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J Clin Periodontol 2016; doi: 10.1111/jcpe.

12559

Non-surgical periodontal Raluca Cosgarea1,2,, Raluca Juncar2,


Christian Heumann3, Roxana Tristiu2,
Liana Lascu2, Nicole Arweiler1,

treatment in conjunction with 3 Andreas Stavropoulos4 and


Anton Sculean5
1
Department of Periodontology, Philipps

or 7 days systemic University Marburg, Marburg, Germany;


2
Clinic for Prosthetic Dentistry, University
Iuliu Hatieganu, Cluj-Napoca, Romania;

administration of amoxicillin and


3
Department for Statistics, Ludwig-
Maximilians University, Munich, Germany;
4
Department of Periodontology, Faculty of
dentistry, Malmo University, Malmo , Sweden;

metronidazole in severe 5
Department of Periodontology, School of
Dental Medicine, University of Bern, Bern,
Switzerland

chronic periodontitis patients.


A placebo-controlled randomized
clinical study
Cosgarea R, Juncar R, Heumann C, Tristiu R, Lascu L, Arweiler N, Stavropoulos
A, Sculean A. Non-surgical periodontal treatment in conjunction with 3 or 7 days
systemic administration of amoxicillin and metronidazole in severe chronic
periodontitis patients. A placebo-controlled randomized clinical study. J Clin
Periodontol 2016; doi: 10.1111/jcpe.12559.

Abstract
Aim: To evaluate the effect of 3 or 7 days systemic administration of amoxicillin
(AMX) and metronidazole (MET) or placebo as adjunct to non-surgical peri-
odontal treatment in severe chronic periodontitis patients.
Methods: One hundred and two patients with severe chronic periodontitis [e.g. 1
site with probing pocket depth (PD) 6 mm per quadrant] were randomly
divided into three equally sized groups and treated with either scaling and root
planing within 24 h (SRP) + placebo (Group A) or SRP + AMX + MET (both

500 mg 9 3 times daily) for 3 days (Group B) or SRP + AMX + MET (both Dr. Raluca Cosgarea presented this paper
500 mg 9 3 times daily) for 7 days (Group C). PD, clinical attachment level for the Jaccard-EFP Research Prize
competition at EuroPerio8 in London.
(CAL), bleeding on probing (BOP), full-mouth plaque scores (FMPS) and gingi-
val bleeding index (GBI) were assessed prior to treatment (baseline), and at 3 and Key words: amoxicillin; metronidazole;
6 months post-treatment. The primary outcome variable was the difference (D) in non-surgical periodontal treatment; systemic
the number of sites with PD 6 mm. antibiotics
Results: Ninety-one patients completed the study. At both 3 and 6 months, all
three treatment protocols resulted in statistically significant improvements com- Accepted for publication 26 March 2016
pared to baseline for all evaluated clinical parameters (p < 0.001). At 6 months,

Conflict of interest and sources of funding statement


The authors declare to have no conflict of interest regarding this study. The study has been funded by the authors own
institutions.

2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 1
2 Cosgarea et al.

a statistically significantly greater reduction in the mean number of sites with


PD 6 mm was observed in group B (28.62  15.32 sites) and group C
(30.45  15.04 sites) compared to the placebo group (17.10  14.68 sites). Fur-
thermore, both the 3- and the 7-day antibiotic regimen resulted in statistically sig-
nificantly higher clinical improvements compared to the placebo group (p < 0.05).
Conclusion: The present findings indicate that in patients with severe chronic peri-
odontitis, non-surgical periodontal therapy in conjunction with a 3 or 7 days sys-
temic administration of AMX + MET may lead to significantly greater clinical
improvements compared to non-surgical therapy alone.

Periodontal treatment aims at reduc- thereof (Slots 2004, Guentsch et al. weighted mean PD improvement of
tion in the subgingival oral biofilm, 2008, Herrera et al. 2008, 2012, 1.41 mm and a CAL gain of
including pathogenic species, to Heitz-Mayfield 2009, Flemmig et al. 0.94 mm, whereas Sgolastra et al.
achieve homeostasis. This is mainly 2011, Griffiths et al. 2011). The most (2012) obtained a PD reduction of
accomplished by mechanical removal frequent regime includes a combina- 0.43 mm and a CAL gain
of the bacterial deposits from the tion of amoxicillin (AMX) and of 0.21 mm for the adjunctive use of
tooth surfaces, i.e. scaling and root metronidazole (MET) and several AMX and MET versus SRP alone,
planing (SRP). However, bacteria studies have shown statistically sig- respectively.
residing in root concavities, dentin nificant reduction in periodontal However, dosage and duration of
tubules or within soft tissues are not pathogens and inflammatory cytoki- the prescribed antibiotic regime vary
easily reached with mechanical nes after SRP with adjunctive use of greatly in the literature. Several stud-
instrumentation, and therefore SRP AMX + MET compared to SRP ies have evaluated the effect of
rarely leads to complete elimination alone (Pavicic et al. 1994, Goutoudi 375 mg AMX and 250/500 mg
of the subgingival biofilm (Cugini et al. 2004, Cionca et al. 2009, 2010, MET, three times daily (TID), for
et al. 2000, Carvalho et al. 2005). Ribeiro Edel et al. 2009, Mestnik 78 days as adjuncts to SRP (van
Furthermore, inefficient reduction in et al. 2010, 2012, Yek et al. 2010, Winkelhoff et al. 1989, Pavicic et al.
the subgingival microbial load is Griffiths et al. 2011, Heller et al. 1994, Flemmig et al. 1998, Ehmke
associated with unsuccessful treat- 2011, Silva et al. 2011, Varela et al. et al. 2005, Cionca et al. 2009, 2010,
ment outcomes. For example, 2011, Feres et al. 2012, de Lima Oli- Ribeiro Edel et al. 2009); other stud-
persistence of Aggregatibacter actino- veira et al. 2012). Several clinical ies have used a dosage of 500 mg 3
mycetemcomitans (A. actinomycetem- studies have provided evidence for TID for 7 days (Guerrero et al.
comitans), Porphyromonas gingivalis significantly better clinical outcomes, 2005, Yek et al. 2010, Griffiths et al.
(P. gingivalis) and other bacterial i.e. probing pocket depth (PD) 2011), or 500 mg AMX and 400/
species after periodontal treatment reduction and clinical attachment 250 mg MET, 3 TID for 1014 days
has been associated with additional level (CAL) gain, following the (Matarazzo et al. 2008, Mestnik
tissue destruction (Renvert et al. adjunctive use of AMX + MET to et al. 2010, 2012, Heller et al. 2011,
1990, Mombelli et al. 1994, 2000), SRP compared to the treatment with Silva et al. 2011, Feres et al. 2012,
whereas improved clinical outcomes SRP alone (van Winkelhoff et al. Rodrigues et al. 2012). In perspec-
have been observed when such peri- 1989, Pavicic et al. 1994, Winkel tive, irrespective dosage and dura-
odontopathogenic bacteria were not et al. 2001, Matarazzo et al. 2008, tion, it is important that AB should
detected (Grossi et al. 1994, Haffajee Cionca et al. 2009, 2010, Ribeiro be taken in a minimum bactericidal
& Socransky 1994, Dahlen et al. Edel et al. 2009, Mestnik et al. 2010, concentration and for a minimum
1996). 2012, Yek et al. 2010, Griffiths et al. duration (Vogelman & Craig 1986)
Given these limitations, the 2011, Heller et al. 2011, Silva et al. to limit the risk for side effects, espe-
adjunctive use of antibacterial agents 2011, Varela et al. 2011, Feres et al. cially the development of microbial
(antibiotics and antiseptics) may be 2012). A recent meta-analysis on the antibiotic resistance. Antibiotic resis-
considered. The rationale is that adjunctive systemic use of antibiotics tance leads to the development of
after mechanical disruption of the in the non-surgical treatment of peri- dangerous resistant strains with an
biofilm through instrumentation, odontitis showed a statistically sig- impact on the success of antimicro-
bacteria become more susceptible to nificant additional PD reduction bial therapy of life-threatening infec-
such agents (Marsh 2005). A large (0.55  0.37 mm, on average) for tions (Lassmann et al. 2007, Fair &
variety of antibiotics (AB) has the use of AMX and MET as com- Tor 2014), and its prevalence contin-
indeed been investigated as possible pared to what was achieved with ues to increase globally (Roberts
adjunct to SRP: amoxicillin (with or SRP alone after 12 months (Keestra et al. 2006, Snydman et al. 2010,
without clavulanic acid), metronida- et al. 2015). These results are in line Nagy et al. 2011, Karlowsky et al.
zole, clindamycin, doxycycline, with data reported in two previously 2012). Resistant strains can appear
azithromycin, moxifloxacin, tetracy- published meta-analyses: Zandbergen de novo during a single long-term
cline, spiramycin and combinations et al. (2013) obtained a full-mouth infection in association with
2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
SRP with a 3 or 7-day antibiotic regimen 3

long-term AB intake, especially periodontal therapy in patients with istration of AB before dental
when low drug doses are prescribed, severe chronic periodontitis (ChP). treatment
which in turn may lead to poor drug no liver disease.
compliance and/or incomplete pene-
tration of the drug in all tissues Material and Methods Exclusion criteria were as follows:
(Lipsitch & Levin 1997, Musher
et al. 2002, Lieberman et al. 2011). Trial design, patient population, inclusion
non-surgical periodontal therapy
within the previous 12 months
With regard to periodontal therapy,
some studies have shown a decline in
and exclusion criteria
systemic or local use of AB
The hypothesis to be tested in this within the previous 3 months
resistance frequencies of oral biofilm
species after AB removal (Seppala prospective, randomized, placebo- medication that could interact
controlled, double-masked clinical with AMX or MET (e.g. cou-
et al. 1997, Barbosa & Levy 2000, marin derivates, containing alco-
Feres et al. 2002). For example, trial was that the systemic use of
AMX and MET administered for 3 hol derivates, 5-fluor-uracyl/
Feres et al. (2002) observed that the disulfiram derivates, amprenavir
percentage of antibiotic-resistant or 7 days as adjunct to SRP leads to
superior clinical results compared oral solutions, lopinavir/ritonavir
strains 90 days after antibiotic treat- oral solution)
with SRP alone.
ment was similar to that at prior to
AB intake, which indicates that any
Sample size calculation was per- medication with a possible influence
formed before starting the study, con- on the periodontium (e.g. Ciclos-
possible increase in the percentage of porin A, compounds of Phenytoin,
sidering the possibility to detect a
resistant subgingival species during calcium channel blockers).
difference in five sites (Silva et al.
AB intake appears to be only tran-
sient (Feres et al. 2002).
2011, Feres et al. 2012) with a pregnancy or lactation.
Nevertheless, the theoretical pos- PD 6 mm (Matuliene et al. 2008)
and a standard deviation of 6 sites The study was conducted accord-
sibility of development of microbial ing to the Declaration of Helsinki
antibiotic resistance, in general, can- (Cionca et al. 2009, Feres et al. 2012)
between AB and control groups at (1964, revision 2008) and approved
not be completely excluded. Consid- by the Ethical Committee of the
ering this, as well as other undesired 6 months, as clinically important. A
study power of 90% at a statistical Faculty of Medicine and Pharmacy
effects associated with prolonged AB of Cluj-Napoca (Application #514/
regimes e.g. taste disturbance, significance level of 0.05 was reached
with 30 subjects per treatment group. 09.01.2012). Prior to participation,
headache, severe diarrhoea, nausea/ all eligible subjects were informed of
vomiting, hypersensitivity, renal and Taking into account a possible attri-
tion of 13%, 34 subjects per the purpose of the study, and the
liver toxicity, problems with compli- possible risks and benefits of their
treatment group were included.
ance regarding intake and high costs participation. Informed written con-
and in light of recently advocated One hundred and two subjects
were recruited from the patients sent to participate in this study was
AB regimens as adjunct to SRP over obtained from all subjects prior to
longer periods (i.e. 2 weeks) (Matar- seeking dental treatment at the
University Clinic of Cluj-Napoca inclusion in this study. The study
azzo et al. 2008, Mestnik et al. 2010, was registered in the ISRCTN reg-
2012, Heller et al. 2011, Silva et al. (University Iuliu Hatieganu, Cluj-
Napoca, Romania) between January istry (study ID ISRCTN17605083).
2011, Feres et al. 2012, Rodrigues
et al. 2012), it appears relevant to 2012 and January 2014. To be
included in the study, subjects had Treatment protocol
attempt optimizing the duration of
the AB intake. Indeed, in many to fulfil following criteria: This study was a prospective, ran-
areas of general medicine, shorter, >30 years of age domized, placebo-controlled, double-
high-dosage regimens compared to 12 natural teeth present in the masked clinical trial.
older regimens have been success- oral cavity distributed in all four All subjects enrolled in the study
fully employed (Green & Rothrock quadrants were allocated according to a com-
1993, Gooch et al. 1996, Barnett clinical (i.e. 1 site per quadrant puter-generated list to one of the fol-
et al. 1997, de Boer et al. 1997, with PD 6 mm) and radio- lowing three treatment groups:
Schrag et al. 2001, Chastre et al. graphic signs of generalized severe SRP + placebo (for 7 days; control
2003, Dunbar et al. 2003, Milo et al. chronic periodontitis (Armitage group A, n = 34), SRP + AMX +
2005, Joshi 2011). 1999) MET (both 500 mg TID 9 3 days
At the time being, it remains full-mouth plaque scores (FMPS) afterwards placebo TID 9 4 days;
unknown whether a short-term (e.g. 25% (OLeary et al. 1972) group B, n = 34) and SRP + AMX +
3 days) administration of systemically healthy, i.e. absence MET (both 500 mg TID 9 7 days;
AMX + MET as adjunct to non-sur- of a known condition that may group C, n = 34). Treatment alloca-
gical periodontal therapy may pro- influence the severity or progres- tion was performed according to a
vide additional benefits to scaling sion of periodontal disease (e.g. block randomization procedure and
and root planing (SRP) alone. Thus, Down Syndrome, HIV, Diabetes the randomization list was concealed
the aim of this study was to evaluate Mellitus types 1 and 2) to all examiners, except for the person
the potential effect of 3- or 7-day no head and neck radiation in charge for delivering the pills to the
systemic administration of AMX therapy patients (RT).
and MET as adjunct to SRP over no infectious or heart diseases At baseline (i.e. prior to SRP), at
SRP alone during non-surgical that need prophylactic admin- 3 and 6 months after SRP,
2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
4 Cosgarea et al.

assessment of the medical and smok- medications and instructed them on persons (LL, EB). The data were
ing history, oral hygiene and clinical how to take them. Each patient then transferred into a statistical
periodontal parameters was per- received four identical bottles: bottles software program (SPSS statistics
formed by one calibrated examiner No. 1 and 2 were with pills for the 21, IBM, Armonk, NY, USA), and
(RJ), blinded to the treatment group. first 3 days after SRP; bottles No. 3 an experienced professional statisti-
Patients were asked about their and 4 were distributed for the follow- cian (CH) performed all analyses.
smoking habits; those smoking 10 ing 4 days. All subjects had to take The statistical unit was the patient,
cigarettes per day for the last 5 years one pill from each bottle every 8 h. and all sites with PD 4 mm at
were defined as smokers (Ammen- The placebo group (group A) had baseline were considered for the sta-
heuser et al. 1997). Oral hygiene sta- only placebo pills in all bottles; tistical analyses. The primary out-
tus and gingival inflammation were Group B had AMX and MET in bot- come variable was the difference (D)
assessed by FMPS (OLeary et al. tles No. 1 and 2, and placebo pills in in the number of sites per patient
1972) and full-mouth bleeding scores bottles No. 3 and 4. Group C had with PD 6 mm between baseline
[gingival bleeding index; GBI AMX and MET in all four bottles. and 6 months. Secondary variables
(Ainamo & Bay 1975)] at four sites All bottles were prepared by the phar- were average changes in BOP, GBI,
per tooth as percentage values. Prob- macy of the University of Medicine FMPS, PD, CAL, number of sites
ing PD and vertical CAL were and Pharmacy Iuliu Hatieganu with PD 6 mm, number of sites
recorded at six sites per tooth to the Cluj-Napoca. All capsules were taste- with PD 5 mm, the total number
nearest millimetre using a periodon- less with identical appearance. of sites with PD = 4 mm and BOP+
tal probe (PCPUNC 15, Hu Friedy, Patients were recalled at 2 weeks, or with PD 5 mm and their D. p
Chicago, IL, USA). The reference 3 months and 6 months after comple- values < 0.05 were considered to be
point for the CAL measurements tion of SRP. At these appointments, statistically significant.
was considered the cementenamel information about any adverse Comparisons within the groups
junction (CEJ); if the CEJ had been events, compliance regarding intake between the various time points were
modified by restorative treatment, of the study medication and intake of performed using Paired t-test and
then the reference point was consid- any additional concomitant medica- Wilcoxon Signed Ranks Test.
ered the most apically located mar- tion was collected by asking the Adjusting for baseline values and
gin of the restoration. Bleeding on patients. Furthermore, at 3 and smoking, comparisons among the
probing (BOP) was assessed as the 6 months, GBI, FMPS, periodontal groups at the various time points
percentage of sites showing bleeding clinical parameters and BOP were were performed by means of ANCOVA
30 s after probing. recorded by one experienced clinician using the Bonferroni adjustment.
Oral hygiene instruction sessions, (RJ), who was blinded to treatment By mean of a Poisson regression
including professional prophylaxis, allocation. Finally, at the 3- and 6- analysis, the relationship between the
were performed until each patient month appointments supragingival number of sites with PD 6 mm at
had a FMPS 25%. Once the calculus was removed, but residual 6 months and the following vari-
desired FMPS was reached, SRP was periodontal pockets, i.e. pockets with ables: AB for 3 days, AB for 7 days,
performed within 24 h by one experi- PD = 4 mm + BOP, or PD 5 mm, smoking, gender, baseline BOP,
enced periodontist (RC) blinded to were not re-instrumented. FMPS, GBI, baseline mean PD,
the treatment allocation. In particu- baseline mean CAL, severe disease
lar, all pockets with PD 4 mm were Intra-examiner reproducibility
(i.e. >25 sites with PD 6 mm at
scaled and root planed to the bottom baseline) was determined.
of the pocket with ultrasonic instru- Ten patients, each with 10 teeth (sin-
ments (Kavo Sonicflex Scaler; Kavo gle and multi-rooted) with
Results
Dental GmbH, Biberach, Germany) PD 6 mm on at least one aspect
and Gracey curets (Hu Friedy, Chi- of each tooth, were used to calibrate
Patients
cago, IL, USA), under local anaesthe- the examiner. The examiner evalu-
sia; subsequently, the pockets were ated the patients on two separate Mean age of the 102 included patients
thoroughly rinsed with 0.2% occasions 48 h apart, prior to com- (65 females, 64%) was
chlorhexidine digluconate solution mencing the study. Calibration was 43.37  9.85 years, and 35 (34%)
(Corsodyl, GlaxoSmithKline, Brent- accepted if the two sets of measure- were smokers. Non-surgical peri-
ford, London, UK). The patients ments of PD and CAL did not differ odontal therapy was performed
were then instructed to rinse twice 1 mm in >90% of the cases. The between April 2012 and April 2014.
daily for 2 min. with a 0.2% mean intra-examiner reliability was Eleven subjects were lost during fol-
chlorhexidine digluconate solution 0.87 for PD and 0.76 for CAL low-up due to the following reasons:
(Corsodyl, GlaxoSmithKline), and (Cohens Kappa Analyses). additional AB intake for other medi-
to brush their teeth with 0.2% cal reasons (n = 4), moved to another
chlorhexidine digluconate tooth paste Statistical analyses
town (n = 2) and non-compliance
(Elugel, Pierre Fabre, Paris, France) with the appointments (n = 5). Thus,
for 14 days. At the end of the SRP All sampled data were introduced per protocol analyses included only
sessions, one clinician (RT) allocated into a database by one person (LI), the 91 patients [mean age
the patients to one of the three treat- and checked for errors by compar- 43.05  9.84 years, 57 females
ment groups according to the ran- ison with the original patients charts (62%), 33 smokers (36%)] who com-
domization protocol, gave their by two additional independent pleted the study (Figure 1, Table 1).
2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
SRP with a 3 or 7-day antibiotic regimen 5

Clinical findings

The clinical parameters registered at


baseline, 3 months and 6 months are
presented in Table 2. No statistical
differences were observed among the
groups at baseline for any of the
evaluated parameters (p > 0.05). At
3 and 6 months, all investigated
parameters demonstrated statistically
highly significant improvements
compared to baseline in all treatment
groups (p < 0.001, paired t-test and
Wilcoxon Signed Ranks Test). At
both 3 and 6 months, statistically
significantly greater improvements
(p < 0.05) in the two antibiotic
groups compared to the placebo
group were observed regarding sev-
eral of the evaluated parameters
(Table 2).
In particular, at 6 months, aver-
age PD reduction in the placebo
group (1.90  0.69 mm) was signifi-
cantly smaller compared to the 3-
day (2.54  0.62 mm) or the 7-day
AB regime (2.76  0.65 mm)
groups. Significantly larger CAL
gains were also recorded in groups B
and C (1.68  0.55 mm and
1.77  0.53 mm, respectively) com-
pared to the placebo group
(1.13  0.74 mm) at 6 months
Fig 1. Flowchart of the study. PCR, plaque control record; SRP, scaling and root (Table 2). When looking separately
planning. at moderately deep (46 mm) and
deep (7 mm) sites, statistically sig-
There was no statistical significant Adverse events
nificantly greater PD reductions
difference between the groups regard- Adverse effects including headaches, (p < 0.05) were obtained both at 3
ing gender, smoking status (Table 1) musculoskeletal pain, taste disorders and 6 months in the two AB groups
and baseline clinical parameters (e.g. metallic taste), vertigo, gastroin- as compared with the placebo group
(Table 2). Patient compliance with testinal disorders (i.e. nausea, diar- (Table 2). Also, statistically signifi-
AB intake was excellent; all patients rhoea), fever and shivering were cantly higher CAL gains (p < 0.05)
reported taking all the given pills, and reported by one or two patients in were obtained in the two AB groups
the only deviation from schedule was each treatment group, with no appar- compared with the placebo group at
that a few patients took occasionally ent differences among groups 6 months (Table 2).
the pills with a few hours difference (Table S1). None of the subjects pre- The total number of sites with
from the advised 8 h interval. sented allergies or candida infections. PD 6 mm in group B, decreased
from 921 sites at baseline, to 76 and
Table 1. Demographic characteristics 52 sites at 3 and 6 months, respec-
tively; in group C, it was reduced
Variables Group A Group B Group C
from 1100 sites at baseline, to 176
Gender (Female/male %) 21/12 22/11 20/14 and 156 sites at 3 and 6 months,
Age (years) 42.5  9.64 42.3  9.73 44.3  10.3 respectively. In the placebo group,
Smoker (%) 11 11 13 the decrease in the total number of
GBI (%) sites with PD 6 mm from baseline
Baseline 7.92  7.79 8.03  11.04 13.50  18.82 (767 sites) to 3 (211 sites) and
3 months 5.37  8.35 3.08  4.09 4.05  5.95 6 months (254 sites) was smaller com-
6 months 4.12  5.59 2.03  2.45 3.55  5.11
pared to the two AB groups. On aver-
FMPS (%)
Baseline 19.86  6.11 17.29  6.04 19.51  5.72 age, 28.62  15.32 less sites per
3 months 33.13  22.46 32.04  20.07 37.06  17.85 patient in group B and 30.45  15.04
6 months 37.28  17.92 31.49  19.24 28.75  19.59 less sites per patient in group C, com-
pared to baseline, presented at
GBI, gingival bleeding index (Ainamo & Bay 1975); FMPS, full-mouth plaque score after 6 months a PD 6 mm. The
OLeary et al. (1972).

2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
6 Cosgarea et al.

Table 2. Mean values and group comparisons (ANCOVA adjusted for baseline values and smoking) of PD, CAL, BoP, GBI, FMPS, number
(No.) of sites with PD 6 mm, with PD 5 mm, with PD = 4 BOP+ and PD 5 and their differences (D) between the follow-ups and
baseline (mean  SD)
Variables Group A Group B Group C Group comparisons Smoker
Non-smoker
(SRP + Placebo) (SRP + AB 3 days) (SRP + AB 7 days) p value A-B p value A-C p value
N = 30 N = 30 N = 31

PD (mm)
Baseline 5.45  0.61 5.46  0.50 5.79  0.58
3 months 3.47  0.42 3.03  0.39 3.16  0.62 0.001* 0.007* 0.10
6 months 3.52  0.48 2.90  0.45 2.97  0.45 <0.001* <0.001* 0.04*
baseline3 month 1.97  0.58 2.43  0.53 2.63  0.80
baseline-6 month 1.90  0.69 2.54  0.62 2.76  0.65
CAL (mm)
Baseline 5.92  1.24 5.80  1.16 6.14  1.18
3 months 4.68  1.19 4.40  1.15 4.54  1.29 0.403 0.089 0.151
6 months 4.76  1.22 4.12  1.16 4.29  1.14 0.001* <0.001* 0.055
baseline3 months 1.24  0.64 1.44  0.51 1.60  0.68
baseline6 months 1.13  0.74 1.68  0.55 1.77  0.53
PD 46 mm (mm)
Baseline 4.88  0.22 4.90  0.25 4.94  0.21
3 months 3.20  0.37 2.83  0.36 2.87  0.48 0.001* 0.004* 0.021*
6 months 3.26  0.46 2.72  0.39 2.70  0.37 <0.001* <0.001* 0.044*
baseline3 months 1.68  0.44 2.07  0.40 2.07  0.55
baseline6 months 1.62  0.53 2.17  0.46 2.22  0.39
CAL of PD 46 mm (mm)
Baseline 5.48  1.09 5.32  1.14 5.36  0.98
3 months 4.42  1.14* 4.10  1.16* 4.16  1.17* 0.66 0.82 0.43
6 months 4.53  1.19* 3.87  1.14* 3.96  1.07* 0.004* 0.007* 0.287
baseline3 months 1.06  0.66 1.21  0.43 1.20  0.56
baseline6 months 0.94  0.72 1.40  0.47 1.36  0.44
PD >7 mm (mm)
Baseline 7.73  0.58 7.63  0.62 7.97  0.92
3 months 4.77  1.10 3.73  0.76 4.06  1.08 <0.001* 0.015* 0.079
6 months 4.94  1.14 3.64  0.91 3.85  0.92 <0.001* <0.001* 0.003*
baseline3 months 2.86  1.24 3.89  0.89 3.91  1.44
baseline6 months 2.66  1.31 3.96  0.98 4.08  1.36
CAL of PD >7 mm (mm)
Baseline 7.72  1.01 7.97  1.49 8.06  1.48
3 months 5.92  1.18 5.56  1.53 5.74  1.74 0.105 0.27 0.204
6 months 6.00  1.17 5.15  1.64 5.46  1.54 0.001* 0.01* 0.052
baseline3 months 1.79  1.20 2.41  1.11 2.31  0.99
baseline6 months 1.67  1.30 2.82  1.16 2.52  0.94
BoP (%)
Baseline 64.93  24.66 64.06  34.33 71.27  26.55
3 months 16.05  10.67 11.62  9.10 9.92  7.59 0.19 0.018* 0.99
6 months 13.07  9.02 9.47  5.34 7.75  6.64 0.23 0.013* 0.82
GBI (%)
Baseline 7.92  7.79 8.03  11.04 13.50  18.82
3 months 5.37  8.35 3.08  4.09 4.05  5.95 0.56 1.00 0.57
6 months 4.12  5.59 2.03  2.45 3.55  5.11 0.40 1.00 0.022*
FMPS (%)
Baseline 19.86  6.11 17.29  6.04 19.51  5.72
3 months 33.13  22.46 32.04  20.07 37.06  17.85 1.00 1.00 0.76
6 months 37.28  17.92 31.49  19.24 28.75  19.59 0.95 0.33 0.078
No. PD 6
Baseline 25.32  16.86 30.70  14.93 36.89  16.91
3 months 7.54  5.62 2.53  3.59 6.29  6.72 <0.001* 0.148 0.282
6 months 8.47  6.14 1.93  3.28 5.03  5.77 <0.001* <0.001* 0.023*
baseline3 months 17.78  14.73 28.16  14.41 30.60  16.10
baseline6 months 17.10  14.68 28.62  15.32 30.45  15.04
No. PD 5
Baseline 41.71  19.62 48.30  19.85 54.43  19.80
3 months 11.54  7.13 6.40  6.75 10.54  9.41 0.004* 0.367 0.289
6 months 12.60  8.40 5.41  6.45 8.71  8.52 <0.001* 0.004* 0.046*
baseline3 months 30.17  16.22 41.90  18.73 43.89  19.31
baseline6 months 29.76  16.66 42.55  20.31 44.25  16.56

2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
SRP with a 3 or 7-day antibiotic regimen 7

Table 2. (continued)
Variables Group A Group B Group C Group comparisons Smoker
Non-smoker
(SRP + Placebo) (SRP + AB 3 days) (SRP + AB 7 days) p value A-B p value A-C p value
N = 30 N = 30 N = 31

No. PD = 4 BOP+ and PD 5


Baseline 54.79  23.45 62.83  22.31 68.75  23.06
3 months 14.21  8.14 8.07  7.57 12.07  9.85 0.002* 0.159 0.335
6 months 14.63  9.47 6.67  7.08 10.03  9.60 <0.001* 0.004* 0.038*
baseline3 months 40.57  19.67 54.76  21.61 56.67  21.98
baseline6 months 41.76  19.05 55.77  23.48 57.29  19.79

PD, pocket depth; CAL, clinical attachment level; BOP, bleeding on probing; GBI, gingival bleeding index (Ainamo & Bay 1975); FMPS,
full-mouth plaque score after OLeary et al. (1972).
*Statistical significant p values.

Table 3. Poisson regression analyses for the number of residual sites with PD 6 mm at difference in the number of pockets
6 months after non-surgical periodontal therapy as related to placebo group (group A) with PD 6 mm between baseline
and 6 months after treatment. This
Variables Exp. 95% CI p value
coefficient
is a relevant outcome variable after
periodontal therapy, as it has been
Group B (AB for 3 days) 0.24 0.170.32 <0.001* previously observed that patients
Group C (AB for 7 days) 0.33 0.250.43 <0.001* with a large number of residual
Female gender 0.75 0.590.93 0.010* pockets 6 mm show a statistically
Smoker 1.35 1.071.69 0.010* significantly higher risk for further
25 sites with PD 6 mm 1.26 0.951.65 0.103 attachment loss, and thus require
at baseline
further treatment usually surgical
BOP baseline 1.00 0.991.01 0.16
GBI baseline 0.98 0.970.99 0.027*
therapy (Matuliene et al. 2008,
FMPS baseline 0.99 0.991.00 0.66 2010). Likewise, several studies have
Mean PD baseline 1.42 1.141.79 0.002* previously investigated the effect of
Mean CAL baseline 1.30 0.911.15 0.60 AB as adjunct to non-surgical peri-
odontal treatment in various treat-
PD, pocket depth; CAL, clinical attachment level; BOP, bleeding on probing; GBI, gingival ment protocols by using as endpoint
bleeding index (Ainamo & Bay 1975); FMPS, full-mouth plaque score after OLeary et al.
the number of sites of specific depths
(1972).
*Statistically significant p values. Reference categories are as follows: Group A, Male, Non- (Cionca et al. 2009, Feres et al.
Smoker (Exp. Coefficient equals). 2012, Arweiler et al. 2014). Other
studies have chosen mean full-mouth
PD or CAL as endpoint (Winkel
reduction in the number of sites with smoking, baseline GBI and baseline et al. 2001, Ehmke et al. 2005,
PD 6 mm from baseline to mean PD influenced statistically sig- Matarazzo et al. 2008, Silva et al.
6 months in group A (17.10  14.68 nificant the residual number of sites 2011, Feres et al. 2012) for evaluat-
sites) was statistically significantly less with PD 6 mm: groups B and C ing the efficacy of various antibiotic
compared to that in the two AB showed 4.19 and 3.00 times less sites regimens. However, using mean val-
groups. with PD 6 mm, respectively, com- ues instead of frequencies is prob-
The numbers of sites with pared to group A (Table 3). Smok- lematic; shallow sites showing
PD 6 mm, PD 5 mm and the ers had 1.35 times more chances to limited improvements even after
total number of sites with show sites with PD 6 mm at treatment compared to deeper sites
PD = 4 mm and BOP+ or with 6 months after treatment. Female in terms of numerical values (Winkel
PD 5 mm in the placebo group patients had 0.74 times less chances et al. 2001, Ehmke et al. 2005,
(group A) were statistically signifi- to show sites with PD 6 mm at Cionca et al. 2009, Silva et al. 2011,
cantly higher as compared to the 3- 6 months after treatment (Table 3). Feres et al. 2012) are likely to signifi-
day AB group (group B) at both cantly dilute the effect observed in
recall time points; when compared to deeper sites, which are actually in
Discussion
the 7-day AB group (group C), need for further treatment.
group A exhibited statistically signif- This study has evaluated the clinical The results of this study showed
icantly higher number of residual outcomes following non-surgical that both, a 3- or 7-day antibiotic
pockets with PD 6 mm, with periodontal therapy in conjunction regimen as adjunct to SRP exhibited
PD 5 mm and a total number of with adjunctive AMX and MET superior clinical results than those
sites with PD = 4 mm and BOP+ or administered systemically for 3 or obtained by SRP alone. Specifically,
with PD 5 mm at 6 months for 7 days compared with SRP alone the use of AB as adjunct to SRP
(Table 2). in patients with generalized severe resulted in statistically significantly
The regression analysis showed chronic periodontitis. The main out- higher clinical improvements than
that, at 6 months, AB, gender, come variable in this study was the those obtained in the placebo group
2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
8 Cosgarea et al.

regarding the number of sites with several studies have shown that deep an increasing problem globally. It
PD 6 mm, the number of sites pockets profit more by AB adminis- appears thus relevant to attempt
with PD 5 mm and their differ- tration as compared to shallow sites optimizing AB intake if this should
ences before and after treatment (), (Winkel et al. 2001, Ehmke et al. be considered as standard adjunct to
the total number of sites with 2005, Cionca et al. 2009, Silva et al. periodontal therapy; of course it is
PD = 4 and BOP+ and mean PD 2011, Feres et al. 2012). In general, important that the AB is given in an
reduction and CAL gain (Tables 2 the average additional PD reduction adequate (minimum) bactericidal
and 3). obtained from the adjunct use of AB dose for an adequate (minimum)
Comparable improvements after in the moderately deep pockets in length of time (Vogelman & Craig
SRP combined with systemic this study (ca. 0.5 mm) is compara- 1986). Various dosages of AB have
AMX + MET have been reported by ble to that reported in the recent previously been employed in the var-
Feres et al. (Feres et al. 2012); for meta-analysis of Keestra et al. ious studies evaluating the effect of
example, at 1 year after non-surgical (2015) mentioned earlier. However, SRP in combination with AB, but
treatment 6.9  10 sites with when interpreting the results of this the optimal dose (single drug or
PD 6 mm in the placebo group study, it is important to point out combination of AB) for the treat-
versus 1.2  2.2 sites in the that due to its design (i.e. the study ment of periodontitis has not yet
AMX + MET group were obtained was set up as a superiority trial of been clearly defined. For example,
(Feres et al. 2012). However, the the two AB regimes over SRP alone) many studies evaluating AMX as
antibiotic regimen in that study was direct comparisons between the two adjunct to SRP have used dose
substantially different from herein, AB regimes are not appropriate as ranges 375500 mg TID for 7
i.e. MET (400 mg TID) and AMX such comparisons would be under- 14 days (van Winkelhoff et al. 1989,
(500 mg TID) for 14 days. Interest- powered and might lead to erro- Guerrero et al. 2005, Matarazzo
ingly, their results after 1 year are neous conclusions. et al. 2008, Cionca et al. 2009, Yek
comparable with the results obtained Furthermore, by means of a Pois- et al. 2010, Griffiths et al. 2011,
after 6 months in the 3 or 7 days son regression model, AB, female Silva et al. 2011, Feres et al. 2012).
AB regimens of this study. In gender, smoking, initial mean PD Studies evaluating MET have used
another study evaluating the out- and initial mean GBI were shown to ranges 250400 mg TID (Lindhe
come of SRP and AMX + MET, a statistically influence the number of et al. 1983, van Winkelhoff et al.
lower number of sites with residual pockets with PD 6 mm 1989, Loesche et al. 1992, Winkel
PD 5 mm was obtained after after treatment. The finding that AB et al. 2001, Ehmke et al. 2005,
6 months comparing to that had a major positive influence on the Matarazzo et al. 2008, Silva et al.
observed herein (Cionca et al. 2009), clinical outcomes is in agreement with 2011). More important is that the
i.e. 3.0  4.3 sites in the placebo the results of the logistic regression antibiotic should be given in an ade-
group and 0.4  0.8 in the AB analyses performed in the studies by quate bactericidal dose for an ade-
group. The lower number of deep Cionca et al. (2009) and Feres et al. quate length of time. MET reaches
sites observed in Cionca et al. (2012) where AB was the only vari- an effective serum concentration in
(Cionca et al. 2009) compared to able that significantly influenced the an adult for a concentration of 20
that obtained herein, may well be primary outcome variable. In con- 25 mg/kg body weight (van Winkel-
due to the fact that only patients trast to Cionca et al., where smoking hoff et al. 1999). Therefore, for a
with moderate-to-severe ChP (i.e. had no statistically significant influ- 70 kg patient, the daily needed MET
presenting at least four teeth with ence, the results of this study indicate dose would be 14001750 mg (Win-
PD > 4 mm and CAL 2 mm) were that smokers had a 0.74 (1/1.35) kel et al. 1997, van Winkelhoff et al.
included in the former study, higher number of residual sites with 1999). A more recent study (Cionca
whereas only generalized severe ChP PD 6 mm compared to non-smo- et al. 2009) used a MET dosage of
patients with at least 1 tooth per kers, irrespective of treatment group. 500 mg TID for 7 days in combina-
quadrant with PD 6 mm were This is also recognizable when look- tion with AMX 375 mg TID for
included in this study. Indeed, in ing at the smoking-adjusted analyses 7 days, showing significant clinical
our study double as much number for the number of sites with and microbiological results for the
of sites with PD 5 mm were pre- PD 6 mm, PD 5 mm and AB group (Cionca et al. 2009, 2010).
sent in each treatment group com- PD 4 mm and BOP+, where smok- In this study the AB protocol con-
pared to those in the study by ers had significantly more (p < 0.05) sisted of MET 500 mg TID and
Cionca et al. (Cionca et al. 2009). of these specific sites at 6 months as AMX 500 mg TID, both for 3 and
Similarly, these differences regarding compared to non-smokers (Table 2). 7 days. Thus, the AB regimen used
the severity of baseline clinical peri- This is in agreement with previous herein falls within the effective daily
odontal conditions of the patients findings, which have shown that dose for the average adult patient.
included in the above-mentioned smoking is strongly associated with Regarding the aspect of AB
studies and those included herein poorer clinical and microbiological administration duration, several stud-
may also explain the larger average responses after conventional or ies have shown that resistant micro-
clinical improvements (PD reduction regenerative periodontal therapy bial strains can appear de novo when
and CAL gain) observed herein in (Winkel et al. 2001, Van der Velden low-drug doses are prescribed for
comparison to what observed Cionca et al. 2003, Hughes et al. 2006). long-term infections (Lipsitch &
et al. and Feres et al. (Cionca et al. In perspective, development of Levin 1997, Musher et al. 2002,
2009, Feres et al. 2012). Indeed, microbial strains resistant to AB is Lieberman et al. 2011). Therefore, in
2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
SRP with a 3 or 7-day antibiotic regimen 9

several areas of general medicine AB et al. 2008, Cionca et al. 2009, Silva streptococcal pharyngitis in children. The
Cochrane Database Systematic Reviews 8,
administration in high dosage and for et al. 2011, Feres et al. 2012) and a
CD004872. doi:10.1002/
shorter intervals has been evaluated standard deviation of 6 (Cionca et al. 14651858.CD004872.pub3.
for various infections (Green & 2009, Feres et al. 2012) between the Altamimi, S., Khalil, A., Khalaiwi, K. A., Milner,
Rothrock 1993, Gooch et al. 1996, treatment groups at 6 months, with a R., Pusic, M. V. & Al Othman, M. A. (2009)
Barnett et al. 1997, de Boer et al. study power set at 90% and a signifi- Short versus standard duration antibiotic ther-
apy for acute streptococcal pharyngitis in chil-
1997, Schrag et al. 2001, Chastre cance level of 0.05. When considering dren. The Cochrane Database Systematic
et al. 2003, Dunbar et al. 2003, Milo the results obtained herein (i.e. differ- Reviews, 21, CD004872. doi:10.1002/14651858.
et al. 2005, Joshi 2011). For example, ence in the number of sites with CD004872.pub2.
in two recent reviews on short-term PD 6 mm between baseline and Ammenheuser, M. M., Hastings, D. A., Whorton,
E. B. Jr & Ward, J. B. Jr (1997) Frequencies of
AB administration in acute strepto- 6 months, a standard deviation of hprt mutant lymphocytes in smokers, non-smo-
coccal pharyngitis in children (Alta- approximately 15, 30 subjects per kers, and former smokers. Environmental and
mimi et al. 2009, 2012), it was group and a desired power of 90% Molecular Mutagenesis 30, 131138.
concluded that a 3-day oral AB regi- with a statistical significance level at Armitage, G. C. (1999) Development of a classifi-
cation system for periodontal diseases and con-
men yielded comparable clinical and 0.05), the minimum detectable differ- ditions. Annals of Periodontology 4, 16.
microbiological efficacy to that of ence between the two AB groups is Arweiler, N. B., Pietruska, M., Pietruski, J.,
standard treatment of 10 days. Fur- approximately 11 sites. If a difference Skurska, A., Dolinska, E., Heumann, C., Ausc-
thermore, the short duration treat- in five sites with an assumed SD of 15 hill, T. M. & Sculean, A. (2014) Six-month
ment had shorter periods of clinical should have been detected with results following treatment of aggressive peri-
odontitis with antimicrobial photodynamic
symptoms (fever, throat soreness) 80% power and the significance level therapy or amoxicillin and metronidazole. Clin-
and a lower risk of early clinical treat- set at 0.05142 patients would have ical Oral Investigations 18, 21292135.
ment failure. Similar findings favour- been needed in each group; to detect Barbosa, T. M. & Levy, S. B. (2000) The impact of
ing shorter AB administration have a difference of two sites, 884 patients antibiotic use on resistance development and
persistence. Drug Resistance Updates 3, 303311.
been reported for acute urinary tract would have been needed per group. Barnett, E. D., Teele, D. W., Klein, J. O., Cabral,
infections (Michael et al. 2003), intra- Such high numbers are unfortunately H. J. & Kharasch, S. J. (1997) Comparison of
abdominal infections (Sawyer et al. almost impossible to achieve under ceftriaxone and trimethoprim-sulfamethoxazole
2015) and infectious episodes in gen- usual settings. However, post hoc for acute otitis media. Greater Boston Otitis
Media Study Group. Pediatrics 99, 2328.
eral surgery units (Hedrick et al. power calculation revealed a power de Boer, W. A., van Etten, R. J., Schade, R. W.,
2006). Further data that are in sup- for the overall F-Test of 92% power, Ouwehand, M. E., Schneeberger, P. M., van
port for our decision to evaluate the whereas when adjusting for pair-wise Unnik, A. J. & Tytgat, G. N. (1997) One-day
3- and the 7 day AB therapy are those comparisons related to the placebo intensified lansoprazole-quadruple therapy for
cure of Helicobacter pylori infection. Alimen-
obtained by Feres et al. (2002): the group, the power was 85% (Tukey tary Pharmacology & Therapeutics 11, 109112.
transient increase in resistant bacte- Test) and 84% (Bonferroni Test). In Carvalho, L. H., DAvila, G. B., Leao, A., Gon-
rial species was at 3 days of AMX context, to determine the equivalence calves, C., Haffajee, A. D., Socransky, S. S. &
and MET administration lesser than or non-inferiority of the 3-day Feres, M. (2005) Scaling and root planing, sys-
temic metronidazole and professional plaque
that obtained for the 7 days regimen. adjunctive AMX and MET therapy
removal in the treatment of chronic periodonti-
Thus, a 3-day AB regimen appeared over the 7-day AB administration, tis in a Brazilian population IImicrobiological
as a logical duration to be also evalu- further studies with the proper design results. Journal of Clinical Periodontology 32,
ated, but neither final conclusions on are necessary. 406411.
the clinical relevance of the 3-day reg- In conclusion, these findings have Chastre, J., Wolff, M., Fagon, J. Y., Chevret, S.,
Thomas, F., Wermert, D., Clementi, E., Gon-
imen nor one on the possibility that shown that in patients with severe zalez, J., Jusserand, D., Asfar, P., Perrin, D.,
similar results might have been chronic periodontitis SRP in con- Fieux, F. & Aubas, S. (2003) Comparison of 8
obtained with even shorter AB junction with a 3- or 7-day systemic vs 15 days of antibiotic therapy for ventilator-
administration can be made. administration of AMX and MET associated pneumonia in adults: a randomized
trial. JAMA 290, 25882598.
In this study, a trend for better may lead to significantly greater clin- Cionca, N., Giannopoulou, C., Ugolotti, G. &
clinical outcomes after 7 days of AB ical improvements compared to SRP Mombelli, A. (2009) Amoxicillin and metron-
was observed. Nevertheless, a direct alone. idazole as an adjunct to full-mouth scaling and
comparison regarding the clinical root planing of chronic periodontitis. Journal
of Periodontology 80, 364371.
findings between the two AB regimes
Acknowledgements Cionca, N., Giannopoulou, C., Ugolotti, G. &
would not be appropriate, as any Mombelli, A. (2010) Microbiologic testing and
comparisons would be underpowered The authors would like to thank the outcomes of full-mouth scaling and root plan-
and might lead to erroneous conclu- study nurses Livia Indolean and ing with or without amoxicillin/metronidazole
in chronic periodontitis. Journal of Periodontol-
sions. A valid comparison between Erika Batiz for data entries and
ogy 81, 1523.
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Clinical Relevance Principal findings: Both 3- and 7-day Practical implications: In patients
Scientific rationale for the study: It antibiotic (AB) regimes resulted in with severe chronic periodontitis,
remains unclear whether a short- statistically significant improvements non-surgical periodontal therapy in
term systemic administration (e.g. for all evaluated clinical parameters, conjunction with a 3- or 7-day
for 3 days) of amoxicillin (AMX) when compared to SRP, at 3 and antibiotic protocol with
and metronidazole (MET), as 6 months after treatment. Both AB AMX + MET may yield greater
adjunct to non-surgical periodontal regimens showed greater mean PD clinical improvements than non-
treatment (SRP) in severe chronic reductions and CAL gains, but also surgical therapy alone.
periodontitis patients, may provide a reduced number of sites with deep
additional clinical benefits com- pockets, e.g. PD 6 mm, compared
pared to SRP. to the SRP group.

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