Accepted Manuscript

Amoxicillin/clavulanic acid 2000/125 mg to prevent complications due to infectionfollowing completely bone-impacted lower third molar removal: a clinical trial

Iciar Arteagoitia, MD, PhD Eva Ramos, PhD Gorka Santamaría, DS, PhD LuisBarbier, MD, PhD Julio Alvarez, MD, PhD Joseba Santamaría, MD, PhD

PII: S2212-4403(14)01238-3

DOI: 10.1016/j.oooo.2014.08.014

Reference: OOOO 993

To appear in: Oral Surgery, Oral Medicine, Oral Pathology and OralRadiology

Received Date: 19 May 2014

Revised Date: 5 August 2014

Accepted Date: 25 August 2014

Please cite this article as: Arteagoitia I, Ramos E, Santamaría G, Barbier L, Alvarez J, Santamaría J,Amoxicillin/clavulanic acid 2000/125 mg to prevent complications due to infection following completelybone-impacted lower third molar removal: a clinical trial, Oral Surgery, Oral Medicine, Oral Pathologyand Oral Radiology (2014), doi: 10.1016/j.oooo.2014.08.014.

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Amoxicillin/clavulanic acid 2000/125 mg to prevent complications due to

infection following completely bone-impacted lower third molar

removal: a clinical trial

1. Iciar ARTEAGOITIA MD, PhD 1

2. Eva RAMOS PhD 3, 3. Gorka SANTAMARÍA DS, PhD 1 4. Luis BARBIER MD, PhD 1,2 5. Julio ALVAREZ MD, PhD 1,2 6. Joseba SANTAMARÍA MD, PhD 1,2,

1Stomatology I Department, Research group UPV/EHU IT821-13, University of the Basque Country, Leioa, Bizkaia, Spain 2Maxillofacial Group, BioCruces Health Research Institute, Cruces University Hospital. 3College of Pharmacists, Vizcaya, Spain

CORRESPOUNDING AUTOR

Dr Joseba Santamaria

Hospital Universitario de Cruces

Plaza de Cruces s/n

48903 Barakaldo, Bizkaia

Spain

Tel.: n34 656723213

e-mail: jsz@clinicaimd.com

WORD COUNT:

Abstract: 152

Complete manuscript: 3659

Number of references: 27

Number of tables: 5

Number of figures: 3

EudraCT database number: 2008-005663-34

Funding: This research was funded by a grant (EC-08/00068) from the

Carlos III Health Institute of the Spanish Ministry of Health, Social Services

and Equality.

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1.- ABSTRACT

Objective

To determine the effect of amoxicillin/clavulanic acid to prevent infection

following completely bone-impacted lower third molar removal.

Study design

A randomized double-blind placebo-controlled clinical trial including 118

adults randomly allocated to placebo (60 patients) or antibiotic treatment

(58 patients): 2 g amoxicillin/125 mg clavulanic acid 2 hours before the

surgery and post-operatively twice a day for 4 days. Infection was

clinically assessed until week 8 after surgery. Adverse events, as well as

clinical and surgical variables were recorded. Analysis was by intention to

treat.

Results

Infections developed in five patients in the placebo group, all in the first

postoperative week, and in two in the antibiotic group, both after the first

week, the difference not being statistically significant (P=0.278, NNT 19 [8-

∞]). There were no relaBonships between any variables studied and

infection. No serious adverse events were reported.

Conclusion

There is insufficient evidence to recommend routine use of this antibiotic

treatment.

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Statement of Clinical Relevance

In completely bone-impacted lower third molar removal, treatment with

amoxicillin/clavulanic acid 2000/125 mg is not effective for preventing

post-operative infections. Nevertheless, antibiotics are frequently

prescribed in clinical practice.

2.- INTRODUCTION

Surgical removal of unerupted impacted lower third molars is a common

procedure. However, there is no consensus1-3

on the use of antibiotics to

minimise infectious complications. Despite the fact that several different

studies4-14

have not demonstrated their effectiveness and that there is a

well-documented increase in bacterial resistance worldwide15

,

prophylactic use of antibiotics is very widespread in this type of surgery16

.

Completely bone-impacted lower third molars (CDT code D724017

) are, in

theory, the most difficult teeth to remove. This type of surgery is

associated with a high use of prophylactic antibiotics16

. There have

previously been no well-designed clinical trials providing evidence on the

usefulness of antibiotics in removal of this type of impacted teeth.

Given this, we designed a clinical trial, with the objective of assessing the

efficacy of an antibiotic regimen based on oral amoxicillin/clavulanic acid

at a dose of 2000/125 mg every 12 hours for 4 days compared to placebo.

The first dose was administered 2 hours before surgery.

3.- MATERIAL AND METHODS

We designed a single-centre, double-blind, randomised placebo-controlled

clinical trial with parallel groups. The trial was approved by the Ethics

Committee of Cruces University Hospital and the Spanish Agency of

Medicines and Medical Devices. It was conducted in compliance with

current legislation and the ethical principles of the Declaration of Helsinki,

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and it was registered on the EudraCT database (number: 2008-005663-

34).

The clinical trial was carried out in the Oral and Maxillofacial Unit of

Cruces University Hospital in the Basque Country, Spain. All patients over

18 years old undergoing completely bone-impacted lower third molar

removal for any indication were candidates for the study. The exclusion

criteria were: having unstable systemic diseases, risk factors for

endocarditis, an infection or taken antibiotics within the previous 10 days,

or an allergy or known intolerance to any study medication as well as, for

women, being pregnant or breastfeeding. All the surgical procedures were

performed under local and regional anaesthesia.

We performed an a priori sample size calculation using the online

software developed by GlaxoSmithKline´s Department of Biometrics,

assuming infection rates of 15.2%18

in the control group (CG) and 0.9% in

the experimental group (EG) with a type I error of 0.05 and a power of

80%. This indicated that we would need to recruit 118 patients if there

were no dropouts. (We estimated, however, that potentially 10% of

participants would be lost to follow-up.)

Consecutive patients who gave written informed consent for both the

surgery and participating in the clinical trial were randomly assigned to

one of the two groups using randomisation codes generated by the C4-

SDP software MAS Module. Patients assigned to the EG received an

opaque bottle with 18 tablets of amoxicillin/clavulanic acid 1000/62.5 mg

(Augmentine Plus®, GlaxoSmithKline), while patients in the CG received an

opaque bottle with 18 tablets of placebo (Laboratorium Sanitatis). All

participants were also provided with a box of 40 sachets of ibuprofen 600

mg (Espidifen®) and a 200 ml bottle of 0.12% chlorhexidine mouthwash

(Lacer chlorhexidine®).

At the first appointment, patients were selected, after confirmation by

panoramic radiography they met the inclusion criteria; that is, it was

checked that they had a completely bone-impacted lower third molar and

that they did not met any of the exclusion criteria. If in the panoramic

radiograph there appeared to be contact between the roots of the

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impacted lower third molar and the inferior alveolar nerve canal, a cone-

beam computed tomography scan was carried out before surgery. Patients

were provided with information about the surgical procedure and clinical

trial, and they had the informed consent form explained to them and were

given a copy.

In the second appointment, it was again checked that patients met the

selection criteria. We collected the signed informed consent forms and

each patient, having given their written consent, was assigned a

consecutive treatment number in accordance with the blind randomisation

process. A 5-ml sample of blood was taken for measuring the pre-surgery

levels of C-reactive protein (CRP, in mg/dl). The Hospital Pharmacy Unit

was in charge of the management of the medication and patients took two

tablets of antibiotic or placebo 2 hours before surgery.

All the operations were carried out by the same maxillofacial surgeon

using a standardised procedure: local and regional anaesthesia with 3.6 ml

of articaine (Ultracain®) with epinephrine 40/0.01 mg/ml for blocking the

inferior alveolar and buccal nerves. A full thickness mucoperiosteal flap

was elevated and reflected. The incision was made with a surgical scalpel

blade no. 15, forming an envelope flap extending from the mesial of the

second molar to the ramus with lateral divergence of the posterior

extension. Bone removal and tooth sectioning was performed with a hand

piece with a round bur. After the extraction, the socket was debrided and

irrigated with 3 ml of 0.12% chlorhexidine for 1 minute. Soft tissue was

sutured with 3-0 absorbable suture. In this second appointment, we also

recorded data on demographic, clinical, radiological and surgical variables

(Table I).

During the trial, one patient requested to be withdrawn from the study,

while two patients were excluded from the analysis given that their

operation lasted more than 60 minutes and one patient due to the

presence of residual root, requiring a CBCT scan. (See the flow chart in

Figure 1.)

After surgery, each patient was provided with a list of postoperative

instructions. Patients were trained to assess themselves during the first

week after surgery and complete a form recording their body temperature,

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how wide they were able to open their mouth in mm, and pain based on a

visual analogue scale (Figure 2). They were reminded about the treatment

regimen, that is, two tablets from the opaque bottle (antibiotic or placebo)

every 12 hours for 4 days. For analgesia, they were prescribed ibuprofen

(600 mg Espidifen®), and instructed take one sachet every 8 hours for as

long as pain relief was necessary. Finally, they were given a dose cup for

chlorhexidine (Lacer®) and told to use 10 ml of the mouthwash to rinse

their mouth for 20 seconds, 3 times a day, throughout the first week.

Patients’ participation in the clinical trial was documented in case report

forms. All patients had a contact telephone number to call for advice at

any time of day and night.

All participants underwent a physical examination 7 days after surgery. In

this visit, we collected a 5-ml blood sample for measuring CRP levels. A

single blinded observer assessed the postoperative variables for each

patient (Table II) and determined whether or not there was infection at

this stage (day 7). The record sheets on self-assessment of pain, mouth

opening and body temperature were collected, as was any leftover

medication, and any adverse reactions were recorded.

Patients were followed-up until week 8 after surgery, all requests for

advice or medical attention being dealt with over the telephone or by

seeing the patient in person for a clinical examination, as appropriate. In

the case of clinical examinations, the same single observer again assessed

each of the postoperative variables to determine whether (or not) there

was infection on the day of the visit.

Infection was defined on the basis of previously published clinical criteria:

• CRP ≥2.2 mg/dl

• Body temperature > 37.8°C for over 24 hours with no other

identifiable cause

• Intraoral abscess diagnosed by fluctuation or pus discharge

• Severe pain persisting or increasing 48 hours after surgery

accompanied by (moderate or severe) intraoral inflammation

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and/or (moderate or severe) intraoral erythema and/or limited

mouth opening.

• Severe pain after day 7 accompanied by intraoral inflammation

(moderate or severe) and/or intraoral erythema (moderate or

severe) with no other identifiable cause which improves with

antibiotic treatment.

We have not included dry socket as a criterion for infection, although we

have record it as absence of a clot with necrotic remains present in the

alveolus accompanied by severe mandibular pain.

In the cases diagnosed with infection, we broke the blind and

administered the corresponding rescue medication: patients from the EG

were prescribed oral metronidazole (two 250-mg tablets every 8 hours for

7 days; Flagyl®, Sanofi-Aventis), while those from the CG were

administered amoxicillin/clavulanic acid (two 1000/62.5-mg tablets every

12 hours for 7 days; Augmentine Plus®) and oral metronidazole (two 250-

mg tablets every 8 hours for 7 days; Flagyl®). Rescue analgesia was

provided with metamizole (one 750-mg capsule every 8 hours for as long

as pain relief was necessary; Nolotil®)

The study data were entered into an Excel database. Statistical analysis

was carried out using SPSS 15.0 statistical software. The homogeneity of

the study groups was assessed with chi-square tests, Fisher’s exact tests

and ANOVA. The difference in the response variables between the EG and

the CG were analysed using a two-tailed Pearson’s chi-square test, two-

tailed Fisher’s exact test, or ANOVA, depending on the nature of the

variables (qualitative or quantitative).

The clinical significance of administering antibiotics compared to placebo

was investigated by calculating the following measures of risk: relative risk

(RR), relative risk reduction (RRR), and absolute risk reduction (ARR). The

number of patients needed to treat (NNT) to prevent one adverse event

was also calculated, as was the number of patients that having received

antibiotics, rather than placebo, had an adverse event (i.e., the number

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needed to harm, NNH). The analysis was carried out on an intention-to-

treat basis.

Multivariate logistic regression analysis was carried out to determine

whether (or not) there were confounding or interfering variables.

Two interim analyses were performed by an independent researcher after

the recruitment of 33 and 86 patients, respectively. In these interim

analyses, results did not meet any of the criteria for stopping the trial

early, namely, 1) detection of serious or unexpected adverse effects, 2)

observation of markedly better outcomes in the experimental group,

raising ethical issues and meaning that it would not have made sense to

continue giving the placebo; 3) failure to meet the recruitment targets; or

4) appearance of data from other research that suggested the trial should

not be continued.

4.- RESULTS

We recruited 118 patients, 60 being assigned to the EG and 58 to the CG.

Patient demographic, clinical, radiological and surgical characteristics are

summarised in Table I.

With regards to the postoperative variables recorded on day 7 after

surgery, there were statistically significant differences between groups in

four variables: intraoral oedema, maximum postoperative mouth opening

and pain on intraoral and extraoral palpation (Table II).

According to the data from the self-assessment sheets completed by

patients during the week after surgery (recording pain, maximum mouth

opening and body temperature), there was a greater mouth opening and

lower perception of pain in the EG 2 days after surgery (Figure 3), while

mean body temperature values recorded were below what is considered a

high temperature (37.8C°).

Seven patients (5.9%) were diagnosed with infections, five in the CG

(8.6%) and two in the EG (3.3%) (p=0.278, Fisher’s exact test). The

probability of infection in the control group was three-fold higher than in

the EG and the ARR was 5%. The number of patients needed to treat (NTT)

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was 19 (CI 8-∞), implying that to prevent one case of infecBon anBbioBcs

would need to be given to 19 patients, but the confidence interval

included infinity (Table III)

All the patients with infection from the CG were diagnosed during the first

week after surgery, while those with infection in the EG were diagnosed

later (p=0.02, Fisher exact test). The day of diagnosis, group and

characteristics of patients with infections are listed in Table IV. No

confounding or interfering factors were identified in the multivariate

logistic regression analysis.

We recorded the medication returned and any adverse reactions up to

day 7 after surgery. Among the entire sample, only four patients, all in the

CG, returned any tablets of the study medication (in their case, placebo).

With regards to ibuprofen (Espidifen®), fewer sachets were returned by

CG patients (18.66 ± 5.19 [17.29-20.02] vs 21.65 ± 4.93 [20.38-22.92] in

the EG), the difference being significant (p=0.002, Fisher’s exact test). No

significant differences were found between the groups in the amount of

chlorhexidine returned.

The adverse reactions observed were expected, mild in nature and short

in duration (Table V) and were more frequent in the EG (p=0.009, Fisher’s

exact test); in no cases was it considered necessary to break the blind due

to these events. The NNH was 7 (4-19).

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5.- DISCUSSION

The study design was intended to minimise random and systematic errors.

The sample size was calculated a priori. Given that it was a placebo-

controlled randomised clinical trial, individuals were randomly assigned to

one of the study groups, the aim being to reduce confounding bias. In

addition, we have investigated potential intermediate variables and found

no significant associations.

We attempted to minimise selection bias, recruiting all eligible subjects

who attended Cruces University Hospital for this type of intervention, and

had no losses to follow-up, the four patients not included in the analysis

not being lost but rather excluded for other reasons. (Figure 1)

Information bias (misclassification) is a common error in all studies that

assess the variable infection clinically4-14,18-23

. Although there may still be

some degree of this type of bias in the study, we strived to minimise it by

using a single experienced observer and analysing the CRP levels 2 hours

before and 7 days after surgery. In fact, however, CRP levels were not

found to be useful for the diagnosis of infection.

In order to increase the external validity of the study, the exclusion criteria

were not very restrictive. Accordingly, the results can be generalised to

the population requiring in-hospital surgery for the removal of lower third

molars. Specifically, smoking was not an exclusion criterion and nor was

taking other types of medication during the study period, other authors

having excluded such cases5,7-9,11-14,19-23

. The conditions under which this

clinical trial was performed were the same as normal working conditions.

It should be highlighted that the person responsible for the tooth

extraction was a maxillofacial surgeon. Further, we note that before

suturing, the residual alveolus was irrigated with 0.12% chlorhexidine for 1

minute and that patients used a 0.12% chlorhexidine mouthwash for 7

days.

To minimise attrition bias in the comparisons, we have not excluded from

the analysis patients who may not have followed the treatment properly.

That is, we have performed intention-to-treat analysis, with patients

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remaining in the group to which they were randomly allocated, regardless

of whether they followed the pharmacological treatment correctly.

All patients were requested to return leftover medication at their follow-

up appointment on day 7, allowing us to assess adherence. Notably, none

of the patients returned antibiotic/placebo tablets which suggests a high

degree of compliance (the reason why four patients in the CG returned

medication being that they developed infections and started to be given

antibiotics).. On the other hand, patients did return anti-inflammatory

medication and antiseptic mouthwash, and none were excluded for having

larger unused amounts of these types of medications.

We should highlight from our results the low rate of infection in the CG

(8.62%), lower than that published by many other authors: Pasupathy6

(2011), 10.33%; López-Cedrun19

(2011), 12.5%; Bezerra7 (2011), 11.76%;

Monaco20

(2009), 14.82%; Ataoglu11

(2008), 18%; Kaczmarzyk12

(2007),

14.81%; Lacasa21

(2007), 16%; Arteagoitia18

(2005), 12.9%; Graziani23

(2005), 20%; Bergdahl13

(2004), 21.7%; and Poeschl14

(2004), 9.88%. We

do not have data to assess the potentially protective effect of the use of

chlorhexidine both for the intraoperative irrigation of the surgical alveolus

and for mouthwashes throughout the first week after surgery. Although

Larsen24

determined that use of a perioperative 0.12% chlorhexidine

gluconate rinse was associated with at least a 50% reduction in alveolar

osteitis compared with control groups.

The timing of infections is also important. Infections were observed during

the first week after surgery in the five patients from the CG and later in

the two patients from the EG. Considering these data, it is possible that

factors related to difficulties in tissue healing and/or bacterial

proliferation may be involved in infections developing beyond one week

after surgery.

The NTT obtained in this study is high, 19 patients (95%, CI 8-∞).

Moreover, to take a clinical decision, we should not only take into account

this result, indicating it may be necessary to treat an infinite number of

patients with this antibiotic to avoid one case of infection. We should also

bear in mind that the use of antibiotics may have serious adverse effects.

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Additionally, we must remember that that the abuse and misuse of

antibiotics increases antibiotic resistance. For all these reasons, we agree

with the conclusion of the Cochrane meta-analysis published in 201225

, on

the prophylactic use of antibiotics in third molar extractions, that

physicians should consider carefully treating a patient with prophylactic

antibiotic therapy with the goal of preventing infections as it may do more

harm than good.

When completely bone-impacted lower third molar removal is carried out

under the conditions of our trial, that is, using 0.12% chlorhexidine both

intraoperatively and as regular mouthwashes for 7 days after surgery, we

cannot recommend the use of amoxicillin/clavulanic acid to prevent

postoperative infection. However, in the postoperative period, patients

given antibiotics reported less pain and could open their mouths further

than those given placebo.

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CONCLUSIONS

In the removal of completely bone-impacted lower third molars

performed under the same surgical conditions as our trial, antibiotic

therapy has been more effective for pain relief, reduction in oedema and

enabling mouth opening than placebo, but not for the prevention of

postoperative infections. Infections occurred during the first week in

controls and later in those given the antibiotics under study. The adverse

effects, although mild were more common in patients on antibiotics. In

our opinion, the benefits are insufficient to recommend the use of this

antibiotic for this type of surgery.

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Table I.

Demographic, clinical, radiological and surgical variables recorded. Homogeneity of the

control and experimental groups

Demographic variables. Age: age on the day of the first appointment. Ethnic group: the three patients in

the Others category were of Latin American origin

Clinical variables. Smoking status was recorded at the first appointment in terms of the number of

cigarettes consumed per day. The use of contraceptives, psychoactive drugs or other drugs was assessed

by asking patients directly and reviewing their medical record. C-reactive protein (CRP) levels in mg/dl

were measured by immunoturbidimetry. Mouth opening in mm was measured with a TheraBite® ruler.

Radiological variables: The relevant variables were measured in the panoramic radiograph by a single

observer. We measured the minimum thickness of the cortical bone above the third molar. The site and

the inclination of the impacted lower third molars were determined using the classifications of Winter 26

and of Pell and Gregory27

.

Surgical variables. The surgical time was measured using a stopwatch from the first incision until the last

suture was completed. Tooth sectioning and the extent of bone removal were assessed by the surgeon.

Among the patients lost to follow-up, we only report the surgical variables for three patients, data on

the fourth case being omitted on explicit request of the patient.

Table II.

Analysis of the postoperative variables recorded by the surgeon 7 days after surgery by

treatment given

Dehiscence: separation of the surgical wound in millimetres

Perceived pain on a visual analogue scale: painless=0, mild 0-40, moderate 41-70, severe 71-

100.

Table III.

Risk measures

Table IV.

Patients diagnosed with infections: characteristics of the postoperative variables used

for the diagnosis of infection at day of diagnosis

CRP level 7 days after surgery was not a criterion for infection in any of these patients. In all cases, CRP

levels were below 2.2 mg/dl. mod: moderate; sev: severe

Table V.

Adverse events by treatment group

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Figure 1. Flow chart diagram

Figure 2. Form for recording body temperature, mouth opening and pain

measured with a visual analogue scale

Figure 3. a) Mean mouth opening, b) Perceived pain score and c) Body

temperature recorded by patients over the 7 days after surgery

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Acknowledgements: We are grateful to José Ignacio Pijoan for help with

the design of the study and interim statistical analysis.

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JM Lacasa, JA Jimenez, V Ferras, M Bossom, O Sola-Morales, C Garcia-Rey, L Aguilar, J Garau. Prophylaxis versus pre-emptive treatment for infective and inflammatory complications of surgical third molar removal: a randomized, double-blind, placebo-controlled, clinical trial with sustained release amoxicillin/clavulanic acid (1000/62.5mg). Int J Oral Maxillofac Surg. 2007;36(4):321-7. 22

LR Halpern, TB Dodson. Does prophylactic administration of systemic antibiotics prevent postoperative inflammatory complications after third molar surgery? J Oral Maxillofac Surg. 2007;65(2):177-85. 23

F Graziani, L Corsi, M Fornai, L Antonioli, M Tonelli, S Cei, et al. Clinical evaluation of piroxicam-FDDF and azithromycin in the prevention of complications associated with impacted lower third molar extraction. Pharmacol Res. 2005;52(6):485-90. 24 PE Larsen The effect of a chlorhexidine rinse on the incidence of alveolar osteitis following the surgical removal of impacted mandibular third molars. J Oral Maxillofac Surg. 1991 Sep;49(9):932-7. 25 G Lodi, L Figini, A Sardella, A Carrassi, M Del Fabbro, S Furness. Antibiotics to prevent complications following tooth extractions. Cochrane Database Syst Rev. 2012;11:CD003811.

26 GB Winter. Impacted mandibular third molars. St. Louis: Ed. Amer. Med. Book Co.;1926.

27

GJ Pell, GT Gregory. Impacted mandibular third molars: classifications and modified technique for removal. Dent Digest. 1933;39:330-8.

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Table I.

Control group

Experimental

group

Total

p

Patients lost to follow-up

(n=4) Age

mean (SD)

31.48 (9.40)

25.57 (6.48)

28.47 (8.55)

0.001c

38.75 (11.03)

Ethnic group caucasian oriental black others

57 0 0 1

58 0 0 2

115 0 0 3

1.000a

3 0 1 0

Sex male female

26 28

32 32

58 60

0.841b 2 2

Smoking status no <10 cig/day 10-20 cig/day >20 cig/day

36 13 7 2

39 14 7 0

75 27 14 2

0.695a

1 3 0 0

Contraceptives no yes

49 9

48 12

97 21

0.524b 4 0

Psychoactive drugs no yes

53 5

57 3

110 8

0.487a 4 0

Other drugs no yes

40 18

41 19

81 37

0.941b 3 1

Preoperative CRP (mg/dl)

mean (SD) 0.24 (0.38) 0.17 (0.21) 0.20 (0.31) 0.205c 0.11 (0.07)

Preoperative mouth opening (mm)

mean (SD) 49.09 (5.15) 52.01 (5.62) 50.58 (5.57)

0.004c 53.50 (3.70)

Bone thickness (mm)

mean (SD) 2.04 (0.79) 1.95 (0.75) 2.00 (0.77) 0.512c 3.50 (3.00)

Site right (4.8) left (3.8)

24 34

35 25

59 59

0.066b 1 3

Inclination vertical mesioangular distoangular horizontal

9 22 2

25

13 30 1 16

22 52 3

41

0.219a

0 1 0 3

Surgical time (minutes)

mean (SD) 16.40 (8.44) 13.87 (6.06) 15.11 (7.40)

0.063c

Bone removal 1/3 2/3 3/3

33 21 4

40 20 0

73 41 4

0.103a

1 0 2

Tooth sectioning no yes

0 58

0 60

0 118

*

0 3

a: two-tailed Fisher’s exact test *Not tested since tooth sectioning was needed in all patients . b: two-tailed chi- square test c: ANOVA

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Control group

Experimental

group

Total

p

Dehiscence (mm)

0 1 2 3 4

39 3 9 5 2

45 2

12 1 0

84 5

21 6 2

0.237a

Intraoral erythema none mild moderate severe

40 14 4 0

45 15 0 0

85 29 4 0

0.143a

Intraoral oedema none mild moderate severe

42 12 4 0

56 4 0 0

98 16 4 0

0.004a

Intraoral abscess no yes

57 1

60 0

117 1

0.492a

Extraoral erythema none mild moderate severe

56 1 1 0

59 1 0 0

115 2 1 0

0.744a

Alveolitis no yes

58 0

60 0

118 0

*

Postoperative mouth opening (mm)

mean (DE) 43.71 (7.62) 48.38 (7.74) 46.08 (8.00)

0.002c

Pain on intraoral palpation

painless mild moderate severe

27 25 6 0

42 18 0 0

69 43 6 0

0.003a

Pain on extraoral palpation

painless mild moderate severe

39 16 3 0

54 6 0 0

93 22 3 0

0.004a

Postoperative CRP levels (mg/dl)

mean (DE) 0.45 (0.49) 0.34 (0.51) 0.40 (0.50) 0.240c

a: two-tailed Fisher’s exact test b: two-tailed Chi-square test c: ANOVA * Not tested since all patients developed alveolits

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RISK MEASURES

Value (range)

Absolute risk in the experimental group (95% CI)

0.03 (-0.01. 0.08)

Absolute risk in the control group (95% CI)

0.09 (0.01. 0.16)

Relative risk, RR (95% CI)

0.39 (0.08. 1.91)

Relative risk reduction, RRR (95% CI)

0.61 (-0.91. 0.92)

Absolute risk reduction, ARR (95% CI)

0.05 (-0.03. 0.14)

Number needed to treat, NNT (95% CI)

19(8-∞)

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No

. of

pat

ien

ts

Gro

up

Hig

h

tem

per

atu

re

Deh

isce

nce

Intr

aora

l er

yth

ema

Intr

aora

l o

edem

a

Intr

aora

l ab

sces

s

Ext

rao

ral

eryt

hem

a

Alv

eolit

is

Mo

uth

o

pen

ing

Pai

n o

n

intr

aora

l p

alp

atio

n

Pai

n o

n

extr

aora

l p

alp

atio

n

D

ay o

f d

iag

no

sis

afte

r su

rger

y

2

E

no

0

mod

mod no none

no

22

sev

sev

22

10

C

no

0 mod mod no

none no

35

sev

sev

4

11

E

no

0 mod mod no

none no

40

sev

sev

10

41

C

yes

3 mod mod

no mod no

23

mod

mod

3

75

C

no

0 mod mod

no none

no

19

sev

sev

3

95

C

no

0

mod

mod

yes

none no

32

mod

mod

7

116

C

no

0

mod

mod

no

none no

39

sev

sev

2

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control

group

(placebo)

Experimental

group

(antibiotics)

Total

%

None 56 48 104 88.1

Nausea and vomiting 0 1 1 0.9

Diarrhoea 1 8 9 7.6

Abdominal pain 0 1 1 0.9

Vaginal candidiasis 0 2 2 1.7

Others 1 0 1 0.9

Total 58 60 118

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In completely bone-impacted lower third molar removal, treatment with

amoxicillin/clavulanic acid 2000/125 mg is not effective for preventing

post-operative infections. Nevertheless, antibiotics are frequently

prescribed in clinical practice.