Systemic antibiotics for symptomatic apical periodontitis and acute apical abscess in adults

Abstract

Background

Dental pain can have a detrimental effect on quality of life. Symptomatic apical periodontitis and acute apical abscess are common causes of dental pain and arise from an inflamed or necrotic dental pulp, or infection of the pulpless root canal system. Clinical guidelines recommend that the first‐line treatment for these conditions should be removal of the source of inflammation or infection by local operative measures, and that systemic antibiotics are currently only recommended for situations where there is evidence of spreading infection (cellulitis, lymph node involvement, diffuse swelling) or systemic involvement (fever, malaise). Despite this, there is evidence that dentists frequently prescribe antibiotics in the absence of these signs. There is concern that this could contribute to the development of antibiotic‐resistant bacteria. This review is the second update of the original version first published in 2014.

Objectives

To evaluate the effects of systemic antibiotics provided with or without surgical intervention (such as extraction, incision and drainage of a swelling, or endodontic treatment), with or without analgesics, for symptomatic apical periodontitis and acute apical abscess in adults.

Search methods

We searched Cochrane Oral Health's Trials Register (26 February 2018 (discontinued)), CENTRAL (2022, Issue 10), MEDLINE Ovid (23 November 2022), Embase Ovid (23 November 2022), CINAHL EBSCO (25 November 2022) and two trials registries, and performed a grey literature search. There were no restrictions on language or date of publication.

Selection criteria

Randomised controlled trials of systemic antibiotics in adults with a clinical diagnosis of symptomatic apical periodontitis or acute apical abscess, with or without surgical intervention (considered in this situation to be extraction, incision and drainage, or endodontic treatment) and with or without analgesics.

Data collection and analysis

Two review authors independently screened the results of the searches against inclusion criteria, extracted data and assessed risk of bias. We used a fixed‐effect model in the meta‐analysis as there were fewer than four studies. We contacted study authors to request missing information. We used GRADE criteria to assess the certainty of the evidence.

Main results

There was one new completed trial on this topic since the last update in 2018. In total, we included three trials with 134 participants.

Systemic antibiotics versus placebo with surgical intervention and analgesics for symptomatic apical periodontitis or acute apical abscess

One trial (72 participants) compared the effects of a single preoperative dose of clindamycin versus a matched placebo when provided with a surgical intervention (endodontic chemo‐mechanical debridement and filling) and analgesics to adults with symptomatic apical periodontitis. We assessed this study at low risk of bias. There were no differences in participant‐reported pain or swelling across trial arms at any time point assessed. The median values for pain (numerical rating scale 0 to 10) were 3.0 in both groups at 24 hours (P = 0.219); 1.0 in the antibiotic group versus 2.0 in the control group at 48 hours (P = 0.242); and 0 in both groups at 72 hours and seven days (P = 0.116 and 0.673, respectively). The risk ratio of swelling when comparing preoperative antibiotic to placebo was 0.50 (95% confidence interval (CI) 0.10 to 2.56; P = 0.41). The certainty of evidence for all outcomes in this comparison was low.

Two trials (62 participants) compared the effects of a seven‐day course of oral phenoxymethylpenicillin (penicillin VK) versus a matched placebo when provided with a surgical intervention (total or partial endodontic chemo‐mechanical debridement) and analgesics to adults with acute apical abscess or symptomatic necrotic tooth. Participants in both trials also received oral analgesics. We assessed one study at high risk of bias and the other at unclear risk of bias. There were no differences in participant‐reported pain or swelling at any time point assessed. The mean difference for pain (short ordinal numerical scale 0 to 3, where 0 was no pain) was −0.03 (95% CI −0.53 to 0.47) at 24 hours; 0.32 (95% CI −0.22 to 0.86) at 48 hours; and 0.08 (95% CI −0.38 to 0.54) at 72 hours. The standardised mean difference for swelling was 0.27 (95% CI −0.23 to 0.78) at 24 hours; 0.04 (95% CI −0.47 to 0.55) at 48 hours; and 0.02 (95% CI −0.49 to 0.52) at 72 hours. The certainty of evidence for all the outcomes in this comparison was very low.

Adverse effects, as reported in two studies, were diarrhoea (one participant in the placebo group), fatigue and reduced energy postoperatively (one participant in the antibiotic group) and dizziness preoperatively (one participant in the antibiotic group).

Systemic antibiotics without surgical intervention for adults with symptomatic apical periodontitis or acute apical abscess

We found no studies that compared the effects of systemic antibiotics with a matched placebo delivered without a surgical intervention for symptomatic apical periodontitis or acute apical abscess in adults.

Authors' conclusions

The evidence suggests that preoperative clindamycin for adults with symptomatic apical periodontitis results in little to no difference in participant‐reported pain or swelling at any of the time points included in this review when provided with chemo‐mechanical endodontic debridement and filling under local anaesthesia. The evidence is very uncertain about the effect of postoperative phenoxymethylpenicillin for adults with localised apical abscess or a symptomatic necrotic tooth when provided with chemo‐mechanical debridement and oral analgesics. We found no studies which compared the effects of systemic antibiotics with a matched placebo delivered without a surgical intervention for symptomatic apical periodontitis or acute apical abscess in adults.

Plain language summary

What are the effects of antibiotics on pain and swelling caused by inflammation or infection at the root of the tooth in adults?

Key messages

– A single dose of antibiotics probably makes little to no difference to pain and swelling when taken before root canal treatment.

– The evidence is very uncertain about the effect of antibiotics taken after debridement (a procedure involving partial or total cleaning of the inside of the root canal) on pain or swelling.

– No study examined the effect of antibiotics on their own, without dental treatment, when provided for two conditions commonly responsible for causing dental pain.

How can apical periodontitis and apical abscess arise?

Dental pain is a common problem and can arise when the nerve within a tooth dies due to decay or injury. When this causes inflammation in the bone around the end of the affected tooth, it is known as apical periodontitis. When this causes symptoms, normally pain, this is described as symptomatic apical periodontitis.

Without treatment, bacteria can infect the tooth and cause a collection of pus around the end of the root (known as an apical abscess). This can lead to swelling and spreading of the infection.

How is toothache caused by apical periodontitis or apical abscess treated?

The recommended treatment for these conditions is removal of the dead nerve and associated bacteria. This is usually done by extraction of the tooth or cleaning of the root canal system (called chemo‐mechanical debridement). Sometimes people will have the root canal filled the same day (complete root canal treatment) or they may return at a later date for filling of the root canal system and restoration (filling) of the tooth.

Antibiotics are only recommended when there is severe infection that has spread from the root of the tooth. However, some dentists still routinely prescribe antibiotics to people with these conditions who have no signs of spreading infection, or without dental treatment to remove the dead or infected material. Use of antibiotics contributes to the development of antibiotic‐resistant bacteria (where bacteria are no longer killed by the antibiotic). Therefore, it is important that antibiotics are only used when they are likely to result in benefit for the person.

What did we want to find out?

We wanted to find out if antibiotics improve the pain and swelling reported by adults with toothache caused by symptomatic apical periodontitis or apical abscess. We were interested in the effects of antibiotics when they were given with or without dental treatment and with or without painkillers.

What did we do?

We searched for studies that looked at antibiotics compared to dummy medication (placebo) in adults with these conditions. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and size.

What did we find?

We found three studies (one of which was new for this update). In total, we included 134 participants in the analysis. All studies were conducted in university dental schools and evaluated the use of oral (taken by mouth) antibiotics in the reduction of pain reported by adults after having total or partial chemo‐mechanical debridement under local anaesthetic (injection of a numbing medicine into the gum around the affected tooth). In one trial, participants received a single dose of antibiotics before their dental treatment. In two trials, participants received a seven‐day course of antibiotics after their dental treatment.

In the study comparing a single dose of oral antibiotics versus placebo before complete root canal treatment, there were no differences in pain or swelling reported by participants in the two groups. The evidence suggests a single dose of antibiotics results in little to no difference in pain and swelling when taken before root canal treatment.

The two studies comparing a course of antibiotics versus placebo after partial or total chemo‐mechanical debridement found there were no differences in pain or swelling between the groups. However, the evidence is very uncertain.

No study examined the effect of antibiotics on their own without surgical dental treatment.

Two studies reported side effects among participants. One person who received the placebo medication had diarrhoea (loose stools). One person who received antibiotics after dental treatment experienced tiredness and reduced energy after their treatment and another who received antibiotics before dental treatment experienced dizziness.

What are the limitations of the evidence?

Our confidence in the evidence relating to a single‐dose of antibiotics taken before complete root canal treatment is low because we have very serious concerns that the study may not have included a sufficient number of participants to detect a difference between the groups and we cannot exclude the possibility of a beneficial effect.

We are not confident in the evidence about the effect of a course of antibiotics taken after partial or total chemo‐mechanical debridement because the studies were small and, in one of the studies, many participants dropped out before the end.

How up to date is this evidence?

The evidence was up to date to 25 November 2022.

Summary of findings

Summary of findings 1. Preoperative antibiotics with a surgical intervention and analgesics for managing symptomatic apical periodontitis and acute apical abscess in adults.

Preoperative dose of systemic antibiotics with a total chemo‐mechanical debridement and root filling for managing symptomatic apical periodontitis in adults
Patient or population: adults with a symptomatic apical periodontitis (no signs of spreading infection or systemic involvement) Settings: university dental school, Egypt Intervention: single dose of systemic antibiotics (clindamycin), total chemo‐mechanical debridement and root filling Comparison: matched placebo, total chemo‐mechanical debridement and root filling
Outcomes	Illustrative comparative risks*		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Matched placebo, total chemo‐mechanical debridement and root filling	Systemic antibiotics, total chemo‐mechanical debridement and root filling
Pain at 24 hours Ordinal scale from 0 to 10	The median pain at 24 hours in the control groups was: 3 (range: 0–10)	The median pain at 24 hours in the intervention group was the same (median: 3, range: 0–8)	—	72 (1 study)	⊕⊕⊝⊝ Lowa	—
Pain at 72 hours Ordinal scale from 0 to 10	The median pain at 72 hours in the control group was: 0 (range: 0–10)	The median pain at 72 hours in the intervention group was the same (median: 0, range: 0–7)	—	72 (1 study)	⊕⊕⊝⊝ Lowa	—
Pain at 7 days Ordinal scale from 0 to 10	The median pain at 7 days in the control group was: 0 (range: 0–3)	The median pain at 7 days in the intervention group was the same (median: 0, range: 0–1)	—	72 (1 study)	⊕⊕⊝⊝ Lowa	—
Swelling at 24 hours	No data available for this outcome		—	—	—	—
Swelling at 72 hours	No data available for this outcome		—	—	—	—
Swelling at 7 days Binary outcome	4/36 (11.1%) participants reported swelling	2/36 (5.6%) participants reported swelling	RR 0.50 (0.10 to 2.56)	72 (1 study)	⊕⊕⊝⊝ Lowa	—
Adverse effects	No adverse effects reported	1 participant reported dizziness	—	72 (1 study)	⊕⊕⊝⊝ Lowa	—
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk is based on the assumed risk in the comparison group and the relative effect of the intervention. CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: we are very uncertain about the estimate.

^a Downgraded two levels due to very serious imprecision.

Summary of findings 2. Postoperative antibiotics with a surgical intervention and analgesics for managing symptomatic apical periodontitis and acute apical abscess in adults.

Postoperative systemic antibiotics with total/partial chemo‐mechanical debridement and analgesics for adults with a symptomatic necrotic tooth or localised acute apical abscess
Patient or population: adults with a symptomatic necrotic tooth or localised acute apical abscess (no signs of spreading infection or systemic involvement) Settings: university dental schools, USA Intervention: 7 days of postoperative systemic antibiotics (phenoxymethylpenicillin), partial or total chemo‐mechanical debridement and analgesics Comparison: matched placebo, partial or total chemo‐mechanical debridement and analgesics
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Matched placebo, partial or total chemo‐mechanical debridement and analgesics	Systemic antibiotics, partial or total chemo‐mechanical debridement and analgesics
Pain at 24 hours Short ordinal numerical scale from 0 to 3	The mean pain at 24 hours ranged across control groups from: 1.0 to 1.68	The mean pain at 24 hours in the intervention groups was 0.03 lower (0.53 lower to 0.47 higher)	—	61 (2 studies)	⊕⊝⊝⊝ Very lowa,b,c	—
Pain at 72 hours Short ordinal scale from 0 to 3	The mean pain at 72 hours ranged across control groups from: 0.3 to 0.82	The mean pain at 72 hours in the intervention groups was 0.08 higher (0.38 lower to 0.54 higher)	—	61 (2 studies)	⊕⊝⊝⊝ Very lowa,b,c	—
Pain at 7 days Short ordinal scale from 0 to 3	The mean pain at 7 days was 0.32	The mean pain at 7 days in the intervention groups was 0.05 lower (0.41 lower to 0.30 higher)	—	41 (1 study)	⊕⊝⊝⊝ Very lowb,c	—
Swelling at 24 hours Different short ordinal numerical scales	The mean swelling at 24 hours in the control groups was 0.59d	The mean swelling at 24 hours in the intervention groups was 0.27 standard deviations higher (0.23 lower to 0.78 higher)	—	62 (2 studies)	⊕⊝⊝⊝ Very lowa,b,c,e	This converts back into a 36% increase (95% CI 31% decrease to 105% increase) of control mean for antibiotics (based on 1 study at unclear risk of bias).
Swelling at 72 hours Different short ordinal numerical scales	The mean swelling at 72 hours in the control groups was 0.59d	The mean swelling at 72 hours in the intervention groups was 0.02 standard deviations higher (0.49 lower to 0.52 higher)	—	61 (2 studies)	⊕⊝⊝⊝ Very lowa,b,c,e	This converts back into a 2% increase (95% CI 55% decrease to 59% increase) of control mean for antibiotics (based on 1 study at unclear risk of bias).
Swelling at 7 days Short ordinal scale from 0 to 3	The mean swelling a 7 days in the control group was 0.14	The mean swelling at 7 days in the intervention group was 0.02 higher (0.28 lower to 0.32 higher)	—	41 (1 study)	⊕⊝⊝⊝ Very lowb,c	—
Adverse effects	1 participant reported diarrhoea	1 participant reported fatigue and reduced energy postoperatively	—	61 (2 studies)	⊕⊝⊝⊝ Very lowa,b,c	—
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval.
GRADE Working Group grades of evidence High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: we are very uncertain about the estimate.

^a Downgraded one level due to high risk of bias in one study.
^b Downgraded two levels due to very serious imprecision (small group sizes) in two studies.
^c Downgraded one level due to indirectness in one study (intervention restricted to partial/total chemo‐mechanical debridement).
^d Re‐expressed from the standardised mean difference into the short ordinal numerical scale used by Henry 2001. Results should be interpreted with caution since back‐translation of the effect size was based on the results of only one study.
^e Downgraded one level due to inconsistency (moderate to severe heterogeneity).

Background

Description of the condition

Dental pain can have a detrimental effect on an individual's social functioning and quality of life (Pau 2005; Reisine 1995). In the USA National Health and Nutrition and Examination Survey (NHANES) 2015 to 2018, 24% of adults reported experiencing dental pain 'occasionally' or 'often' in the last year with the incidence highest in younger people and those from lower socioeconomic groups (Aldosari 2021). Among adults presenting with acute dental conditions, approximately 16% will have symptomatic apical periodontitis and a further 20% will have an acute apical abscess (Cope 2016).

Apical periodontitis arises following injury to the pulpal tissues of a tooth caused by dental caries, tooth fracture, trauma or iatrogenic damage. While the dental pulp can recover from reversible pulpitis resulting from a mild to moderate injury, persistent or extensive damage results in irreversible levels of inflammation within the pulpal tissues. Should this occur, an individual might experience symptoms of irreversible pulpitis. Without treatment, irreversibly inflamed teeth then undergo pulpal necrosis and bacterial colonisation of the root canal system (Abbott 2004; Bergenholtz 2010).

Apical periodontitis (also known as periapical periodontitis) is an inflammatory lesion of the periradicular tissues that arises principally due to the egress of irritants, such as bacteria and toxins, from an inflamed or necrotic pulp (Torabinejad 1994). Its evolutionary role is protective: to contain the root canal bacteria and prevent the spread of infection. While the vast majority of cases are asymptomatic, exacerbations of apical periodontitis can present as symptomatic apical periodontitis or an acute apical abscess (Bergenholtz 2010).

Symptomatic apical periodontitis can arise either from a formerly healthy tooth that has subsequently undergone pulpal breakdown or from a tooth with a previously asymptomatic apical periodontitis. It is characterised by a dull or throbbing pain that is exacerbated by biting. The affected tooth usually has a negative or delayed positive response to vitality testing and is often highly sensitive to percussive forces (Bergenholtz 2010).

It should be noted that in determining the health of pulpal tissues, the term 'vitality testing' is commonly used. True 'vitality' tests attempt to examine the presence of pulp blood flow, while 'sensibility' tests employ the use of thermal or electrical stimuli to elicit a response from innervated tissue (Chen 2009). Although neither can definitively indicate the health of the dental pulp, they remain useful diagnostic aids, commonly used in both clinical practice and scientific studies.

Acute apical abscesses develop in the presence of a pre‐existing apical periodontitis (Carrotte 2004). The persistent presence of infective material within the pulpless root canal system and around the apex of a tooth can lead to a massive influx of polymorphonuclear leukocytes into the periradicular tissues, leading to tissue liquefaction and pus formation (Bergenholtz 2010). Also known as a periapical, dentoalveolar or alveolar abscess, an apical abscess is characterised by the accumulation of pus in the periradicular tissues and can present as either an acute or a chronic lesion. Individuals with acute apical abscesses typically complain of a rapid onset, spontaneous pain; tenderness of the tooth to pressure; pus formation and swelling of associated tissues (Glickman 2009). Left untreated, the abscess may spread, resulting in a potentially serious head and neck infection accompanied by fever, malaise and lymph node involvement (Abbott 2004). Since symptomatic apical periodontitis and acute apical abscess represent a continuum of the same disease process, it is appropriate to consider both conditions in this review.

Description of the intervention

Clinical guidelines currently recommend that the first‐line treatment for teeth with either symptomatic apical periodontitis or an acute apical abscess is the removal of the source of inflammation or infection by local, operative measures (Lockhart 2019; Palmer 2020; SDCEP 2016). This could involve extraction of the offending tooth or extirpation (removal) of the pulpal tissues, possibly in combination with the incision and drainage of any swelling present.

Systemic antibiotics are currently only recommended for situations where there is evidence of spreading infection (cellulitis, lymph node involvement, diffuse swelling) or systemic symptoms (fever, malaise) (Lockhart 2019; SDCEP 2016). Despite this, there is evidence that antibiotics are often prescribed by dentists to people with symptomatic apical periodontitis or acute apical abscess in the absence of these signs (Cope 2016; Germack 2017; Rodríguez‐Fernández 2023). In one study in Croatia, approximately 60% of individuals attending an emergency dental service with apical periodontitis received a prescription for systemic antibiotics and a third of these received no surgical intervention (Bjelovucic 2019).

How the intervention might work

Doctors and dentists may prescribe systemic antibiotics to minimise the signs and symptoms of symptomatic apical periodontitis or acute apical abscess, and to treat or prevent the development of a serious orofacial swelling with systemic involvement. Antibiotics can be prescribed pre‐ or postoperatively, and as an adjunctive or stand‐alone treatment. People prescribed antibiotics may be given analgesics at the same time.

Why it is important to do this review

There is international concern about the overuse of antibiotics and the emergence of antibiotic‐resistant bacterial strains (World Health Organization 2015). Since dentists prescribe approximately 7% to 11% of antibiotics dispensed in primary care in high‐income countries, it is important not to underestimate the potential contribution of the dental profession to the development of antibiotic resistance (Al‐Haroni 2007; ARHAI 2020; Halling 2017; Thornhill 2019a). Furthermore, dentists frequently prescribe antibiotics for prolonged periods (seven days or longer) and often use broad‐spectrum agents (Durkin 2017). In addition to driving antibiotic resistance, the use of antibiotics in situations where their use is not indicated is a misuse of resources, it increases the risk of potentially fatal anaphylactic reactions and antibiotic‐related colitis (Clostridioides difficile), and it exposes people to unnecessary adverse effects (Costelloe 2010; Gonzales 2001; Thornhill 2019b). Furthermore, antibiotic prescribing for common medical problems may increase patient expectations for antibiotics, leading to increased prescribing in order to meet expectations (Coenen 2006; Little 1997).

It is important that antibiotics are prescribed only when they are likely to result in clinical benefit. Symptomatic apical periodontitis and acute apical abscess are two of the most common presentations at urgent dental care (Cope 2016). If systemic antibiotics are effective in the treatment of symptomatic apical periodontitis or acute apical abscess then it is important that the nature of any benefits are quantified. However, if antibiotics are ineffective, people are being unnecessarily exposed to harmful adverse effects and the increased possibility of developing antibiotic‐resistant bacterial colonies. Therefore, the objective of this review was to evaluate the effects of systemic antibiotics for symptomatic apical periodontitis and acute apical abscess in adults. This is an update of the original version that was first published in 2014, and updated in 2018 (Cope 2014; Cope 2018).

Objectives

To evaluate the effects of systemic antibiotics provided with or without surgical intervention (such as extraction, incision and drainage of a swelling, or endodontic treatment), with or without analgesics, for symptomatic apical periodontitis or acute apical abscess in adults.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) with parallel group design in the review. We excluded cluster‐RCTs.

Types of participants

Studies of adults (18 years of age or older), male or female, who presented with a single tooth with a clinical diagnosis of either symptomatic apical periodontitis or acute apical abscess.

Should a study have included only a subset of eligible participants, we would have requested individual participant data for only those eligible. If participant‐level data could not be retrieved, we would have excluded the study.

Types of interventions

Active intervention

Administration of any systemic antibiotic (either oral or intravenous) at any dosage prescribed in the symptomatic phase of apical periodontitis or acute apical abscess with or without analgesics, and with or without surgical intervention (extraction, incision and drainage or endodontic treatment).

Control

Administration of a matched placebo prescribed in the symptomatic phase of apical periodontitis or acute apical abscess with or without analgesics, and with or without surgical intervention.

Types of outcome measures

Eligible studies reported one or more primary or secondary outcomes. In instances where studies may have been excluded on the basis of having no eligible outcomes, we would have contacted study authors to confirm no eligible outcomes were measured.

Primary outcomes

• Participant‐reported pain and swelling, measured on either a continuous scale, such as visual analogue scale (VAS), or using binary or dichotomous outcomes.

• Clinician‐reported measures of infection, such as swelling, temperature, trismus (reduced mouth opening), regional lymphadenopathy or cellulitis. These outcomes may have been reported as continuous, categorical or dichotomous variables.

Primary outcomes were assessed at 24, 48 and 72 hours, and seven days postoperatively.

Secondary outcomes

• Participant‐reported quality of life measures.

• Type, dose and frequency of analgesics used.

• Any adverse effects or harms (hypersensitivity or other reactions) attributed to antibiotics or analgesics, complications of surgical treatment or hospitalisations.

Secondary outcomes were assessed across the duration of the study.

Search methods for identification of studies

Electronic searches

For the original review (Cope 2014) and 2018 update (Cope 2018), the Cochrane Oral Health's Information Specialist conducted systematic searches in the following databases for RCTs and controlled clinical trials. For this update, one review author (ALC) conducted the searches. There were no language, publication year or publication status restrictions.

• Cochrane Oral Health's Trials Register (searched 26 February 2018 (discontinued 2022))

• Cochrane Central Register of Controlled Trials (CENTRAL; 2022, Issue 10) in the Cochrane Library

• MEDLINE Ovid (1946 to 23 November 2022)

• Embase Ovid (1980 to 23 November 2022)

• CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to 25 November 2022)

• OpenGrey (to 26 February 2018) (this resource was discontinued on 1 December 2020)

• ZETOC Conference Proceedings (1993 to 26 February 2018) (this resource was retired on 1 August 2022)

• ProQuest Dissertations & Theses Global (to 23 November 2022)

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 strategy designed by Cochrane for identifying RCTs and controlled clinical trials as described in the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 4 (Lefebvre 2022).

The full search strategies used for each database can be found in Appendix 1.

Searching other resources

We searched the following trial registries for ongoing studies.

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov; searched 25 November 2022)

• World Health Organization International Clinical Trials Registry Platform (trialsearch.who.int; searched 25 November 2022)

We checked the reference lists of all included and excluded studies to identify any further trials.

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

Data collection and analysis

Selection of studies

Two review authors (ALC and IGC) independently assessed the titles and abstracts (where available) of the articles identified by the search strategy and made decisions regarding eligibility. The search was designed to be sensitive and include controlled clinical trials; these were filtered out early in the selection process if they were not randomised. We obtained the full‐text versions of all articles being considered for inclusion, and those with insufficient information in the title or abstract to make a clear decision. We resolved any disagreements by discussion. We excluded studies later found not to meet the inclusion criteria and recorded them in the Characteristics of excluded studies table.

Data extraction and management

Two review authors (ALC and IGC) independently extracted the outcome data from the included studies using a piloted standard data extraction form. The review authors discussed the results and resolved any disagreements. In cases where uncertainties persisted, we contacted the study authors for clarification. We entered study details into the Characteristics of included studies table.

We extracted the following characteristics.

• Study methodology: study design, methods of allocation, method of randomisation, randomisation concealment, blinding, time of follow‐up, loss to follow‐up, country conducted in, number of centres, recruitment period and funding source.

• Participants: sampling frame, diagnostic criteria, inclusion criteria, exclusion criteria, number of participants in each group, baseline group demographics and clinical diagnosis.

• Intervention: type of antibiotic, dose, frequency and duration of course. Information about co‐interventions, for example, surgical treatment or analgesia.

• Outcomes: primary outcomes at 24, 48 and 72 hours and seven days, and secondary outcomes as previously described (see Primary outcomes; Secondary outcomes).

Non‐English language abstracts were first translated by volunteer translators from the lead author's institution. Should this translation have revealed a potentially eligible study, we would have submitted it for professional translation.

Assessment of risk of bias in included studies

Two review authors (ALC and IGC) independently assessed the risk of bias of the included studies using the Cochrane RoB 1 tool and resolved any disagreements by discussion. We completed a risk of bias table for each included study following the recommended methods for assessing the risk of bias in studies included in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011). The RoB 1 tool addresses specific key domains including sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other bias. We tabulated relevant information describing what happened, as reported in the study or revealed by correspondence with the study authors, for each included study, along with a judgement of low, high or unclear risk of bias for each individual domain.

The summary assessment of the risk of bias of each included study (overall risk of bias) was as follows.

• Low risk of bias (plausible bias unlikely to seriously alter the results) if we assessed all key domains at low risk of bias.

• Unclear risk of bias (plausible bias that raises some doubt about the results) if we assessed one or more key domains at unclear risk of bias.

• High risk of bias (plausible bias that seriously weakens confidence in the results) if we assessed one or more key domains at high risk of bias.

We also presented the results graphically.

Measures of treatment effect

For dichotomous outcomes, we expressed the estimate of effect of the intervention as risk ratios (RR) with 95% confidence intervals (CI). For continuous outcomes (such as mean VAS scores), we reported mean differences (MD) (or standardised mean differences (SMD) when studies used different scales measuring the same concept) and their corresponding 95% CI or median values.

Unit of analysis issues

We anticipate that, by the nature of the outcome variables being recorded, studies included in future updates may involve repeat observations. Results from more than one time point for each study cannot be combined in a standard meta‐analysis without a unit‐of‐analysis error. Therefore, we assessed outcomes at 24, 48 and 72 hours, and seven days postoperatively, as the data allowed.

We excluded cluster‐RCTs from the review.

Given the nature of the conditions and intervention under review, it is highly unlikely that cross‐over trials will be suitable for inclusion in future updates.

We considered multi‐arm studies for inclusion in the review. In accordance with recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022), we combined all eligible experimental groups and considered them as a single group and compared them with a combined group of all the eligible control groups.

Dealing with missing data

We contacted the original investigators in cases of missing data.

Assessment of heterogeneity

We planned to assess heterogeneity using the Chi² test (P < 0.10 regarded as statistically significant). For studies judged as clinically homogeneous, we test heterogeneity using the I² statistic, as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022). The I² statistic describes the percentage of variability in effect estimates that is due to heterogeneity rather than sampling error. An I² statistic of 0% to 40% might not be important, 30% to 60% may represent moderate heterogeneity, 50% to 90% may have substantial heterogeneity and 75% to 100% studies has considerable heterogeneity.

Assessment of reporting biases

We examined within‐study selective outcome reporting as a part of the overall risk of bias assessment and contacted study authors for clarification.

If there had been at least 10 studies included in a meta‐analysis, we would have assessed between‐study reporting bias by creating a funnel plot of effect estimates against their standard errors. If we had found asymmetry in the funnel plot during inspection and confirmed this using statistical tests, we would have considered possible explanations and taken it into account in the interpretation of the overall estimate of treatment effects.

Data synthesis

We only carried out meta‐analysis where studies of similar comparisons reported similar outcomes for people with similar clinical conditions. We combined MDs (or SMDs) for continuous outcomes, and combined RRs for dichotomous outcomes, using a fixed‐effect model if there were only two or three studies, or a random‐effects model if there were four or more studies.

Subgroup analysis and investigation of heterogeneity

We planned to investigate clinical heterogeneity by examining the following subgroups should sufficient data relating to the primary outcomes have been available.

• Different antibiotic class (e.g. penicillins versus macrolides). Antibiotic classes may differ in their spectrum of activity and mechanism of action. This might act as a potential effect modifier.

• The effects of accompanying surgical intervention (extraction, incision and drainage, or endodontic treatment). Surgical interventions vary in the route of drainage, amount of necrotic pulpal tissue removed, original tooth structure remaining and postoperative recovery. One or more of these factors may be potential effect modifiers.

Sensitivity analysis

Provided there were sufficient studies for each outcome and intervention, we had planned to undertake sensitivity analysis based on trials judged at low risk of bias.

Summary of findings and assessment of the certainty of the evidence

We developed summary of findings tables using GRADEpro software (GRADEpro GDT), with the GRADE assessment of the certainty of the evidence.

In this review update, we produced two summary of findings tables.

• Comparison 1: preoperative antibiotics with a surgical intervention for managing symptomatic apical periodontitis and acute apical abscess in adults

• Comparison 2: postoperative antibiotics with a surgical intervention for managing symptomatic apical periodontitis and acute apical abscess in adults

If data permit in future review updates, we will produce a third summary of findings table.

• Comparison 3: antibiotics without a surgical intervention for managing symptomatic apical periodontitis and acute apical abscess in adults

We reported the following outcomes and endpoints in the summary of findings tables.

• Pain at 24 hours, 72 hours and seven days

• Swelling at 24 hours, 72 hours and seven days

• Adverse effects

Results

Description of studies

Results of the search

After deduplication, the electronic searches conducted in 2013 yielded 625 references. We identified one additional trial by checking the bibliographies of the selected trials and reviews (Al‐Belasy 2003). After examination of the titles and abstracts where available, we excluded 590 references from further analysis. We obtained full‐text copies of the remaining 36 trials, translated them where required, and subjected them to further evaluation. At this stage, we excluded 34 studies and recorded their characteristics (Characteristics of excluded studies table).

After deduplication, the electronic searches conducted for the 2018 update yielded an additional 190 references not included in the previously published version. We retrieved no additional citations from other sources. After examination of the titles and abstracts where available, we excluded all 190 references from further analysis.

After deduplication, the electronic searches conducted in 2022 yielded 328 references not included in the previous update. We retrieved no additional citations from other sources. After examination of the titles and abstracts where available, we excluded 316 from further analysis. We obtained full‐text copies of the remaining 12 references. At this stage, we excluded nine studies and recorded their characteristics (Characteristics of excluded studies table). Two other studies were completed but not reported (Characteristics of studies awaiting classification table). One additional trial was included in this current update (AlSedawy 2019) (Figure 1).

1.

Study flow diagram.

Included studies

Three RCTs satisfied the inclusion criteria (AlSedawy 2019; Fouad 1996; Henry 2001). See Characteristics of included studies table for further details.

Trial designs and settings

All studies were of parallel group design, one had three arms (Fouad 1996), and the two others had two arms (AlSedawy 2019; Henry 2001). Two studies were conducted at university dental schools in the USA (Fouad 1996; Henry 2001), and one at a university dental school in Egypt (AlSedawy 2019). All were based at a single centre. One study was supported by a university research fund and the others did not declare funding sources. Only one study reported a sample size calculation (AlSedawy 2019).

Participants

We included 134 participants in the analysis for this review, with 72 participants in AlSedawy 2019, 21 in Fouad 1996, and 41 in Henry 2001. All studies were conducted on otherwise healthy adults.

Participants in Fouad 1996 had a mean age of 36 years (standard deviation (SD) 13.7 years) and had a clinical diagnosis of acute apical abscess with pulpal necrosis, periapical pain or swelling, or both (Table 3). Potential participants were excluded if their temperature was elevated (judged by investigators to be above 100 °F (37.8 °C) or if they had malaise or fascial space involvement).

1. Baseline characteristics for penicillin and placebo trial arms (Fouad 1996).

Trial arm	Penicillin (n = 13)	Placebo (n = 15)	P value
Gender	4W:8Ma	6W:7Mb	—
Mean age in years	34.92 (SD 17.33)	37.17 (SD 9.40)	0.696
Mean baseline pain	2.40 (SD 1.08)	2.00 (SD 1.10)	0.410
Mean baseline swelling	1.91 (SD 1.51)	2.00 (SD 1.48)	0.866

M: men; n: number in group; SD: standard deviation; W: women.
Unpublished data from personal communication.
^aGender of 1 participant not recorded.
^bGender of 2 participants not recorded.

Participants in Henry 2001 had a mean age of 37 years (SD 16.5 years) in the penicillin arm and 38 years (SD 18.8 years) in the placebo arm (Table 4). All had a symptomatic necrotic tooth with a periapical radiolucency and no mucosal sinus tract.

2. Baseline characteristics for penicillin and placebo trial arms (Henry 2001).

Variable	Penicillin (n = 19)	Placebo (n = 22)	P value
Age in years	37 (SD 16.5)	38 (SD 18.8)	0.884
Gender	10W:9M	10W:12M	0.647
Weight in pounds	172 (SD 28.4)	170 (SD 41.3)	0.874
Estimated lesion area in mm	14.0 (SD 16.5)	24.8 (SD 22.6)	0.105
Median baseline pain	2.00 (IQR 0–4.00)	2.00 (IQR 1.00–3.00)	0.463
Median baseline percussion pain	2.00 (IQR 0–4.00)	2.00 (IQR 0–4.00)	0.868
Median baseline swelling	1.00 (IQR 0–3.00)	0 (IQR 0–1.00)	0.097

IQR: interquartile range; M: men; n: number in group; SD: standard deviation; W: women.

Participants in AlSedawy 2019 had a mean age of 31.5 years (SD 9.5 years) in the penicillin arm and 34.8 years (SD 11.2 years) in the placebo arm (Table 5). All had a clinical diagnosis of symptomatic apical periodontitis in a mandibular posterior tooth (based on participants' chief complaint, history, and clinical and radiographic examination). Participants were excluded if they had a draining sinus tract or 'weeping canals'. Participants who had been taking antibiotics during the last month or anti‐inflammatory drugs 12 hours before the treatment were also excluded.

3. Baseline characteristics for clindamycin and placebo trial arms (AlSedawy 2019).

Variable	Penicillin (n = 36)	Placebo (n = 36)	P value
Age in years	31.5 (SD 9.5)	34.8 (SD 11.2)	0.187
Sex	28W:8M	22W:14M	0.125
Tooth type (number)			0.155
Premolar	13 (36.1%)	19 (52.8%)
Molar	23 (63.9%)	17 (47.2%)
Number of canals			0.074
1	13 (36.1%)	17 (47.2%)
2	0 (0%)	2 (5.6%)
3	16 (44.4%)	15 (41.7%)
4	7 (19.4%)	2 (5.6%)
Median preoperative pain intensity	4 (range 1–10)	5 (range 1–10)	0.695
Preoperative pain incidence (number)			0.892
Mild	16 (44.4%)	14 (38.9%)
Moderate	11 (30.6%)	12 (33.3%)
Severe	9 (25.0%)	10 (27.8%)
Median preoperative pain on percussion intensity	5 (range 1–10)	6 (range 1–10)	0.968
Preoperative pain on percussion incidence (number)			0.881
Mild	10 (27.8%)	9 (25.0%)
Moderate	11 (30.6%)	13 (36.1%)
Severe	15 (41.7%)	14 (38.9%)

M: men; n: number in group; SD: standard deviation; W: women.

One trial had more male participants (Fouad 1996), one more female participants (AlSedawy 2019), and the other had similar numbers of male and female participants (Henry 2001). There were no clear differences in the intra‐study baseline characteristics of participants (Table 3; Table 4; Table 5).

Intervention

Comparison 1: preoperative systemic antibiotics versus a matched placebo provided in conjunction with a surgical intervention

Participants in AlSedawy 2019 received clindamycin 600 mg (Dalacin C, Pfizer Egypt, under authority of Pfizer Inc, USA) as two tablets of 300 mg each, orally 30 minutes before treatment. Participants in the placebo group received a matched placebo taken according to the same regimen.

All participants underwent total chemo‐mechanical debridement and root filling at the baseline visit. All participants were instructed to take an analgesic (ibuprofen 200 mg (Brufen tablets, Abbott Pharmaceuticals, Italy)) should pain have arisen.

Comparison 2: postoperative systemic antibiotics versus a matched placebo provided in conjunction with a surgical intervention

In Fouad 1996, participants underwent total or partial chemo‐mechanical debridement under local anaesthesia with temporary restoration at the baseline visit. In Henry 2001, all participants underwent total chemo‐mechanical debridement with temporary restoration at the baseline visit.

In Fouad 1996, participants in the penicillin group received oral penicillin (phenoxymethyl) VK 1 g following treatment and then 500 mg every six hours for seven days. Participants in the placebo group received a matched placebo taken according to the same regimen. In Henry 2001, participants in the penicillin group received oral penicillin VK 500 mg (Wyeth Laboratories, Philadelphia, Pennsylvania) tablets every six hours for seven days. Participants in the placebo group received a matched placebo (lactose) taken according to the same regimen.

In Fouad 1996, all participants also received ibuprofen 600 mg immediately before treatment, on four occasions during the next 24 hours, and then as required (Fouad 1996). In Henry 2001, all participants received a bottle of ibuprofen 200 mg tablets (Advil, Whitehall Laboratories, New York, New York) with instructions to take two tablets every four to six hours as required. Each participant also received a labelled bottle of paracetamol (acetaminophen) with codeine (Tylenol #3, McNeil Consumer Products, Fort Washington, Pennsylvania) with dosing instructions, to take if two ibuprofen did not relieve their discomfort. One participant was given Percocet (oxycodone plus paracetamol (acetaminophen)) instead (Henry 2001).

Comparison 3: systemic antibiotics versus a matched placebo provided without a surgical intervention

We found no studies comparing systemic antibiotics versus a matched placebo provided without a surgical intervention.

Heterogeneity of interventions

There was heterogeneity with respect to the operative treatment, type, doses, and duration of antibiotics given to participants in the intervention arms and type, dose and frequency of analgesics provided to participants between the included studies.

Outcomes

Primary outcomes

All studies reported participant‐reported pain. Two utilised a short ordinal numerical scale graded from 0 to 3, where 0 was no pain (Fouad 1996; Henry 2001). Fouad 1996 determined this score by converting the value from a VAS on the post‐treatment card into a whole number rank. AlSedawy 2019 measured pain on an 11‐point numerical rating scale. This was subsequently transformed to a short ordinal scale for some analyses.

Studies measured pain at the following time points:

• 6 hours, 12 hours, 24 hours, 48 hours and 72 hours (Fouad 1996);

• day 1, day 2, day 3, day 4, day 5, day 6 and day 7 (Henry 2001);

• 6 hours, 12 hours, 24 hours, 48 hours, 72 hours and day 7 (AlSedawy 2019).

All studies also measured participant‐reported swelling. In Henry 2001, investigators utilised a short ordinal numerical scale graded from 0 to 3. Fouad 1996 recorded increase or decrease in swelling compared with baseline on a short ordinal numerical scale graded from 0 to 4. AlSedawy 2019 recorded the incidence of participant‐reported swelling at any point during the seven‐day follow‐up as a binary variable (unpublished information from study authors).

Studies measured swelling at the following time points:

• 6 hours, 12 hours, 24 hours, 48 hours and 72 hours (Fouad 1996);

• day 1, day 2, day 3, day 4, day 5, day 6 and day 7 (Henry 2001);

• day 7 (AlSedawy 2019).

One study included participant‐reported percussion pain measured on a short ordinal numerical scale graded from 0 to 3 (Henry 2001).

One study included incidence of endodontic flare‐up (Fouad 1996). This was measured dichotomously and was clinician‐assessed based on the presence of: no relief or an increase in the severity of pain; no resolution or an increase in the size of swelling, fever, trismus or difficulty swallowing; signs of a drug allergy or any other abnormal symptoms.

Secondary outcomes

Henry 2001 reported the number and type of analgesics required and AlSedawy 2019 reported the total number of analgesics. In Fouad 1996, participants recorded whether they required additional analgesia; however, this information was not reported and was not available after contacting the investigators.

Two studies reported adverse effects (AlSedawy 2019; Fouad 1996).

Handling of data/data assumptions made in the review

For comparison 1, we compared pain and swelling scores at 24, 48 and 72 hours and seven days postoperatively. For the purposes of the analysis, we made the assumption that the data points from Henry 2001 (day 1, day 2 and day 3) were sufficiently analogous to those measured in Fouad 1996 to be combined.

We presented data for participant‐reported swelling in AlSedawy 2019 at day seven. This variable covers the period immediately postoperatively until day seven.

Excluded studies

We excluded the majority of references as they were not RCTs. Other excluded studies had no placebo control or had other characteristics that did not satisfy the inclusion criteria (see Characteristics of excluded studies table).

Studies awaiting classification

Two studies are awaiting classification as they are completed but results are awaited (NCT03007342; NCT03033147; Characteristics of studies awaiting classification table).

Ongoing studies

We found no ongoing studies.

Risk of bias in included studies

The review authors' judgements about each risk of bias item for each included study are given in Figure 2.

2.

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

Allocation

Randomisation

We considered all three studies at low risk of bias for random sequence generation.

Allocation concealment

We assessed studies to have adequate concealment of allocation prior to assignment. In Fouad 1996, individuals enrolling participants into the trial were not aware of the upcoming allocation sequence; envelopes were sequentially numbered, opaque and sealed; envelopes for the penicillin and placebo groups were identical in appearance and weight, and were only opened after being assigned to the participant. In Henry 2001, participants received sequentially numbered drug containers of identical appearance in accordance with the randomisation sequence produced prior to the experiment. AlSedawy 2019 concealed allocation using sequentially numbered opaque sealed containers.

Blinding

We judged studies to have employed adequate measures to ensure that active and placebo tablets had identical appearance, and, therefore, we considered risk of performance bias to be low for all studies. Similarly, we considered all studies to have low risk of detection bias as blinding was unlikely to have been broken.

Incomplete outcome data

We considered Fouad 1996 at high risk of attrition bias. Rates of withdrawal were in excess of 20% across groups, with higher rates of withdrawal from the placebo than the penicillin group. We judged differential attrition as likely to be related to treatment outcomes. In Henry 2001, we were unable to judge risk of bias due to insufficient reporting of relative attrition rates and reasons for withdrawal and, therefore, the risk for this domain was unclear. In AlSedawy 2019, there were no reported dropouts; therefore, the risk of attrition bias was low.

Selective reporting

We judged one study at unclear risk of reporting bias. In Fouad 1996, investigators did not report whether the need for additional analgesia differed between the two trial arms, although this information was collected on the post‐treatment card. There was no evidence of selective reporting in Henry 2001 and all expected outcomes were presented. In AlSedawy 2019, investigators did not report participant‐reported swelling, but unpublished data were shared following communication with the study team. We judged these latter two studies at low risk of reporting bias.

Other potential sources of bias

We judged trials to be at low risk of other potential sources of bias.

Overall risk of bias

One study had high overall risk of bias (Fouad 1996), one had unclear overall risk of bias (Henry 2001), and one had low overall risk of bias (AlSedawy 2019) (Figure 2).

Effects of interventions

See: Table 1; Table 2

Comparison 1: preoperative systemic antibiotics versus a matched placebo provided in conjunction with a surgical intervention

One trial (72 participants) at low risk of bias compared a single preoperative dose of clindamycin against a matched placebo when provided with total chemo‐mechanical debridement and root filling for adults with symptomatic apical periodontitis (AlSedawy 2019). The certainty of evidence for all the outcomes in this comparison was low.

Primary outcomes

This trial reported no differences in participant‐reported pain at 24, 48, 72 hours or seven days (Table 6), or participant‐reported swelling up to seven days (Analysis 1.1).

4. Participant‐reported pain at 24, 48 and 72 hours and seven days (AlSedawy 2019).

Time point	Clindamycin (n = 36)		Placebo (n = 36)		P value*
	Median	Range	Median	Range
24 hours	3	0–8	3	0–10	0.219
48 hours	1	0–9	2	0–10	0.242
72 hours	0	0–7	0	0–10	0.116
7 days	0	0–1	0	0–3	0.673

*Mann‐Whitney U test.

1.1. Analysis.

Comparison 1: Preoperative antibiotics with a surgical intervention, Outcome 1: Swelling at 7 days

For the antibiotic group:

• median pain at 24 hours was 3.0 (range 0 to 8), compared to a median of 3 in the control group (range 0 to 10) (P = 0.219);

• median pain at 48 hours was 1 (range 0 to 9), compared to a median of 2 in the control group (range 0 to 10) (P = 0.242);

• median pain at 72 hours was 0 (range 0 to 7), compared to a median of 0 in the control group (range 0 to 10) (P = 0.116);

• median pain at seven days was 0 (range 0 to 1), compared to a median of 0 in the control group (range 0 to 3) (P = 0.673).

For the antibiotic group:

• RR for swelling by day seven was 0.50 (95% CI 0.10 to 2.56; P = 0.41; Analysis 1.1). The absolute risk of swelling in the placebo group was 11.1%.

Secondary outcomes

AlSedawy 2019 reported the number of participants who required analgesics.

For the antibiotic group:

• RR for analgesic use was 0.87 (95% CI 0.48 to 1.55; P = 0.629; Analysis 1.2).

1.2. Analysis.

Comparison 1: Preoperative antibiotics with a surgical intervention, Outcome 2: Number of participants who required ibuprofen

During the seven‐day follow‐up period in AlSedawy 2019 (72 participants, unclear risk of bias), one participant in the antibiotic group reported dizziness.

Comparison 2: postoperative systemic antibiotics versus a matched placebo provided in conjunction with a surgical intervention

Two studies, one at unclear risk of bias (Henry 2001) and one at high risk of bias (Fouad 1996), provided data for this comparison. Both compared seven days of oral penicillin V potassium (penicillin VK) against a matched placebo when provided alongside partial or total chemo‐mechanical debridement for otherwise healthy adults with localised acute apical abscess or symptomatic necrotic tooth. The certainty of evidence for all the outcomes in this comparison was very low.

Primary outcomes

The meta‐analysis of participant‐reported pain at data points 24, 48 and 72 hours was based on data from two trials (61 participants) in which antibiotics were given for seven days. One study was at high risk of bias (Fouad 1996), and one at unclear risk of bias (Henry 2001). Analysis of the seven‐day time point was based on data from one study (41 participants) at unclear risk of bias (Henry 2001).

For the antibiotic group:

• MD at 24 hours was −0.03 (95% CI −0.53 to 0.47; P = 0.91; Analysis 2.1);

• MD at 48 hours was 0.32 (95% CI −0.22 to 0.86; P = 0.24; Analysis 2.2);

• MD at 72 hours was 0.08 (95% CI −0.38 to 0.54; P = 0.73; Analysis 2.3);

• MD at seven days was −0.05 (95% CI −0.41 to 0.30; P = 0.76; Analysis 2.4).

2.1. Analysis.

Comparison 2: Postoperative antibiotics with a surgical intervention, Outcome 1: Pain at 24 hours

2.2. Analysis.

Comparison 2: Postoperative antibiotics with a surgical intervention, Outcome 2: Pain at 48 hours

2.3. Analysis.

Comparison 2: Postoperative antibiotics with a surgical intervention, Outcome 3: Pain at 72 hours

2.4. Analysis.

Comparison 2: Postoperative antibiotics with a surgical intervention, Outcome 4: Pain at 7 days

The analysis of participant‐reported percussion pain at data points 24, 48 and 72 hours was based on data from one study (41 participants) at unclear risk of bias (Henry 2001).

For the antibiotic group:

• MD at 24 hours was −0.32 (95% CI −0.85 to 0.21; P = 0.23; Analysis 2.9);

• MD at 48 hours was 0.09 (95% CI −0.44 to 0.62; P = 0.74; Analysis 2.10);

• MD at 72 hours was 0.05 (95% CI −0.55 to 0.65; P = 0.87; Analysis 2.11);

• MD at seven days was 0.06 (95% CI −0.29 to 0.41; P = 0.73; Analysis 2.12).

2.9. Analysis.

Comparison 2: Postoperative antibiotics with a surgical intervention, Outcome 9: Percussion pain at 24 hours

2.10. Analysis.

Comparison 2: Postoperative antibiotics with a surgical intervention, Outcome 10: Percussion pain at 48 hours

2.11. Analysis.

Comparison 2: Postoperative antibiotics with a surgical intervention, Outcome 11: Percussion pain at 72 hours

2.12. Analysis.

Comparison 2: Postoperative antibiotics with a surgical intervention, Outcome 12: Percussion pain at 7 days

The analysis of participant‐reported swelling at data points 24 hours (62 participants), 48 hours (61 participants) and 72 hours (61 participants) was based on data from two studies, one at high risk of bias (Fouad 1996), and one at unclear risk of bias (Henry 2001). Analysis of the seven‐day time point was based on data from one study (41 participants) at unclear risk of bias (Henry 2001). We used SMDs to combine the different scales used for the 24‐, 48‐ and 72‐hour data points.

For the antibiotic group:

• SMD at 24 hours was 0.27 (95% CI −0.23 to 0.78; Analysis 2.5). This converts back into a 36% increase (95% CI 31% decrease to 105% increase) of control mean for antibiotics. Re‐expressed from the SMD into the short ordinal numerical scale used by Henry 2001. Results should be interpreted with caution since back‐translation of the effect size was based on the results of only one study;

• SMD at 48 hours was 0.04 (95% CI −0.47 to 0.55; Analysis 2.6). This converts back into a 4% increase (95% CI 49% decrease to 58% increase) of control mean for antibiotics. Re‐expressed from the SMD into the short ordinal numerical scale used by Henry 2001. Results should be interpreted with caution since back‐translation of the effect size was based on the results of only one study;

• SMD at 72 hours was 0.02 (95% CI −0.49 to 0.52; Analysis 2.7). This converts back into a 2% increase (95% CI 55% decrease to 59% increase) of control mean for antibiotics. Re‐expressed from the SMD into the short ordinal numerical scale used by Henry 2001. Results should be interpreted with caution since back‐translation of the effect size was based on the results of only one study;

• MD at seven days was 0.02 (95% CI −0.28 to 0.32; P = 0.90; Analysis 2.8).

2.5. Analysis.

Comparison 2: Postoperative antibiotics with a surgical intervention, Outcome 5: Swelling at 24 hours

2.6. Analysis.

Comparison 2: Postoperative antibiotics with a surgical intervention, Outcome 6: Swelling at 48 hours

2.7. Analysis.

Comparison 2: Postoperative antibiotics with a surgical intervention, Outcome 7: Swelling at 72 hours

2.8. Analysis.

Comparison 2: Postoperative antibiotics with a surgical intervention, Outcome 8: Swelling at 7 days

The analysis of clinician‐assessed incidence of endodontic flare‐up over a three‐day follow‐up period was based on data from one study (19 participants) at high risk of bias (Fouad 1996).

For the antibiotic group:

• RR of endodontic flare‐up was 0.27 (95% CI 0.01 to 4.90; P = 0.37; Analysis 2.13).

2.13. Analysis.

Comparison 2: Postoperative antibiotics with a surgical intervention, Outcome 13: Incidence of endodontic flare‐up

Secondary outcomes

The analysis of the number of analgesic tablets required during the seven‐day follow‐up period was based on data from one study (41 participants) at unclear risk of bias (Henry 2001).

For the antibiotic group:

• MD for total number of ibuprofen tablets was 1.58 (95% CI −4.55 to 7.71; P = 0.61; Analysis 2.14);

• MD for total number of paracetamol (acetaminophen) with codeine tablets was −0.31 (95% CI −3.94 to 3.32; P = 0.87; Analysis 2.15).

2.14. Analysis.

Comparison 2: Postoperative antibiotics with a surgical intervention, Outcome 14: Total number of ibuprofen tablets

2.15. Analysis.

Comparison 2: Postoperative antibiotics with a surgical intervention, Outcome 15: Total number of paracetamol (acetaminophen) with codeine tablets

During the three‐day follow‐up period in Fouad 1996 (20 participants, high risk of bias), one participant in the placebo group reported diarrhoea and one participant in the antibiotic group reported fatigue and reduced energy postoperatively.

Comparison 3: systemic antibiotics versus a matched placebo provided without a surgical intervention

We found no studies comparing systemic antibiotics versus a matched placebo provided without a surgical intervention.

Discussion

Summary of main results

The review process identified three RCTs suitable for inclusion (AlSedawy 2019; Fouad 1996; Henry 2001). One trial (72 participants) at low risk of bias compared the effects of preoperative clindamycin compared to a matched placebo in adults with symptomatic apical periodontitis when provided with total chemo‐mechanical debridement and root filling under local anaesthesia. Two trials (62 participants) assessed the effects of penicillin VK compared with a matched placebo in adults with localised apical abscess or a symptomatic necrotic tooth (no signs of spreading infection or systemic involvement) when provided in conjunction with partial or total chemo‐mechanical debridement conducted under local anaesthesia, and oral analgesics. There were no differences in primary outcomes (participant‐reported pain, swelling, percussion pain or incidence of endodontic flare‐up) or secondary outcomes (analgesic use or incidence of adverse events) between participants who had received antibiotics and participants who had received a matched placebo. The evidence suggests that preoperative clindamycin for adults with symptomatic apical periodontitis results in little to no difference in participant‐reported pain or swelling at any of the time points included in this review when provided with total chemo‐mechanical debridement and root filling under local anaesthesia. The evidence is very uncertain about the effect of postoperative antibiotics for adults with localised apical abscess or a symptomatic necrotic tooth when provided with partial or total chemo‐mechanical debridement and oral analgesics. However, we considered this body of evidence (three studies, one at low overall risk of bias, one at unclear overall risk of bias and one at high overall risk of bias) to have heterogeneous quality (low‐certainty evidence for one comparison, very low‐certainty evidence for the other) and, therefore, some findings, particularly those relating to postoperative antibiotics, should be interpreted with caution.

We found no studies that reported the effects of systemic antibiotics versus a matched placebo for symptomatic apical periodontitis or acute apical abscess when provided without a surgical intervention.

Overall completeness and applicability of evidence

We employed a comprehensive search strategy and we are confident that the majority of published trials are included in this review. We excluded no studies due to language.

The three included trials addressed the first of the two comparisons, that is, to compare the effect of systemic antibiotics versus a placebo for symptomatic apical periodontitis or acute apical abscess provided in conjunction with an operative intervention in adults (AlSedawy 2019; Fouad 1996; Henry 2001). One of the included trials assessed the effect of a single preoperative dose of a lincosamide antibiotic (clindamycin). Two trials assessed the effect of a seven‐day postoperative course of penicillin VK. We found no trials assessing the second comparison, which compared antibiotics and a placebo for symptomatic apical periodontitis or acute apical abscess when provided without a surgical intervention.

The participants included in the three trials can be considered broadly representative of people who would consult a dentist due to symptomatic apical periodontitis or an acute apical abscess as participants came from a wide age range and most had moderate pain at the baseline visit. However, the trials excluded participants with comorbidities or who may have been immunocompromised. Therefore, the results of this review may not be generalisable to a group of people who may be at higher risk of infection. While future trials should endeavour to obtain a representative sample, it is unlikely to be feasible or ethical to conduct placebo‐controlled trials in these groups of people.

Of the two trials which included participants with acute apical abscess, one excluded participants with signs of spreading infection and systemic involvement (Fouad 1996), and the other included only a small number of participants with evidence of severe infections at baseline (Henry 2001). Therefore, the results of this review may not be generalisable to people with severe swelling or other signs of spreading infection or systemic involvement arising from an acute apical abscess.

All the included studies were conducted at university dental schools. In the trials, practitioners who either worked, or were senior endodontic graduate students, in specialist endodontics departments completed endodontic treatment. It is reasonable to consider that these practitioners had endodontic skills in excess of those of an average primary care dentist. The specialist settings in which the trials were conducted were also unlikely to face the time constraints encountered in routine clinical practice. Therefore, the intervention provided within these studies may only have limited applicability to the treatment routinely provided at emergency appointments in general dental practice, where treatment decisions are often dictated by time pressures (Palmer 2000). Therefore, more trials in a primary care setting would enhance the evidence base for answering the questions posed by this review.

We found no trials assessing the effect of other surgical interventions, such as dental extraction, or incision and drainage of a swelling. Since dental extraction is a common treatment for both symptomatic apical periodontitis and acute apical abscess (Cope 2016), the effects of this intervention could be considered in future trials.

Two trials measured the harms as well as the benefits of interventions. This is important as antibiotics can have adverse effects such as hypersensitivity reactions, gastrointestinal upset and the risk of development of antibiotic‐resistant bacterial colonies. Several of the outcome measures in the included trials were participant‐centred, such as pain, percussion pain and swelling. Since both pain and discomfort are known to impact an individual's quality of life (Skevington 1998), future trials should also consider formally measuring oral health‐related quality of life outcomes to assess the beneficial and harmful effects of this intervention in more detail.

Quality of the evidence

The certainty of the evidence for the first comparison (preoperative antibiotics) was low, downgraded due to very serious imprecision (Table 1). The certainty of the evidence for the second comparison (postoperative antibiotics) was very low, downgraded due to risk of bias, imprecision, inconsistency and indirectness (Table 2).

Given the considerable number of antibiotics prescribed by dentists to adults with acute dental conditions and the problems associated with indiscriminate use of antibiotics, the paucity of high‐quality trials evaluating the effects of systemic antibiotics in the management of symptomatic apical periodontitis and acute apical abscess is disappointing. Only three studies met the inclusion criteria for this review; we judged only one at low overall risk of bias. Two trials had methodological flaws relating to attrition bias, low statistical power or the selective reporting of outcomes. As a result, the overall certainty of evidence for one comparison was low and the other was very low.

Across all included trials, small group sizes mean that studies were likely to lack the statistical power to detect differences between intervention and placebo groups and contribute to imprecision in estimates of effect size. Therefore, caution should be exercised when interpreting the results presented in this review. Fouad 1996 and Henry 2001 did not report sample size calculations. Whilst AlSedawy 2019 reported a sample size calculation, it is likely that investigators underestimated the SD of pain scores a priori. Wide SDs in participant‐reported pain values were a feature of all three included trials and, therefore, any investigators seeking to establish similar studies in the future should ensure sample size calculations are based on best‐available evidence.

Potential biases in the review process

Two review authors independently extracted data and assessed the methodological quality of each study, minimising potential bias.

Although in the most recent update we did not search grey literature databases due to the retirement of these resources, we are confident that the extensive search of electronic databases, dissertations and clinical trial registries employed in this review has captured relevant literature and minimised the likelihood that we missed any relevant trials. We applied no language or publication restrictions in our search.

In the event of incomplete or unclear reporting of trial data, we contacted the trial authors to obtain any unpublished data or clarification of results.

Despite these efforts, it must be acknowledged that there is a small possibility that there were additional studies (published and unpublished) that we did not identify. It is possible that additional literature searches, such as searching non‐English language databases and handsearching relevant journals, would have found additional studies.

Agreements and disagreements with other studies or reviews

In 2019, the American Dental Association published a systematic review assessing the evidence of the effects of antibiotic therapy compared with no antibiotic therapy, used alone or as adjuncts to definitive conservative dental treatment for the treatment of symptomatic irreversible pulpitis with or without symptomatic apical periodontitis, pulp necrosis and symptomatic apical periodontitis, or pulp necrosis and localised acute apical abscess in people who are immunocompetent (Tampi 2019). The authors included two trials relating to pulp necrosis and symptomatic apical periodontitis and pulp necrosis and localised acute apical abscess. Both trials are included in the current review. Review authors concluded that there may be both "benefit and harm over 7 days (very low to low certainty evidence). The magnitude of additional harms related to antibiotic use for any condition were potentially large (very low to moderate certainty evidence)."

One 2016 review assessed the effects of antibiotics to treat endodontic infections and pain (Aminoshariae 2016). Unlike the current review, this 2016 review included participants with pulp necrosis and asymptomatic apical periodontitis along with symptomatic participants. Those authors concluded that, "The best available clinical evidence signals no indications for prescribing antibiotics preoperatively or postoperatively to prevent endodontic infection or pain unless the spread of infection is systemic, the patient is febrile, or both."

Authors' conclusions

Implications for practice.

The evidence suggests that a single preoperative dose of clindamycin for adults with symptomatic apical periodontitis results in little to no difference in participant‐reported pain or swelling at any of the time points included in this review when provided with total chemo‐mechanical debridement and root filling under local anaesthesia. The evidence is very uncertain about the effect of postoperative phenoxymethylpenicillin for adults with localised apical abscess or a symptomatic necrotic tooth when provided with partial or total chemo‐mechanical debridement and oral analgesics. There were no studies identified which compared the effects of systemic antibiotics with a matched placebo delivered without a surgical intervention for symptomatic apical periodontitis or acute apical abscess in adults.

Since antibiotic use is recognised as a major contributor to antimicrobial resistance, dental professionals should be judicious in their use of these agents and should refer to evidence‐based best practice guidelines when managing people with acute dental conditions.

Implications for research.

Adequately powered and well‐designed randomised controlled trials are needed to clarify the effects of systemic antibiotics with or without operative intervention in the management of symptomatic apical periodontitis and acute apical abscess. However, all future trials should be carefully designed to ensure the potential benefits of providing systemic antibiotics to participants outweigh risks associated with antibiotic usage, both adverse effects and the possible contribution to antibiotic resistance.

Future studies should consider both utilising validated participant‐ and clinician‐reported outcome measures, and report results according to CONSORT guidelines (www.consort-statement.org/).

What's new

Date	Event	Description
7 May 2024	New citation required but conclusions have not changed	Conclusions unchanged. Change of review authors.
7 May 2024	New search has been performed	One new study added (72 participants). New comparison added (preoperative antibiotics) Searches updated. New search terms (ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform). New databases searched (ProQuest Dissertations & Theses Global). Other databases no longer available (ZETOC, OpenGrey, Cochrane Oral Health Trials Register).

History

Protocol first published: Issue 10, 2012
Review first published: Issue 6, 2014

Date	Event	Description
21 August 2018	New citation required but conclusions have not changed	Conclusions are the same. Change of review authors.
26 February 2018	New search has been performed	Searches updated. No additional eligible studies identified.

Appendices

Appendix 1. Search strategies

Cochrane Oral Health's Trials Register search strategy

From October 2013, searches of Cochrane Oral Health's Trials Register were conducted for this review using the Cochrane Register of Studies and the search strategy below:

1. ((antibiotic* or anti‐biotic* or "anti biotic*" or antibacterial* or anti‐bacterial* or "anti bacterial*" or antiinfect* or anti‐infect* or "anti infect*" or antimicrobial* or anti‐microbial* or "anti microbial*"):ti,ab) AND (INREGISTER)

2. ((penicillin* or amoxicillin or amoxycillin or co‐amoxiclav or ampicillin or erythromycin or clindamycin*):ti,ab) AND (INREGISTER)

3. ((doxycycline* or metronidazole or azithromycin or co‐amoxiclav or oxytetracycline or cefalexin or cephalexin or cefradine or cephradine or clarithromycin):ti,ab) AND (INREGISTER)

4. ((tetracycline or actimoxi or amoxicilline or amoxil or BRL‐2333 or clamoxyl or hydroxyampicillin or penamox or polymox or trimox or wymox or amoxi‐clav or amoxi‐clavulanate or augmentin or BRL‐25000):ti,ab) AND (INREGISTER)

5. ((clavulanate or clavulin or coamoxiclav or spektramox or synulox or phenoxymethylpenicillin or apocillin or beromycin or berromycin or betapen or fenoxymethylpenicillin or "Pen VK" or "v‐cillin K" or vegacillin or clont or danizol ):ti,ab) AND (INREGISTER)

6. ((trichazol* or trichapol or trivazol or satric or metrogyl or flagyl or gineflavir or metrodzhil or nidagyl or chlolincocin or chlorlincocin or cleocin or "dalacin c"):ti,ab) AND (INREGISTER)

7. (#1 or #2 or #3 or #4 or #5 or #6) AND (INREGISTER)

8. ((abscess* or periapical or peri‐apical or “peri apical”):ti,ab) AND (INREGISTER)

9. (#7 and #8) AND (INREGISTER)

A previous search of Cochrane Oral Health's Trials Register was conducted in June 2012, using the Procite software and the search strategy below:

((antibiotic* or anti‐biotic* or "anti biotic*" or antibacterial* or anti‐bacterial* or "anti bacterial*" or antiinfect* or anti‐infect* or "anti infect*" or antimicrobial* or anti‐microbial* or "anti microbial*" or penicillin* or amoxicillin or amoxycillin or co‐amoxiclav or ampicillin or erythromycin or clindamycin* or doxycycline* or metronidazole or azithromycin or co‐amoxiclav or oxytetracycline or cefalexin or cephalexin or cefradine or cephradine or clarithromycin or tetracycline or actimoxi or amoxicilline or amoxil or BRL‐2333 or clamoxyl or hydroxyampicillin or penamox or polymox or trimox or wymox or amoxi‐clav or amoxi‐clavulanate or augmentin or BRL‐25000 or clavulanate or clavulin or coamoxiclav or spektramox or synulox or phenoxymethylpenicillin or apocillin or beromycin or berromycin or betapen or fenoxymethylpenicillin or "Pen VK" or "v‐cillin K" or vegacillin or clont or danizol or trichazol* or trichapol or trivazol or satric or metrogyl or flagyl or gineflavir or metrodzhil or nidagyl or chlolincocin or chlorlincocin or cleocin or "dalacin c") AND abscess* or periapical or peri‐apical or "peri apical"))

Cochrane Central Register of Controlled Trials (CENTRAL) search strategy

#1 MeSH descriptor Anti‐Infective Agents explode all trees

#2 MeSH descriptor Penicillins explode all trees

#3 (antibiotic* in All Text or anti‐biotic* in All Text or "anti biotic*" in All Text)

#4 (antibacterial* in All Text or anti‐bacterial* in All Text or "anti bacterial*" in All Text)

#5 (antiinfect* in All Text or anti‐infect* in All Text or "anti infect*" in All Text)

#6 (antimicrobial* in All Text or anti‐microbial* in All Text or "anti microbial*" in All Text)

#7 (penicillin* in All Text or amoxicillin in All Text or amoxycillin in All Text or co‐amoxiclav in All Text or ampicillin in All Text or erythromycin in All Text or clindamycin* in All Text or doxycycline* in All Text or metronidazole in All Text or azithromycin in All Text or co‐amoxiclav in All Text or oxytetracycline in All Text or cefalexin in All Text or cephalexin in All Text or cefradine in All Text or cephradine in All Text or clarithromycin in All Text or tetracycline in All Text)

#8 (actimoxi in All Text or amoxicilline in All Text or amoxil in All Text or BRL‐2333 in All Text or clamoxyl in All Text or hydroxyampicillin in All Text or penamox in All Text or polymox in All Text or trimox in All Text or wymox in All Text or amoxi‐clav in All Text or amoxi‐clavulanate in All Text or augmentin in All Text or BRL‐25000 in All Text or clavulanate in All Text or clavulin in All Text or coamoxiclav in All Text or spektramox in All Text or synulox in All Text)

#9 (phenoxymethylpenicillin in All Text or apocillin in All Text or beromycin in All Text or berromycin in All Text or betapen in All Text or fenoxymethylpenicillin in All Text or "Pen VK" in All Text or "v‐cillin K" in All Text or vegacillin in All Text)

#10 (clont in All Text or danizol in All Text or trichazol* in All Text or trichapol in All Text or trivazol in All Text or satric in All Text or metrogyl in All Text or flagyl in All Text or gineflavir in All Text or metrodzhil in All Text or nidagyl in All Text)

#11 (chlolincocin in All Text or chlorlincocin in All Text or cleocin in All Text or "dalacin c" in All Text)

#12 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11)

#13 MeSH descriptor Periapical diseases explode all trees

#14 (dental* in All Text near/5 absces* in All Text)

#15 ( (tooth in All Text near/5 absces* in All Text) or (teeth in All Text near/5 absces* in All Text) )

#16 ( (periapical in All Text near/5 absces* in All Text) or (peri‐apical in All Text near/5 absces* in All Text) or (apical in All Text near/5 absces* in All Text) )

#17 ( (periapical in All Text near/5 periodont* in All Text) or (peri‐apical in All Text near/5 periodont* in All Text) or (apical in All Text near/5 periodont* in All Text) )

#18 ( (periapical in All Text near/5 inflam* in All Text) or (peri‐apical in All Text near/5 inflam* in All Text) or (apical in All Text near/5 inflam* in All Text) )

#19 ( (periapical in All Text near/5 infect* in All Text) or (peri‐apical in All Text near/5 infect* in All Text) or (apical in All Text near/5 infect* in All Text) )

#20 ( (dentoalveol* in All Text near/5 absces* in All Text) or (dento‐alveol* in All Text near/5 absces* in All Text) or (alveol* in All Text near/5 absces* in All Text) )

#21 ( (periradicular in All Text near/5 absces* in All Text) or (peri‐radicular in All Text near/5 absces* in All Text) or (radicular in All Text near/5 absces* in All Text) )

#22 (#13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21)

#23 (#12 and #22)

MEDLINE Ovid search strategy

1. exp Anti‐Infective Agents/

2. exp Penicillins/

3. (antibiotic$ or anti‐biotic$ or anti biotic$).tw.

4. (antibacterial$ or anti‐bacterial$ or anti bacterial$).tw.

5. (antiinfect$ or anti‐infect$ or anti infect$).tw.

6. (antimicrobial$ or anti‐microbial$ or anti microbial$).tw.

7. (penicillin$ or amox?cillin or co‐amoxiclav or ampicillin or erythromycin or clindamycin$ or doxycycline$ or metronidazole or azithromycin or co‐amoxiclav or oxytetracycline or cefalexin or cephalexin or cefradine or cephradine or clarithromycin or tetracycline).tw.

8. (actimoxi or amoxicilline or amoxil or BRL‐2333 or clamoxyl or hydroxyampicillin or penamox or polymox or trimox or wymox or amoxi‐clav or amoxi‐clavulanate or augmentin or BRL‐25000 or clavulanate or clavulin or coamoxiclav or spektramox or synulox).tw.

9. (phenoxymethylpenicillin or apocillin or beromycin or berromycin or betapen or fenoxymethylpenicillin or Pen VK or v‐cillin K or vegacillin).tw.

10. (clont or danizol or trichazol$ or trichapol or trivazol or satric or metrogyl or flagyl or gineflavir or metrodzhil or nidagyl).tw.

11. (chlolincocin or chlorlincocin or cleocin or dalacin c).tw.

12. or/1‐11

13. exp Periapical diseases/

14. (dental$ adj5 absces$).tw.

15. ((tooth or teeth) adj5 absces$).tw.

16. ((periapical adj5 absces$) or (peri‐apical adj5 absces$) or (apical adj5 absces$)).tw.

17. ((periapical adj5 periodont$) or (peri‐apical adj5 periodont$) or (apical adj5 periodont$)).tw.

18. ((periapical adj5 inflam$) or (peri‐apical adj5 inflam$) or (apical adj5 inflam$)).tw.

19. ((periapical adj5 infect$) or (peri‐apical adj5 infect$) or (apical adj5 infect$)).tw.

20. ((dentoalveol$ adj5 absces$) or (dento‐alveol$ adj5 absces$) or (alveol$ adj5 absces$)).tw.

21. ((periradicular adj5 absces$) or (peri‐radicular adj5 absces$) or (radicular adj5 absces$)).tw.

22. or/13‐21

23. 12 and 22

The above subject search was linked to the Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying randomised trials (RCTs) in MEDLINE: sensitivity maximising version (2008 revision) as referenced in Chapter 4.S1 and detailed in box 3.c of the Cochrane Handbook for Systematic Reviews of Interventions, Technical Supplement to Chapter 4: Searching for and selecting studies (updated March 2022) (Lefebvre 2022).

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

Embase Ovid search strategy

1. exp Antiinfective agent/

2. exp Penicillin derivate/

3. (antibiotic$ or anti‐biotic$ or "anti biotic$").tw.

4. (antibacterial$ or anti‐bacterial$ or "anti bacterial$").tw.

5. (antiinfect$ or anti‐infect$ or "anti infect$").tw.

6. (antimicrobial$ or anti‐microbial$ or "anti microbial$").tw.

7. (penicillin$ or amox?cillin or co‐amoxiclav or ampicillin or erythromycin or clindamycin$ or doxycycline$ or metronidazole or azithromycin or co‐amoxiclav or oxytetracycline or cefalexin or cephalexin or cefradine or cephradine or clarithromycin or tetracycline).tw.

8. (actimoxi or amoxicilline or amoxil or BRL‐2333 or clamoxyl or hydroxyampicillin or penamox or polymox or trimox or wymox or amoxi‐clav or amoxi‐clavulanate or augmentin or BRL‐25000 or clavulanate or clavulin or coamoxiclav or spektramox or synulox).tw.

9. (phenoxymethylpenicillin or apocillin or beromycin or berromycin or betapen or fenoxymethylpenicillin or "Pen VK" or "v‐cillin K" or vegacillin).tw.

10. (clont or danizol or trichazol$ or trichapol or trivazol or satric or metrogyl or flagyl or gineflavir or metrodzhil or nidagyl).tw.

11. (chlolincocin or chlorlincocin or cleocin or "dalacin c").tw.

12. or/1‐11

13. exp Tooth periapical disease/

14. (dental$ adj5 absces$).tw.

15. ((tooth or teeth) adj5 absces$).tw.

16. ((periapical adj5 absces$) or (peri‐apical adj5 absces$) or (apical adj5 absces$)).tw.

17. ((periapical adj5 periodont$) or (peri‐apical adj5 periodont$) or (apical adj5 periodont$)).tw.

18. ((periapical adj5 inflam$) or (peri‐apical adj5 inflam$) or (apical adj5 inflam$)).tw.

19. ((periapical adj5 infect$) or (peri‐apical adj5 infect$) or (apical adj5 infect$)).tw.

20. ((dentoalveol$ adj5 absces$) or (dento‐alveol$ adj5 absces$) or (alveol$ adj5 absces$)).tw.

21. ((periradicular adj5 absces$) or (peri‐radicular adj5 absces$) or (radicular adj5 absces$)).tw.

22. or/13‐21

23. 12 and 22

This subject search was linked to an adapted version of the Cochrane Centralised Search Project filter for identifying RCTs in Embase Ovid (see www.cochranelibrary.com/help/central‐creation‐details.html for information):

1. random$.ti,ab.

2. factorial$.ti,ab.

3. (crossover$ or cross over$ or cross‐over$).ti,ab.

4. placebo$.ti,ab.

5. (doubl$ adj blind$).ti,ab.

6. (singl$ adj blind$).ti,ab.

7. assign$.ti,ab.

8. allocat$.ti,ab.

9. volunteer$.ti,ab.

10. CROSSOVER PROCEDURE.sh.

11. DOUBLE‐BLIND PROCEDURE.sh.

12. RANDOMIZED CONTROLLED TRIAL.sh.

13. SINGLE BLIND PROCEDURE.sh.

14. or/1‐13

15. (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.)

16. 14 NOT 15

CINAHL EBSCO search strategy

S1 (MH "Antiinfective Agents+")

S2 (MH "Penicillins+")

S3 (antibiotic* or anti‐biotic* or "anti biotic*")

S4 (antibacterial* or anti‐bacterial* or "anti bacterial*")

S5 (antiinfect* or anti‐infect* or "anti infect*")

S6 (antimicrobial* or anti‐microbial* or "anti microbial*")

S7 (penicillin* or amoxicillin or amoxycillin or co‐amoxiclav or ampicillin or erythromycin or clindamycin* or doxycycline* or metronidazole or azithromycin or co‐amoxiclav or oxytetracycline or cefalexin or cephalexin or cefradine or cephradine or clarithromycin or tetracycline)

S8 (actimoxi or amoxicilline or amoxil or BRL‐2333 or clamoxyl or hydroxyampicillin or penamox or polymox or trimox or wymox or amoxi‐clav or amoxi‐clavulanate or augmentin or BRL‐25000 or clavulanate or clavulin or coamoxiclav or spektramox or synulox)

S9 (phenoxymethylpenicillin or apocillin or beromycin or berromycin or betapen or fenoxymethylpenicillin or "Pen VK" or "v‐cillin K" or vegacillin)

S10 (clont or danizol or trichazol* or trichapol or trivazol or satric or metrogyl or flagyl or gineflavir or metrodzhil or nidagyl)

S11 (chlolincocin or chlorlincocin or cleocin or "dalacin c")

S12 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11

S13 (MH "Periapical Diseases")

S14 (dental* N5 absces*)

S15 ((tooth N5 absces*) or (teeth N5 absces*))

S16 ((periapical N5 absces*) or (peri‐apical N5 absces*) or (apical N5 absces*))

S17 ((periapical N5 periodont*) or (peri‐apical N5 periodont*) or (apical N5 periodont*))

S18 ((periapical N5 inflam*) or (peri‐apical N5 inflam*) or (apical N5 inflam*))

S19 ((periapical N5 infect*) or (peri‐apical N5 infect*) or (apical N5 infect*))

S20 ((dentoalveol* N5 absces*) or (dento‐alveol* N5 absces*) or (alveol* N5 absces*))

S21 ((periradicular N5 absces*) or (peri‐radicular N5 absces*) or (radicular N5 absces*))

S22 S13 or S14 or S15 or S16 or S17 or S18 or S19 or S20 or S21

S23 S12 and S22

US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) search strategy

dental abscess AND antibiotic

dental abscess AND penicillin

dental abscess AND antibacterial

dental abscess AND antimicrobial

dental abscess AND antiinfective

periapical abscess AND antibiotic

periapical abscess AND penicillin

periapical abscess AND antibacterial

periapical abscess AND antimicrobial

periapical abscess AND antiinfective

periapical periodontitis AND antibiotic

periapical periodontitis AND penicillin

periapical periodontitis AND antibacterial

periapical periodontitis AND antimicrobial

periapical periodontitis AND antiinfective

apical abscess AND antibiotic

apical abscess AND penicillin

apical abscess AND antibacterial

apical abscess AND antimicrobial

apical abscess AND antiinfective

apical periodontitis AND antibiotic

apical periodontitis AND penicillin

apical periodontitis AND antibacterial

apical periodontitis AND antimicrobial

apical periodontitis AND antiinfective

World Health Organization International Clinical Trials Registry Platform search strategy

dental abscess AND antibiotic

dental abscess AND penicillin

dental abscess AND antibacterial

dental abscess AND antimicrobial

dental abscess AND antiinfective

periapical abscess AND antibiotic

periapical abscess AND penicillin

periapical abscess AND antibacterial

periapical abscess AND antimicrobial

periapical abscess AND antiinfective

periapical periodontitis AND antibiotic

periapical periodontitis AND penicillin

periapical periodontitis AND antibacterial

periapical periodontitis AND antimicrobial

periapical periodontitis AND antiinfective

apical abscess AND antibiotic

apical abscess AND penicillin

apical abscess AND antibacterial

apical abscess AND antimicrobial

apical abscess AND antiinfective

apical periodontitis AND antibiotic

apical periodontitis AND penicillin

apical periodontitis AND antibacterial

apical periodontitis AND antimicrobial

apical periodontitis AND antiinfective

OpenGrey search strategy

dental abscess* AND antibiotic*

dental abscess* AND penicillin*

dental abscess* AND antibacterial*

dental abscess* AND antimicrobial*

dental abscess* AND antiinfect*

periapical abscess* AND antibiotic*

periapical abscess* AND penicillin*

periapical abscess* AND antibacterial*

periapical abscess* AND antimicrobial*

periapical abscess* AND antiinfect*

ZETOC Conference Proceedings search strategy

dental abscess* AND antibiotic*

dental abscess* AND penicillin*

dental abscess* AND antibacterial*

dental abscess* AND antimicrobial*

dental abscess* AND antiinfect*

periapical abscess* AND antibiotic*

periapical abscess* AND penicillin*

periapical abscess* AND antibacterial*

periapical abscess* AND antimicrobial*

periapical abscess* AND antiinfect*

ProQuest Dissertations & Theses Global search strategy

noft((dental abscess* OR apical abscess* OR periapical abscess* OR apical periodontitis* OR periapical periodontitis*) AND (antibacterial* OR antibiotic* OR pencillin* OR amoxicillin OR clindamycin OR co‐amoxiclav OR coamoxiclav))

Data and analyses

Comparison 1. Preoperative antibiotics with a surgical intervention.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Swelling at 7 days	1	72	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.10, 2.56]
1.2 Number of participants who required ibuprofen	1	72	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.48, 1.55]

Comparison 2. Postoperative antibiotics with a surgical intervention.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Pain at 24 hours	2	61	Mean Difference (IV, Fixed, 95% CI)	‐0.03 [‐0.53, 0.47]
2.2 Pain at 48 hours	2	61	Mean Difference (IV, Fixed, 95% CI)	0.32 [‐0.22, 0.86]
2.3 Pain at 72 hours	2	61	Mean Difference (IV, Fixed, 95% CI)	0.08 [‐0.38, 0.54]
2.4 Pain at 7 days	1	41	Mean Difference (IV, Fixed, 95% CI)	‐0.05 [‐0.41, 0.30]
2.5 Swelling at 24 hours	2	62	Std. Mean Difference (IV, Fixed, 95% CI)	0.27 [‐0.23, 0.78]
2.6 Swelling at 48 hours	2	61	Std. Mean Difference (IV, Fixed, 95% CI)	0.04 [‐0.47, 0.55]
2.7 Swelling at 72 hours	2	61	Std. Mean Difference (IV, Fixed, 95% CI)	0.02 [‐0.49, 0.52]
2.8 Swelling at 7 days	1	41	Mean Difference (IV, Fixed, 95% CI)	0.02 [‐0.28, 0.32]
2.9 Percussion pain at 24 hours	1	41	Mean Difference (IV, Fixed, 95% CI)	‐0.32 [‐0.85, 0.21]
2.10 Percussion pain at 48 hours	1	41	Mean Difference (IV, Fixed, 95% CI)	0.09 [‐0.44, 0.62]
2.11 Percussion pain at 72 hours	1	41	Mean Difference (IV, Fixed, 95% CI)	0.05 [‐0.55, 0.65]
2.12 Percussion pain at 7 days	1	41	Mean Difference (IV, Fixed, 95% CI)	0.06 [‐0.29, 0.41]
2.13 Incidence of endodontic flare‐up	1	19	Risk Ratio (M‐H, Fixed, 95% CI)	0.27 [0.01, 4.90]
2.14 Total number of ibuprofen tablets	1	41	Mean Difference (IV, Fixed, 95% CI)	1.58 [‐4.55, 7.71]
2.15 Total number of paracetamol (acetaminophen) with codeine tablets	1	41	Mean Difference (IV, Fixed, 95% CI)	‐0.31 [‐3.94, 3.32]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

AlSedawy 2019.

Study characteristics
Methods	RCT Number of centres: 1 (Faculty of Dentistry, Cairo University, Egypt) Recruitment period: not stated Design: parallel group 2‐arm RCT
Participants	Adults aged 18–60 years with symptomatic apical periodontitis in a mandibular premolar or molar Group 1 (clindamycin) Mean age: 31.5 years (SD 9.5 years); female gender: 28 (78%); tooth type: molar 64%; number of canals: 3 (44%); median preoperative pain intensity: 4 (range 1–10); preoperative pain incidence: mild 44%; median preoperative pain on percussion intensity: 5 (range 1–10); preoperative pain on percussion intensity: severe 42%. Group 2 (placebo) Mean age: 34.7 years (SD 11.2 years); female gender: 22 (61%); tooth type: molar 47%; number of canals: 1 (47%); median preoperative pain intensity: 5 (range 1–10); preoperative pain incidence: mild 39%; median preoperative pain on percussion intensity: 6 (range 1–10); preoperative pain on percussion intensity: severe 39%. The clinical diagnosis of symptomatic apical periodontitis was based on the participant's chief complaint, history taking, and clinical and radiographic examination. Participants actively experienced pain on percussion or biting. The target tooth may or may not have responded to pulp vitality tests; the tooth may be with or without periapical radiolucency. Participant should be in good health as determined by a written health history. Participants were excluded if they had signs of spreading infection or systemic involvement, a draining sinus tract or weeping canals. Participants who had been taking antibiotics during the last month or anti‐inflammatory drugs 12 hours before the treatment were also excluded. Number of participants at randomisation: 72 Number of participants included in the analysis: group 1: 36; group 2: 36
Interventions	Endodontic treatment: all participants underwent total chemo‐mechanical debridement of the affected tooth and root filling under local anaesthetic on day 0. Root canal treatment was done by crown‐down approach through rotary instrumentation using a Revo S rotary system. Irrigation was done between every 2 consecutive instruments using 2 mL of 2.5% sodium hypochlorite and 19% EDTA gel. For final irrigation, 5 mL of 2.5% sodium hypochlorite was used followed by 5 mL of 17% EDTA for 1 minute, then 10 mL of distilled water. Access cavity was filled with temporary restorative material. Participants were then assigned to a trial arm. Group 1: oral clindamycin 600 mg (2 × 300 mg tablets), 30 minutes before treatment Group 2: oral matched placebo taken according to the same regimen Analgesics: all participants received a supply of ibuprofen. "In case of pain, the participant was instructed to take an analgesic of 200 mg Ibuprofen (Brufen tablets, Abbott Pharmaceuticals, Italy)." (unpublished information from study authors).
Outcomes	Primary outcomes Participant‐reported pain recorded on an 11‐point numerical rating scale at 6, 12, 24, 48, 72 hours, and day 7 using a diary. This scale was recategorised by investigators onto a short ordinal numerical scale. 0 represented "no pain"; 1–3 represented "mild pain"; 4–6 represented "moderate pain" and 7–10 represented "severe pain". Participant‐reported swelling was recorded as either present or absent over the 7‐day follow‐up. Cases of swelling were confirmed by the investigator (unpublished information from study authors). Secondary outcomes Adverse events Requirement for analgesics
Notes	Funding source: not stated Sample size calculation: stated. Powered to detect a difference of 0.5 (SD 0.7).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Each participant had the same chance of being assigned to either group by a random sequence that was generated using a computer software (Microsoft Excel) by an investigator not involved in patient enrolment [sic]."
Allocation concealment (selection bias)	Low risk	Quote: "Allocation was concealed by the use of sequentially numbered opaque sealed containers."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The patient and the operator were blinded (double blind study). The placebo (control) was similar to the clindamycin (intervention) capsule and both intervention and control capsules, were pre‐packed in similar opaque containers."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Primary outcome measures were participant‐assessed and it was highly unlikely blinding was broken.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts.
Selective reporting (reporting bias)	Low risk	1 outcome (swelling) not published but unpublished data provided by study authors.
Other bias	Low risk	No other sources of bias identified.

Fouad 1996.

Study characteristics
Methods	RCT Number of centres: 1 (Department of Endodontics, University of Iowa, USA) Recruitment period: 3.5 years Design: parallel group 3‐arm RCT (only 1 experimental group and 1 control group eligible for inclusion)
Participants	Adults presenting for emergency treatment Group 1 (penicillin) Mean age 34.92 years (SD 17.33 years); gender: 4 women, 8 men (1 gender not recorded); mean baseline pain: 2.40 (SD 1.08); mean baseline swelling: 1.91 (SD 1.51) Group 2 (placebo) Mean age 37.17 years (SD 9.40 years); gender: 6 women, 7 men (2 gender not recorded); mean baseline pain: 2.00 (SD 1.10); mean baseline swelling: 2.00 (SD 1.48) Included participants had a clinical diagnosis of acute apical abscess with pulpal necrosis with periapical pain or swelling, or both. Participants were excluded if they had: elevated temperature (> 37.8 ºC (100 ºF)); malaise; fascial space involvement; allergy to penicillin or cephalosporins; diseases or medications compromising the immune system; renal failure or any other significant renal or hepatic impairment; people who had taken antibiotics in the 2‐week period prior to their visit; pregnant or lactating or taking oral contraceptives Number of participants at randomisation: group 1: 13; group 2: 15 Number of participants included in the analysis: group 1: 10; group 2: 11
Interventions	Endodontic treatment: all participants had the affected tooth treated by total or partial chemo‐mechanical debridement on day 0. This involved delivery of local anaesthesia, assessment of the tooth, determination of working length, partial/total cleaning and shaping of the canals with copious irrigation with 2.6% sodium hypochlorite. Canals were dried and calcium hydroxide paste applied and the access cavity temporised with Cavit (a light‐cured temporary sealing compound for temporary restoration of cavities) or IRM (intermediate restorative material is a polymer‐reinforced zinc oxide‐eugenol composition restorative material designed for intermediate restorations). Some participants also underwent incision and drainage of a localised intraoral swelling, if judged to be clinically indicated. Participants were then assigned to a trial arm. Group 1: oral penicillin (phenoxymethyl) VK 500 mg, 1 g after endodontic treatment followed by 500 mg 6‐hourly for 7 days Group 2: oral matched placebo taken according to the same regimen Group 3: neither medication Analgesics: all participants received ibuprofen 600 mg immediately before treatment, 4 times daily for 24 hours and then as needed
Outcomes	Primary outcomes Participants were required to complete a post‐treatment card recording their experiences up to 3 days postoperatively. This card was then returned to the authors via post. Pain was assessed using a VAS, which was then converted into a short ordinal numerical scale from 0 to 3: 0 = pain of no clinical significance; 1 = mild pain; 2 = moderate pain; 3 = severe pain Postoperative swelling relief was recorded on a simple categorical scale ('no swelling', 'much less', 'slightly less', 'same', 'slightly more') with participants required to compare current levels of swelling to those they had experienced preoperatively. The categorical scale was then given scores from 0 to 4: 0 = no swelling; 1 = significant reduction in swelling; 2 = slight decrease in swelling; 3 = same size swelling as before; 4 = an increase in the size of swelling Incidence of flare‐up: measured dichotomously and was clinician‐assessed based on the presence of: no relief or an increase in the severity of pain; no resolution or an increase in the size of swelling, fever, trismus or difficulty swallowing; signs of a drug allergy or any other abnormal symptoms Secondary outcomes Incidence of participant‐reported adverse effects Type and frequency of additional analgesic medication
Notes	Funding source: not stated Sample size calculation: not stated
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A statistician provided random numbers" (email from study author) Comment: the participants appeared to be equally distributed between the penicillin and placebo groups.
Allocation concealment (selection bias)	Low risk	Study author confirmed that there was no way for the individual(s) enrolling participants into the trial to know the upcoming allocation sequence; study envelopes were sequentially numbered, opaque and sealed; and study envelopes were only opened once the participant was enrolled into the trial.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study author confirmed that the placebo looked exactly the same as the penicillin tablets.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Participants recorded the outcome measures and were blinded to their group assignment.
Incomplete outcome data (attrition bias) All outcomes	High risk	Following randomisation, there were 13 participants in the penicillin group and 15 in the placebo group. 3 participants in each group did not return their post‐treatment card and were judged to have dropped out. A further 2 participants in the placebo group were withdrawn (1 at 6 hours and 1 at 24 hours) after returning with symptoms necessitating further treatment. The missing data related to these 2 participants were likely to be related to treatment outcomes (levels of pain or swelling, or both). Attrition for both arms of the trial was in excess of 20%, and was higher in the placebo than the penicillin group. Furthermore, following personal communication with trial authors, it was identified that there was incomplete baseline data (age, gender, baseline pain or swelling) for 5 study participants across the 2 trial arms. Since the numbers of participants recruited to each group were low, baseline characteristics of these 5 individuals may have led to differences between the penicillin and placebo groups.
Selective reporting (reporting bias)	Unclear risk	Primary outcome measures reported, 1 secondary outcome (additional analgesia) not reported.
Other bias	Low risk	No other sources of bias identified.

Henry 2001.

Study characteristics
Methods	RCT Number of centres: 1 (The Ohio State University College of Dentistry, USA) Recruitment period: not stated Design: parallel group 2‐arm RCT
Participants	Adults presenting for emergency treatment Group 1 (penicillin) Mean age 37 years (SD 16.5 years); gender: 10 women, 9 men; median baseline pain: 2.00 (SD 2.00); median baseline percussion pain: 2.00 (SD 2.00); median baseline swelling: 1.00 (SD 2.00) Group 2 (placebo) Mean age 38 years (SD 18.8 years); gender: 10 women, 12 men; median baseline pain: 2.00 (SD 1.00); median baseline percussion pain: 2.00 (SD 2.00); median baseline swelling: 0 (SD 1.00) Included participants had a symptomatic necrotic tooth and actively had spontaneous pain. To be eligible, the affected tooth had to test negative to an electric pulp test (Analytic Technology Corp, Redmond, Washington, USA) and ice; have a periapical radiolucency and not have had previous endodontic treatment. Included participants were in good health (as determined by written and verbal history), had not received antibiotics in the 30 days prior to enrolment into the trial and did not have a probable or actively draining sinus tract. Number of participants at randomisation: not stated in paper, approximately 51 (from personal communication) Number of participants included in the analysis: group 1: 19; group 2: 22
Interventions	Endodontic treatment: all participants underwent total chemo‐mechanical debridement of the affected tooth on day 0. Canals were prepared using a step‐back preparation and K‐type files (LD Caulk, Inc, Milford, Delaware) and irrigated with 2.62% hypochlorite. Following instrumentation, canals were dried and a temporary restoration placed (Cavit (a light‐cured temporary sealing compound for temporary restoration of cavities)) Participants were then assigned to a trial arm. Group 1: oral penicillin (phenoxymethyl) VK 500 mg, 6‐hourly for 7 days Group 2: oral matched placebo taken according to the same regimen Analgesics: all participants received a supply of ibuprofen and were advised to take 400 mg (2 × 200 mg tablets) every 4–6 hours, as required. Each participant also received a labelled bottle of paracetamol (acetaminophen) with codeine (30 mg), which they were instructed to take 1 or 2 tablets every 4 hours only if 2 ibuprofen tablets did not relieve their discomfort.
Outcomes	Primary outcomes Participant‐reported pain, percussion pain and swelling experience at the baseline visit and upon rising for 7 days after treatment on categorical scales. Participants received a 7‐day diary to record postoperative symptoms upon rising each day. This was returned at the obturation appointment (typically the end of root canal treatment). Pain was assessed using a short ordinal numerical scale from 0 to 3: 0 = no pain; 1 = mild pain; 2 = moderate pain; 3 = severe pain. Participants used the same scale to rate pain to percussion (achieved by tapping the affected tooth with a finger). Swelling was assessed on a similar ordinal numerical scale from 0 to 3: 0 = no swelling; 1 = mild swelling, a mild puffiness that was not bothersome; 2 = moderate swelling that caused facial distortion and was bothersome; 3 = a severe swelling that caused serious facial distortion and was very bothersome. Secondary outcomes Number and type of pain medication taken.
Notes	Funding source: Graduate Endodontic Student Research Fund and Goldberg Memorial Fund, Graduate Endodontics, College of Dentistry, The Ohio State University Sample size calculation: not stated
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Each patient was assigned a 5‐digit random number from a random number table before the experiment" (email from study author).
Allocation concealment (selection bias)	Low risk	Quote: "The study investigator only gave the labelled bottle to the subject without knowing the content because he only saw the random numbers not the assignment of the drug" (email from study author).
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Each 500 mg gelatin capsule of either penicillin or placebo was identical in form. The 500 mg tablets of penicillin VK were ground into a powder and placed into clear gelatin capsules. The white powder of the lactose placebo was indistinguishable from the white powder of the penicillin tablets when viewed through the capsule."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Primary outcome measures were participant‐assessed and it was highly unlikely blinding was broken.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient reporting of relative attrition rates and reasons for withdrawal precludes judgement of the risk of bias.
Selective reporting (reporting bias)	Low risk	All outcomes were reported.
Other bias	Low risk	No other sources of bias were identified.

EDTA: ethylenediaminetetraacetic acid; RCT: randomised controlled trial; SD: standard deviation; VAS: visual analogue scale.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Achard 1967	Not an RCT
Al‐Belasy 2003	No placebo control
Alves 2000	No placebo control
Angelini 1983	Not an RCT
Anonymous 1968	Not an RCT
Banoczy 1985	Not an RCT
Baratieri 1968	Not an RCT
Brabant 1968	Not an RCT
Brennan 2006	Not all participants met inclusion criteria for clinical diagnosis. No subgroup data available
Citoler Gutierrez 1969	Not an RCT
Cumming 1984	Not an RCT
D'Atri 1973	Not an RCT
Davis 1969	Sample included children; individual participant‐level data not available
De Vries 1974	Not an RCT
Deffez 1992	No placebo control
Diamantes‐Kepiotes 1974	Intervention did not include a systemic antibiotic
Dolci 1982	Not an RCT
Edsor 2021	No placebo control
Flood 1977	Not an RCT
Gabka 1968	Not an RCT
Groshikov 1970	Not an RCT
Haapasalo 1986	Not an RCT
Hood 1978	Not an RCT
Hooley 1969	Not an RCT
Karatas 2020	Ineligible intervention
Khosla 1970	Not an RCT
Krzywicki 1975	Not an RCT
Lewis 1986	No placebo control
Lin 2006	Intervention did not include a systemic antibiotic
Lindeboom 2005	Prevention study not fulfilling inclusion criteria
Lockhart 2019	Ineligible study design
Lorber 1967	Not an RCT
Matijevic 2009	No placebo control
NCT02747082	Ineligible intervention
NCT03761264	Ineligible participants
Nowakowska 1974	Not an RCT
Oeda 1985	No placebo control
Ranta 1988	Not all participants met inclusion criteria for clinical diagnosis. No subgroup data presented
Re 1988	No placebo control
Sabeti 2021	Ineligible control: this trial compared an antiviral agent against a matched placebo, not an antibiotic (i.e. antibacterial agent). As both groups were prescribed the antibiotic amoxicillin ("1 g immediate dose followed by 500 mg, 4 times a day, totally 7 days") there is no comparison between a systemic antibiotic and a matched placebo.
Sowmya 2021	Ineligible intervention
Tampi 2019	Ineligible study design
Tancawan 2015	No placebo control
Zanjir 2020	Ineligible study design

RCT: randomised controlled trial.

Characteristics of studies awaiting classification [ordered by study ID]

NCT03007342.

Methods	2‐arm randomised controlled trial
Participants	Adults with symptomatic apical periodontitis
Interventions	Drug: amoxicillin/clavulanate potassium 875 mg–125 mg oral tablet Drug: placebo
Outcomes	Primary outcome: postoperative pain up to 7 days after endodontic treatment measured using a numerical rating scale. Secondary outcome: swelling at 7 days measured using a questionnaire.
Notes	Study completed but results are awaited.

NCT03033147.

Methods	2‐arm randomised controlled trial
Participants	Adults with symptomatic apical periodontitis
Interventions	Drug: amoxicillin/clavulanate potassium 875 mg–125 mg oral tablet Drug: oral placebo
Outcomes	Primary outcome: postoperative pain up to 7 days after endodontic treatment measured using a numerical rating scale. Secondary outcome: swelling up to 7 days after endodontic treatment measured using a questionnaire.
Notes	Study completed but results are awaited.

Differences between protocol and review

• Grey literature databases OpenGrey and ZETOC Conference Proceedings were retired in December 2020 and August 2022, respectively, so are not included in the 2023 update.

• ProQuest Dissertations & Theses Global was searched as part of the 2023 update.

• Cochrane Oral Health's Trials Register was retired on 30 June 2022.

• We have added additional search terms to the search strategy for ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform.

• We have made a minor alteration to the objectives to specify the difference between antibiotics provided with a surgical intervention and those without.

• We used a fixed‐effect model in the meta‐analysis not a random‐effects model as specified in the protocol. This was because fewer trials were suitable for inclusion than we initially anticipated.

• Due to the low number of studies included in the review, it was not possible to produce a funnel plot to assess reporting bias, conduct either subgroup analysis or proceed with the sensitivity analysis outlined in the protocol.

Contributions of authors

• ALC initiated the review, drafted the protocol, screened search results, extracted the data, performed risk of bias assessment and wrote the final review.

• IGC initiated the review, made amendments to the protocol, screened search results, reviewed data extraction and risk of bias assessment (2018 and 2023 reviews), was the arbiter during study selection and data extraction (2014 review), and was involved in writing the final review.

• NF and FW initiated the review, made amendments to the protocol and were involved in writing the final review.

• WT was the arbiter during study selection and data extraction (2023 review) and was involved in writing the final review.

Sources of support

Internal sources

• None, Other

  None to add

External sources

• Wales School for Primary Care Research, UK

  Financial support for the original review (2014) was provided by the Wales School for Primary Care Research.

• Cochrane Oral Health Global Alliance, Other

  The production of Cochrane Oral Health reviews has been supported financially by our Global Alliance since 2011 (oralhealth.cochrane.org/partnerships-alliances). Contributors over the past year 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 the Swiss Society for 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 Systematic Reviews Programme, NIHR, National Health Service or the Department of Health.

• Health and Care Research Wales, UK

  Anwen L Cope was supported by a Clinical Research Time Award from Health and Care Research Wales (2018 update)

Declarations of interest

ALC: none.

NF: none.

FW: none.

WT: none.

IGC: none.

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