controlled RCTs beyond 6 months
of follow-up for this therapy in sub-
jects with GAgP are still missing in
the literature.
We have recently evaluated the
short-term clinical and microbiologi-
cal outcomes of the adjunctive use
of AMX+MTZ in 30 subjects with
GAgP. Subjects taking adjunctive
antibiotics showed greater improve-
ments 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. Further-
more, 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 antibi-
otics led to a more benecial change
in the subgingival microbial prole
(Mestnik et al. 2010). The present
study is a longitudinal clinical evalua-
tion of this investigation. The micro-
biological 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 dier-
ences in at least 6.6 percentage
points between groups for the pro-
portion 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 pop-
ulation 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 participa-
tion 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 Periodontol-
ogy (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 pre-
senting or with history of peri-
odontal disease).
The exclusion criteria were as fol-
lows: previous subgingival scaling
and root planing, allergy to amoxi-
cillin and metronidazole, smoking,
pregnancy and systemic diseases that
could aect the progression of peri-
odontal disease (e.g. diabetes and
immunological disorders), long-term
administration of anti-inammatory
medication, need of antibiotic cover-
age for routine dental therapy, anti-
biotic therapy in the previous
6 months and allergy to chlorhexi-
dine (CHX).
Experimental design, allocation
concealment and treatment protocol
In this double-blinded, randomized,
placebo-controlled clinical trial, sub-
jects 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 con-
trol 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 sub-
jects received full-mouth supragingi-
val scaling and instruction on proper
home-care techniques. They were
also given the same dentifrice to use
during the period of the study (Col-
gate Total; Anakol Ind. Com.
Ltda- Kolynos do Brasil Colgate
Palmolive Co, Sao Bernardo do
Campo, SP, Brazil). All subjects
received full-mouth SRP per-
formed under local anaesthesia from
four to six appointments lasting
2012 John Wiley & Sons A/S

approximately 1 h each. Treatment
of the entire oral cavity was com-
pleted from 10 to 14 days. SRP was
performed by one trained periodon-
tist 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 num-
ber of each subject on a set of two
packs, according to the therapy
assigned, and gave them to the exam-
iner (M.J.M.). All study personnel,
including the examiner, biostatisti-
cians and participants were kept
blinded as to patient assignment to
treatment. All subjects received clini-
cal monitoring at baseline and at 6
and 12 months post-therapy. Peri-
odontal 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 cap-
sules 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 medi-
cation/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. Visi-
ble plaque (presence or absence),
gingival bleeding (presence or
2012 John Wiley & Sons A/S
MTZ plus AMX in the treatment of GAgP
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-Fri-
edy, Chicago, IL, USA).
Investigator calibration
The examiner participated in a cali-
bration exercise that was performed
in 10 non-study subjects with peri-
odontitis. 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 out-
come variable to determine the supe-
riority 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 individ-
ual 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 fre-
quency of gender, of subjects exhib-
iting dierent categories of residual
sites at 1 year of follow-up and of
self-perceived adverse eects. The
data were evaluated using intention-
to-treat analysis with last observa-
tion 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 calcula-
tion 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 neces-
sary 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 12-
month follow-up visit. Adverse events
were reported previously by Mestnik
et al. (2010). No statistically signi-
cant 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 com-
pleted the course of the antibiotics,
and this information was conrmed
by pill counts.
Clinical findings
Table 1 presents demographic char-
acteristics 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

There were no statistically signicant
eligibility dierences between groups for any
170 excluded. Reason: parameter at baseline (p > 0.05). All
Not meeting inclusion Screening
criteria
therapies led to a statistically signi-
cant decrease in mean PD, CAL and
30 subjects randomized
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
SRP SRP+MTZ+AMX
Allocation
test group in comparison with the
n=15 n=15 control group. The mean PD reduc-
tion and clinical attachment (CA)
gain between baseline and 6 months
or 1 year post-therapy are presented
Lost to follow up: n=0 Lost to follow up: n=0 in Table 2. Subjects taking MTZ
n=15 with complete data n=15 with complete data 6 months
+AMX exhibited a greater reduction
n=15 analyzed n=15 analyzed 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
Lost to follow up: n=2 Lost to follow up: n=2 deep (PD  7 mm) sites (p < 0.01).
Reason: could not be Reason: could not be
contacted
Figure 2 presents changes in mean
contacted
1 year full-mouth CAL for individual sub-
n=13 with complete data n=13 with complete data jects at 1 year post-SRP. The median
n=15 analyzed n=15 analyzed
of CAL change for the 30 subjects
of the study was 0.93 mm. The
number of subjects showing CAL
Fig. 1. Flow chart of the study design. gain within or above this value (0.93
2.30) was 10 and 6 in the Test and
Table 1. Demographic characteristics and mean ( standard deviation) full-mouth clinical Control groups, respectively.
parameters at baseline and at follow-up visits Conversely, the number of subjects
presenting CAL change below 0.93
Variable Time-point Treatment groups MW
(p-value) (0.93 to 0.45) was 5 and 9, for test
SRP SRP+MTZ+AMX and control groups respectively.
(n = 15) (n = 15) Table 3 shows the mean number
and percentage of sites with PD  5
Gender (male/female)* Baseline 4/11 6/9 0.56711 and  6 mm over the course of the
Age (years) Baseline 27.6 3.5 26.8 3.9 0.23423 study. Both treatments were eective
PD (mm) Baseline 4.09 0.62a 4.27 0.71a 0.66311 in reducing the number/percentage
6 months 3.16 0.52b 2.64 0.35b 0.00246 of deep sites (PD  5 and  6mm)
1 year 3.17 0.46b 2.64 0.42b 0.00264
CAL (mm) Baseline 4.23 0.50a 4.47 0.84a 0.39516
during the course of the study
6 months 3.50 0.63b 3.23 0.54b 0.19136 (p < 0.05). At 6 months and 1-year
1 year 3.63 0.58b 3.32 0.74b 0.14089 post-treatment, the test group had
% Sites with less sites with PD  5 mm and
Plaque accumulation Baseline 62.7 22.4a 61.3 19.8a 0.93389  6 mm in comparison with the con-
6 months 34.0 14.0b 35.9 13.7b 0.70889 trol group (p < 0.001). Data for
1 year 33.3 13.2b 35.9 13.6b 0.77153 residual sites at subject level are pre-
Gingival bleeding Baseline 23.7 20.4a 37.3 27.2a 0.64817 sented in Table 4. The upper panel
6 months 7.5 9.1b 3.4 3.8b 0.21281 of Table 4 was organized according
1 year 7.9 7.5b 9.3 8.7b 0.69310
to the individual risk prole for peri-
Bleeding on probing Baseline 63.8 21.3a 77.7 19.7a 0.17093
6 months 16.4 13.5b 10.7 8.8b 0.30947
odontal disease progression pro-
1 year 13.7 10.3b 10.0 7.1b 0.35058 posed by Lang & Tonetti (2003), as
Suppuration Baseline 3.8 9.3a 1.8 3 .8a 0.11869 follows: low risk:  4 sites with PD
6 months 0.3 0.8b 0.5 1.1b 0.63186  5 mm; moderate risk: 58 sites
1 year 0.4 0.9b 0.3 0.6b 0.78988 with PD  5 mm and high risk:  9
sites with PD  5 mm. Fewer sub-
The signicance of dierences between baseline and the follow-up visits was assessed using
Friedman and Dunns multiple comparison tests (dierent letters indicate signicant dier-
jects in the test group (n = 4) still
ences between time points). had high risk for disease progression
The signicance of dierences between groups at each time point was assessed using the at 1 year (  9 sites with PD
MannWhitney (MW) and Chi-square Test (*). Values in bold indicate p < 0.05.  5 mm), in comparison with the
SRP, scaling and root planing; MTZ, metronidazole; AMX, amoxicillin; PD, probing depth; control group (n = 12). Conversely,
CAL, clinical attachment level; SD, standard deviation. eight subjects in the test group and
2012 John Wiley & Sons A/S
 MTZ plus AMX in the treatment of GAgP 959

Table 2. Mean probing depth reduction and clinical attachment gain between baseline and these dierences were statistically
6 months and 1 year post-therapy signicant at 6 months and 1 year
Baseline Variable Time-point Treatment groups MW post-therapies (Table 2). Interesting
PD (p-value) information was also provided by
SRP SRP+MTZ+AMX the results of gain in CA at the
(n = 15) (n = 15) subject level (Fig. 2). From the 15
subjects taking antibiotics, nine were
Full-mouth PD reduction 06 months 0.94 0.38 1.58 0.51 0.00084 among those who have gained more
01 year 0.92 0.47 1.61 0.60 0.00230
CA at 1 year, a totally inverse trend
CA gain 06 months 0.78 0.41 1.23 0.41 0.01074
01 year 0.93 0.47 1.61 0.60 0.00230
seen in the SRP group, which had
46 mm PD reduction 06 months 1.33 0.41 2.09 0.40 0.00021 nine subjects among those who
01 year 1.41 0.47 2.30 0.29 0.00002 gained less CA. These added benet
CA gain 06 months 1.12 0.50 1.72 0.41 0.00302 of MTZ+AMX in improving mean
01 year 1.11 0.63 1.96 0.44 0.00072 PD and CA agree and extend data
 7 mm PD reduction 06 months 2.79 0.74 4.27 1.34 0.00017 from previous RCTs (Guerrero et al.
01 year 2.78 1.09 4.18 1.42 0.00139 2005, Xajigeorgiou et al. 2006, Yek
CA gain 06 months 2.34 0.81 3.43 1.14 0.00024 et al. 2010, Aimetti et al. 2012).
01 year 2.32 1.11 3.35 1.23 0.00227 Although the mean changes in
The signicance of dierences between groups at each time point was assessed using the PD and CA were overall maintained
MannWhitney test (MW). Values in bold indicate p < 0.05. from the 3 months to 1 year of
SRP, scaling and root planing; MTZ, metronidazole; AMX, amoxicillin; PD, probing depth; follow-up, some important clinical
CA, clinical attachment; SD, standard deviation. 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 dier-
ence in mean number of these resid-
ual 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 dier-
ence 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 parame-
ters to evaluate treatment success
Fig. 2. Plots of the mean changes in individual full-mouth mean clinical attachment
and to predict disease recurrence and
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 repre- the need of further treatment (Ren-
sents the median of change in this clinical parameter in all 30 subjects. Positive values vert & Persson 2002, Lang & Tonetti
represent a gain in clinical attachment level (CAL), whereas negative values represent 2003, Matuliene et al. 2008, 2010).
a loss in CAL at 1 year post-SRP. SRP, scaling and root planing; MTZ, metronida- Curiously, the frequency of these
zole; AMX, amoxicillin. 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.
only one in the SRP group showed RCT to provide data up to 1 year of One plausible explanation of this
low risk for disease progression (  4 the adjunctive use of MTZ+AMX in opposite clinical trend may be dier-
sites with PD  5 mm) at the end of the treatment of GAgP. The results ences on the eect of the two treat-
the study period. This same trend indicated that the clinical benets ments in changing the subgingival
was observed for PD  6 mm. At observed with the use of this thera- microbial prole. As clearly demon-
12 months post-treatment, six peutic protocol in the short-term strated in the short-term analysis
subjects in the MTZ+AMX group analysis (Mestnik et al. 2010) were (Mestnik et al. 2010), at 3 months
had  3 sites with PD  6 mm, as maintained and even extended at post-treatment, the group receiving
opposed to 13 subjects in the control 6 months and 1 year post-treatment. adjunctive MTZ+AMX had signi-
group. Subjects taking MTZ+AMX cantly lower levels and proportions
exhibited signicantly greater reduc- of all pathogens from the red
tions in PD and gain in CA than complex and some putative
Discussion
those receiving SRP alone, in the periodontal pathogens from the
To our knowledge, this was the rst full-mouth analysis as well as in ini- orange complex in comparison with
double-blinded placebo-controlled tially intermediate or deep sites. All those receiving SRP alone. The
2012 John Wiley & Sons A/S
960 Mestnik et al.

Table 3. Mean number and (mean percentage) standard deviation of sites with probing 80% that, by convention, is a more
depth  5 mm and probing depth  6 mm at baseline and at follow-up visits acceptable level of power. This
Variable Time-point Treatment groups MW occurred because this RCT was orig-
(p-value) inally designed and powered to
SRP SRP+MTZ+AMX compare the eects of SRP alone or
(n = 15) (n = 15) with MTZ+AMX in the subgingival
microbial prole. Hence, 15 subjects
PD  5 mm Baseline 42.7 15.4a 54.3 17.3a 0.98348 per group would be enough to
(30.9 11.1) (37.7 12.5)
provide 80% of power using the
6 months 19.0 16.0b 7.6 8.9b 0.00606
(12.9 10.6) (5.8 6.8)
microbiological primary outcome
1 year 23.1 13.4b 6.4 7.2b 0.00028 variable (dierences between groups
(16.0 8.8) (5.2 6.1) for proportion of red complex), but
PD  6 mm Baseline 25.5 17.5a 33.5 18.4a 0.22861 not for the clinical outcome variable
(17.0 11.1) (24.3 13.2) used in this study. The main prob-
6 months 8.7 13.3b 3.7 6.5b 0.01637 lem of low powered RCTs is the
(5.9 8.3) (2.8 4.5) increased probability of type II error
1 year 9.9 11.9b 3.3 5.1b 0.00338 (false negative) that is the study
(6.7 7.9) (2.7 4.4) might have been too small to detect
The signicance of dierences between baseline and the follow-up visits was assessed using actual dierences between groups.
Friedman and Dunns multiple comparison tests (dierent letters indicate signicant dier- This was clearly not a problem in
ences between time points). The signicance of dierences between groups at each time this study, as the majority of the
point was assessed using the MannWhitney test (MW). Values in bold indicate p < 0.05 clinical results and the primary
SRP, scaling and root planing; MTZ, metronidazole; AMX, amoxicillin; PD, probing outcome variable evaluated were
depth. statistically signicantly dierent
between the two groups, always in
Table 4. Number and percentage of subjects presenting low (  4 sites with probing depth favour of the antibiotic treatment.
 5 mm), moderate (58 sites with probing depth  5 mm) or high (  9 sites with probing Apparently, this combination of
depth  5 mm) risk for disease progression according to Lang & Tonetti (2003) as well as therapies is so potent in comparison
presenting 0, 12 or  3 sites with probing depth  6 mm at 1 year post-treatment with the mechanical treatment alone
Variable Categories Treatment groups Chi-square that its benets are evident even in
p-value a trial with 75% of chances of
SRP SRP+MTZ+AMX detecting them.
(%) (%) The longitudinal results presented
in this manuscript, together with
Risk for disease Low risk 1 (6.6) 8 (53.3) 0.008 those reported in previous RCTs of
progression Moderate risk 02 (13.4) 3 (20.0) 3- and 6-month (Guerrero et al.
High risk 12 (80.0) 4 (26.7)
Number of 0 0 (0.0) 5 (33.3) 0.031
2005, Mestnik et al. 2010, Yek et al.
PD  6 mm 12 2 (13.4) 4 (26.7) 2010, Baltacioglu et al. 2011, Aimetti
3 13 (86.6) 6 (40.0) et al. 2012) demonstrated that this
treatment protocol (SRP+MTZ
The signicance of dierences between groups was assessed using Chi-Square Test. +AMX) is of great benet for sub-
SRP, scaling and root planing; MTZ, metronidazole; AMX, amoxicillin; PD, probing jects with GAgP. In addition, none
depth.
of these studies reported the occur-
rence of serious adverse events with
remaining presence of high propor- Tonetti (2003), i.e. nine or more sites the use of this combination of drugs.
tion of pathogens at the end of the with PD  5 mm. The only study In conclusion, the results of this
periodontal therapy may increase the that did not found added benets study indicate that the non-surgical
risk of future disease progression for the adjunctive use of MTZ treatment of GAgP is markedly
(Teles et al. 2008, Kinney et al. +AMX in reducing the frequency of improved by the adjunctive
2011). The longitudinal microbiolog- residual pockets used a lower dose use of MTZ+AMX, up to 1 year
ical eects of these treatments will of MTZ, 250 mg (Varela et al. post-treatment.
be presented in a second study and 2011), as opposed to 400500 mg
will certainly contribute to the better applied in all other investigations
understanding of this and other (Guerrero et al. 2005, Xajigeorgiou
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Address:
Marcelo Faveri
Centro de Pos-Graduacao e Pesquisa-
CEPPE
Universidade Guarulhos
Praca Tereza Cristina, 229 Centro
07023-070 Guarulhos, SP
Brazil
E-mail: mfaveri@prof.ung.br
reduction in the mean number of
residual pockets up to 1-year
post-treatment.
Practical implications: The adjunc-
tive use of MTZ+AMX oers addi-
tional clinical benet for the
treatment of subjects with GAgP.