Accepted: 12 March 2017

DOI: 10.1111/jcpe.12721

RANDOMIZED CLINICAL TRIAL

Different antibiotic protocols in the treatment of severe

chronic periodontitis: A 1-year randomized trial

Ivan Borges | Marcelo Faveri | Luciene Cristina Figueiredo | Poliana Mendes

Duarte | Belén Retamal-Valdes | Sheyla Christinne Lira Montenegro | Magda Feres

Department of Periodontology, Dental

Research Division, Guarulhos University,
Guarulhos, São Paulo, Brazil
Correspondence
Magda Feres, Centro de Pós-Graduação e
Pesquisa-CEPPE, Universidade Guarulhos,
Praça Tereza Cristina, Guarulhos, SP, Brazil
Email: mferes@ung.br
Funding information
This study was supported by Research Grant
# 2009/17677-8 from São Paulo Research
Foundation (FAPESP, Brazil)
Abstract
Aim: To evaluate the clinical effects of different dosages of metronidazole (MTZ) and
durations of MTZ + amoxicillin (AMX) in the treatment of generalized chronic perio-
dontitis (GChP).
Material and Methods: Subjects with severe GChP were randomly assigned to receive
scaling and root planing (SRP)-only, or combined with 250 or 400 mg of MTZ + AMX
(500 mg) thrice a day (TID), for 7 or 14 days. Subjects were monitored for 1 year.
Results: One hundred and nine subjects were enrolled. At 1 year, 61.9% and 63.6% of
the subjects receiving AMX + 250 or 400 mg of MTZ for 14 days, respectively, reached
the clinical endpoint for treatment (≤4 sites with probing depth ≥5 mm), against 31.8%
of those taking 250 or 400 mg of MTZ for 7 days (p < .05) and 13.6% of those receiving
SRP-only (p < .05). Fourteen days of MTZ + AMX was the only significant predictor of
subjects reaching the clinical endpoint at 1 year (OR, 5.26; 95% CI, 2.3–12.1, p = .0000).
The frequency of adverse events did not differ among treatment groups (p > .05).
Conclusion: The adjunctive use of 400 or 250 mg of MTZ plus 500 mg of AMX/
TID/14 days offers statistically significant and clinically relevant benefits over those
achieved with SRP alone in the treatment of severe GChP. The added benefits of the
7-days regimen in this population were less evident. (ClinicalTrials.gov
NCT02735395).

KEYWORDS
antimicrobials, clinical outcomes, clinical studies, periodontal disease, periodontal tissues,
treatment planning

1  |  INT RO DUCT ION
The association of scaling and root planing (SRP) with systemic met-
ronidazole (MTZ) and amoxicillin (AMX) has been suggested as an
effective therapeutic protocol for the treatment of severe periodonti-
tis, since 1989 (van Winkelhoff et al., 1989). This protocol has gained
additional strength after the publication of five systematic reviews on
the topic (Rabelo et al., 2015; Sgolastra, Gatto, Petrucci, & Monaco,
2012; Sgolastra, Petrucci, Gatto, & Monaco, 2012; Zandbergen, Slot,
Cobb, & Van der Weijden, 2013; Zandbergen, Slot, Niederman, & Van
der Weijden, 2016) and six randomized clinical trials (RCTs) showing
that the clinical benefits of the adjunctive use of MTZ + AMX last
for 1 to 2 years after antibiotic intake (Feres et al., 2012; Goodson
et al., 2012; Harks et al., 2015; Mestnik et al., 2012; Mombelli,
Almaghlouth, Cionca, Courvoisier, & Giannopoulou, 2015; Tamashiro
et al., 2016).
Despite the well-documented benefits of the adjunctive use of
MTZ + AMX in periodontal treatment, the optimal protocol of ad-
ministration of these agents has not yet been established and there-
fore, the periodontal prescriptions of these drugs are normally based

822  |  © 2017 John Wiley & Sons A/S. wileyonlinelibrary.com/journal/jcpe J Clin Periodontol. 2017;44:822–832.
Published by John Wiley & Sons Ltd
BORGES Et al.
on those used in medicine. However, this is not ideal due to certain
unique features of periodontal diseases that are not normally ob-
served in medical infections, such as the microbial protection afforded
by the subgingival biofilm structure and great variation in concentra-
tion of the drugs in different sites of the oral cavity (Sagan et al., 2005;
Socransky & Haffajee, 2002). The lack of clear guidelines for the use
of antibiotics in periodontal treatment has generated empirical and
heterogeneous antibiotic protocols, which may directly interfere with
the effectiveness of these agents in controlling infection and with the
development of side effects.
The highest degree of variability among the clinical studies eval-
uating the effects of MTZ + AMX in periodontal treatment is in the
dosage of MTZ (250 and 400 mg, thrice a day (TID)) and the duration
of antibiotics intake (7–14 days) (Feres, Figueiredo, Soares, & Faveri,
2015). However, to date, no previous RCTs have directly compared
the impact of these different MTZ + AMX protocols in the treatment
of periodontitis. Therefore, the aim of this study was to evaluate the
clinical effects of different dosages and duration of the systemic ad-
ministration of MTZ + AMX in the treatment of generalized chronic
periodontitis (GChP).
2  |  M AT ER IAL AND ME THO DS
2.1 | Sample size calculation
The ideal sample size to assure adequate power for this study was
based on the percentage of volunteers reaching ≤4 sites with prob-
ing depth (PD) ≥5 mm, which was considered a clinical endpoint
of therapy in a previous study (Feres et al., 2012). Considering
a difference of 44 percentage points between each treatment
group and the control group for volunteers achieving this clinical
endpoint at 1 year post-treatment (Feres et al., 2012) and a sig-
nificance level of 5%, 17 subjects per group would be necessary
to provide a power of 80%. Considering an attrition of 25%, it was
established that at least 22 subjects should be included in each
treatment group.
2.2 | Subject population and inclusion/
exclusion criteria
Subjects diagnosed with untreated GChP (Armitage, 1999) were
selected from the population referred to the Periodontal Clinic of
Guarulhos University (Guarulhos, SP, Brazil). The inclusion criteria
were: ≥30 years of age, ≥15 teeth, at least 30% of the sites with PD
and clinical attachment level (CAL) ≥4 mm and bleeding on prob-
ing (BOP) and ≥6 teeth with at least one site each with PD and
CAL ≥ 5 mm. The exclusion criteria were: pregnancy, breastfeeding,
current smoking and former smoking within the past 5 years, sys-
temic diseases that could affect the progression of periodontitis (e.g.
diabetes), SRP in the previous 12 months, antibiotic therapy in the
previous 6 months, long-term intake of anti-inflammatories, need for
antibiotic pre-medication for dental treatment and allergy to MTZ
and/or AMX.
|
      823
Clinical Relevance
Scientific rationale for the study: Despite the well-documented
benefits of the adjunctive use of MTZ + AMX in periodontal
treatment, the optimal protocol of administration of these
agents has not yet been established. Therefore, the perio-
dontal prescriptions of these drugs are normally based on
those used in medicine, what is not ideal.
Principal findings: 14 days of adjunctive MTZ + AMX was
significantly better than 7 days, in the treatment of general-
ized chronic periodontitis.
Practical implications: SRP combined with MTZ + AMX for
14 days should be the treatment of choice for patients with
severe chronic periodontitis.
2.3 | Experimental design, randomization, treatment
protocol and allocation concealment
In this prospective, parallel, double-blinded, placebo-controlled RCT,
the study coordinator (M.Fe.) used a computer program (https://
www.randomizer.org) to randomize 110 volunteers, in blocks of five,
stratified by two therapists and an allocation ratio of 1:1, to a Control
group: SRP + two placebo pills TID for 14 days; and four test groups:
(i) MTZ 250 mg/7 days: SRP + MTZ (250 mg) + AMX (500 mg)/TID
for 7 days and placebos for another 7 days; (ii) MTZ 400 mg/7 days:
SRP + MTZ (400 mg/TID) + AMX (500 mg)/TID for 7 days and pla-
cebos for another 7 days; (iii) MTZ 250 mg/14 days: SRP + MTZ
(250 mg) + AMX (500 mg)/TID for 14 days; (iv) MTZ 400 mg/14 days:
SRP + MTZ (400 mg) + AMX (500 mg)/TID for 14 days. The adminis-
tration of antibiotics/placebos started immediately after the first ses-
sion of SRP.
Initially, all subjects received supragingival scaling and oral hy-
giene instructions (OHI) and were given the same dentifrice (Colgate
Total; Colgate Palmolive Co, SP, Brazil) to use during the study period.
SRP was performed by two trained periodontists (H.R. and L.B.) using
manual curettes (Hu-Friedy, Chicago, IL, USA) and ultrasonic device
(Cavitron Select SPC, Dentsply professional, York, PA, USA). SRP treat-
ment was completed in two weeks. A full-mouth overall scaling was
performed during the first visit and in the following appointments, the
scaling of specific groups of teeth began, starting with those present-
ing the deepest pockets. All pockets with PD ≥ 5 mm received meticu-
lous SRP under anaesthesia during the first week, and the endpoint for
treatment was “smoothness of the scaled roots”, which was checked
by one of the researchers (I.B.). The one/two sessions at the second
week were specifically for: re-evaluation of SRP, removal of any re-
sidual calculus and monitoring compliance (placebos/antibiotics). OHI
were reinforced at all visits in order to assure low levels of plaque ac-
cumulation during the active phase of treatment.
The Pharmedica Pharmacy (São Paulo, SP, Brazil) prepared the
antibiotics/placebos, with identical appearances, and sent them
to the study coordinator (M.Fe.), who labelled the bottles from 1 to
 |
824       BORGES Et al.
110 according to the treatment assigned in the randomization table.
Allocation concealment was assured by placing the numbered bottles in
indistinguishable plastic bags with the same numbering. All study per-
sonnel were blinded to treatment assignment. Subjects received clinical
monitoring at baseline, 3 and 6 months, and 1 year post-therapies. In
addition, all subjects received periodontal maintenance and OHI every
3 months post-treatments. Guarulhos University Clinical Research
Ethics Committee approved the study protocol (SISNEP513). The study
protocol was registered at ClinicalTrials.gov (NCT02735395).
2.4 | Monitoring of compliance and adverse events
A study assistant monitored the compliance with antibiotics/placebos
intake by calling the patients three times/week during the medication
period. The antibiotic/placebo bottles were checked back at the end
of each week for any possible remaining pills. On the 14th day of the
medication, subjects answered a questionnaire about self-perceived
side effects.
2.5 | Clinical monitoring and calibration exercise
At baseline, 3 and 6 months and 1 year post-therapy, presence or
absence of visible plaque, marginal bleeding, BOP and suppuration
(presence/absence), as well as PD and CAL were assessed at six sites/
tooth, excluding third molars, using the manual periodontal probe
(North Carolina—Hu-Friedy, Chicago, IL, USA). The study examiner
(I.B.) participated in a calibration exercise and the standard error of
measurement was calculated. Intra-examiner variability was 0.21 mm
for PD and 0.26 mm for CAL. The agreement for categorical variables
was 92% (Kappa-light test).
2.6 | Primary outcome variable and
statistical analysis
The primary outcome variable was the difference among groups for the
percentage of volunteers reaching the clinical endpoint of therapy (≤4
sites with PD ≥ 5 mm) (Feres et al., 2012). The normality of the data
was evaluated using the Shapiro–Wilk test. The significance of differ-
ences over the course of the study was sought using repeated meas-
ures ANOVA and Tukey tests, and at each time point (among groups)
using either ANOVA and Tukey tests or ANCOVA with adjustments for
the baseline values, MTZ dose and time interval of antibiotics intake.
The Chi-square test was used to compare the differences in
the frequency of gender, and Fisher exact test was used to com-
pare the differences in the frequency of subjects achieving the
clinical endpoint at 1 year and of self-perceived adverse effects.
Two-way ANOVA was employed to test for interaction between
the four test groups, receiving the different dosages (i.e. MTZ
250 mg, MTZ 400 mg) or different periods of antibiotic intake (i.e.
MTZ + AMX/7 days, MTZ + AMX/14 days) for the mean number
of sites with PD ≥ 5 mm, PD ≥ 6 mm, PD ≥ 7 mm, as well as for
changes in PD and CAL in sites with initial PD 4–6 mm and ≥7 mm.
Additionally, a multiple linear regression analysis was employed
to test the main effect of time, dose, age, gender and PD/CAL/
presence of plaque at baseline in the mean number of sites with
PD > 5 mm at 1 year.
A stepwise forward logistic regression analysis was performed
in order to investigate the impact of predictor variables on the clinical
endpoint for treatment, that is, “presence of ≤4 sites with PD ≥ 5 mm
at 1 year post-therapy (yes/no)”. The predictor variables included age,
time interval of MTZ + AMX administration (7 and 14 days), MTZ dose
(250 and 400 mg), mean PD, CAL and number of sites with PD ≥ 5 mm
(with or without BOP) at baseline. The Number Needed to Treat (NNT)
with adjunctive antibiotic in order to obtain treatment success (≤4 sites
with PD ≥ 5 mm) was calculated using the formula: NNT = 1/ARR, where
ARR = |CER − EER| and CER = control group event rate and EER = exper-
imental group event rate (http://ktclearinghouse.ca/cebm/glossary/nnt).
The Effect Sizes (ES) between groups (Cohen, 1988) were calcu-
lated using “number of sites with PD ≥ 5 mm at 1 year post-therapy”
and the following categories: (i) small ES: 0.20 (0–0.39), (ii) moderate
ES: 0.50 (0.40–0.79) and (iii) large ES: ≥0.80. Subsequently, the 0.2
and 0.5 Minimal Important Differences (MIDs) were also calculated
based on the pooled standard deviation of the groups. Finally, using
the distribution-based method, the clinical relevance was scored as
not clinically relevant, potentially clinically relevant or clinically rele-
vant, based on the relationship among the mean difference of the vari-
able, MIDs and ES (Armijo-Olivo, Warren, Fuentes, & Magee, 2011).
All the analyses of this study were conducted using a statistical
program developed by Sigmund Socransky (Forsyth, USA), as well as
SAS (version 9.3) and GraphPad Prism (version 7.0) software. The data
were evaluated using intention-to-treat analysis with last observa-
tion carried forward and applying Bonferroni’s correction for multiple
comparisons. The level of significance was set at 5%.
3  | RE SULTS
3.1 | Subject retention, adverse effects and
compliance
The study was conducted between July 2011 and May 2014. A total
of 109 subjects entered the study at baseline. Thirteen subjects were
lost over the course of the study and one of the volunteers from the
MTZ 250 mg/14 days group did not come for the baseline appoint-
ment (Figure 1).
No significant differences were observed among groups for the
number of subjects reporting adverse events (p > .05; Table 1). Only
one subject, from the MTZ 400 mg/14 days group did not ingest all
the capsules because of symptoms of allergy to the medication on the
second day of treatment.
3.2 | Clinical findings
3.2.1 | Primary outcome
The number and percentage of subjects achieving the clinical end-
point for treatment according to Feres et al. (2012), that is, ≤4 sites
BORGES Et al. |
      825

800 subjects assessed for eligibility

Screening
690 subjects excluded. Reason:
not meeting inclusion criteria

110 subjects randomized

Allocation
SRP + placebo SRP + MTZ (250 mg) + SRP + MTZ (400 mg) + SRP + MTZ (250 mg) + SRP + MTZ (400 mg) +
AMX (500 mg) – 7 days AMX (500 mg) – 7 days AMX (500 mg) – 14 days AMX (500 mg) – 14 days
Total n: 22 Total n: 22 Total n: 22 Total n: 22 Total n: 22

Did not attend the baseline Did not attend the baseline Did not attend the baseline Did not attend the baseline Did not attend the baseline

Baseline
visit (n= 0) visit (n= 0) visit (n= 0) visit (n= 1) visit (n= 0)
n = 22 analyzed n = 22 analyzed n = 22 analyzed n = 21 analyzed n = 22 analyzed

Lost to follow up: n = 1 Lost to follow up: n = 1 Lost to follow up: n = 1 Lost to follow up: n = 0 Lost to follow up: n = 0

3 months
Reason: could not be contacted Reason: could not be contacted Reason: could not be contacted
n = 21 with complete data n = 21 with complete data n = 21 with complete data n = 21 with complete data n = 22 with complete data
n = 22 analyzed n = 22 analyzed n = 22 analyzed n = 21 analyzed n = 22 analyzed

Lost to follow up: n = 2 Lost to follow up: n = 0 Lost to follow up: n = 1 Lost to follow up: n = 1 Lost to follow up: n = 2

6 months
Reason: could not be contacted Reason: could not be contacted Reason: could not be contacted Reason: could not be contacted
n = 19 with complete data n = 21 with complete data n = 20 with complete data n = 20 with complete data n = 20 with complete data
n = 22 analyzed n = 22 analyzed n = 22 analyzed n = 21 analyzed n = 22 analyzed

Lost to follow up: n = 2 Lost to follow up: n = 0 Lost to follow up: n = 0 Lost to follow up: n = 1 Lost to follow up: n = 1
Reason: could not be contacted Reason: could not be contacted Reason: could not be contacted

1 year
n = 17 with complete data n = 21 with complete data n = 20 with complete data n = 19 with complete data n = 19 with complete data
n = 22 analyzed n = 22 analyzed n = 22 analyzed n = 21 analyzed n = 22 analyzed

F I G U R E   1   Flow chart of the study design. SRP, scaling and root planing; MTZ, metronidazole; AMX, amoxicillin; Placebo: substitute
AMX + MTZ

with PD ≥ 5 mm at 1 year (primary outcome variable) is presented
in Table 2. A lower percentage of subjects reached this outcome in
the control group (13.65%) in comparison with the four test groups
(p < .05). The two groups treated with 14 days of adjunctive antibiot-
ics presented a statistically significantly higher percentage of subjects
achieving the clinical endpoint (MTZ 250 mg, 61.9% and MTZ 400 mg,
63.6%) in comparison with the groups taking antibiotics for 7 days
(MTZ 250 mg and 400 mg, 31.8%).
3.2.2 | Secondary outcomes
All antibiotic groups showed fewer sites with BOP and lower mean
PD at 6 months and 1 year post-treatment (p < .05) in comparison
with the control group. The four antibiotic groups had a greater re-
duction in the percentage of sites with BOP, in mean PD and gain
of CAL between baseline and 1 year, after adjusting for baseline val-
ues (p < .05; Table 1). Overall, the antibiotic groups had fewer sites
with PD ≥ 5 mm, ≥6 mm and ≥7 mm and greater reductions in these
sites between baseline and 1 year post-treatment (Table 3) and in the
number of sites with PD ≥ 5 mm and BOP (Appendix Table S1), in
comparison with the control group. The lowest mean number of sites
with PD ≥ 5 mm and ≥6 mm at 6 months and 1 year was observed
in the two groups taking antibiotics for 14 days (p < .05). These two
groups also had a greater mean reduction in sites with PD ≥ 5 mm
from baseline to 1 year in comparison with the control group (p < .05)
(Table 3).
Table 4 presents secondary factorial analyses for the four antibiotic
groups, considering either the dose or the duration. This type of analysis
allows the evaluation of different experimental factors at the same time,
providing that there is no interaction between them (Piantadosi, 2008).
As no interaction between time of antibiotic intake and MTZ dose was
determined by two-way ANOVA (Appendix Table S2), the main effects
of dose and treatment interval were tested at once (Table 4). No statis-
tically significant differences were observed between the two dosage
subgroups, but the two subgroups taking the antibiotics for either 7
or 14 days differed significantly for several parameters, including the
primary outcome variable (Table 4). Additionally, a multiple linear re-
gression analysis revealed a highly significant main effect for time of
antibiotic intake (p < .001), but no effect for the dose used (Table 5).
Stepwise forward logistic regression analysis showed that 14 days
of MTZ + AMX intake was the only clinical variable that significantly in-
creased the odds (MTZ + AMX: OR, 5.26; 95% CI, 2.3–12.1/p = .0000)
of a subject achieving the clinical endpoint for treatment at 1 year
(Appendix Table S3). The NNT to achieve the clinical endpoint was
three and six, for the 14 days and 7 days groups, respectively.
Appendix Table S4 presents an analysis of clinical relevance using
the variable “number of sites with PD ≥ 5 mm” and distribution-based
methods (Armijo-Olivo et al., 2011). The results indicated that the
 |
826       BORGES Et al.

T A B L E   1   Demographic characteristics of the study population, means (±SD) and adjusted mean reduction (±SEM) of full-mouth clinical
parameters, and number of subjects reporting adverse effects

Treatment groups

SRP + MTZ + AMX (7 Days) SRP + MTZ + AMX (14 Days) p-values
SRP + placebo
Variables Time point (n = 22) 250 mg (n = 22) 400 mg (n = 22) 250 mg (n = 21) 400 mg (n = 22)

Chi-square
Gender (% Baseline 41 36 46 48 46 .95
males)
ANOVA
Age (years) 45.6 ± 8.0 46.6 ± 8.9 45.9 ± 7.8 47.0 ± 8.6 48.5 ± 7.4 .78
% of sites 58.0 ± 17.3 39.1 ± 17.7 45.3 ± 21.3 39.7 ± 16.5 48.9 ± 18.5 .37
with PD Baseline
≤3 mm
% of sites 42.0 ± 17.3 60.9 ± 17.7 54.7 ± 21.3 60.3 ± 16.5 51.1 ± 18.5 .37
with PD
≥4 mm
Number of subjects (%) Fisher
reporting exact test
Nausea or vomiting 1 (4.54) 2 (9.09) 3 (13.63) 2 (9.52) 3 (13.63) >.05
Diarrhoea 1 (4.54) 5 (22.72) 1 (4.54) 2 (9.52) 3 (13.63) >.05
Metallic taste 2 (9.09) 6 (27.27) 3 (13.63) 7 (33.33) 6 (27.27) >.05
Headache or dizziness 1 (4.54) 5 (22.72) 4 (18.18) 2 (9.52) 6 (27.27) >.05
Irritability or bad mood 0 (0.00) 1 (4.54) 2 (9.09) 1 (4.76) 1 (4.54) >.05
Weakness 0 (0.00) 2 (9.09) 2 (9.09) 1 (4.76) 3 (13.63) >.05
Excessive sleep 2 (9.09) 5 (22.72) 3 (13.63) 4 (19.04) 2 (9.09) >.05
Did you manage to take the 22 (100) 22 (100) 22 (100) 21 (100) 21 (95.45) >.05
medications as was
instructed? Number (%) of
subjects answering YES
If necessary, would you take 21 (95.45) 22 (100) 22 (100) 21 (100) 21 (95.45) >.05
the medication again?
Number (%) of subjects
answering YES
ANOVA
a a a a a
% of sites Baseline 61.0 ± 16.3 55.4 ± 17.2 58.2 ± 21.3 55.3 ± 18.8 63.1 ± 19.1 .56
with plaque 3 months 30.2 ± 18.6b 29.4 ± 13.8b 24.6 ± 16.1b 22.1 ± 12.6b 24.0 ± 13.1b .31
accumula- b b b b b
tion 6 months 27.0 ± 19.8 24.8 ± 10.1 25.1 ± 17.3 22.2 ± 14.9 22.9 ± 12.8 .85
1 year 26.0 ± 19.7b 20.8 ± 11.5b 25.8 ± 17.9b 19.4 ± 10.7b 19.1 ± 10.0b .32
ANCOVA
∆ 0–1 year 33.7 ± 2.7 36.3 ± 2.8 32.7 ± 2.7 37.7 ± 2.8 41.5 ± 2.7 .13
ANOVA
% of sites Baseline 45.7 ± 20.2a 48.2 ± 19.5a 47.1 ± 20.8a 38.3 ± 16.8a 50.0 ± 23.1a .38
with 3 months 28.6 ± 16.6 b
26.7 ± 12.0 b
26.9 ± 12.4 b
22.1 ± 13.4 b
23.6 ± 11.1 b
.49
marginal
bleeding 6 months 26.5 ± 14.8b 21.8 ± 9.0b 24.0 ± 13.0b 19.9 ± 13.2b 20.7 ± 7.8b .36
b,A b,B b b,B b,B
1 year 25.5 ± 14.9 17.8 ± 10.2 23.0 ± 11.0 16.7 ± 9.2 18.2 ± 7.6 .03
ANCOVA
∆ 0–1 year 21.3 ± 2.1 28.9 ± 2.1 23.8 ± 2.1 27.1 ± 2.2 28.9 ± 2.1 .06

(Continues)
BORGES Et al. |
      827

T A B L E   1   (Continued)
Treatment groups

SRP + MTZ + AMX (7 Days) SRP + MTZ + AMX (14 Days) p-values
SRP + placebo
Variables Time point (n = 22) 250 mg (n = 22) 400 mg (n = 22) 250 mg (n = 21) 400 mg (n = 22)

ANOVA
% of sites Baseline 67.9 ± 14.6a 64.9 ± 18.5a 68.0 ± 21.2a 62.8 ± 18.9a 69.1 ± 20.5a .80
with 3 months 42.9 ± 17.3 b,A
32.5 ± 12.9 b,B
31.9 ± 15.1 b,B
24.3 ± 14.1 b,B
28.7 ± 13.1 b,B
.00
bleeding on b,A b,B b,B b,B b,B
probing 6 months 39.0 ± 17.4 27.1 ± 10.3 30.7 ± 14.3 23.1 ± 13.0 26.8 ± 9.3 .00
1 year 40.0 ± 17.4b,A 24.0 ± 12.9b,B 28.6 ± 15.3b,B 18.5 ± 12.7b,B 25.1 ± 11.6b,B .00
ANCOVA
∆ 0–1 year 27.0 ± 2.6A 41.9 ± 2.6B 38.5 ± 2.6B 46.5 ± 2.7B 42.5 ± 2.6B .00
ANOVA
PD (mm) Baseline 3.8 ± 0.7a 3.8 ± 0.9a 4.0 ± 0.9a 3.7 ± 0.7a 4.0 ± 0.8a .68
b,A b,A b b,B b,B
3 months 3.0 ± 0.6 2.6 ± 0.4 2.8 ± 0.5 2.5 ± 0.3 2.7 ± 0.4 .00
6 months 3.0 ± 0.6b,A 2.6 ± 0.4b,B 2.6 ± 0.5b,B 2.4 ± 0.3b,B 2.6 ± 0.4b,B .00
b,A b,B b,B b,B b,B
1 year 2.9 ± 0.6 2.4 ± 0.6 2.6 ± 0.5 2.3 ± 0.3 2.5 ± 0.4 .00
ANCOVA
∆ 0–1 year 0.8 ± 0.9A 1.4 ± 0.9B 1.3 ± 0.9B 1.4 ± 0.9B 1.4 ± 0.9B .00
ANOVA
CAL (mm) Baseline 4.4 ± 1.0a 4.5 ± 0.9a 4.7 ± 1.3a 4.2 ± 0.8a 4.8 ± 1.2a .23
b b b b
3 months 4.1 ± 1.1 3.9 ± 1.0 4.2 ± 1.3 3.5 ± 0.8 4.1 ± 1.1b .32
b b b b b
6 months 4.2 ± 1.1 3.9 ± 1.0 4.1 ± 1.4 3.5 ± 0.8 4.2 ± 1.2 .29
1 year 4.1 ± 1.0b 3.7 ± 1.3b 4.0 ± 1.4b 3.4 ± 0.7b 4.0 ± 1.1b .15
ANCOVA
∆ 0–1 year 0.4 ± 1.2A 0.8 ± 1.2B 0.7 ± 1.2B 0.8 ± 1.3B 0.8 ± 1.2B .03

AMX, amoxicillin; CAL, clinical attachment level; MTZ, metronidazole; PD, probing depth; SD, standard deviation; SEM, standard error of the mean; SRP,
scaling and root planing.
The significance of differences among treatment groups at each time point was tested by ANOVA and Tukey tests and by ANCOVA with adjustments for
baseline values (p < .05, different uppercase letters indicate differences among treatment groups). The significance of differences over time was assessed
by repeated measures ANOVA and Tukey tests (different lowercase letters indicate significant differences over time).

T A B L E   2   Number and percentage of subjects who achieved or did not achieve the clinical endpoint for treatment (i.e. ≤4 sites with PD
≥5 mm) according to Feres et al. (2012), at 1-year post-therapies

Treatment groups

SRP + MTZ + AMX (7 Days) SRP + MTZ + AMX (14 Days)

SRP + placebo Chi-square
Low risk (n = 22) 250 mg (n = 22) 400 mg (n = 22) 250 mg (n = 21) 400 mg (n = 22) p-value

Yes 3 (13.6%) A 7 (31.8%) B 7 (31.8%) B 13 (61.9%) C 14 (63.6%) C .00

No 19 (86.4%) 15 (68.2%) 15 (68.2%) 8 (38.1%) 8 (36.4%)

AMX, amoxicillin; MTZ, metronidazole; SRP, scaling and root planing.

Different uppercase letters indicate differences between treatment groups by the Fisher exact test (p < .05).

differences between the 7- and 14-days protocols for this variable
were clinically relevant, independently of the dose used.
4  |  DISCUSSIO N
The data of this study indicate that the duration of the MTZ + AMX
administration had a greater impact in treatment efficacy than the
dosage of MTZ. Of the subjects who took 14 days of antibiotics, 63%
achieved the clinical endpoint for treatment, that is, ≤4 sites with
PD ≥ 5 mm at 1 year, as opposed to ~14% of those treated with SRP-
only and ~30% of those taking the antibiotics for 7 days. In addi-
tion, subjects who took MTZ + AMX during 14 days also exhibited
the best clinical results for most secondary variables, such as mean
reduction in PD and gain in CA in initially deep sites, and reduction
in mean number of sites with PD ≥ 5 mm and ≥6 mm. Multiple linear
 |
828       BORGES Et al.

T A B L E   3   Mean (±SD) and adjusted mean reductions (±SEM) in the number of sites with PD ≥ 5 mm, PD ≥ 6 mm and PD ≥ 7 mm

Treatment groups

SRP + MTZ + AMX (7 Days) SRP + MTZ + AMX (14 Days)

SRP + placebo
Variables Time point (n = 22) 250 mg (n = 22) 400 mg (n = 22) 250 mg (n = 21) 400 mg (n = 22) p-values

ANOVA
Number of sites Baseline 35.6 ± 20.7a 36.0 ± 23.8a 37.7 ± 21.0a 33.7 ± 25.1a 37.4 ± 19.6a .97
with PD ≥ 5 mm 3 months 18.0 ± 14.0 b,A
11.0 ± 11.4 b,B
12.3 ± 9.2 b,B
8.4 ± 10.3 b,C
7.8 ± 8.1b,C
.02
6 months 19.0 ± 14.5b,A 9.5 ± 9.4b,B 10.0 ± 6.7b,B 6.0 ± 6.4C 7.5 ± 6.3b,C .00
b,A b,B b,B c,C c,C
1 year 19.0 ± 14.5 9.5 ± 9.0 9.9 ± 7.5 5.0 ± 4.8 5.7 ± 4.6 .00
ANCOVA
∆ 0–1 year 17.2 ± 1.5A 26.5 ± 1.5 26.6 ± 1.5 30.4 ± 1.6B 30.7 ± 1.5B .00
ANOVA
Number of sites Baseline 22.5 ± 15.2a 25.1 ± 20.5a 24.6 ± 16.4a 20.8 ± 20.9a 22.5 ± 15.9a .93
with PD ≥ 6 mm 3 months 10.2 ± 10.9 b,A
5.0 ± 7.0b,B
5.0 ± 4.5 b,B
2.8 ± 3.9b,C
3.9 ± 4.6b,B .00
b,A b,B b,B b,C b,C
6 months 10.5 ± 10.8 4.7 ± 6.2 4.1 ± 3.1 2.1 ± 3.7 3.4 ± 3.6 .00
1 year 11.0 ± 11.5b,A 4.0 ± 5.2b,B 4.7 ± 4.0b,B 1.7 ± 2.5b,C 2.5 ± 2.6b,C .00
ANCOVA
∆ 0–1 year 12.2 ± 1.2A 19.5 ± 1.2B 18.7 ± 1.2B 21.0 ± 1.2B 20.5 ± 1.2B .00
ANOVA
Number of sites Baseline 11.7 ± 9.3a 16.0 ± 15.7a 14.0 ± 11.5a 10.0 ± 14.2a 11.4 ± 9.5a .53
with PD ≥ 7 mm 3 months 4.9 ± 6.2a,A
2.5 ± 3.7b,B
2.4 ± 2.2 b,B
1.0 ± 1.8b,B
2.0 ± 2.8b,B
.00
6 months 5.4 ± 5.9a,A 2.1 ± 3.5b,B 1.6 ± 1.8b,B 0.8 ± 1.3b,B 2.0 ± 2.6b,B .00
a,A b,B b,B b,B b,B
1 year 5.4 ± 5.9 2.0 ± 3.0 1.9 ± 2.1 0.8 ± 1.4 1.4 ± 1.9 .00
ANCOVA
∆ 0–1 year 7.5 ± 0.7A 11.2 ± 0.7B 10.9 ± 0.7B 11.5 ± 0.7B 11.1 ± 0.7B .00

AMX, amoxicillin; MTZ, metronidazole; PD, probing depth; SD, standard deviation; SEM, standard error of the mean; SRP, scaling and root planing.
The significance of differences among treatment groups at each time point was tested by ANOVA and Tukey tests and by ANCOVA with adjustments for
baseline values (p < .05, different uppercase letters indicate differences among treatment groups). The significance of differences over time was assessed
by repeated measures ANOVA and Tukey tests (different lowercase letters indicate significant differences over time).

regression and an analysis of clinical relevance revealed a statistically
significant and clinically relevant effect for 14 days of MTZ + AMX
intake in the mean number of residual pockets, and this protocol was
the only significant predictor for a subject to reach the clinical end-
point for treatment at 1 year, with an OR of 5.26. Interestingly, the
longer period of antibiotic administration or the higher dose of MTZ
did not have a striking effect on the occurrence of side effects in this
study.
Although the effectiveness of 7 or 14 days of MTZ + AMX admin-
istration has not been directly compared before, one could draw a par-
allel with the protocols used by the different studies. Previous RCTs
have demonstrated marked clinical benefits of 14 days of MTZ + AMX
intake in the treatment of chronic periodontitis (Feres et al., 2012;
Goodson et al., 2012), aggressive periodontitis (Mestnik et al., 2012),
in subjects with diabetes mellitus (Tamashiro et al., 2016) and in smok-
ers (Matarazzo, Figueiredo, Cruz, Faveri, & Feres, 2008). However, the
advantages of this treatment were less evident in a previous study that
used a 10-day protocol and a lower MTZ dose (250 mg/TID) (Varela
et al., 2011). Interestingly, Goodson et al. (2012) who also used a
lower daily dose of MTZ (250 mg/BID), but 14 days of MTZ + AMX
intake, obtained excellent results in comparison with several other
adjunct treatments, including periodontal surgery. Together, these re-
sults support the hypothesis suggested in this study that the adminis-
tration interval is more closely associated to therapeutic success than
the dosage of MTZ. A possible biological plausibility for these find-
ings is the well-known inherent tolerance to antimicrobial agents of
biofilm-associated bacteria (Costerton, Stewart, & Greenberg, 1999;
Socransky & Haffajee, 2002). Probably, longer periods of exposure to
antibiotics would be required to kill microorganisms living in the highly
organized subgingival biofilm structure. Extended periods of antibiotic
administration are commonly used in the treatment of other biofilm-
associated infections, such as osteomyelitis (Haidar, Der Boghossian,
& Atiyeh, 2010; Shuford & Steckelberg, 2003), cystic fibrosis pneu-
monia (Proesmans, Vermeulen, Boulanger, Verhaegen, & De Boeck,
2013; Ratjen, Munck, Kho, Angyalosi, & Group, 2010) and catheter-
associated urinary tract infection (Dow et al., 2004; Hooton et al.,
2010). Another important concept to consider is that, unlike the treat-
ment of most medical infections focused on the elimination of one
or a few pathogens, successful periodontal treatment requires a strik-
ing change in the subgingival microbial profile. This change includes
BORGES Et al. |
      829

T A B L E   4   Percentage of sites that achieved the clinical endpoint for treatment (i.e. ≤4 sites with PD ≥ 5 mm) (Feres et al., 2012), mean
number of sites with PD ≥ 5 mm, ≥6 mm and ≥7 mm at 1 year and mean reduction in the number of these sites from baseline to 1 year, as well
as mean reductions in PD and gains in CAL in initially moderate and deep pockets, considering either the dose or the time of antibiotic
administration

Treatment groups

SRP + MTZ + AMX (7 Days) SRP + MTZ + AMX (14 Days)

Variables Time n = 44 n = 43 p-values

Chi-square
Number (%) of patients that achieved the 14 (31.8%) 27 (62.8%) .005
clinical endpoint

1 year
ANCOVA
Number of sites with PD ≥ 5 mm 9.6 ± 0.8 5.5 ± 0.8 .00
Number of sites with PD ≥ 6 mm 4.2 ± 0.5 2.3 ± 0.5 .00
Number of sites with PD ≥ 7 mm 1.7 ± 0.3 1.3 ± 0.3 .26
Reduction in no of sites with PD ≥ 5 mm 26.6 ± 0.8 30.7 ± 0.8 .00
o
Reduction in n of sites with PD ≥ 6 mm 19.1 ± 0.5 21.0 ± 0.5 .00
Reduction in no of sites with PD ≥ 7 mm 11.4 ± 0.3 11.6 ± 0.3 .26
Gain of CA (mm) in initially moderate sites 1.1 ± 0.1 1.2 ± 0.1 .82
Gain of CA (mm) in initially deep sites ∆ 0–1 year 2.2 ± 0.2 2.8 ± 0.2 .02
Reduction of PD (mm) in initially 1.8 ± 0.1 2.0 ± 0.1 .58
moderate sites
Reduction of PD (mm) in initially deep 3.4 ± 0.2 3.8 ± 0.2 .01
sites

SRP + MTZ (250 mg) + AMX SRP + MTZ (400 mg) + AMX
n = 43 n = 44

Chi-square
Number (%) of patients that achieved the 20 (46.5%) 23 (52.3%) 1.0
clinical endpoint

1 year ANCOVA
Number of sites with PD ≥ 5 mm 7.6 ± 0.9 7.6 ± 0.9 .98
Number of sites with PD ≥ 6 mm 2.9 ± 0.5 3.6 ± 0.5 .37
Number of sites with PD ≥ 7 mm 1.4 ± 0.3 1.3 ± 0.3 .42
Reduction in no of sites with PD ≥ 5 mm 29.6 ± 0.9 27.8 ± 0.8 .13
o
Reduction in n of sites with PD ≥ 6 mm 20.5 ± 0.5 19.7 ± 0.5 .24
Reduction in no of sites with PD ≥ 7 mm 21.9 ± 0.3 10.9 ± 0.3 .16
Gain of CA (mm) in initially moderate sites 1.3 ± 0.1 1.2 ± 0.1 .32
Gain of CA (mm) in initially deep sites ∆ 0–1 year 2.6 ± 0.2 2.3 ± 0.2 .40
Reduction of PD (mm) in initially 1.9 ± 0.1 1.8 ± 0.1 .24
moderate sites
Reduction of PD (mm) in initially deep 3.8 ± 0.2 3.4 ± 0.2 .40
sites

AMX, amoxicillin; CAL, clinical attachment level; MTZ, metronidazole; PD, probing depth; SRP, scaling and root planing. All ANCOVA analyses were ad-
justed for baseline value.

reduction/elimination of pathogens and the concomitant increase in
the proportion of beneficial microorganisms. It has been hypothesized
that the maintenance of low bacterial levels by a longer exposure to
MTZ + AMX probably allows more time for recolonization of the re-
cently scaled pockets by the initial host-compatible colonizers, lead-
ing to a more beneficial biofilm composition and consequently, better
clinical results (Feres et al., 2015). The new health-compatible “climax
biofilm community” formed after 14 days of MTZ + AMX adjunctive
to SRP is quite steady, and the clinical benefits of this treatment last
for 1 to 2 years post-treatment (Feres et al., 2015; Soares et al., 2014;
Socransky et al., 2013; Tamashiro et al., 2016). Once a new health-
compatible biofilm “climax community” is formed, there is no need to
 |
830       BORGES Et al.
T A B L E   5   Multiple linear regression of the effect of time, dose,
age, gender mean probing depth (PD) and clinical attachment level
(CAL), and presence of plaque at baseline
Variables Adjusted p-value
Time (7 days versus 14 days) .0006
Dose (250 mg versus 400 mg) .4585
PD .0631
CAL .5281
Presence of plaque .6243
Age .8607
Gender .3228
Dependent variable: number of sites with PD ≥ 5 mm at 1 year.
repeat the antibiotic course, what in fact should be avoided in order
to prevent recurrent exposure to these drugs and its associated risks.
Another concept to bear in mind is that maintaining low levels of
plaque during and after mechanical/antibiotic therapy is crucial for the
establishment of the new biofilm community and consequently, for
treatment success (Feres, Gursky, Faveri, Tsuzuki, & Figueiredo, 2009;
Soares et al., 2014). The participants of this study did not rinse CHX for
2 months, as in some previous RCTs of our group (Feres et al., 2012;
Mestnik et al., 2012), but they kept low levels of plaque throughout
the study by means of mechanical tools and repeated OHI.
The fact that the dose of MTZ did not influence the clinical ef-
ficacy of treatment was somewhat unexpected and suggest that the
concentration of MTZ in the gingival crevicular fluid would probably
plateau after a daily dose of 750 mg. However, a detailed evalua-
tion of the microbiological effects of different doses of MTZ would
be necessary before making strong recommendations to replace 400
or 500 mg of MTZ with a lower dose, since lower doses of antibi-
otic are important contributory factors to the worldwide increase in
microbial tolerance to these agents (Leekha, Terrell, & Edson, 2011;
Yap, 2013). Furthermore, the clinical trials that used lower dosages of
MTZ (250 mg) and AMX (375 mg) TID for 7 days did not obtain very
encouraging clinical and microbiological benefits with the antibiotic
treatment (Casarin et al., 2012; Ribeiro Edel et al., 2009).
It is important to emphasize that previous RCTs have shown statis-
tically significant clinical benefits with the use of AMX and higher MTZ
dosages (400 or 500 mg) for 7 (Aimetti, Romano, Guzzi, & Carnevale,
2012; Cionca, Giannopoulou, Ugolotti, & Mombelli, 2009; Guerrero
et al., 2005; Xajigeorgiou, Sakellari, Slini, Baka, & Konstantinidis, 2006;
Yek et al., 2010), or even for 3 days (Cosgarea et al., 2016), when com-
pared to SRP alone. In fact, our 7-day groups also showed some signif-
icant clinical benefits over those obtained with SRP. This is a somehow
expected finding since SRP has limitations, especially in severe cases.
Thus, in theory, any adjunctive treatment would have a good prob-
ability of providing superior clinical effects than scaling alone in the
treatment of severe chronic periodontitis. Thus, a main point of con-
sideration while testing different treatments is to define a clear clinical
endpoint for therapy and to compare the effectiveness of the various
protocols to bring patients to this endpoint, a concept commonly used
in medicine, named “treat-to target”. In this perspective, the clinical
endpoint for periodontal treatment (≤4 sites with PD ≥ 5 mm; Feres
et al., 2012) used in this study, which has also been reported in other
six RCTs (Harks et al., 2015; Laleman et al., 2015; Mestnik et al., 2012;
Miranda et al., 2014; Tekce et al., 2015; Teughels et al., 2013), might
represent a good tool for comparing the results of different RCTs in
periodontology. Following this line of thought, an interesting parallel
could be drawn between our data and those published by Harks et al.
(2015), who also reported results for the endpoint variable “≤4 sites
with PD ≥ 5 mm” in a population with less severe chronic periodontitis.
These authors showed that 7 days of adjunctive MTZ (400 mg) + AMX
(500 mg) TID provided results similar to those observed in our group
taking 14 days of antibiotics, that is, ≈60% of the subjects achieved
this clinical endpoint at 2 years post-treatment. The population of
Harks’ study had a mean average of ≈20 sites with PD ≥ 5 mm, as op-
posed to ≈35 sites in our study. Taken together, these data suggest
that the 7-day protocol, although not particularly effective for the pop-
ulation with severe disease from our study, might be adequate to treat
moderate periodontitis. Nonetheless, these findings would need to be
confirmed by RCTs designed to directly compare these two protocols
(7 and 14 days) in subjects with lower levels of periodontal destruction
and treated with the same mechanical protocol. Worth noting is that
although both studies started the antibiotic intake at the first day of
the mechanical treatment, Harks et al. (2015) performed full-mouth
SRP in 2 days, while in this study, we did one full-mouth debridement
at the first day followed by quadrant-wise scaling.
The main weakness of this study is the lack of microbiological data,
which would be important to support the clinical findings and, specially,
to deepen the comparisons between the two MTZ dosages. The main
strength of this study is that this is the first RCT specially designed to
compare antibiotic protocols commonly used in the periodontal prac-
tice. This is a very important matter, since it is well known that long
periods of antibiotic administration, or short antibiotic courses insuf-
ficient to kill target pathogens might increase the risk of developing
microbial antibiotic resistance. Therefore, the decision about the ideal
antibiotic protocol should be based on the best evidence available
(WHO, 2015), and the results of this study represent an important
contribution for the decision-making in the periodontal practice.
In conclusion, the adjunctive use of 400 mg or 250 mg of MTZ
plus 500 mg of AMX, TID for 14 days, offered statistically significant
and clinically relevant benefits over those attained with SRP alone in
the treatment of patients with severe GChP. The added benefits of the
7-day antibiotic regimen in this population were less evident.
ACKNOW LEDG EM E NTS
The authors thank the periodontists Helder Reis and Leonardo
Buss for treating the volunteers of this RCT, and FAPESP (Grant #
2009/17677-8) for supporting this study.
CO NF LICT O F INTEREST
The authors declare no potential conflicts of interest with respect to
the authorship and/or publication of this article.
BORGES Et al.
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How to cite this article: Borges I, Faveri M, Figueiredo LC, et al.
Different antibiotic protocols in the treatment of severe chronic
periodontitis: A 1-year randomized trial. J Clin Periodontol.
2017;44:822–832. https://doi.org/10.1111/jcpe.12721