Systemic complications of use of antibiotics following removal of the third molar: A systematic review

Abstract

There are currently conflicting views on the value of using antimicrobial prophylaxis in dental procedures, including extractions and implants. This review intended to highlight the common use and misuse of antibiotic treatment regimens in a dental setting, particularly in third molar surgery. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, this study has been reported accordingly. The purpose of the present systematic review was to evaluate the use of antibiotics during therapeutic orthodontic treatment involving third molar extractions, with the aim of reducing the likelihood of postoperative complications. The systematic review was conducted using online databases such as the Cochrane Central Register of Controlled Trials, PubMed, and Scopus. A set of inclusion and exclusion criteria was applied, focusing on randomized controlled trials (RCTs) that investigated antibiotic treatment for third molar surgery and were published up to 2021. The total 20 RCTs were included. The findings indicated that amoxicillin, both with and without clavulanic acid, was frequently used as an antibacterial agent in various doses and durations. However, there were no statistically significant differences in postoperative complication rates between the treatment groups. There is currently insufficient evidence to recommend standard antibiotic prophylaxis for healthy young individuals undergoing third molar extraction surgery. Additionally, antibiotic-related adverse events were not statistically different from those observed in placebo groups. Based on our findings, the risk of allergic reactions and the potential for developing antimicrobial resistance necessitate a careful and judicious use of antibiotics in mandibular third molar extraction procedures, even if cost is not a limiting factor.

INTRODUCTION

In recent times, antibiotics have been on the rise and have gained popularity in all medical fraternities, the dental wing being one of them. Among dentists, it has become a general norm to prescribe it to patients who are in dire need of it (surgical cases), along with others, particularly those in whom it is employed just as a prophylactic measure. The aforementioned patient, for whom these medications were required, suffers from various odontogenic infections as a result of extraction.[1]

The most common method in oral surgery is the removal of the third molar; occasionally, difficult wisdom tooth extractions can lead to intraoperative and postoperative problems. According to the study, complications in third molar extraction occur at a rate ranging from 4.6% to 30.9%.[2]

This procedure follows a separate set of antibiotic guidelines. The overall health of patients, along with whether there are any allergies or intolerances, should always be assessed by the clinician. Antimicrobial prevention for sufferers undergoing this type of surgery has become more widely known in recent years.

The advantages and disadvantages of the over-the-top use of antibiotics need to be examined and assessed. In addition to systemic antimicrobial prevention, the current functionality of room decontamination is often carried out during the procedure, and topical home treatments are recommended to be used afterward.[3] In the surgical setting, bacterial infection risk is always present. Understanding which antibiotic therapy is most frequently used after third molar surgical treatment would allow researchers to assess their benefits and drawbacks. Because of the patient’s surgical and clinical circumstances, this article serves the purpose of displaying all protocols while emphasizing those that should be used most frequently and those that are more likely to result in difficulties.[4,5]

In a 2015 study, Lee et al.[6] found that 9.2% of people experienced problems after having their wisdom teeth removed, of which severe pain accounted for 4.8% of the problems, swelling for 2.6%, bleeding for 2.4%, alveolar osteitis for 0.9% of the problems, trismus for 0.5%, and paresthesia for 0.9%. Two maximum common side effects of wisdom tooth removal are dry sockets and infection. Lemierre’s syndrome is among the more uncommon postextraction issues that clinicians need to be aware of.[7] When someone has Lemierre’s syndrome, the internal jugular vein becomes infected with thrombophlebitis, which can lead to possible systemic problems such as septicemia. This necessitates the use of antibiotic medication. Even yet, preoperative antibiotics are usually administered to avoid complications after the extraction.[1]

It is common practice to prescribe preoperative or postoperative antibiotics that are administered systemically for the prevention of infections of third molar extraction problems such as surgical site infections and alveolitis. Among dentists, however, there is disagreement and discussion about this as well. Prophylactic antibiotic treatment is often not recommended for healthy people, and improper antibiotic usage puts patients at risk for systemic complications and side effects and promotes the occurrence of antibiotic resistance. Moreover, meta-analyses and published systematic reviews oppose the prophylactic uses of antibiotics when the cost–benefit ratio is taken into account. In any event, patients receiving this surgical procedure frequently need to utilize additional pharmacological treatments in addition to antibiotic avoidance. The postoperative phase treatment will depend on the length and complexity of the intervention.[8,9,10,11,12]

The extraction of third molars is a routine procedure performed by oral surgeons.

Postoperative antibiotics are essential to reduce the occurrence of infection after the extraction of a third molar. However, the use of antibiotics is associated with adverse events that can range from minor gastrointestinal distress to severe allergic reactions, as well as antimicrobial resistance and the disruption of the body’s normal microbiota. Prolonged antibiotic therapy increases the risk of developing fungal infections, such as oral thrush. Many systematic reviews were available on the use of antibiotics in third-molar extractions; however, there was a scarcity of research focusing on the adverse effects or complications associated with their use. Hence, the objective was to investigate the systemic complications arising from the administration of antibiotics following the extraction of third molars. This review helps clinicians enhance patient outcomes, mitigate the risks of antibiotic resistance, ensure cost-effective healthcare facilities, and promote evidence-based clinical practices in both dentistry and medicine.

MATERIALS AND METHODS

The protocol for this study adhered to the PRISMA-P guidelines, and all modifications were properly documented. The systematic review followed the Cochrane Handbook and the PRISMA statement, as shown in Figure 1. This study was registered with PROSPERO under the registration number CRD42023408672 and adheres to the standards set by the Institute of Medicine.

Figure 1.

(PRISMA) Preferred Reporting Items for Systematic Reviews flow diagram. RCT: randomized controlled trial

Sources of information

This systematic review was carried out and reported using the Cochrane Handbook and the PRISMA declaration.

Search strategy

We conducted an extensive literature search across a variety of electronic databases, including PubMed, Google Scholar, Web of Science, and Scopus. The search included articles published from 2011 to 2022. The related keywords in the following search terms include “third molar extraction,” “dental procedure,” “role of antibiotics,” “antibiotic prophylaxis,” “amoxicillin tablets,” and “antibiotic prophylaxis.”

Eligibility criteria

Studies were assessed for eligibility using the PICOS tool (Population, Intervention, Comparators, Outcomes, and Setting):

• Population (P): Patients of any age and gender undergoing single or multiple tooth extractions of upper or lower third molar teeth. The participants received postoperative antibiotics.

• Intervention (I): Randomized controlled trials (RCTs) focusing on the administration of antibiotics following the removal of the third molar.

• Comparators (C): The results of administering postoperative antibiotics were compared with those of a placebo or control group.

• Outcomes (O): The main outcome of interest was infection following surgery, comparing the group that received postoperative antibiotics (treatment group) with the group that received a placebo (placebo group).

• Setting (S): Primary care, community, or hospital settings.

This structured approach ensured a comprehensive and systematic review of the available literature on the role of antibiotics following third molar extractions.

Criteria for Inclusion:

• Human RCTs, double-blind and placebo-controlled clinical trials.

• Patients undergoing dental extraction.

• Antibiotic prevention.

• Gender: Both male and female.

• Age: 18+.

• Use of antibiotic (amoxicillin).

Criteria for Exclusion:

• Studies published before 2010.

• Animal or in vitro research.

• Incomplete texts.

• Patients with other concomitant illnesses.

• Publications containing inappropriate information.

Data assessment

RevMan software was used to investigate the risk of bias in RCTs, while the Cochrane Collaboration tool was used to assess the risk.[13] The risk assessment for the RCTs that were part of the review was done by two independent reviewers. Any differences have been resolved by discussion and, if required, by contacting a third reviewer.

RESULT

The risk of bias in this research was evaluated using the Cochrane “Risk of Bias tool” for randomized trials. The tool assesses five domains of bias, as depicted in Figures 2 and Figure 3:

Figure 2.

Risk of bias summary: review authors judgments about each risk of bias item for each included study

Figure 3.

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

1. The randomization technique

2. Deviations from intended interventions

3. Incomplete outcome data

4. Measurement of the outcome

5. Bias in the selection of the reported result.

Most of the articles (69%) were rated as low risk based on the overall bias assessment for each selected study.[14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33] All the randomized trials reviewed employed the double-blind methodology. A “low-risk” rating indicates that a reliable method was used to assign patients to different treatments, making the findings trustworthy. An “unclear” rating, which applied to 29% of the studies, suggests some potential for bias, but not enough to invalidate the findings, though some data might be missing. A “high-risk” rating, which applied to 2% of the studies, indicates a significant amount of bias that could affect the findings unreliable, often due to substantial gaps in knowledge or reporting inconsistencies.

Study characteristics

In the present systematic review, a total of 20 studies were enrolled including retrospective and prospective studies.[14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33] All the studies enrolled involved patients who had undergone third molar extractions As shown in Table 1.

Table 1.

Selection criteria for the study

Author	Published	Study design	Antibiotic	Outcomes
López-Cedrún et al.[14]	2011	Medical, prospective, single-center, double-blind, RCT	G1: (2000 mg) Amoxicillin before surgery and (500 mg) Placebo; G2:Only placebo; G3: (2000 mg) placebo and (500 mg amoxicillin	No differences in side effects between the groups.
Siddiqi et al.[15]	2011	Medical, prospective, comparative, single-center, double-blind, RCT, placebo-controlled	G1:(1000 mg) amoxicillin preoperational; in stage 2 surgery patient only received placebo; G2 (1000 mg) amoxicillin preoperational and 500 mg for 2 days	Do not reduce the swelling significantly after the surgery. The authors do not recommend the antibiotic to a healthy person
Bezerra et al.[16]	2011	Medical, prospective, RCT, Slit mouth	Amoxicillin vs placebo	The author does not recommend antibiotic prophylaxis for healthy patients
Pasupathy et al.[17]	2011	Medical, prospective, RCT	G1:(1000 mg) placebo; G2:(1000 mg) amoxicilin; G3: (800 mg) metronidazole	Surgical wound infection, fever, restricted mouth opening on day 7 post-op, and purulent discharge were comparatively more significant in Group 1 than in Group 2, and least significant in Group 3.
Sisalli et al.[18]	2012	Medical, comparative, prospective, single-center, not controlled	G1:(2000 mg) amoxicillin preoperation and (500 mg for 5 days) amoxicillin; G2: (1000 mg IM) ceftazidime pre-operation and (1000 mg MI for 4 more days)	Group 1 (amoxicillin +clavulanicacid)—wound infection, nausea, headache, diarrhea; Group-2 (Ceftazidime)—heartburn
Calvo et al.[19]	2012	Medical, prospective, single-center, RCT	No antibiotics were used	Antibiotic prescriptions are unnecessary before or after third-molar removal in healthy patients
Adde et al.[20]	2012	Medical, comparative, prospective, single-center, not controlled.	G1:(2000 mg) amoxicillin preoperational (500 mg for 5 days); G2:(1000 mg) ceftazidime preoperational (1000 mg IM for 4 days	amoxicillin +clavulanic acid) associated with wound-infection, nausea, headache, diarrhea; Ceftazidime adverse event showed heartburn.
Duvall et al.[21]	2013	Medical, comparative, prospective, single-center, double-blind, RCT, placebo-controlled	Chlorhexidine vs amoxicillin vs placebo	No statistically significant difference in the in the incidence and magnitude of bacteremia between the three groups. However, the placebo group showed the widest range and highest average level of bacteremia, followed by the rinse group, with the antibiotic group having the lowest levels.
Bortoluzzi et al.[22]	2013	Medical, prospective, single-center, double-blind, RCT placebo-controlled	G1:(2g) amoxicilin + (8g) dexamethasone presurgery; G2:(2g) amoxicillin + (8g) placebo; G3: (2g) placebo + dexamethasone (8 mg); G4: (2g) placebo + (8g) placebo	1—alveolar infection, 2 cases of alveolar osteitis. No difference observed in postoperative complexity.
Sane et al.[23]	2013	An open, Medical trial, single-center, double-blind, RCT, placebo-controlled	500 mg azithromycin preoperative	Reduce the incidence of surgical site infection.
Iglesias- Martin et al.[24]	2014	Medical, prospective, RCT	(1g) Amoxicillin vs. amoxicillin and (875/125 mg) clavulanate postoperative	No differences between the two groups. Group 1—People with gastrointestinal complexity.
Crincoli et al.[25]	2014	Medical, prospective, single-center, comparative, double-blind, RCT	(1g for 5 days) Amoxicillin + clavulanic acid postoperation and (1 g 2* for 5 days) sodium cefazolin postoperation	Oral and intramuscular antibiotics yield similar results in preventing postoperative dental complications (P>0.05). Oral administration is associated with a higher likelihood of significant gastrointestinal problems (P=0.003).
Busa et al.[26]	2014	Medical, prospective, single-center, double-blind, RCT	G1: (2,000 mg) amoxicillin/clavulanic + (1000 mg 2* for 5 days); G2: chloramphenicol; G3: (2000 mg) amoxicillin/clavulanic acid+ (1000 mg 2* for 5 days	The research failed in finding differences about bacterial growth. Local administration of antibiotics is a viable option for third-molar removal operation.
Lee et al.[27]	2014	Medical, retrospective, single, center, comparative, controlled not RCT	G1:(100 mg 3* days for 1 week) cefditoren pivoxil; G2 : no antibiotic	Antibiotic prophylaxis to prevent postoperative inflammatory difficulties is unnecessary in the removal of mandibular third molar.
Arteagoitia et al.[28]	2015	Medical, prospective, RCT	Amoxicillin vs placebo	Infection, pain, trismus, and mouth opening
Xue et al.[29]	2015	Medical, prospective, RCT, slit mouth	Amoxicillin vs placebo	Alveolar osteitis and wound infection.
Milani et al.[30]	2015	Medical, prospective, randomized clinical trials, Slit mouth	Amoxicillin vs placebo preoperative.	No difference found in groups.
Braimah et al.[31]	2017	Medical, prospective, RCT	Two different routes of amoxicillin vs levofloxacin.	Quality of life (QoL) was evaluated 3 groups with distinct antibiotic medication protocols.
Sidana et al.[32]	2017	Medical, Prospective, and RCT	Group 1: anti-inflammatory drugs postoperation; G2 (500 mg) amoxicillin for 3 days + anti-inflammatory drugs; G3:(500 mg) amoxicillin; G4: anti-inflammatory drug.	In pain, swelling, or postremoval difficulty, there were no differences between the groups.
Mariscal-Cazalla et al.[33]	2021	Medical, prospective, RCT	Group-1 (750 mg) amoxicillin; Group 2 after operation; Group 3-placebo before and after operation.	In Group 3, pain and inflammation are greater than in Groups 1 and 2.

Antibiotics prescribed

The antibiotics prescribed across the studies included amoxicillin, which was used in studies.[1,2,3,4,5,7,8,9,11,12,13,15,16,17,18,19,20] Ceftazidime was prescribed in studies,[5,7] while clavulanic acid was used in studies.[5,7,11,12,13] Additionally, chlorhexidine was prescribed in study.[21]

Side effects of antibiotics

• Systemic side outcomes of antibiotics after removal of the M3 involved headache, diarrhea, gastrointestinal reactions, fever, and nausea.

• Local side outcomes of antibiotics after removal of the M3 involved pain, edema, bleeding, swelling, DS, wound infection, and trismus and alveolar osteitis.

DISCUSSION

The utilization of antibiotics in dental practice is widespread in India. However, their use in third-molar surgeries remains controversial.[34] Numerous research articles have investigated the effectiveness of antibiotics in the third-molar surgical procedure. The main concern regarding the use of systemic antibiotics in third-molar surgery is to prevent complications such as alveolitis and surgical site infections. On the other hand, when the antibiotic is prescribed, other than benefits, risk factors associated with the antibiotic must be considered in dental procedures.[35] In this systematic review, we focused on the complications associated with the use of antibiotics during third-molar extraction.

In this systematic review, we enrolled 20 trial studies that evaluated the effectiveness of several antibiotic classes in preventing DS, infections, and other postsurgical complications after third molar removal. In all the studies mentioned, only the third molar was removed. In this systematic review, most studies utilized either clavulanic acid or amoxicillin following wisdom tooth extraction[14,15,16,17,18,20] with a placebo as the control.

In this systematic review, Siddiqi et al.[15] conducted a study where one group received antibiotics during the first surgical visit, while the other group received antibiotics for 2 days following surgery. Placebo capsules were administered during the second surgical visit or vice versa. With a statistical P value (>0.05), the study’s findings showed no differences between the two groups’ infection rates, discomfort, swelling, trismus, or temperature. The results showed prophylactic antibiotics should not be routinely given to non-immunocompromised patients because it will not provide a statistically meaningful influence on postoperative infections in third-molar surgery. These results are in agreement with those of Arora et al.,[36] who noted that both Group I (amoxicillin and clavulanic acid) and Group II (placebo) experienced postoperative problems such erythema and dehiscence. However, there was no noteworthy difference in swelling and pain recovery between Group I and Group II as both groups utilized drugs for recovery. Notably, signs of alveolar osteitis were absent in the antibiotic regimen group at any site, while suture site aspirates revealed positive microbial cultures in nine patients on the third day. This study concluded that patients having lengthy, contaminated procedures should especially take postoperative antibiotics.

In the present review, Xue et al.[29] reported the following outcomes in the treatment group: 4 cases of alveolar osteitis (2%), 2 wound infections (1%), and 14 other reactions, which included gastrointestinal issues (n = 4), bleeding (n = 2), ulcers (n = 2), and fever (n = 6). In the placebo group, there were 6 cases of alveolar osteitis (3%), 2 wound infections (1%), and 22 other reactions, which included bleeding (n = 6), ulcers (n = 2), and fever (n = 14). The study concluded that prophylactic amoxicillin (or clindamycin) was ineffective in preventing or reducing postoperative inflammatory complications following the removal of impacted mandibular third molars.

In our current review, Bezerra et al.[16] conducted a study examining the impact of administering amoxicillin as a prophylactic measure before third molar extraction to prevent postoperative inflammatory or infectious complications. The study revealed that 43.05% of cases experienced postoperative inflammatory or infectious events, including alveolitis (one case in the experimental group on day 3 and one case in the control group on day 7). Also, 3 cases in the control group exhibited purulent drainage. The findings of the study concluded that administering prophylactic antibiotics before third-molar extraction surgery did not lead to a significant reduction in the incidence of associated inflammatory events.

In the meta-analysis conducted by Marghalani et al.,[37] healthy individuals undergoing extractions of third molars, results from the meta-analysis revealed significant findings regarding antibiotic prophylaxis over placebo, showing a decreased risk of infection, reduced risk of alveolar osteitis (participants from nine trials), and diminished pain experience. However, participants receiving antibiotic prophylaxis exhibited a significantly higher risk of mild and transient antibiotic-related adverse events compared to the placebo groups (RR 1.98, 95% CI 1.10 to 3.59; 930 participants). This review concluded that due to the low risk of infection in healthy young adults, prescribing antibiotics poses a substantial risk of adverse effects. Furthermore, overuse of antibiotics can lead to antibiotic resistance, making future treatments more difficult. This study does not support the recommendation of antibiotics for healthy patients undergoing third molar extractions.

According to Bhuvaraghan A. et al.,[38] antibiotics were prescribed for the prevention of infective endocarditis, while routine prescriptions for dental procedures could be dangerous, as in the case of pregnancy and liver damage.

Similarly, in a study conducted by Limeres J et al.,[39] the results showed that out of a total 52 patients who received amoxicillin in combination with clavulanic acid, 9 patients experienced nausea and 21 suffered from diarrhea. In our investigation, most of the study trials suggest that prophylactic antibiotic therapy is typically unnecessary in healthy patients. Misuse of antibiotics exposes patients to potential adverse reactions and fosters the emergence of antibiotic resistance. Regularly administering antibiotics for every third-molar removal can have unfavorable repercussions; thus, it is important to treat each patient uniquely. Before prescribing antibiotics, it is crucial to consider factors such as the surgical time technical challenges, patient age, systemic disorders, and allergy history. Antibiotic prescriptions without a medical need could expose individuals to the risk of side effects and contribute to antimicrobial resistance (AMR).

The limitations of this systematic review include the variability in methodologies among the included studies, such as differences in study designs, participant demographics, and follow-up periods. Additionally, factors such as patient comorbidities, surgical techniques, and postoperative care protocols may have varied across studies, potentially confounding the association between antibiotic use and systemic complications.

CONCLUSIONS

According to the research, amoxicillin with or without clavulanic acid is the most commonly used antibiotic for third-molar removal in dental settings. However, evidence suggests that the routine use of antibiotics may not always be justified and can have negative consequences for patients. It is important to recognize that extracting a third molar without antibiotics in cases of acute, chronic inflammation or toxic infection is rarely considered. Before prescribing antibiotics, dentists must consider factors such as the duration of the procedure, technical challenges, patient age, systemic disorders, and allergy history. Unnecessary antibiotic prescriptions can expose patients to side effects and contribute to the growing problem of AMR. The review concludes that the widespread use of penicillin for preventing infections after third-molar extraction may be more harmful than beneficial. Researchers are working to reduce the number of antibiotics prescribed in clinical settings and to identify specific clinical conditions that truly require antibiotic treatment.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.