When can i stop taking antibiotics after wisdom teeth removal

Cochrane Database Syst Rev. 2021; 2021(2): CD003811.

Abstract

Background

The most frequent indications for tooth extractions, generally performed by general dental practitioners, are dental caries and periodontal infections. Systemic antibiotics may be prescribed to patients undergoing extractions to prevent complications due to infection. This is an update of a review first published in 2012.

Objectives

To determine the effect of systemic antibiotic prophylaxis on the prevention of infectious complications following tooth extractions.

Search methods

Cochrane Oral Health’s Information Specialist searched the following databases: Cochrane Oral Health Trials Register (to 16 April 2020), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2020, Issue 3), MEDLINE Ovid (1946 to 16 April 2020), Embase Ovid (1980 to 16 April 2020), and LILACS (1982 to 16 April 2020). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases.

Selection criteria

We included randomised, double‐blind, placebo‐controlled trials of systemic antibiotic prophylaxis in patients undergoing tooth extraction(s) for any indication.

Data collection and analysis

At least two review authors independently performed data extraction and 'Risk of bias' assessment for the included studies. We contacted trial authors for further details where these were unclear. For dichotomous outcomes, we calculated risk ratios (RR) and 95% confidence intervals (CI) using random‐effects models. For continuous outcomes, we used mean differences (MD) with 95% CI using random‐effects models. We examined potential sources of heterogeneity. We assessed the certainty of the body of evidence for key outcomes as high, moderate, low, or very low, using the GRADE approach.

Main results

We included 23 trials that randomised approximately 3206 participants (2583 analysed) to prophylactic antibiotics or placebo. Although general dentists perform dental extractions because of severe dental caries or periodontal infection, only one of the trials evaluated the role of antibiotic prophylaxis in groups of patients affected by those clinical conditions.

We assessed 16 trials as being at high risk of bias, three at low risk, and four as unclear. 

Compared to placebo, antibiotics may reduce the risk of postsurgical infectious complications in patients undergoing third molar extractions by approximately 66% (RR 0.34, 95% CI 0.19 to 0.64; 1728 participants; 12 studies; low‐certainty evidence), which means that 19 people (95% CI 15 to 34) need to be treated with antibiotics to prevent one infection following extraction of impacted wisdom teeth. Antibiotics may also reduce the risk of dry socket by 34% (RR 0.66, 95% CI 0.45 to 0.97; 1882 participants; 13 studies; low‐certainty evidence), which means that 46 people (95% CI 29 to 62) need to take antibiotics to prevent one case of dry socket following extraction of impacted wisdom teeth.

The evidence for our other outcomes is uncertain: pain, whether measured dichotomously as presence or absence (RR 0.59, 95% CI 0.31 to 1.12; 675 participants; 3 studies) or continuously using a visual analogue scale (0‐to‐10‐centimetre scale, where 0 is no pain) (MD −0.26, 95% CI −0.59 to 0.07; 422 participants; 4 studies); fever (RR 0.66, 95% CI 0.24 to 1.79; 475 participants; 4 studies); and adverse effects, which were mild and transient (RR 1.46, 95% CI 0.81 to 2.64; 1277 participants; 8 studies) (very low‐certainty evidence). 

We found no clear evidence that the timing of antibiotic administration (preoperative, postoperative, or both) was important.

The included studies enrolled a subset of patients undergoing dental extractions, that is healthy people who had surgical extraction of third molars. Consequently, the results of this review may not be generalisable to all people undergoing tooth extractions.

Authors' conclusions

The vast majority (21 out of 23) of the trials included in this review included only healthy patients undergoing extraction of impacted third molars, often performed by oral surgeons. None of the studies evaluated tooth extraction in immunocompromised patients. We found low‐certainty evidence that prophylactic antibiotics may reduce the risk of infection and dry socket following third molar extraction when compared to placebo, and very low‐certainty evidence of no increase in the risk of adverse effects. On average, treating 19 healthy patients with prophylactic antibiotics may stop one person from getting an infection. It is unclear whether the evidence in this review is generalisable to patients with concomitant illnesses or patients at a higher risk of infection. Due to the increasing prevalence of bacteria that are resistant to antibiotic treatment, clinicians should evaluate if and when to prescribe prophylactic antibiotic therapy before a dental extraction for each patient on the basis of the patient's clinical conditions (healthy or affected by systemic pathology) and level of risk from infective complications. Immunocompromised patients, in particular, need an individualised approach in consultation with their treating medical specialist. 

Plain language summary

Are antibiotics an effective way to prevent infection following tooth removal?

What is the problem?

Teeth that are affected by decay or gum disease or painful wisdom teeth are often removed (extracted) by dentists. Tooth extraction is a surgical procedure that leaves a wound in the mouth that can become infected. Infection can lead to swelling, pain, development of pus, fever, as well as ‘dry socket’ (where the tooth socket is not filled by a blood clot, and there is severe pain and bad odour).

These complications are unpleasant for patients and may cause difficulty with chewing, speaking, and teeth cleaning, and may even result in days off work or study. Treatment of infection is generally simple and involves drainage of the infection from the wound and patients receiving antibiotics.

Why is this question important?

Antibiotics work by killing the bacteria that cause infections, or by slowing their growth. However, some infections clear up by themselves. Taking antibiotics unnecessarily may stop them working effectively in future. This ‘antimicrobial resistance’ is a growing problem throughout the world.

Antibiotics may also cause unwanted effects such as diarrhoea and nausea. Some patients may be allergic to antibiotics, and antibiotics may not mix well with other medicines.

Dentists frequently give patients antibiotics at the time of the extraction as a precaution in order to prevent infection occurring in the first place. This may be unnecessary and may lead to unwanted effects.

What did we want to find out?

We wanted to know whether giving antibiotics as a preventive measure reduces infection and other complications after tooth extraction. We also wanted to understand whether antibiotics work differently in healthy people compared with people with health conditions such as diabetes or HIV.

What did we do?

We searched for studies that assessed the effectiveness of antibiotics compared to placebo (sham medicine), given when no infection was present in order to prevent infection following tooth extraction. Studies could include people of any age undergoing tooth extraction.

Where possible, we pooled the studies’ results and analysed them together. We also assessed the quality of each study to judge the reliability (certainty) of evidence of individual studies and the body of evidence.

What we found

We found 23 included studies with a total of more than 3200 participants, who received either antibiotics (of different kinds and dosages) or placebo immediately before or just after tooth extraction, or both.

Four studies were conducted in Spain, three each in Brazil, Sweden, and the UK, two in India, and one each in Colombia, Denmark, Finland, France, Poland, New Zealand, Nigeria, and the USA. All but one study included healthy patients in their 20s. Twenty‐one studies assessed the removal of wisdom teeth in hospital dental departments, one assessed the removal of other teeth and one assessed complex oral surgery. None of the included studies assessed tooth extraction in general dental practice for the removal of decayed teeth.

Main results

Antibiotics given just before or just after surgery (or both) may reduce the risk of infection and dry socket after the removal of wisdom teeth by oral surgeons. However, antibiotics may cause more (generally brief and minor) unwanted effects for these patients. We found no evidence that antibiotics prevent pain, fever, swelling, or problems with restricted mouth opening in patients who have had wisdom teeth removed.

There was no evidence to judge the effects of preventive antibiotics for extractions of severely decayed teeth, teeth in diseased gums, or extractions in patients who are sick or have low immunity to infection.

How reliable are the results?

Our confidence in the results is limited because we had concerns about aspects of the design and reporting of all of the included studies.

What does this mean?

We did not find studies in patients with depressed immune systems, other illnesses, or in young children or older patients, therefore the results of our review probably do not apply to people who may be at high risk of infection. Also, extractions were mainly carried out by oral surgeons, so the review may not apply to dentists working in general practice.

Another concern, which cannot be assessed by clinical studies (i.e. studies testing new medical approaches in people), is that widespread use of antibiotics by people who do not have an infection is likely to contribute to the development of antimicrobial resistance.

We concluded that antibiotics given to healthy people when they are having teeth extracted may help prevent infection, but the decision to use an antibiotic should be judged on an individual patient basis based on their state of health and possible complications of getting an infection.

How up‐to‐date is this review?

This is an updated review. The evidence is current to April 2020.

Summary of findings

Background

Description of the condition

Tooth extraction is a very common surgical procedure, and is most frequently done by general dental practitioners. In spite of the steady decrease in routine extraction of permanent teeth registered in recent decades (McCaul 2001; Sleeman 1995; Thomas 1994), and a significant decline in the prevalence and incidence of severe tooth loss (Kassebaum 2014), general dental practitioners from European countries may extract up to seven teeth per week (McCaul 2001; Worthington 1999). The highest tooth extraction rate per patient is amongst patients in the sixth and seventh decade of life (Chrysanthakopoulos 2011). The main reasons for extraction of permanent teeth are caries and periodontal disease, in variable proportions according to age of patients and country (see Table 2). Wisdom teeth failing to erupt or erupting only partially represent a distinct category of dental elements named impacted (third molar) teeth. Impacted wisdom teeth are extracted either because of local inflammatory problems, or with the aim of avoiding possible future complications (although a recent Cochrane Review did not find sufficient evidence to support or reject routine prophylactic removal of asymptomatic impacted wisdom teeth in adults) (Ghaeminia 2020)).

1

Studies of reasons for tooth extraction

For surgery to be considered successful, it should minimise patient discomfort in the postoperative period after tooth extraction as much as possible. Complications such as pain, swelling, trismus, fever, and dry socket are unpleasant for patients and may cause difficulty in chewing, speaking, and performing oral hygiene, and alteration of other activities of daily living, resulting in days off from work or study. All of these complications depend on inflammatory response, but they can be due to subsequent infection, for example if surgical trauma is in a contaminated area (where severe caries or periodontitis is present) or where more complex and aggressive procedures are performed (e.g. ostectomy).

Signs of postextraction infectious complications include abscess, pain, fever, swelling, trismus. Another complication of putative bacterial origin is alveolar osteitis (dry socket), a painful condition that follows the dissolution of the blood clot that occurs as a result of bacterial invasion. The overall incidence of postoperative infections is relatively low (Bortoluzzi 2010; Bouloux 2007; Jaafar 2000); however, antibiotics are frequently prescribed prophylactically, particularly in cases of complex surgical extractions and/or surgical extractions and people with systemic conditions potentially causing immunodeficiency, such as HIV infection, diabetes, and cancer (Epstein 2000).

Description of the intervention

A range of antibiotics are effective, in association with clinical treatment (e.g. drainage of abscess), in treating dental infections, which have been used to prevent dental infections as well. These include amoxicillin, erythromycin, clindamycin, doxycycline, and metronidazole, which are usually administered orally, between one and four times daily. Alternatively, antibiotics can also be administered by parenteral or local routes.

How the intervention might work

The oral environment contains a range of bacteria that have the potential to cause painful infections in wounds, even after tooth extractions. Antibiotics are effective in treating such infections and are also likely to prevent the development of painful wound infections.

Before prescribing an antibiotic for prophylaxis purposes, the clinician should:

1. decide if the prophylaxis is appropriate;

2. determine the bacterial flora most likely to cause postoperative infection;

3. choose an antibiotic with the narrowest antibacterial spectrum required;

4. choose the less expensive drug if two drugs are otherwise of equal antibacterial spectrum, efficacy, toxicity, and ease of administration;

5. administer dose at the right time;

6. administer antibiotics for a short period;

7. avoid antibiotics likely to be used in the treatment of serious sepsis;

8. do not use antibiotic prophylaxis to overcome poor surgical technique;

9. review antibiotic prophylaxis protocols regularly, as both cost and hospital antibiotic resistance patterns may change (Dellinger 1994).

However, the optimal timing of the dose or doses of prophylactic antibiotic therapy is unclear. Antibiotics may be administered as a large single dose prior to the extraction, or as a course of antibiotics taken over the postoperative period, or some combination of these. In addition, adverse effects such as diarrhoea or allergy due to antibiotics are also possible.

Why it is important to do this review

In 2010, a systematic review showed that both long duration and multiple courses of antibiotics prescribed in general medical practice were consistently associated with the development of bacterial resistance, in particular individuals who received more antibiotic courses had a higher chance of developing bacterial resistance to the antibiotic (Costelloe 2010). According to the Centers for Disease Control and Prevention (CDC) report on antibiotic resistance threats, more than 2.8 million antibiotic‐resistant infections occur in the USA each year, and more than 35,000 people die as a result (Antibiotic Resistance Threats in the United States). Even when addressing severe orofacial infections, increasing antibiotic resistance has been reported to potentially affect patient outcome (Kim 2017).

According to the European Commission (EU), the overuse and misuse of antibiotics are the main causes of microbial resistance to drugs. For this reason, an action plan to tackle microbial resistance to drugs was presented in 2011, the first aim of which was to ensure that antimicrobials are used appropriately both in humans and animals. A particularly high prescribing habit was reported amongst dentists (Ford 2017; Marra 2016), with just a slight reduction in the last decade (Khalil 2015; Preus 2017; Teoh 2018; Thornhill 2019a). Dental prescribing accounts for a significant proportion of total antibacterial prescribing in primary care (7% to 10%) (Dar‐Odeh 2010; Khalil 2015; Preus 2017; Suda 2019; Teoh 2018; Thornhill 2019a). In addition, antibiotics used in dental practice can cause potentially serious adverse drug reactions and interactions (Thornhill 2019). Of note, even in settings for which guidelines are available, there is inappropriate prescribing, with overuse of prophylactic antibiotic therapy as high as 80% observed (Suda 2019), and the use of amoxicillin/clavulanic acid has recently increased in the UK and Australia (Teoh 2018; Thornhill 2019a). Better evidence is needed regarding the use of antibiotic prophylaxis in people undergoing tooth extraction, in order to determine appropriate use (EU Commission 2011; EU Commission 2019).

There is high heterogeneity amongst studies describing possible complications of dental extractions; the terminology used to classify signs of infection as well as timing of patient evaluation after dental extraction can vary widely between trials. In particular, pain, swelling, and trismus may be present two to three days after dental surgery, which do not represent a sign of infection and may be due to surgical trauma. On the contrary, persistence of signs and symptoms from six to seven days after a dental extraction may be related to the presence of bacterial infection.

This systematic review summarises the evidence on the effects of systemic antibiotics prescribed to prevent infectious complications following tooth extraction. It updates a review published in 2012 (Lodi 2012). A separate Cochrane Review that evaluated interventions to manage dry socket following tooth extraction was published in 2012 (Daly 2012).

Objectives

• To assess the effects of antibiotic prophylaxis on the incidence of infectious complications following tooth extraction.

• To assess the effects of antibiotic prophylaxis following tooth extraction in immunosuppressed patients (e.g. HIV infection, AIDS, diabetes, transplants) or patients with other conditions (e.g. bone diseases).

• To assess the effects of antibiotic prophylaxis in particular procedures, such as extraction of impacted teeth or wisdom teeth.

Methods

Criteria for considering studies for this review

Types of studies

We assessed randomised controlled trials (RCTs) with a double‐blind design (participants and assessors). We included cross‐over studies, providing the interval (or washout period) between interventions was at least six weeks.

Types of participants

Anyone undergoing a tooth extraction, including extraction of impacted teeth.

Types of interventions

Active

Any regimen of systemic antibiotic prophylaxis (i.e. prescribed in the absence of infection) administered before or after tooth extraction. Topical antibiotic therapy was not included.

Types of outcome measures

The main outcome measures considered in this review dealt with postsurgical complications of putative infectious nature.

Primary outcomes

• Postsurgical infectious complications, which may occur with one or more of the following: pain, fever, swelling, trismus.

Secondary outcomes

• Pain at sixth to seventh day.

• Fever at sixth to seventh day.

• Swelling at sixth to seventh day.

• Trismus at sixth to seventh day.

• Dry socket (alveolar osteitis).

• Any adverse event.

We did not consider for inclusion trials that reported the outcomes of endocarditis incidence, bacteraemia, or serum markers of infection only.

Search methods for identification of studies

Electronic searches

Cochrane Oral Health’s Information Specialist conducted systematic searches in the following databases for RCTs and controlled clinical trials without language or publication status restrictions:

• Cochrane Oral Health Trials Register (searched 16 April 2020) (Appendix 1);

• Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 3) in the Cochrane Library (searched 16 April 2020) (Appendix 2);

• MEDLINE Ovid (1946 to 16 April 2020) (Appendix 3);

• Embase Ovid (1980 to 16 April 2020) (Appendix 4);

• LILACS BIREME Virtual Health Library (Latin American and Caribbean Health Science Information database; from 1982 to 16 April 2020) (Appendix 5).

Subject strategies were modelled on the search strategy designed for MEDLINE Ovid; where appropriate, they were combined with subject strategy adaptations of the highly sensitive search strategies designed by Cochrane for identifying RCTs and controlled clinical trials as described in the Technical Supplement to Chapter 4 of the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2019).

Searching other resources

Cochrane Oral Health's information specialist searched the following trial registries for ongoing studies:

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov; searched 16 April 2020) (Appendix 6);

• World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch; searched 16 April 2020) (Appendix 7).

We checked the reference lists of all eligible trials and existing reviews for additional studies.

We checked that none of the studies included in this review were retracted due to error or fraud.

We did not perform a separate search for adverse effects of interventions used; we considered adverse effects described in the included studies only.

Data collection and analysis

Two review authors performed all steps of data collection and analysis independently, with any disagreements resolved by discussion.

Selection of studies

Two review authors independently examined the title and abstract of each article resulting from the different search strategies. The search was designed to be sensitive and to include controlled clinical trials; these were filtered out early in the selection process if they were not randomised. Where studies appeared to meet the inclusion criteria for this review, or where data in the title and abstract were insufficient to permit a clear decision, we obtained the full report of the study. At least two review authors assessed the full reports to determine whether studies met the inclusion criteria, with any disagreements resolved by discussion. We recorded studies excluded at this or subsequent stages as well as the reasons for their exclusion in the Characteristics of excluded studies table. We prepared a flow chart to summarise the results of the search (Figure 1).

Data extraction and management

All studies that met the inclusion criteria for this review underwent 'Risk of bias' assessment and data extraction using a specially designed data extraction form. At least two review authors extracted data independently, entering the data into a spreadsheet. Any disagreements were discussed and agreement reached. When necessary we contacted authors for clarification or missing information.

We recorded the following data for each trial.

• Year of publication, country of origin, number of centres, source of study funding, recruitment period.

• Details of the participants including demographic characteristics and criteria for inclusion and exclusion, type of teeth being extracted and reasons, numbers randomised to each treatment group.

• Details of the type of antibiotic, dose, mode of administration, time of administration relative to the extraction procedure and duration of antibiotic treatment.

• Details of other concomitant treatments ‐ type of anaesthetic, mouth rinses, pain management.

• Details of the outcomes reported, including method of assessment, and time(s) assessed.

• Description of operators.

• Sample size calculation.

Assessment of risk of bias in included studies

Review authors GL, LA, EV, MP, and MM independently assessed the risk of bias of the included trials. The same review authors (GL, LA, EV, MP, MM) independently assessed the full‐text papers, unblinded, resolving any disagreements through discussion and consensus. We used the Cochrane 'Risk of bias' tool described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). It is a two‐part tool, addressing seven specific domains:

• random sequence generation (selection bias);

• allocation concealment (selection bias);

• blinding of participants and personnel (performance bias);

• blinding of outcome assessment (detection bias);

• incomplete outcome data (attrition bias);

• selective reporting (reporting bias);

• other bias.

We completed a 'Risk of bias' table for each included study (see Characteristics of included studies), and presented the results graphically by study and by domain across all studies. For each domain, we entered relevant information from the study in the 'Risk of bias' table, and on the basis of this information, or information gained directly from study authors, assigned a judgement of 'low', 'high', or 'unclear' risk of bias.

We categorised the overall risk of bias of each trial as:

• low if we assigned low risk of bias for all key domains;

• unclear if we assigned unclear risk of bias for one or more key domains; or

• high if we assigned high risk of bias for one or more key domains.

Measures of treatment effect

The primary measure of intervention effect was reduction in the incidence of infectious complications, such as alveolar osteitis (dry socket), pain, fever, swelling, or trismus between the control and intervention groups.

For dichotomous outcomes, we expressed the estimates of effects of an intervention as risk ratios (RR) or odds ratios (OR) if paired, together with 95% confidence intervals (CIs). For continuous outcomes, we used mean differences (MD) and standard deviation (SD) for each group in order to express the estimate of effect as MD with 95% CI. We planned that if studies reported continuous outcomes on different scales, we would use standardised mean difference (SMD) to pool these data in meta‐analyses. For paired data (split‐mouth studies), we used the generic inverse variance method (Higgins 2017).

Unit of analysis issues

The statistical unit of analysis was the participant.

For studies with more than two control arms, we selected the one we considered most appropriate for comparison.

In the case of split‐mouth cross‐over trials where each participant had two extraction procedures, these had to be separated by a period of at least six weeks.

Dealing with missing data

Whenever possible, we obtained missing data from tables and graphs. Where data were missing or unclear, we attempted to contact the study authors to request clarification or additional data.

Assessment of heterogeneity

We assessed heterogeneity by inspection of the point estimates and confidence intervals on the forest plots. We assessed the variation in treatment effects by means of Cochran's test for heterogeneity and quantified by the I2 statistic. We considered heterogeneity statistically significant if the P value was < 0.1. A rough guide to the interpretation of the I2 statistic is given in the Cochrane Handbook for Systematic Reviews of Interventions: 0% to 40% might not be important; 30% to 60% may represent moderate heterogeneity; 50% to 90% may represent substantial heterogeneity; 75% to 100%, considerable heterogeneity (Higgins 2017).

Assessment of reporting biases

Only a proportion of research projects conducted are ultimately published in an indexed journal and become easily identifiable for inclusion in systematic reviews. Reporting biases arise when the reporting of research findings is influenced by the nature and direction of the findings of the research. We attempted to minimise potential reporting biases, including publication bias, time lag bias, multiple (duplicate) publication bias, and language bias in this review.

Where there were more than 10 studies reporting on a given outcome, we prepared a funnel plot. If there was asymmetry in the funnel plot indicating possible publication bias, we undertook statistical analysis using the methods introduced by Egger 1997 (continuous outcome) and Rücker 2008 (dichotomous outcome).

We attempted to avoid time lag bias, multiple (duplicate) publication bias, and language bias by conducting a detailed, sensitive search, including searching for ongoing studies. There were no language restrictions, and we found translators for potentially relevant trials published in languages other than English.

Data synthesis

We only conducted meta‐analysis if there were studies of similar comparisons reporting the same outcome measures. We combined RRs for dichotomous data, and MDs for continuous data, using random‐effects models provided there were more than three studies in the meta‐analysis. For two or three studies in a meta‐analysis, we used the fixed‐effect model.

When trials employed more than one experimental group (multi‐arm parallel trials), the number of participants in the placebo group was subdivided for each experimental group in the meta‐analysis to avoid overcounting.

Subgroup analysis and investigation of heterogeneity

Whenever possible, we undertook subgroup analyses based on time of administration (pre, post, or pre‐post procedure) and the presence or absence of people with systemic conditions (HIV, diabetes, cancer, etc.).

Sensitivity analysis

We planned to undertake a sensitivity analysis including only studies at low overall risk of bias, but due to the small number of such studies we did not do so (Gbotolorun 2016; Leon Arcila 2001; Milani 2015).

Summary of findings and assessment of the certainty of the evidence

We developed a 'Summary of findings' table for the main outcomes of this review using GRADEpro GDT software (GRADEpro GDT). We used the mean risk in the placebo groups of the included studies as the assumed risk for each outcome, and calculated the corresponding risk using the RR (or MD) estimate obtained from the meta‐analysis. We assessed the certainty of the body of evidence with reference to the overall risk of bias of the included studies, the directness of the evidence, the consistency of the results, the precision of the estimates, the risk of publication bias, and the magnitude of the effect. We categorised the certainty of the body of evidence for each of the main outcomes as high, moderate, low, or very low.

Results

Description of studies

See Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.

Results of the search

Our electronic searches identified a total of 1847 references. Two review authors scanned the titles and abstracts of these references and excluded 1783 as not relevant to this review. We retrieved full‐text versions of 64 potentially eligible papers and excluded 43 studies after close reading (see Characteristics of excluded studies table). We identified two further studies from searches of reference lists of the included studies. A total of 23 studies met the inclusion criteria for this review (Figure 1).

Included studies

Characteristics of trial design and setting

For a summary of the characteristics of each included study, see Characteristics of included studies.

Of the 23 included studies, four were conducted in Spain (Arteagoitia 2005; Arteagoitia 2015; Lacasa 2007; López‐Cedrún 2011), three in Sweden (Bergdahl 2004; Bystedt 1980; Bystedt 1981), three in the UK (Kaziro 1984; MacGregor 1980; Mitchell 1986), three in Brazil (Bezerra 2011; Bortoluzzi 2013; Milani 2015), two in India (Pasupathy 2011; Sekhar 2001), and one each in Colombia (Leon Arcila 2001), Denmark (Ritzau 1992), Finland (Happonen 1990), France (Sixou 2012), Poland (Kaczmarzyk 2007), New Zealand (Barclay 1987), Nigeria (Gbotolorun 2016), and the USA (Halpern 2007).

Twenty‐two studies used a parallel‐group design, and one was a split‐mouth cross‐over trial, Bezerra 2011, where each participant had two extraction procedures, which were separated by a period of at least 45 days. Twelve studies had two treatment arms (Arteagoitia 2005; Arteagoitia 2015; Barclay 1987; Bergdahl 2004; Gbotolorun 2016; Halpern 2007; Leon Arcila 2001; López‐Cedrún 2011; MacGregor 1980; Mitchell 1986; Ritzau 1992; Sixou 2012); 10 studies had three treatment arms (Bortoluzzi 2013; Bystedt 1981; Happonen 1990; Kaczmarzyk 2007; Kaziro 1984; Lacasa 2007; López‐Cedrún 2011; Milani 2015; Pasupathy 2011; Sekhar 2001); and one study had three subtrials, each with two or three arms (Bystedt 1980). The data from these separately randomised subtrials were then combined and were unsuitable for inclusion in meta‐analysis.

Characteristics of participants

Twenty‐two of the 23 included studies randomised a total of 3206 participants to either an antibiotic or placebo. The remaining study used an unusual design and did not state exactly how many participants were randomised and analysed (MacGregor 1980). Overall, 2583 participants were analysed in this review.

All of the included studies compared at least one antibiotic regimen with placebo in people undergoing dental extraction. Three trials described extraction procedures using general anaesthesia (Halpern 2007; Kaziro 1984; MacGregor 1980).

In 21 of the 23 included studies participants underwent extraction of third molars only. Two studies only included participants who underwent intra‐alveolar extractions or complex oral surgery, respectively (Gbotolorun 2016; Sixou 2012). Of the 21 studies that included participants who underwent third molar extraction, 14 included only mandibular third molars (Arteagoitia 2005; Barclay 1987; Bergdahl 2004; Bystedt 1980; Bystedt 1981; Happonen 1990; Kaczmarzyk 2007; Lacasa 2007; López‐Cedrún 2011; MacGregor 1980; Mitchell 1986; Pasupathy 2011; Ritzau 1992; Sekhar 2001).

Sixteen studies included participants with impacted teeth only (Arteagoitia 2005; Arteagoitia 2015; Barclay 1987; Bezerra 2011; Bystedt 1980; Bystedt 1981; Halpern 2007; Happonen 1990; Kaczmarzyk 2007; Kaziro 1984; Leon Arcila 2001; MacGregor 1980; Milani 2015; Mitchell 1986; Pasupathy 2011; Sekhar 2001); two studies participants with either impacted or partially impacted teeth (López‐Cedrún 2011; Ritzau 1992); one study participants with only partially impacted teeth (Bergdahl 2004); one study participants with single inferior third molar only (Bortoluzzi 2013); one study participants with "teeth needing surgical extraction" (Lacasa 2007); and one study different surgical interventions (only data from tooth extractions were considered for this review) (Sixou 2012). Finally, only one study assessed the effect of antibiotic prophylaxis in participants who required extraction of any tooth due to caries or periodontal disease (Gbotolorun 2016).

In one trial (Barclay 1987), participants had a history of non‐acute pericoronitis, and in another trial (Bergdahl 2004), 41% of participants had pericoronitis at some stage and were entered into the trial "after objective and subjective symptoms of pericoronitis had ceased"; participants in both of these studies were thus likely to be at higher risk of infectious complications. Recent episodes of local infection was a reason for exclusion in two other studies (Lacasa 2007; Sekhar 2001). In the remaining trials, participants were considered healthy at baseline, and systemic conditions, including those causing immunosuppression, were often a reason for exclusion from the trial (see Characteristics of included studies).

Characteristics of interventions

In 21 out of the 23 included trials, the antibiotics were administered orally; one study used intravenous penicillin or clindamycin (Halpern 2007), and one study administered penicillin intramuscularly (MacGregor 1980).

We classified the antibiotic interventions into three groups based on the time of administration relative to the extraction (studies with three or more arms may be included in more than one group).

The antibiotics selected for use in the studies were amoxicillin (Bezerra 2011; Bortoluzzi 2013; Leon Arcila 2001; López‐Cedrún 2011; Milani 2015; Pasupathy 2011; Sixou 2012), a combination of amoxicillin/clavulanate (Arteagoitia 2005; Arteagoitia 2015; Lacasa 2007), or a combination of amoxicillin and metronidazole (Gbotolorun 2016), azidocillin (Bystedt 1980; Bystedt 1981), clindamycin (Bystedt 1980; Halpern 2007; Kaczmarzyk 2007), doxycycline (Bystedt 1980), erythromycin (Bystedt 1980), metronidazole (Barclay 1987; Bergdahl 2004; Kaziro 1984; Pasupathy 2011; Ritzau 1992; Sekhar 2001), penicillin (Halpern 2007; MacGregor 1980), phenoxymethylpenicillin (Happonen 1990), and tinidazole (Happonen 1990; Mitchell 1986).

Details of specific dosage regimens are recorded in the Characteristics of included studies for each study.

Characteristics of outcomes

Seventeen studies investigated pain (Arteagoitia 2005; Arteagoitia 2015; Barclay 1987; Bezerra 2011; Bortoluzzi 2013; Bystedt 1980; Bystedt 1981; Gbotolorun 2016; Happonen 1990; Kaczmarzyk 2007; Kaziro 1984; Lacasa 2007; López‐Cedrún 2011; MacGregor 1980; Milani 2015; Sekhar 2001; Sixou 2012). Arteagoitia 2005 and Sekhar 2001 evaluated pain at 2 and 6 days; Arteagoitia 2015, Barclay 1987, Bezerra 2011, and López‐Cedrún 2011 at 7 days; Bystedt 1980 and Bystedt 1981 at 2, 5, and 7 days; Happonen 1990 at 6 days; Kaczmarzyk 2007 at 1, 2, and 7 days; Kaziro 1984 at day 4 and 8; Gbotolorun 2016 and Lacasa 2007 at 1, 3, and 7 days; Bortoluzzi 2013 at day 1, 3, 4, and 5; MacGregor 1980 at 4 days; Milani 2015 at 4 and 7 days; and Sixou 2012 at 7 and 21 days.

Eight studies recorded fever (Arteagoitia 2005; Bystedt 1981; Happonen 1990; Kaczmarzyk 2007; Lacasa 2007; López‐Cedrún 2011; Milani 2015; Pasupathy 2011): one study reported fever at 24 hours only (Arteagoitia 2005); two studies recorded the presence of fever at 6 to 7 days after surgery (López‐Cedrún 2011; Pasupathy 2011); and five studies recorded fever at different time points (Bystedt 1981; Happonen 1990; Kaczmarzyk 2007; Lacasa 2007; Milani 2015).

Six studies included swelling at day 6 to 7 amongst outcomes (Arteagoitia 2015; Bystedt 1981; Kaczmarzyk 2007; Lacasa 2007; López‐Cedrún 2011; Sekhar 2001).

Seven studies investigated trismus amongst outcomes (Bortoluzzi 2013; Bystedt 1981; Happonen 1990; Kaczmarzyk 2007; Lacasa 2007; Milani 2015; Pasupathy 2011): 3 studies registered trismus at different days of follow‐up (Bystedt 1981 at 2, 5, and 7 days; Kaczmarzyk 2007 at 1, 2, and 7 days; Lacasa 2007 at 1, 3, and 7 days); 3 studies evaluated trismus at 6 or 7 days after surgery (Happonen 1990; Milani 2015; Pasupathy 2011); and 1 study did not report the timing of trismus evaluation (Bortoluzzi 2013).

Six studies reported the development of dry socket with different timings of evaluation (Arteagoitia 2005; Bergdahl 2004; Bortoluzzi 2013; Bystedt 1981; Gbotolorun 2016; Ritzau 1992). In particular, Ritzau 1992 evaluated this complication with a follow‐up at 7 days; Arteagoitia 2005 with a follow‐up at 7 days and 8 weeks; Bergdahl 2004 with a follow‐up between 2 and 4 days after surgery; Bystedt 1981 with a follow‐up at 2, 5, and 7 days; and Gbotolorun 2016 with a follow‐up at day 3 and 7. One study did not report the exact timing of dry socket evaluation (Bortoluzzi 2013) .

Seven of the 23 included trials reported the presence or absence of adverse effects per participant (Arteagoitia 2005; Arteagoitia 2015; Barclay 1987; Bystedt 1981; Kaczmarzyk 2007; Lacasa 2007; Milani 2015).

Studies without useable data

Four of the included trials did not report data in a form that was suitable for inclusion in meta‐analysis (Bystedt 1980; Kaziro 1984; MacGregor 1980; Sixou 2012).

The authors of Bystedt 1980 conducted three independent subtrials, but reported data combining all of these subtrials. We were therefore unable to draw any conclusions because data about experimental and control groups for each subtrial were missing. The authors of Kaziro 1984 did not report the number of participants included in the outcome assessments, but used graphs to show the percentage of participants with infection, pain, and swelling. Fewer participants in the antibiotic group complained of infection or pain, but there were not estimates of variance, thus the statistical significance (if any) cannot be determined from this report. The trial by MacGregor 1980 compared a single dose of intramuscular penicillin with placebo, followed up the enrolled participants for four days, and only stated that there were not significant differences with regard to pain, swelling, and trismus between antibiotic and placebo groups. Unfortunately, no data were provided to substantiate this claim. The authors of Sixou 2012 did not report the results as they were stated in the "Materials and Methods" section. This paper was interesting because it dealt with the extraction of teeth other than third molars, but it was not possible to analyse the data as reported.

Risk of bias in included studies

Overall risk of bias

We assessed three included trials as at low risk of bias for all domains (Gbotolorun 2016; Leon Arcila 2001; Milani 2015). We assessed four trials as at unclear risk of bias because information in the trial report or available from the authors was insufficient to determine risk of bias in at least one domain (Arteagoitia 2015; Bortoluzzi 2013; Halpern 2007; MacGregor 1980). We assessed the remaining 16 trials as at high overall risk of bias because each trial was at high risk of bias in one or more domains (Figure 2; Figure 3).

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Blinding

Double‐blinding was one of our inclusion criteria, thus all included studies were at low risk of both performance and detection bias.

Incomplete outcome data

Most of the included trials had relatively low rates of participants excluded from the analysis due to loss to follow‐up or withdrawal from the trial. However, these trials also reported low event rates for the outcomes of interest, which meant that even small numbers of excluded participants could have introduced bias.

Four trials reported that all the randomised participants were included in the analysis (Bortoluzzi 2013; Bystedt 1981; Leon Arcila 2001; Mitchell 1986). In five trials, attrition was between < 1% and 4%, and losses were equally distributed between study arms (Arteagoitia 2005; Arteagoitia 2015; Bergdahl 2004; Halpern 2007; Milani 2015). Two studies, Gbotolorun 2016 and Sixou 2012, had higher attrition, 12%, and 13% respectively, but they were relatively large in terms of numbers of participants (171 and 250), and the losses were equally distributed between study arms. In the split‐mouth cross‐over study by Bezerra 2011, two participants were lost to follow‐up, but due to the study design, this was not considered to have introduced a risk of attrition bias. We assessed these 12 trials as at low risk of attrition bias.

Three trials did not report the number of randomised participants included in the analysis, and as these trials were published more than 25 years ago, we were unable to obtain this information (Bystedt 1980; Kaziro 1984; MacGregor 1980). We assessed these three trials as at unclear risk of attrition bias.

Four trials reported an overall exclusion of participants from outcome evaluation of between 8% and 17%, and noted that losses were unequally distributed between antibiotic and placebo groups (Barclay 1987; Lacasa 2007; López‐Cedrún 2011; Sekhar 2001). A further four trials reported that between 5% and 14% of participants were excluded from the outcome evaluation, and did not describe the reasons for exclusion or the treatment groups from which participants were excluded (Happonen 1990; Kaczmarzyk 2007; Pasupathy 2011; Ritzau 1992) We assessed these eight trials as at high risk of attrition bias.

Selective reporting

Selective reporting is difficult to assess in the absence of a trial protocol. We based our assessment of reporting bias on three factors: whether the trial report contained in the results section, data on all the outcome measures described in the methods section of the report; whether planned outcome measures included those that would reasonably be expected to have been included in such a trial; and whether both point estimates and variances were reported.

Eleven trials reported complete data on all the outcomes that were listed in their methods sections and were thus assessed as at low risk of reporting bias (Arteagoitia 2015; Barclay 1987; Bortoluzzi 2013; Gbotolorun 2016; Halpern 2007; Kaczmarzyk 2007; Leon Arcila 2001; López‐Cedrún 2011; MacGregor 1980; Milani 2015; Ritzau 1992).

The authors of Pasupathy 2011 did not mention the outcomes to be evaluated in the patients and methods section, thus we assessed this study as at unclear risk of reporting bias.

We assessed the remaining 11 trials as at high risk of reporting bias because they did not report prespecified outcomes or reported them incompletely so that they could not be entered in a meta‐analysis.

Other potential sources of bias

We assessed six trials as at unclear risk of other bias (Bergdahl 2004; Bystedt 1980; Kaziro 1984; Lacasa 2007; López‐Cedrún 2011; Sekhar 2001). In one study, the follow‐up duration was too short (four days), and it was unclear whether participants who experienced acute pericoronitis before the trial, were treated with antibiotics (Bergdahl 2004). No description of characteristics of participants by randomised group at baseline was available in Bystedt 1980 and Kaziro 1984. In Lacasa 2007 and López‐Cedrún 2011, a statistically significant difference in duration of operations between two study arms was recorded. The need for osteotomy was significantly lower in one of the groups in Sekhar 2001.

No other sources of bias were identified in the remaining 17 trials.

Effects of interventions

See: Table 1

Summary of findings 1

Antibiotic compared to placebo for people undergoing tooth extraction

The results from the 19 trials providing useable data are described below in subgroups according to the timing of antibiotic administration (preoperatively, postoperatively, or both pre‐ and postoperatively). For most outcomes, there was either no difference between subgroups or too few studies to evaluate subgroup differences, with the exception of pain measured as a continuous variable. Subgroup analysis based on the immune status of participants was not possible, as studies on immunosuppressed people, or those with underlying health conditions that may have influenced their immune system, were not identified by our searches.

Postsurgical infectious complications

The overall pooled estimate from all 12 parallel‐arm RCTs that reported the outcome of postsurgical infectious complications showed that the use of antibiotics reduced the risk of infection (risk ratio (RR) 0.34, 95% confidence interval (CI) 0.19 to 0.64; 1728 participants; 12 studies; I2 = 28%) (Analysis 1.1). There was no difference between the subgroups (P = 0.10), and the overall meta‐analysis heterogeneity was not considered to be important (P = 0.17, I2 = 28%). The rate of infections ranged from 0 to 56% in the placebo group and 0 to 16% in the antibiotic group. There is a reduction in the risk of infection from a mean of 8.5% (64/757) in the placebo group to 2.6% (27/1035) in the antibiotic group (Table 3).

2

Raw outcome data ‐ postsurgical infectious complications

Analysis

Comparison 1: Antibiotic versus placebo, Outcome 1: Postsurgical infectious complications (6th to 7th day)

Pre‐ and postoperative prophylaxis

In three trials (Arteagoitia 2015; Happonen 1990; Leon Arcila 2001), antibiotics or placebo was administered before and after the tooth extraction procedure. Leon Arcila 2001 recorded no infectious complications in either group. The overall estimate in the subgroup showed no difference between groups in reported infections (RR 0.98, 95% CI 0.38 to 2.52; 356 participants; 3 studies; I2 = 0%) (Analysis 1.1).

Pain (dichotomous (yes/no) on sixth to seventh day)

The overall pooled estimate from the three parallel arm‐RCTs that reported pain as a dichotomous outcome was RR 0.59 (95% CI 0.31 to 1.12; 675 participants; 3 studies; I2 = 59%) (Analysis 1.2) (Arteagoitia 2005; Bystedt 1981; Sekhar 2001). We detected substantial heterogeneity in the overall meta‐analysis and in the postoperative prophylaxis subgroup. The mean rate of the presence of pain at day 6 to 7 was 11.8% (46/390) in the antibiotic group and 12.6% (36/285) in the placebo group (Table 4).

3

Raw outcome data ‐ pain (dichotomous) day 6 to 7

Analysis

Comparison 1: Antibiotic versus placebo, Outcome 2: Pain (dichotomous on 6th to 7th day)

Preoperative prophylaxis

Only one trial employing preoperative prophylaxis reported pain as a dichotomous outcome at day 6 (Sekhar 2001), and found no difference between the antibiotic and placebo groups (RR 1.10, 95% CI 0.57 to 2.12; 61 participants; 1 study; I2 not applicable) (Analysis 1.2).

Postoperative prophylaxis

Two trials reported pain as a dichotomous outcome in this subgroup (Arteagoitia 2005; Sekhar 2001). There was no difference in this outcome between antibiotic and placebo groups (RR 0.48, 95% CI 0.15 to 1.52; 554 participants; 2 studies; I2 = 71%). There was moderate heterogeneity (Analysis 1.2).

Pre‐ and postoperative prophylaxis

Only one trial reported pain as a dichotomous outcome in this subgroup (Bystedt 1981). Antibiotic prophylaxis was associated with less pain than placebo (RR 0.36, 95% CI 0.13 to 0.98; 60 participants; 1 study; I2 not applicable) (Analysis 1.2).

Pain (continuous, VAS on seventh day)

Six trials reported pain as a continuous outcome by visual analogue scale (VAS) 0 to 10 cm, where 10 is the most pain (Arteagoitia 2015; Barclay 1987; Bezerra 2011; Kaczmarzyk 2007; López‐Cedrún 2011; Sekhar 2001). The trial by López‐Cedrún 2011 did not report SD, thus it could not be included in meta‐analysis (both preoperative prophylaxis and postoperative prophylaxis), nor could the trial with a split‐mouth cross‐over design be included (preoperative prophylaxis) (Bezerra 2011).

The mean difference for the four parallel‐arm RCTs that reported pain with VAS score showed no statistically significant difference between the antibiotic and placebo groups (MD −0.26, 95% CI −0.59 to 0.07; 422 participants; 4 studies; I2 = 44%; Table 5) (Arteagoitia 2015; Barclay 1987; Kaczmarzyk 2007; Sekhar 2001). Heterogeneity for subgroup differences was substantial (I2 = 77.2%; P = 0.01), which could be explained by the fact that trials in the pre‐ and postoperative prophylaxis subgroup highlighted a protective tendency of antibiotics against pain (Analysis 1.3).

4

Raw outcome data ‐ pain (continuous, measured by VAS) at day 6 to 7

Analysis

Comparison 1: Antibiotic versus placebo, Outcome 3: Pain score (VAS 0 to 10 cm where 0 = no pain) 7th day

Preoperative prophylaxis

The two trials that reported the VAS score in each group at day 6 to 7 showed no difference between antibiotic and placebo groups (MD −0.10, 95% CI −0.44 to 0.24; 106 participants; 2 studies; I2 = 0%) (Analysis 1.3) (Kaczmarzyk 2007; Sekhar 2001). The trial by López‐Cedrún 2011 did not report SD, thus it could not be included in the meta‐analysis; however, the authors reported that VAS pain in the antibiotic group was significantly lower than in the placebo group. Similarly, the trial with a split‐mouth cross‐over design showed a significantly lower pain level in the antibiotic group compared with the placebo group (Bezerra 2011).

Postoperative prophylaxis

Only one trial reported pain VAS score at day 6 in this subgroup (Sekhar 2001). No differences were recorded between antibiotic and placebo groups (MD 0.10, 95% CI −0.22 to 0.42; 64 participants; 1 study; I2 not applicable) (Analysis 1.3). The trial by López‐Cedrún 2011 did not report SD, thus it could not be included into meta‐analysis; however, the authors reported that VAS pain in the antibiotic group was significantly lower than in the placebo group.

Pre‐ and postoperative prophylaxis

Three trials evaluated the pain VAS score in this subgroup (Arteagoitia 2015; Barclay 1987; Kaczmarzyk 2007). These trials reported a protective role of antibiotics against pain (MD −0.75, 95% CI −1.22 to −0.28; 252 participants; 3 studies; I2 = 0%) (Analysis 1.3).

Fever (sixth to seventh day)

Six trials reported fever as an outcome (Bystedt 1981; Happonen 1990; Lacasa 2007; López‐Cedrún 2011; Milani 2015; Pasupathy 2011).

López‐Cedrún 2011 and Pasupathy 2011 reported fever data in a way that did not permit inclusion in the meta‐analysis.

The overall pooled estimate from the four parallel‐arm RCTs that reported the outcome related to fever at day 6 or 7 showed no differences between the group who underwent antibiotic prophylaxis and the placebo group (RR 0.66, 95% CI 0.24 to 1.79; 475 participants; 4 studies; I2 not applicable) (Analysis 1.4) (Bystedt 1981; Happonen 1990; Lacasa 2007; Milani 2015). Notably, only one trial recorded episodes of fever amongst participants (Happonen 1990). The rate of fever episodes in the antibiotic group was 2.4% (8/328), whilst the rate in the placebo group was 4.1% (6/147) (Table 6).

5

Raw outcome data ‐ fever at day 6 to 7

Analysis

Comparison 1: Antibiotic versus placebo, Outcome 4: Fever (6th to 7th day)

Preoperative prophylaxis

Only two trials employing preoperative prophylaxis reported the outcome related to fever, with no cases recorded in either study arm (Lacasa 2007; Milani 2015).

Postoperative prophylaxis

Three trials employing postoperative prophylaxis reported the outcome related to fever in this subgroup (Bystedt 1981; Happonen 1990; Lacasa 2007), but two of them did not record cases in either study arm (Bystedt 1981; Lacasa 2007). Only one trial recorded cases of participants with fever in both arms, with no significant differences between the antibiotic and placebo groups (RR 0.66, 95% CI 0.24 to 1.79; 296 participants; I2 not applicable) (Analysis 1.4) (Happonen 1990).

Pre‐ and postoperative prophylaxis

Only one study employing pre‐ and postoperative prophylaxis reported data on fever, and recorded no cases in either group (Milani 2015).

Swelling day 7

Six trials reported swelling as an outcome (Arteagoitia 2015; Bystedt 1981; Kaczmarzyk 2007; Lacasa 2007; López‐Cedrún 2011; Sekhar 2001).

We did not include Bystedt 1981 (pre‐ and postoperative prophylaxis) in meta‐analysis because the outcome was reported in a graph, or Lacasa 2007 (preoperative prophylaxis, pre‐ and postoperative prophylaxis), which reported the value without SD.

The overall pooled estimate from the four parallel‐arm trials that reported the outcome of swelling showed no differences between the group who underwent antibiotic prophylaxis and the placebo group (RR 0.80, 95% CI 0.50 to 1.27; 452 participants; 4 studies; I2 = 44%) (Analysis 1.5) (Arteagoitia 2015; Kaczmarzyk 2007; López‐Cedrún 2011; Sekhar 2001). Overall heterogeneity was moderate, ranging from absent to substantial in the subgroups, whilst the test for subgroups differences was absent. The rate of swelling at day 7 was 25.3% (74/293) in the antibiotic group and 29.6% (47/159) the placebo group (Table 7).

6

Raw data ‐ swelling at day 6 to 7

Analysis

Comparison 1: Antibiotic versus placebo, Outcome 5: Swelling (7th day)

Preoperative prophylaxis

Three trials employing preoperative prophylaxis reported the results related to swelling on the seventh day after surgery (Kaczmarzyk 2007; López‐Cedrún 2011; Sekhar 2001). There was no statistical difference between the antibiotic and placebo groups (RR 1.13, 95% CI 0.69 to 1.83; 165 participants; 3 studies; I2 = 0%). Heterogeneity was absent (Analysis 1.5).

Postoperative prophylaxis

Two trials employing postoperative prophylaxis reported this outcome in this subgroup (López‐Cedrún 2011; Sekhar 2001), with no difference between the antibiotics and placebo groups (RR 0.68, 95% CI 0.35 to 1.34; 128 participants; 2 studies; I2 = 35%). Heterogeneity was probably not important (Analysis 1.5).

Pre‐ and postoperative prophylaxis

Two trials employing pre‐ and postoperative prophylaxis reported this outcome (Arteagoitia 2015; Kaczmarzyk 2007), with no difference between the antibiotics and placebo groups (RR 0.54, 95% CI 0.10 to 2.98; 159 participants; 2 studies; I2 = 73%). Heterogeneity was substantial (Analysis 1.5).

Trismus (dichotomous) day 7

Seven studies investigated trismus amongst outcomes (Bortoluzzi 2013; Bystedt 1981; Happonen 1990; Kaczmarzyk 2007; Lacasa 2007; Milani 2015; Pasupathy 2011).

Four studies that provided data unsuitable for quantitative analysis were not included in the meta‐analysis (Bystedt 1981; Happonen 1990; Lacasa 2007; Milani 2015). The overall pooled estimate from the three parallel‐arm trials that reported the outcome of trismus showed no differences between the antibiotics and placebo groups (RR 0.77, 95% CI 0.42 to 1.41; 199  participants; 3 studies; I2 = 0%) (Analysis 1.6) (Bortoluzzi 2013; Kaczmarzyk 2007; Pasupathy 2011). Heterogeneity was absent in the overall meta‐analysis, and the test for subgroups differences was not significant. The rate of trismus at day 6 to 7 was 16.0% (21/131) in the antibiotic group and 22.1% (15/68) in the placebo group (Table 8).

7

Raw data ‐ trismus at day 6 to 7

Analysis

Comparison 1: Antibiotic versus placebo, Outcome 6: Trismus (7th day)

Preoperative prophylaxis

Three trials employing preoperative prophylaxis evaluated trismus at day 6 to 7 (Bortoluzzi 2013; Kaczmarzyk 2007; Pasupathy 2011), finding no evidence of a benefit of antibiotic prophylaxis (RR 0.73, 95% CI 0.36 to 1.46; 158 participants; 3 studies; I2 = 0%; Analysis 1.6).

Postoperative prophylaxis

No trials employing postoperative prophylaxis reported trismus.

Pre‐ and postoperative prophylaxis

Only one trial employing pre‐ and postoperative prophylaxis evaluated trismus (Kaczmarzyk 2007), finding no evidence of a difference between antibiotic and placebo (RR 0.93, 95% CI 0.27 to 3.14; 41 participants; Analysis 1.6).

Dry socket

Fourteen trials reported the outcome of dry socket: 13 parallel‐arm RCTs (Arteagoitia 2005; Arteagoitia 2015; Barclay 1987; Bergdahl 2004; Bortoluzzi 2013; Bystedt 1980; Bystedt 1981; Gbotolorun 2016; Halpern 2007; Kaczmarzyk 2007; López‐Cedrún 2011; Pasupathy 2011; Ritzau 1992), and one split‐mouth cross‐over RCT (Bezerra 2011).

The pooled estimate for all 13 parallel‐arm trials that reported on dry socket was RR 0.66 (95% CI 0.45 to 0.97; 1882 participants; 13 studies; I2 = 0%; Analysis 1.7). Overall heterogeneity was absent, as was heterogeneity between subgroups. The postoperative prophylaxis group showed moderate heterogeneity. The rate of infections ranged from 0 to 56% in the placebo group and 0 to 16% in the antibiotic group. There was a reduction in the risk of infection from a mean of 6.3% (56/890) in the placebo group to 3.8% (40/1060) in the antibiotic group (Table 9).

Analysis

Comparison 1: Antibiotic versus placebo, Outcome 7: Dry socket (6th to 7th day)

Postoperative prophylaxis

Three trials employing postoperative prophylaxis reported the outcome of dry socket. The trial by López‐Cedrún 2011 did not detect any dry socket in either group, whilst the remaining trials showed no difference between antibiotic and placebo groups (RR 0.82, 95% CI 0.12 to 5.54; 704 participants; 3 studies; I2 = 41%) (Arteagoitia 2005; Gbotolorun 2016). Heterogeneity was moderate (Analysis 1.7).

Pre‐ and postoperative prophylaxis

Five trials employing pre‐ and postoperative prophylaxis reported dry socket (Arteagoitia 2015; Barclay 1987; Bystedt 1980; Bystedt 1981; Kaczmarzyk 2007). The pooled estimate showed a reduction in the risk of dry socket among those taking postoperative prophylaxis (RR 0.50, 95% CI 0.28 to 0.90; 454 participants; 5 studies; I2 = 0%). Heterogeneity was absent (Analysis 1.7).

Adverse effects

The overall pooled estimate from the eight parallel‐arm trials that reported the outcome of side effects showed no differences between the group who underwent antibiotic prophylaxis and the placebo group (RR 1.46, 95% CI 0.81 to 2.64; 1277 participants; 8 studies; I2 = 53%; Analysis 1.8). Heterogeneity was moderate, whilst the heterogeneity for subgroup differences was not important (I2 = 18.8%; P = 0.29). Heterogeneity could be explained by how different authors diagnosed relevant side effects. Indeed, the two studies from the same author demonstrated a significant difference between groups, with side effects more prevalent in the antibiotic group (Arteagoitia 2005; Arteagoitia 2015). The rate of side effects was 10.3% (78/756) in the antibiotic group and 6.9% (36/521) in the placebo group (Table 10); the nature of the side effects included diarrhoea, abdominal pain, and others (Table 11).

9

Raw data ‐ adverse effects

10

Nature of adverse effects when in studies as an outcome

Analysis

Comparison 1: Antibiotic versus placebo, Outcome 8: Adverse events (6th to 7th day)

Postoperative prophylaxis

Three trials employing postoperative prophylaxis reported this outcome (Arteagoitia 2005; Lacasa 2007; López‐Cedrún 2011). There was no significant difference between groups (RR 1.26, 95% CI 0.24 to 6.51; 666 participants; 3 studies; I2 = 77%). Heterogeneity was substantial, and it should be highlighted that the trial by Arteagoitia 2005, which had the largest sample, reported a significant prevalence of side effects in the antibiotic group (Analysis 1.8).

Pre‐ and postoperative prophylaxis

Four trials employing pre‐ and postoperative prophylaxis reported this outcome (Arteagoitia 2015; Barclay 1987; Kaczmarzyk 2007; Milani 2015). Milani 2015 reported no adverse effects in either group. There was no significant difference between the antibiotic and placebo group (RR 2.44, 95% CI 0.95 to 6.24; 294 participants; 4 studies; I2 = 36%). Heterogeneity was not important. Arteagoitia 2015 was the only trial that showed a significant difference between groups, with side effects more prevalent in the antibiotic group (Analysis 1.8).

Discussion

Summary of main results

We included 23 double‐blind, placebo‐controlled trials with more than 3206 participants (2583 analysed) in the review. Participants in 21 studies underwent extraction of third molar (wisdom) teeth; participants in one study underwent routine intra‐alveolar extraction; and one study enrolled patients who needed complex oral surgery with an estimated intervention length of less than 90 minutes, including avulsion with alveolectomy, avulsion of a tooth under mucous membrane, avulsion of impacted tooth, or multiple avulsions (> 3 teeth). None of the included studies were of patients undergoing tooth extraction in general dental practice, for the removal of severely decayed teeth; even the study focused on intra‐alveolar extractions included patients from the dental outpatient department of a general hospital. 

Sixteen of the included trials were at high risk of bias, four were at unclear risk of bias, and the remaining three were at low risk of bias.

Antibiotics, administered to prevent infection in patients undergoing wisdom tooth extraction, may reduce the risk of infection by approximately 66% (low‐certainty evidence) (Table 1). We found no clear evidence that the timing of antibiotic administration (preoperative, postoperative, or both) was important.

There may be no difference between antibiotics and placebo for the outcomes of pain (whether measured dichotomously or continuously), fever, swelling, or trismus seven days after tooth extraction (very low‐certainty evidence).

Whilst antibiotic prophylaxis seems to reduce the risk of infection and dry socket, these outcomes still occur in some healthy people who take antibiotic prophylaxis associated with the extraction of impacted third molars. It is interesting to note that the rate of infection in the placebo groups in the included trials varied between zero, Bortoluzzi 2013; Gbotolorun 2016; Leon Arcila 2001; Sekhar 2001, and 56%, Mitchell 1986, with a mean of 8.5% across the placebo groups of the included studies (Table 3). Based on the evidence presented in this review, the use of prophylactic antibiotics may reduce infection to a mean of 2.6%, which means that approximately 19 (95% CI 15 to 34) people would need to receive antibiotic prophylaxis to prevent one infection.

The incidence of dry socket in the placebo group varied between zero, Arteagoitia 2015; Halpern 2007; López‐Cedrún 2011; Pasupathy 2011, and 34%, Barclay 1987, with a mean of 6.3%. This means that approximately 46 (95% CI 29 to 521) healthy people would need to be treated with prophylactic antibiotics to prevent one case of dry socket (Table 9).

Using prophylactic antibiotics might result in at least one adverse event for every 32 people treated (9 to 77 number needed to treat for an additional harmful outcome), though adverse effects reported in the trials were generally mild and transient.

Overall completeness and applicability of evidence

We conducted a comprehensive search including both electronic and handsearching through reference lists. We identified 23 randomised, double‐blind, placebo‐controlled trials that involved a combined total of approximately 2600 (analysed) participants. All but one trial included healthy patients in their 20s who were undergoing extraction of impacted teeth (mainly of the lower jaw), thus making the results of our review sound in regards to the effectiveness of antibiotic prophylaxis of infectious complications in healthy young people undergoing wisdom tooth extractions, which is a very large proportion of surgical tooth extractions. However, we identified no trials of patients attending general dental practices for tooth extraction due to caries or periodontitis; in one trial, most of patients attending the dental outpatient department of a general hospital had extraction mainly due to caries or periodontitis (Gbotolorun 2016). The identified trials did not include patients with depressed immune systems, patients with other illnesses, young children, or elderly people. Indeed, it is unlikely to be feasible or ethical to conduct placebo‐controlled trials in this group of patients. The results of this review may or may not be generalisable to this group, who would be expected to be at higher risk of infection. However, extrapolating from the results of this review, it may be that in people at higher risk of infectious complications, antibiotic prophylaxis may be more effective, with a lower 'number needed to treat' with antibiotics in order to prevent one infection; this is particularly important given that in such patients, an infective complication can have more serious consequences due to the impaired ability of the immune system to avoid spreading of the infection.

Another limit to generalisability of our results regards the clinical skill of the operators, who in the included studies were mainly oral surgery specialists working in referral centres. Whether results would be similar for general dental practitioners is unclear.

Adverse event frequency and severity can be important determinants in deciding whether to administer a preventive treatment. As is the case for many medical areas, the quality and quantity of information about adverse effects of interventions in these trials was inadequate (Ioannidis 2009). However, based on dropout rates and the adverse effects in the eight trials that reported the frequency of adverse effects per participant, it seems likely that adverse effects were generally mild and well tolerated.

We could not draw any conclusions on the extent to which the use of prophylactic antibiotics in association with tooth extraction in healthy people may affect the subsequent development of strains of bacteria resistant to antibiotics in common use in these situations (EU Commission 2011; EU Commission 2019).

Quality of the evidence

Although this review was restricted to double‐blind, placebo‐controlled trials, only three of the included trials were at low risk of bias overall (four trials were at unclear risk and 16 were at high risk of bias). The most common sources of bias were missing outcome data and selective reporting. In trials such as many of those included in this review, where the outcome events are uncommon even in the placebo group, losses to follow‐up can potentially result in misleading results.

We evaluated the certainty of the body of evidence included in this review using the GRADE approach (see Table 1). The certainty of the evidence was very low for most outcomes due to high or unclear risk of bias, confidence intervals that crossed the line of no effect, and heterogeneity between studies. We graded the certainty of the evidence for the outcomes postsurgical infectious complications and dry socket as low due to high risk of bias. We downgraded the evidence for indirectness, as most of the trials were performed only in healthy patients undergoing wisdom tooth extractions.

The evidence concerning the use of prophylactic antibiotics in patients undergoing extraction for severe caries or periodontitis came from a single study (Gbotolorun 2016).

Potential biases in the review process

Data from some of the studies included in the current review, namely the older ones, could not be entered in the meta‐analysis due to poor reporting, which prevented data extraction. This may have introduced reporting bias into the review. The funnel plots for the primary outcome of postsurgical infectious complications (Figure 4) and secondary outcome dry socket (Figure 5) showed no evidence of publication bias (note that the points on the plot are not independent because three of the trials are included in two subgroups (Kaczmarzyk 2007; Lacasa 2007; López‐Cedrún 2011)).

Funnel plot of comparison: antibiotic versus placebo, outcome: infectious complications.

Funnel plot of comparison: antibiotic versus placebo, outcome: dry socket.

In the protocol for this review, we planned to only include trials where the important clinical outcome of infection was reported. In this update, we made it more explicit that we excluded trials that only reported other or intermediate outcomes (endocarditis incidence, bacteraemia, or serum marker of infection). We consider that these changes have resulted in higher quality, clinically relevant trials being included in the review.

Agreements and disagreements with other studies or reviews

A previous review in 2007 included a different group of studies due to the use of different inclusion criteria, which considered mandibular third molar extractions only and did not limit the review to double‐blind studies. Ren 2007 concluded that antibiotic administration was effective in preventing wound infection, although they reported a higher number needed to treat for an additional harmful outcome: "on average 25 patients needed to be treated with systemic antibiotics to prevent 1 case of extraction wound infection" in this group of healthy patients.

More recently, several other systematic reviews and meta‐analyses have assessed studies focused on third molar surgery (thus with different inclusion criteria than the current review), and they also focused on a specific antibiotic molecule. Three meta‐analyses focused on the use of amoxicillin, finding that it does not reduce the risk of infection or dry socket (or both) after third molar extraction (Arteagoitia 2016; Isiordia‐Espinoza 2015; Menon 2019). Conversely, the association of amoxicillin/clavulanic acid seems to be effective (Arteagoitia 2016; Menon 2019). Nevertheless, Arteagoitia 2016 did not support the routine prescription of antibiotic due the number needed to treat for an additional beneficial outcome, the low prevalence of infection, the potential adverse reactions to antibiotics, and the lack of serious complications in placebo groups.

A couple of meta‐analyses reported discordant results about the effectiveness of nitromimidazoles to reduce the risk of dry socket or infection (or both) in third molar extraction (Isiordia‐Espinoza 2018; Ramos 2016).

Authors' conclusions

Implications for practice

Most of the literature shed light on a subset of patients undergoing dental extractions: healthy people who had surgical extraction of third molars. There is low‐certainty evidence that in this subset of patients, the use of prophylactic antibiotics reduces the risk of infectious complications. We found no clear evidence that the timing of antibiotic administration (preoperative, postoperative, or both) is important. On average, treating 19 healthy patients with prophylactic antibiotics may prevent one infection. Consequently, when deciding whether to use antibiotic prophylaxis to prevent infective complications following tooth extractions in healthy patients, the practitioner should consider the possible increased risk of mild adverse effects (at least one for every 30 people treated), the low rate of infectious complications (approximately 40 people treated to prevent one case of dry socket), and the lack of serious complications even in the absence of antibiotic prophylaxis. Another important aspect of reconsidering the routine prescription of antibiotic prophylaxis is the growing emphasis on limiting the use of antibiotics in order to stop increasing microbial resistance to drugs. Evidence is lacking about the effects of prophylactic antibiotics in patients with concomitant illnesses or patients at a higher risk of infection.

Implications for research

The evidence for the effectiveness of antibiotic prophylaxis in preventing infectious complications cannot be generalised to either non‐healthy patients or less invasive intra‐alveolar extraction lacking alveolectomy. Future trials should investigate prophylactic antibiotics effectiveness in patients at high risk of infective complications, such as immunocompromised people and people who have experienced infective complications following previous extractions, although undertaking research in these groups of people may not be possible or ethical. Conversely, the single trial investigating intra‐alveolar extractions for severe caries or periodontal disease in healthy patients failed to find any significant role for antibiotic prophylaxis in preventing infectious complications. Future studies should also measure the outcomes of symptoms and clinical assessment using standardised measures and time points, and report these according to CONSORT guidelines.

Feedback

Comment from Dr John Curran, February 2013

Summary

Very good review. Unfortunately the difficulty of designing a randomised trial still exists partly due to ethical requirements and logistics ‐e.g. with third molar surgery assessment of difficulty and surgical ability are hard to measure. Post‐operative assessment also needs to be done sooner than the 7 days used in the review. Little has changed in but I believe that in patient age groups most prevalent in the North America context the incidence of infection is even lower than reported ‐i.e. antibiotic usage should be highly selective.

Reply

Thank you for your interest in our work and for your comment.
I absolutely agree that real incidence of infectious complications in a population similar to study groups is likely to be lower, and for that reason we did not really recommend for regular antibiotic prophylaxis. Unfortunately because of the lack of studies on patients at higher risk, no evidence is available on cases for which antibiotic prophylaxis is (anecdotally) recommended.

Contributors

Summary: John Curran.
Reply: Giovanni Lodi.

What's new

History

Protocol first published: Issue 3, 2002
Review first published: Issue 11, 2012

Acknowledgements

Our thanks to Laura MacDonald for editorial and scientific support, Anne Littlewood for literature search, and Lisa Winer for copyediting. We thank Anne‐Marie Glenny, Helen Worthington, Phil Riley, Nikolaus Palmer, Heba Hussein, and Jennifer Hilgart for their comments. We acknowledge Luisa Fernandez‐Mauleffinch, Lara Figini, and Jo Weldon for contributions to previous versions of this review.

Appendices

Appendix 1. Cochrane Oral Health Trials Register search strategy

Cochrane Oral Health’s Trials Register is available via the Cochrane Register of Studies. For information on how the register is compiled, see oralhealth.cochrane.org/trials

From February 2019, searches of the Cochrane Oral Health Trials Register were undertaken via the Cochrane Register of Studies, using the search strategy below:

1 MESH DESCRIPTOR Tooth Extraction EXPLODE ALL AND INREGISTER
2 exodontia AND INREGISTER
3 ((tooth near/4 extract*) or (teeth near/4 extract*) or ("third molar*" near/4 extract*) or (3rd and (molar* near/4 extract*)) or "dental extract*" or (tooth near/4 remov*) or (teeth near/4 remov*) or ("third molar*" near/4 remov*) or ("3rd molar*" near/4 remov*) or (tooth near/4 surg*) or (teeth near/4 surg*) or ("third molar*" near/4 surg*) or ("3rd molar*" near/4 surg*)) AND INREGISTER
4 #1 or #2 or #3
5 MESH DESCRIPTOR Molar EXPLODE ALL AND INREGISTER
6 MESH DESCRIPTOR Tooth, Impacted AND INREGISTER
7 ("wisdom tooth" or "wisdom teeth" or (third near/3 molar)) AND INREGISTER
8 "impacted tooth" AND INREGISTER
9 "impacted teeth" AND INREGISTER
10 (#5 or #6 or #7 or #8 or #9)
11 (extract* or remov* or surg*) AND INREGISTER
12 (#10 and #11)
13 (#4 or #12)
14 MESH DESCRIPTOR Anti‐Bacterial Agents EXPLODE ALL AND INREGISTER
15 MESH DESCRIPTOR Antibiotic prophylaxis AND INREGISTER
16 MESH DESCRIPTOR Erythromycin EXPLODE ALL AND INREGISTER
17 MESH DESCRIPTOR Metronidazole AND INREGISTER
18 MESH DESCRIPTOR Tetracyclines AND INREGISTER
19 MESH DESCRIPTOR Clindamycin AND INREGISTER
20 MESH DESCRIPTOR Teicoplanin AND INREGISTER
21 MESH DESCRIPTOR Vancomycin AND INREGISTER
22 MESH DESCRIPTOR Floxacillin AND INREGISTER
23 MESH DESCRIPTOR Gentamicins AND INREGISTER
24 MESH DESCRIPTOR Cephalexin AND INREGISTER
25 (antibiot* or "anti biot*" or anti‐biot*) AND INREGISTER
26 (penicillin* or erythromycin* or metronidazol* or cephalosporin*) AND INREGISTER
27 (sulphonamide* or tetracycline* or clindamycin* or clindamicin* or augmentin* or flagyl* or amoxyl* or amoxil* or co‐amox* or antifungal* or anti‐fungal* or "anti fungal*" or teicoplanin* or vancomycin* or vancomicin* or flucloxacillin* or floxacillin* or gentamicin* or gentamycin* or cephalexin*) AND INREGISTER
28 (antibacterial or anti‐bacterial or "anti bacterial") AND INREGISTER
29 #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28
30 (#13 and #29)

Previous searches of the register were undertaken via the Procite software, using the search strategy below:

((extract* or remov* or exodontia or "impacted teeth" or "impacted tooth" or "oral surg*" or (tooth and surg*) or (teeth and surg*) or ("third molar*" and surg*)) AND (antibiotic* or erthromycin* or metronidaz* or tetracycline* or clindamycin* or teicoplanin* or vancomycin* or floxacillin* or gentamicin* or cephalexin* or "anti biotic*" or anti‐biotic* or penicillin* or antibacterial* or anti‐bacterial* or "anti bacterial*" or erthromycin* or cephalsporin* or suphonamide* or clindamicin* or augmentin* or flagyl* or amoxyl* or amoxil* or co‐amox* or antifungal* or anti‐fungal* or "anti fungal*" or vancomicin* or flucloxacillin* or floxacillin* or gentamycin* or cephalexin*))

Appendix 2. Cochrane Central Register of Controlled Trials (CENTRAL) search strategy

#1        MeSH descriptor Tooth extraction explode all trees 
#2        exodontia in All Text
#3        ((tooth in All Text near/4 extract* in All Text) or (teeth in All Text near/4 extract* in All Text) or ("third molar*" in All Text near/4 extract* in All Text) or (3rd in All Text and (molar* in All Text near/4 extract* in All Text) ) or "dental extract*" in All Text or (tooth in All Text near/4 remov* in All Text) or (teeth in All Text near/4 remov* in All Text) or ("third molar*" in All Text near/4 remov* in All Text) or ("3rd molar*" in All Text near/4 remov* in All Text) or (tooth in All Text near/4 surg* in All Text) or (teeth in All Text near/4 surg* in All Text) or ("third molar*" in All Text near/4 surg* in All Text) or ("3rd molar*" in All Text near/4 surg* in All Text))
#4        (#1 or #2 or #3)
#5        MeSH descriptor Molar explode all trees
#6        MeSH descriptor Tooth, impacted this term only
#7        ("wisdom tooth" in All Text or "wisdom teeth" in All Text or (third in All Text near/3 molar in All Text))
#8        "impacted tooth" in All Text
#9        "impacted teeth" in All Text
#10      (#5 or #6 or #7 or #8 or #9)
#11      (extract* in All Text or remov* in All Text or surg* in All Text)
#12      (#10 and #11)
#13      (#4 or #12)
#14      MeSH descriptor Anti‐Bacterial Agents explode all trees
#15      MeSH descriptor Antibiotic prophylaxis this term only
#16      MeSH descriptor Erythromycin explode all trees
#17      MeSH descriptor Metronidazole this term only
#18      MeSH descriptor Tetracyclines this term only
#19      MeSH descriptor Clindamycin this term only
#20      MeSH descriptor Teicoplanin this term only
#21      MeSH descriptor Vancomycin this term only
#22      MeSH descriptor Floxacillin this term only
#23      MeSH descriptor Gentamicins this term only
#24      MeSH descriptor Cephalexin this term only
#25      (antibiot* in All Text or "anti biot*" in All Text or anti‐biot* in All Text)
#26      (penicillin* in All Text or erythromycin* in All Text or metronidazol* in All Text or cephalosporin* in All Text)
#27      (sulphonamide* in All Text or tetracycline* in All Text or clindamycin* in All Text or clindamicin* in All Text or augmentin* in All Text or flagyl* in All Text or amoxyl* in All Text or amoxil* in All Text or co‐amox* in All Text or antifungal* in All Text or anti‐fungal* in All Text or "anti fungal*" in All Text or teicoplanin* in All Text or vancomycin* in All Text or vancomicin* in All Text or flucloxacillin* in All Text or floxacillin* in All Text or gentamicin* in All Text or gentamycin* in All Text or cephalexin* in All Text)
#28      (antibacterial in All Text or anti‐bacterial in All Text or "anti bacterial" in All Text)   
#29      (#14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28)
#30      (#13 and #29)

Appendix 3. MEDLINE Ovid search strategy

1.         exp TOOTH EXTRACTION/
2.         exodontia.mp.                                    
3.         ((tooth adj4 extract$) or (teeth adj4 extract$) or ("third molar$" adj4 extract$) or ("3rd molar$" adj4 extract$) or "dental extract$" or (tooth adj4 remov$) or (teeth adj4 remov$) or ("third molar$" adj4 remov$) or ("third molar$" adj4 remov$) or (tooth adj4 surg$) or (teeth adj4 surg$) or ("third molar$" adj4 surg$) or ("3rd molar$" adj4 surg$)).mp.           
4.         1 or 2 or 3                               
5.         MOLAR/                                 
6.         TOOTH IMPACTED/                                    
7.         ("wisdom tooth" or "wisdom teeth" or (third adj3 molar$) or (3rd adj3 molar$)).mp.                        
8.         "impacted tooth".mp.                         
9.         "impacted teeth".mp.                         
10.       (5 or 6 or 7 or 8 or 9) and (extract$ or remov$ or surg$).mp.                       
11.       10 or 4                                    
12.       exp ANTIBIOTICS/                            
13.       ANTIBIOTIC PROPHYLAXIS/                                  
14.       ERYTHROMYCIN/                           
15.       METRONIDAZOLE/                          
16.       TETRACYCLINES/                           
17.       CLINDAMYCIN/                                
18.       TEICOPLANIN/                                 
19.       VANCOMYCIN/                                
20.       FLOXACILLIN/                                  
21.       GENTAMICINS/                                
22.       CEPHALEXIN/                                  
23.       (Antibiot$ or "anti biot$" or anti‐biot$).mp.
24.       (penicillin$ or erythromycin$ or Metronidazol$ or Cephalosporin$).mp.
25.       (antibacterial or anti‐bacterial or "anti bacterial").mp.
26.       (sulphonamide$ or tetracycline$ or clindamycin$ or clindamicin$ or augmentin$ or flagyl$ or amoxyl$ or amoxil$ or co‐amox$ or antifungal$ or anti‐fungal$ or "anti fungal$" or teicoplanin$ or vancomycin$ or vancomicin$ or flucloxacillin or floxacillin or gentamicin$ or gentamycin$ or cephalexin$).mp.                 
27.       or/12‐26                                  
28.       27 and 11

This subject search was linked to the Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying randomised trials in MEDLINE: sensitivity‐maximising version (2008 revision) as referenced in Lefebvre C, Glanville J, Briscoe S, Littlewood A, Marshall C, Metzendorf M‐I, Noel‐Storr A, Rader T, Shokraneh F, Thomas J, Wieland LS. Technical Supplement to Chapter 4: Searching for and selecting studies. In: Higgins JPT, Thomas J, Chandler J, Cumpston MS, Li T, Page MJ, Welch VA (eds). Cochrane Handbook for Systematic Reviews of InterventionsVersion 6. Cochrane, 2019. Available from: www.training.cochrane.org/handbook (Lefebvre 2019).

1. randomized controlled trial.pt.
2. controlled clinical trial.pt.
3. randomized.ab.
4. placebo.ab.
5. drug therapy.fs.
6. randomly.ab.
7. trial.ab.
8. groups.ab.
9. or/1‐8
10. exp animals/ not humans.sh.
11. 9 not 10

Appendix 4. Embase Ovid search strategy

1.         exp TOOTH EXTRACTION/
2.         exodontia.ti,ab.                                   
3.         ((tooth adj4 extract$) or (teeth adj4 extract$) or ("third molar$" adj4 extract$) or ("3rd molar$" adj4 extract$) or "dental extract$" or (tooth adj4 remov$) or (teeth adj4 remov$) or ("third molar$" adj4 remov$) or ("third molar$" adj4 remov$) or (tooth adj4 surg$) or (teeth adj4 surg$) or ("third molar$" adj4 surg$) or ("3rd molar$" adj4 surg$)).ti,ab.
4.         1 or 2 or 3                               
5.         exp TOOTH/                          
6.         ("wisdom tooth" or "wisdom teeth" or (third adj3 molar$) or (3rd adj3 molar$)).ti,ab.                                   
7.         "impacted tooth".ti,ab.                                    
8.         "impacted teeth".ti,ab.                                    
9.         or/5‐8                          
10.       (extract$ or remov$ or surg$).ti,ab.                           
11.       9 and 10                                 
12.       4 or 11                                    
13.       exp ANTIBIOTIC AGENT/                            
14.       ANTIBIOTIC PROPHYLAXIS/                                  
15.       METRONIDAZOLE/                          
16.       (Antibiot$ or "anti biot$" or anti‐biot$).ti,ab.                            
17.       (penicillin$ or erythromycin$ or Metronidazol$ or Cephalosporin$).ti,ab.
18.       (antibacterial or anti‐bacterial or "anti bacterial").ti,ab.                                  
19.       (sulphonamide$ or tetracycline$ or clindamycin$ or clindamicin$ or  anti‐fungal$ or "anti fungal$" or teicoplanin$ or vancomycin$ or vancomicin$ or flucloxacillin or floxacillin or gentamicin$ or gentamycin$ or cephalexin$).ti,ab.
20.       or/13‐19                                  
21.       12 and 20

This subject search was linked to the Cochrane search filter for identifying randomised trials in Embase (2016 version) as referenced in Lefebvre C, Glanville J, Briscoe S, Littlewood A, Marshall C, Metzendorf M‐I, Noel‐Storr A, Rader T, Shokraneh F, Thomas J, Wieland LS. Technical Supplement to Chapter 4: Searching for and selecting studies. In: Higgins JPT, Thomas J, Chandler J, Cumpston MS, Li T, Page MJ, Welch VA (eds). Cochrane Handbook for Systematic Reviews of InterventionsVersion 6. Cochrane, 2019. Available from: www.training.cochrane.org/handbook (Lefebvre 2019)

1. Randomized controlled trial/
2. Controlled clinical study/
3. random$.ti,ab.
4. randomization/
5. intermethod comparison/
6. placebo.ti,ab.
7. (compare or compared or comparison).ti.
8. ((evaluated or evaluate or evaluating or assessed or assess) and (compare or compared or comparing or comparison)).ab.
9. (open adj label).ti,ab.
10. ((double or single or doubly or singly) adj (blind or blinded or blindly)).ti,ab.
11. double blind procedure/
12. parallel group$1.ti,ab.
13. (crossover or cross over).ti,ab.
14. ((assign$ or match or matched or allocation) adj5 (alternate or group$1 or intervention$1 or patient$1 or subject$1 or participant$1)).ti,ab.
15. (assigned or allocated).ti,ab.
16. (controlled adj7 (study or design or trial)).ti,ab.
17. (volunteer or volunteers).ti,ab.
18. human experiment/
19. trial.ti.
20. or/1‐19
21. random$ adj sampl$ adj7 ("cross section$" or questionnaire$1 or survey$ or database$1)).ti,ab. not (comparative study/ or controlled study/ or randomi?ed controlled.ti,ab. or randomly assigned.ti,ab.)
22. Cross‐sectional study/ not (randomized controlled trial/ or controlled clinical study/ or controlled study/ or randomi?ed controlled.ti,ab. or control group$1.ti,ab.)
23. (((case adj control$) and random$) not randomi?ed controlled).ti,ab.
24. (Systematic review not (trial or study)).ti.
25. (nonrandom$ not random$).ti,ab.
26. "Random field$".ti,ab.
27. (random cluster adj3 sampl$).ti,ab.
28. (review.ab. and review.pt.) not trial.ti.
29. "we searched".ab. and (review.ti. or review.pt.)
30. "update review".ab.
31. (databases adj4 searched).ab.
32. (rat or rats or mouse or mice or swine or porcine or murine or sheep or lambs or pigs or piglets or rabbit or rabbits or cat or cats or dog or dogs or cattle or bovine or monkey or monkeys or trout or marmoset$1).ti. and animal experiment/
33. Animal experiment/ not (human experiment/ or human/)
34. or/21‐33
35. 20 not 34

Appendix 5. LILACS BIREME Virtual Health Library search strategy

(Mh Tooth extraction or Mh Extracción Dental or Mh Extração Dentária or ((Tw tooth or Tw teeth or Tw molar$ or Tw dental) and (Tw extrac$ or Tw remov$ or Tw surg$))) [Words] and (Mh Anti‐Bacterial Agents or Mh Agentes Antibacterianos or Mh Antibiotic Prophylaxis or Profilaxis Antibiótica or Mh Antibioticoprofilaxia or antibiot$ or "anti biot$" or anti‐biot$ or antibacte$ or anti‐bacte$ or "anti bacte$" or penicillin$ or erythromycin$ or metronidazol$ or cephalosporin$ or sulphonamide$ or tetracycline$ or clindamycin$ or clindamicin$ or augmentin$ or flagyl$ or amoxyl$ or amoxil$ or co‐amox$ or teicoplanin$ or vancomycin$ or vancomicin$ or flucloxacillin$ or floxacillin$ or gentamicin$ or gentamycin$ or cephalexin$) [Words]

The above subject search was linked to the Brazilian Cochrane Center filter for LILACs via BIREME:

Pt randomized controlled trial OR Pt controlled clinical trial OR Mh randomized controlled trials OR Mh random allocation OR Mh double‐blind method OR Mh single‐blind method) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Pt clinical trial OR Ex E05.318.760.535$ OR (Tw clin$ AND (Tw trial$ OR Tw ensa$ OR Tw estud$ OR Tw experim$ OR Tw investiga$)) OR ((Tw singl$ OR Tw simple$ OR Tw doubl$ OR Tw doble$ OR Tw duplo$ OR Tw trebl$ OR Tw trip$) AND (Tw blind$ OR Tw cego$ OR Tw ciego$ OR Tw mask$ OR Tw mascar$)) OR Mh placebos OR Tw placebo$ OR (Tw random$ OR Tw randon$ OR Tw casual$ OR Tw acaso$ OR Tw azar OR Tw aleator$) OR Mh research design) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Ct comparative study OR Ex E05.337$ OR Mh follow‐up studies OR Mh prospective studies OR Tw control$ OR Tw prospectiv$ OR Tw volunt$ OR Tw volunteer$) AND NOT (Ct animal AND NOT (Ct human and Ct animal)))and not (Ct ANIMAL AND NOT (Ct HUMAN and Ct ANIMAL)))

Appendix 6. US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov search strategy

Expert search (filter: Interventional studies)

( tooth extraction OR tooth removal OR exodontia OR "impacted teeth" OR "impacted tooth" ) AND ( antibiotic OR erthromycin OR metronidaz OR tetracycline OR clindamycin OR teicoplanin OR vancomycin OR floxacillin OR gentamicin OR cephalexin OR "anti biotic" OR anti‐biotic OR penicillin OR antibacterial OR anti‐bacterial OR "anti bacterial" OR erthromycin OR cephalsporin OR suphonamide OR clindamicin OR augmentin OR flagyl OR antifungal OR anti‐fungal OR "anti fungal" OR vancomicin OR flucloxacillin OR floxacillin OR gentamycin OR cephalexin )

Appendix 7. World Health Organization International Clinical Trials Registry Platform search strategy

tooth AND removal AND antibiotic OR tooth AND extraction AND antibiotic OR tooth AND remove AND antibiotic OR tooth AND extract AND antibiotic

tooth AND removal AND antibacterial OR tooth AND extraction AND antibacterial OR tooth AND remove AND antibacterial OR tooth AND extract AND antibacterial

tooth AND removal AND metronidazole OR tooth AND extraction AND metronidazole OR tooth AND remove AND metronidazole OR tooth AND extract AND metronidazole

tooth AND removal AND penicillin OR tooth AND extraction AND penicillin OR tooth AND remove AND penicillin OR tooth AND extract AND penicillin

Notes

New search for studies and content updated (no change to conclusions)

Data and analyses

Comparison 1

Antibiotic versus placebo

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Characteristics of ongoing studies [ordered by study ID]

Differences between protocol and review

Quasi‐randomised studies are no longer eligible for inclusion in the review because less biased evidence is available from randomised controlled trials.

We decided to include only double‐blind, placebo‐controlled studies because we believe that these studies are likely to provide the best evidence to inform practice.

We clarified that we were excluding trials where the only outcomes were endocarditis incidence, bacteraemia, or serum marker of infection.

Some of the secondary outcomes (persistence of pain, presence of swelling, trismus, fever) were considered at six to seven days after dental surgery as possible symptoms or signs of infection. Their presence before this timing could not be considered as a real complication of the intervention but possibly due to the surgical trauma.

Contributions of authors

• Conceiving, designing, and co‐ordinating the review: Giovanni Lodi (GL), Elena Varoni (EV), Lorenzo Azzi (LA), Monica Pentenero (MP), Maddalena Manfredi (MM).

• Screening search results and retrieved papers against the inclusion criteria: GL, EV, LA, MP, MM.

• Appraising the quality of papers: GL, MM, EV, LA, MP.

• Extracting data from papers: GL, LA, EV, MP, MM, Andrea Sardella (AS).

• Writing to authors of papers for additional information: GL, LA; AS, Antonio Carrassi (AC).

• Data management for the review and entering data into Review Manager 5: GL, LA, EV, MP, MM.

• Analysis and interpretation of data: GL, EV, LA, MP, MM.

• Preparing the 'Summary of findings' table: GL, LA, EV, MP, MM.

• Providing a clinical perspective: GL, LA, EV, MP, MM, Massimo Del Fabbro (MDF).

• Writing the text of the review: GL, EV, LA, MP, MM.

• Preparing the Plain language summary: GL, AS, AC, MDF.

• Providing comments on a draft of the review: GL, EV, LA, MP, MM, AC, MDF, AS.

Sources of support

Internal sources

• Manchester Academic Health Sciences Centre (MAHSC) and the NIHR Manchester Biomedical Research Centre, UK

• Division of Dentistry, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK

External sources

• Cochrane Oral Health Global Alliance, UK

  The production of Cochrane Oral Health reviews has been supported financially by our Global Alliance since 2011 (oralhealth.cochrane.org/partnerships-alliances). Contributors in the last two years have been the American Association of Public Health Dentistry, USA; AS‐Akademie, Germany; the British Association for the Study of Community Dentistry, UK; the British Society of Paediatric Dentistry, UK; the Canadian Dental Hygienists Association, Canada; the Centre for Dental Education and Research at All India Institute of Medical Sciences, India; the National Center for Dental Hygiene Research & Practice, USA; New York University College of Dentistry, USA; and Swiss Society of Endodontology, Switzerland.

• National Institute for Health Research (NIHR), UK

  This project was supported by the NIHR, via Cochrane Infrastructure funding to Cochrane Oral Health. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Evidence Synthesis Programme, the NIHR, the NHS or the Department of Health and Social Care.

Declarations of interest

GL: none
LA: none
EV: none
MP: none
MDF: none
AC: none
AS: none
MM: none

References

References to studies included in this review

Arteagoitia 2005 {published data only}

• Arteagoitia I, Diez A, Barbier L, Santamaria G, Santamaria J. Efficacy of amoxicillin/clavulanic acid in preventing infectious and inflammatory complications following impacted mandibular third molar extraction. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 2005;100(1):e11-8. [PubMed] [Google Scholar]

Arteagoitia 2015 {published data only}

• Arteagoitia I, Ramos E, Santamaria G, Barbier L, Alvarez J, Santamaria J. Amoxicillin/clavulanic acid 2000/125 mg to prevent complications due to infection following completely bone-impacted lower third molar removal: a clinical trial. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology 2015;119:8-16. [PubMed] [Google Scholar]

Barclay 1987 {published data only}

• Barclay JK. Metronidazole and dry socket: prophylactic use in mandibular third molar removal complicated by non-acute pericoronitis. New Zealand Dental Journal 1987;83:71-5. [PubMed] [Google Scholar]

Bergdahl 2004 {published data only}

• Bergdahl M, Hedstrom L. Metronidazole for the prevention of dry socket after removal of partially impacted mandibular third molar: a randomised controlled trial. British Journal of Oral & Maxillofacial Surgery 2004;42(6):555-8. [PubMed] [Google Scholar]

Bezerra 2011 {published and unpublished data}

• Bezerra T. Poster Board Number: 16: Prophylaxis versus placebo treatment for infective and inflammatory complications of surgical third molar removal: a split-mouth, double-blind, controlled, clinical trial with amoxicillin (500 mg). Journal of Oral and Maxillofacial Surgery 2010;68(9 (Suppl)):e69. [PubMed] [Google Scholar]
• Bezerra TP, Studart-Soares EC, Scaparo HC, Pita-Neto IC, Batista SH, Fonteles CS. Prophylaxis versus placebo treatment for infective and inflammatory complications of surgical third molar removal: a split-mouth, double-blind, controlled, clinical trial with amoxicillin (500 mg). Journal of Oral & Maxillofacial Surgery 2011;69(11):e333-9. [PubMed] [Google Scholar]

Bortoluzzi 2013 {published data only}

• Bortoluzzi MC, Capella DL, Barbieri T, Pagliarini M, Cavalieri T, Manfro R. A single dose of amoxicillin and dexamethasone for prevention of postoperative complications in third molar surgery: a randomized, double-blind, placebo controlled clinical trial. Journal of Clinical Medicine Research 2013;5:26-33. [PMC free article] [PubMed] [Google Scholar]

Bystedt 1980 {published data only}

• Bystedt H, Nord CE, Nordenram A. Effect of azidocillin, erythromycin, clindamycin and doxycycline on postoperative complications after surgical removal of impacted mandibular third molars. International Journal of Oral Surgery 1980;9(3):157-65. [PubMed]

Bystedt 1981 {published data only}

• Bystedt H, Konow L, Nord CE. A comparison of the effect of phenoxymethylpenicillin and azidocillin on postoperative complications after surgical removal of impacted mandibular third molars. Swedish Dental Journal 1981;5(5-6):225-34. [PubMed] [Google Scholar]

Gbotolorun 2016 {published data only}

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López‐Cedrún 2011 {published and unpublished data}

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Adde 2012 {published data only}

• Adde CA, Soares MS, Romano MM, Carnaval TG, Sampaio RM, Aldarvis FP, et al. Clinical and surgical evaluation of the indication of postoperative antibiotic prescription in third molar surgery. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology 2012;114:S26-31. [DOI: 10.1016/j.tripleo.2011.08.018] [PubMed] [CrossRef] [Google Scholar]

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References to ongoing studies

CTRI/2019/12/022342 {published data only}

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EudraCT 2017‐004986‐28 {published data only}

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