Efficacy of amoxicillin and amoxicillin/clavulanic acid in the prevention ...

Med Oral Patol Oral Cir Bucal-AHEAD OF PRINT - ARTICLE IN PRESS

Journal section: Oral Surgery Publication Types: Review

Amoxicillin in the prevention of infectious complications after tooth extraction

doi:10.4317/medoral.21139 http://dx.doi.org/doi:10.4317/medoral.21139

Efficacy of amoxicillin and amoxicillin/clavulanic acid in the prevention of infection and dry socket after third molar extraction. A systematic review and meta-analysis María-Iciar Arteagoitia 1, Luis Barbier 2, Joseba Santamaría 3, Gorka Santamaría 4, Eva Ramos 5

MD, DDS, PhD, Associate Professor, Stomatology I Department, University of the Basque Country (UPV/EHU), BioCruces Health Research Institute, Spain; Consolidated research group (UPV/EHU IT821-13) 2 MD PhD, Chair Professor, Maxillofacial Surgery Department, BioCruces Health Research Institute, Cruces University Hospital, University of the Basque Country (UPV/EHU), Spain; Consolidated research group (UPV/EHU IT821-13) 3 MD, DDS, PhD, Professor and Chair, Maxillofacial Surgery Department, BioCruces Health Research Institute, Cruces University Hospital, University of the Basque Country (UPV/EHU), Bizkaia, Spain; Consolidated research group (UPV/EHU IT821-13) 4 DDS, PhD, Associate Professor, Stomatology I Department, University of the Basque Country (UPV/EHU), BioCruces Health Research Institute, Spain; Consolidated research group (UPV/EHU IT821-13) 5 PhD, Degree in Farmacy, BioCruces Health Research Institute, Cruces University Hospital. Spain 1

Correspondence: Servicio Cirugía Maxilofacial, Hospital Universitario de Cruces, Plaza de Cruces s/n, Barakaldo (Bizkaia), Spain, [email protected]

Please cite this article in press as: Arteagoitia MI, Barbier L, Santamaría J, Santamaría G, Ramos E. Efficacy of amoxicillin and amoxicillin/clavulanic acid in the prevention of infection and dry socket after third molar extraction. A systematic review and metaanalysis. Med Oral Patol Oral Cir Bucal. (2016), doi:10.4317/medoral.21139

Received: 02/11/2015 Accepted: 23/12/2015

Abstract

Background: Prophylactic use of amoxicillin and amoxicillin/clavulanic acid, although controversial, is common in routine clinical practice in third molar surgery. Material and Methods: Our objective was to assess the efficacy of prophylactic amoxicillin with or without clavulanic acid in reducing the incidence of dry socket and/or infection after third molar extraction. We conducted a systematic review and meta-analysis consulting electronic databases and references in retrieved articles. We included double-blind placebo-controlled randomized clinical trials published up to June 2015 investigating the efficacy of amoxicillin with or without clavulanic acid on the incidence of the aforementioned conditions after third molar extraction. Relative risks (RRs) were estimated with a generic inverse-variance approach and a random effect model using Stata/IC 13 and Review Manager Version 5.2. Stratified analysis was performed by antibiotic type. Results: We included 10 papers in the qualitative review and in the quantitative synthesis (1997 extractions: 1072 in experimental groups and 925 in controls, with 27 and 74 events of dry socket and/or infection, respectively). The overall RR was 0.350 (p37.8º intraoral abscess draining pus; severe pain that persists or increases 48 h after surgery together with intraoral inflammation and/or intraoral erythema; severe pain 7 days after surgery together with intraoral inflammation and/or intraoral erythem Oral temperature >37.8º; intraoral abscess draining pus; severe pain that persists or increases 48 h after surgery together with intraoral inflammation and/or intraoral erythema; severe pain 7 days after surgery together with intraoral inflammation and/or intraoral erythema Infection: purulent discharge, alveolitis and body temperature >37.5ºC Dry socket: postoperative pain at the extraction site, that increases between day 1 and 3 after surgery, together with total or partial disintegration of the blood clot in the socket, with or without halitosis

Criteria applied for the diagnosis of dry socket and alveolar infection are the same as those previously described by other authors (Arteagoitia et al and Bouloux et al).

Post-operative C reactive protein levels >10 mg/l and alpha-1 antitrypsin levels >370 mg/dl in blood considered indicators of infection

Antibiotic regimen

E (n=60): oral amoxicillin /clavulanic acid 2000/125 mg 2 hours before surgery + oral amoxicillin / clavulanic acid 2000/125 mg q12h for 4 days after surgery C (n=58): oral placebo 2 hours before surgery + oral placebo q12 h for 4 days after surgery

Quantitative outcome measure Scheduled postoperative appointments Randomisation method

E: 14 patients C: 2 patients

All adverse reactions were mild: 2 people with Using C4-SDP software vomiting, 2 stomach (Glaxo S.A., Tres Cantos, ache, 1 mycosis, and Madrid, Spain 11 with diarrhoea.

E : 1.47% (1/68) C : 5.88% (4/68)

E (n=68): oral amoxicillin 1 g 1 h before surgery 3, 7 and 14 days after Not described C (n=68): oral placebo 1 surgery h before surgery By the tossing of a coin by a blinded researcher E1 (n=12): oral amoxicillin 2 g + dexamethasone 8 mg 6090 min before surgery E2 (n=12): oral amoxicillin 2 g + placebo 8 mg 60-90 min before surgery E3 (n=14): oral placebo 2 g + dexamethasone 8 mg 60-90 before surgery C (n=12): oral placebo 2 g + placebo 8 mg 60-90 min before surgery E (n=30): oral amoxicillin 1000 mg 60 min before surgery (8:00 a.m.) + amoxicillin 500 mg at 4:00 p.m. and 12:00 p.m. after surgery + oral amoxicillin 500 mg q8h for 4 days after surgery C (n=30): placebo

Losses to follow-up

E: 12 patients (nausea and vomiting E : 3.33% (2/60) 1; diarrhoea 8; C : 8.62% (5/58) abdominal pain 1; vaginal candidiasis 2; 4 patients lost 7 days after surgery others 0) to follow-up, C: 2 patients C:3 and E:1 Using C4-SDP software (nausea and vomiting (Glaxo S.A., Tres Cantos, 0; diarrhoea 1; Madrid, Spain) abdominal pain 0; vaginal candidiasis 0; Others 1)

E (n=259): oral E : 1.93% (5/259) amoxicillin /clavulanic C : 12.99% (30/231) acid 500/125 mg q8h for 4 days after surgery 7 days after surgery C (n=231): placebo following the same regimen

Adverse reactions

E1 : 0% (0/12) E2 : 8.33% (1/12) E3 : 7.14% (1/14) C : 8.33% (1/12)

4 patients lost to follow-up, (2 in each group): all for failing to attend postoperative appointments

9 declined to participate, 1 for failed to attend postoperative appointmentsr1 for pregnancy

Not described

Not described

Not described

Not described

Not specified By draw

E : 6.67% (2/30) C : 6.67% (2/30) 1,3 and 7 days after surgery Not described



Table 2 Continue. Main characteristics of the 10 randomized double-blind placebo-controlled studies included in the qualitative analysis.

Lacasa (15) (2007) Spain January 2002 to December 2002

Purulent discharge in the alveolus and/or excessive inflammation with fluctuation with/without pain Amoxicillin /clavulanic - Local abscess. acid - Facial or neck cellulitis and other signs of infections Metamizole 575 mg q8h such as pain, heat, redness for at least 2 days after and/or fever surgery. - Osteitis defined as absence of absence of blood clot of the orifice and presence of a putrid smell and intense neuralgic type pain Amoxicillin

- Infection: purulent discharge and/or excessive Ibuprofen 600 mg inflammation with or Lopez-Cedrún (16) immediately after without pain. Palpable (2011) surgery + ibuprofen 600 nodules in neck and facial or Spain mg q12h for 5 days. neck cellulitis. Not specified Metamizole 2 g (rescue - Dry socket: disintegration analgesia) of blood clot in the alveolus Salt water mouth rinse and halitosis, as well as after meals severe neuropathic pain

Pasupathy (17) (2011) India Not specified

Amoxicillin and metronidazole Ibuprofen 600mg q8h for 5 days after surgery.

- Increase in body temperature - Purulent discharge from the wound

Amoxicillin

Siddiqi (18) (2010) New Zeeland Not specified

Xue (19) (2015) China January to December 2013

Ibuprofen 400 mg before surgery + ibuprofen 400 mg q6h for 2 days after surgery Paracetamol 500 mg + codeine phosphate 8 mg q6h for 2 days after surgery Chlorhexidine mouthwash 0.2% 10 ml before surgery + 10 ml q8h for 3 days after surgery

Amoxicillin (clindamycin, if allergy to amoxicillin) Loxoprofen before or after operation as necessary.

- Dry socket: halitosis, pain and lack of blood clot together with bone tissue necrosis

Not specified

E1 (n=75): oral amoxicillin/clavulanic acid 2000/125 mg before surgery + placebo for 5 days after surgery E2 (n=72): oral placebo before surgery + oral amoxicillin/clavulanic acid 2000/125 mg for 5 days after surgery C (n=75): placebo before and after surgery, under the same conditions as experimental groups E1 (n=39): amoxicillin 2000 mg orally 2 h before surgery + placebo q8h for 5 days after surgery E2 (n=44): placebo 2 hours before surgery + amoxicillin 500 mg q8h for 5 days after surgery C (n=40): placebo 2 h before surgery + placebo q8 h for 5 days after surgery E1 (n=31): oral amoxicillin 1g 1 h before surgery E2 (n=29): oral metronidazole 800 mg 1h before surgery C (n=29): placebo

E1 : 5.33% (4/75) E2 : 2.78% (2/72) C : 16.00% (12/75)

E1: 48% of patients had some type of adverse reaction 1, 3 and 7 days after E2: 54.7% of patients surgery had some type of adverse reaction Described as randomised, C: 69.3% of patients randomisation method not had some type of specified adverse reaction

E2: 3 patients lost to followup at day 1, as they withdrew their consent (before day 1 assessment)

E1:nausea 1;diarrhoea 2; stomachache 3;cutaneous eruption 1, headache 1,others 5 E2:vomiting 1; nausea 1; diarrhoea 1; stomach ache 2; cutaneous eruption 1;headache 1, others 3. C: nausea 2;diarrhoea 1; stomach ache 1; headache 3;others 7

E1: 3 lost to follow-up,2 for technical problems; C: 4 lost to followup,1 for technical problems; E2:1 lost to follow up

E1 : 0% (0/39) E2 : 0% (0/44) C : 12.50% (5/40) 7 days after surgery By a pharmacists using a random alphanumeric code

E1 : 6.45% (2/31) E2 : 0% (0/29) C : 10.33% (3/29) 7 days after surgery

E (n=192): oral amoxicillin 500 mg 1h before surgery + oral amoxicillin 500 mg q 8h for 3 days after surgery (or oral clindamycin 300 mg if allergy to amoxicillin) C (n=192): placebo at the same times before and after surgery

Not described

5 patients lost to follow-up for failing to adhere to the follow-up protocol

Using a table created using Random Software (version 2, Social Psychology)

Group 1(n=192): 1st appointment: oral amoxicillin 1 g 1 h before surgery, 2nd E (Group 1 + Group 2): appointment: placebo 1.05% (2/190) under the same regimen or C (Group 1 + Group 2): vice versa 2.10% (4/190) Group 2(n=188): 1st appointment: oral amoxicillin 1 g 1 h before surgery + amoxicillin 500 mg q8h for 2 days after surgery; 2nd appointment: placebo under the same regimen or viceversa

Not described

9 patients were excluded from the analysis: 8 lost to followup and 1 for using antibiotics during the follow-up period.

1, 3, 7 and 14 days after surgery By asking patients to select one of two sequentially-numbered

E: 12 patients (gastrointestinal adverse reactions 4; ulcers 2, fever 6) 2 and 10 days after C: 16 patients surgery (gastrointestinal adverse reactions 0; Using computer-generated gastrointestinal random numbers adverse reactions 2, fever 14) E: 3.13% (6/192) C: 4.17% (8/192)

15 patients excluded, but the reasons were not specified

E: experimental group, C: control group, n=number of third molars extracted. - In studies with a split-mouth design (those of Bezerra, Siddiqi, Bulut and Xue), the rates of infections have been calculated taking n as the number of third molars removed, rather than the number of patients in the study. - In studies using antibiotics other than amoxicillin for patients allergic to this drug, if it was not specified how many patients were treated with alternative antibiotics, calculations have been based on assuming that all patients were treated with amoxicillin or amoxicillin/clavulanic acid.



Fig. 1. Risk of bias in studies included in the systematic review. - All the studies were considered low risk in terms of performance and detection bias, given that a double-blind design was a selection criterion for the meta-analysis. - In studies with a split-mouth design, it was considered that that there might be other sources of bias given the duration of the washout period (no more than 4 weeks in all cases).

Fig. 2. Forest Plots. Overall forest plot: graphical representation of the estimates of the RRs and 95% CIs based on the samples in each of the studies, including both those that used amoxicillin and those that used amoxicillin/clavulanic acid, together with their relative weights. Amoxicillin forest plot. Amoxicillin/clavulanic acid forest plot.


are shown for the overall analysis and for the analysis stratified by antibiotic (amoxicillin or amoxicillin/clavulanic acid). - Synthesis of the results: Analysis of the overall efficacy of amoxicillin with or without clavulanic acid: The quantitative analysis included 1997 extractions: 1072 in experimental groups and 925 in control (placebo) groups, with 27 and 74 reported events of dry socket and/or infection respectively. The overall RR was found to be 0.350, with a 95% CI of 0.214 to 0.574, this being significant (p