Q U I N T E S S E N C E I N T E R N AT I O N A L
ORAL SURGERY
Willian Caetano Rodrigues
Antibiotic prophylaxis for third molar extraction in healthy patients: Current scientific evidence Willian Caetano Rodrigues, DDS, MSc1/Roberta Okamoto, DDS, MSc, PhD2/Eduardo Piza Pellizzer, DDS, MSc, PhD3/ Ana Cláudia Nazareno dos Anjos Carrijo, MD4/Rafael Santiago de Almeida, DDS5/Willian Morais de Melo, DDS, MSc6 Third molar extraction is one of the most frequently performed procedures in the dental clinic, and it is associated with innumerable trans- and postoperative complications, such as pain, trismus, edema, localized alveolar osteitis, and surgical site infection. Some authors advocate the use of local or systemic antibiotics to reduce the incidence of these postoperative complications. However, several studies have revealed an insignifi-
cant gain after using antibiotics. Despite the risks of allergic reactions, toxicity, and the development of resistant microorganisms, about 50% of dentists routinely prescribe the use of prophylactic antibiotics for this purpose. The goal of this paper is to evaluate the scientific evidence that justifies antibiotic prescription to healthy patients undergoing third molar extraction. (Quintessence Int 2015;46:149–161; doi: 10.3290/j.qi.a32825)
Key words: antibiotics, prophylaxis, therapeutics, third molar
Surgery for third molar (M3) extraction is one of the most frequently performed procedures in the dental clinic,1,2 whether by specialists or by general practitioners, and is associated with innumerable trans- and postoperative complications, such as pain, jaw fracture, injury to other teeth, temporomandibular joint dysfunction, trismus, swelling, bleeding, localized alveolar 1
Specialist in Implantology and Orthodontics, Surgery & Integrated Clinic Department, Araçatuba Dental School, São Paulo State University (FOA - UNESP), São Paulo, Brazil.
2
Professor, Surgery & Integrated Clinic Department, Araçatuba Dental School, São Paulo State University (FOA - UNESP), São Paulo, Brazil.
3
Professor, Dental Materials and Prosthodontics, Araçatuba Dental School, São Paulo State University (FOA - UNESP), São Paulo, Brazil.
4
Specialist in Internal Medicine, Private Practice, São Paulo, Brazil.
5
Specialist in Orthodontics, Surgery & Integrated Clinic Department, Araçatuba Dental School, São Paulo State University (FOA - UNESP), São Paulo, Brazil.
6
PhD Student, Surgery & Integrated Clinic Department, Araçatuba Dental School, São Paulo State University (FOA - UNESP), São Paulo, Brazil.
Correspondence: Dr Willian Caetano Rodrigues, Rua Pres. Bernardes, 482, apto 12, Ed. Imperial, Vila Santo Antônio, Araçatuba, CEP 16015353, São Paulo, Brazil. Email: [email protected]
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osteitis (painful dry socket), lost workdays, and nerve damage.3,4 Surgical site infection is the greatest cause for concern because if left untreated, it can progress to cellulitis and abscesses of the fascial spaces (Figs 1 and 2) that eventually lead the patient to hospitalization and further serious consequences.5 M3 extraction is usually considered clean-contaminated surgery, but the organisms involved are part of the normal oral flora, and therefore are not a usual source of postextraction infection. Nevertheless, many professionals recommend preventive use of antibiotics for minor oral surgeries even if the patient does not present any prior symptomatology or comorbidity.6,7 The presumption of this practice is that antibiotics will prevent the occurrence of delayed healing after surgery.8 For patients more susceptible to infections, such as diabetics or chronic corticosteroid users, and especially those at increased risk of endocarditis, antibiotic prophylaxis is already consolidated in the scientific litera-
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Fig 1 Side view of swelling related to cellulitis and fascial abscess caused by complications after extraction of the mandibular right third molar. Penrose drain installed after extra oral drainage under general anesthesia.
Fig 2 Intraoral drainage of abscess caused by complications after extraction of the mandibular right third molar.
ture.1,9,10 Controversy exists regarding healthy patients who are subject to minor oral surgery such as mandibular M3 extraction.11 Some authors allege that the use of local or systemic antibiotics reduces the incidence of inflammatory and infectious postoperative complications associated with this type of procedure.2,3,8,12-18 Others are opposed to this practice, as the results of their studies did not demonstrate statistically significant reduction in the incidence of such problems by the administration of antibiotics to non-immunocompromised patients.1,4,10,19-22,23 The subject is of interest to both maxillofacial surgeons and general clinicians, and the intent of this literature review is to present scientific evidence regarding the effectiveness of antibiotics in preventing infectious and inflammatory complications (IC) after surgery for extraction of M3s in healthy patients.
and “prophylaxis or therapy or prophylactic or therapeutics or therapeutic” and “third molar or third molars”. By limiting the search to articles written only in English, 124 references were found. After this preliminary survey of potentially relevant publications, three authors (WCR, ACC, and RA) independently assessed the abstracts and selected only those that fully fitted the inclusion criteria proposed for this literature review: • discuss use of local or systemic prophylactic antibiotics for the extraction of M3s • involve only healthy patients (American Society of Anesthesiologists’ Classes I and II) • fall within the following types of study: systematic literature reviews, meta-analyses, randomized clinical trials, retrospective and prospective epidemiologic studies, cross-sectional and prospective comparative studies.
METHOD AND MATERIALS The strategy for identification of the studies used in this literature review was searching the database PubMed/ MEDLINE in the period from 1 January 2003 to 30 April 2014, with the descriptors: “antibiotic or antibiotics”
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The following exclusion criteria were applied: • papers published in any language other than English • animal model experiments • in vitro studies
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• • • • •
case reports case series without control groups literature reviews interviews or personal commentaries by renowned authors studies involving unhealthy patients (ASA III and IV).
After the reading the selected papers, the reference lists were studied for additional relevant references.
RESULTS The search in PubMed/MEDLINE according to the period, descriptors, applied limits, and inclusion/exclusion criteria allowed the selection of 36 references. The full texts were obtained, carefully evaluated, and their references lists checked. This allowed the inclusion of two further relevant articles: the American Heart Association (AHA) guide,10 for information on endocarditis prophylaxis, and a meta-analysis24 that provided guidelines for assessing the methodologic quality of the studies, with regard to internal validity, external validity, and statistical analysis. In total, 38 publications were obtained: 8 systematic reviews, 20 randomized controlled clinical trials, and 10 nonrandomized comparative controlled studies. Among the 30 clinical studies, only three multicenter and 11 placebo-controlled studies were found. Other authors had used the split-mouth technique (4) or control groups with no medication. Patients and professionals were double-blind in 20 clinical studies, and in four studies only patients were blind. In quantitative terms, the clinical studies included between 19 and 890 patients. Considering the criteria proposed by Olivo et al,24 the majority of clinical studies (23) used appropriate statistical analysis. There were eight papers in which the sample was less than desirable for a level of more substantial evidence. Qualitatively there was also a widely variety with respect to age, single or multiple extractions of M3s, and non-randomized distribution in relation to the gender of the patients (Table 1). Most of the clinical studies evaluated the efficacy of antibiotics’ systemic action (25), and amoxicillin was
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used in 11 studies, followed by amoxicillin/clavulanic acid (7), clindamycin (5), azithromycin (3), metronidazole (3), penicillin (2), ampicillin (1), moxifloxacin (1), cefazolin (1), ceftazidime (1), and cefeditoren pivoxil (1). The oral route of administration was preferred by the authors (23), and the parenteral route was chosen in just four studies. In nine cases the oral administration occurred at 1 hour in advance, and in three studies the medication was started 2 hours before surgery; in other cases, the use of antibiotics was started immediately after the procedure. In eight studies the systemic antibiotic coverage was extended for 5 days postoperatively, and in 11 studies by only 3 or 4 days. An intraalveolar topical antibiotic was found in five clinical trials, and the following active principles were evaluated: tetracycline (2), minocycline (2), and chloramphenicol (1). In all clinical studies evaluated, both anti-inflammatory and analgesic were prescribed in the postoperative period, but the possible consequences of drug interaction among antibiotic and these medications were evaluated in only one study.12 The implications of local interventions such as methods of oral hygiene and the use of intraoral antiseptics with chlorhexidine were discussed in only two clinical studies.25,26 Only one of the systematic reviews highlighted these aspects.6 Table 1 lists some of these aspects and also the conclusions of several authors on the recommendation or not to use antibiotics to prevent or minimize the incidence of postoperative infection and/or inflammatory complications after third molar extraction.
DISCUSSION The greater the depth of the M3 to be extracted in relation to the occlusal plane, the greater the need for osteotomy and the more extensive the surgical procedure.8,27 Consequently, there is greater trauma to the surrounding tissues and an intensification of the inflammatory process, with pronounced discomfort to the patient.26 The intensity of pain, swelling, and trismus are related to mechanical and biochemical factors inherent to the procedure, and may affect the patient’s quality of
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Table 1
Studies arranged in chronological order, with brief information of their characteristics, sample size, follow-up period, and the main conclusions of the authors
Study
Study design
Sample/follow-up
Antibiotic and dosage
Conclusions
Foy et al
Clinical, prospective, multicenter, comparative
n = 116 patients; 464 M3 extracted; 43% male; follow-up 2 weeks
G1: ampicillin (1.0 g IV) or clindamycin (300 mg IV) for allergic to β-lactams just before surgery. CG: no antibiotic
Systemic (IV) antibiotic should be used just in in patients with higher risk for complications after third molar surgery because it can improve clinical recovery.
Poeschl et al1
Clinical, prospective, single center, randomized controlled
n = 288 patients; 528 M3 extracted; follow-up 4 weeks; 0.2% chlorhexidine mouthwash
G1: amoxicillin/clavulanic acid (1000 mg/250 mg OR, 2 × day for 5 days). G2: clindamycin (300 mg OR, 3 × day for 5 days). CG: no antibiotic
There was no reduction in the rates of complications and the authors do not recommend the routine use of preemptive antibiotics.
Sanchis et al25
Clinical comparative, single center
n = 200 patients; 200 M3 extracted; 32 % male; follow-up 1 week; oral hygiene control
G1: (n = 100) paste containing 4% (9 mg) tetracycline + 500 mg amoxicillin (8/8 h for 4 days). CG: (n = 100) no medicine in the alveolus + amoxicillin 500 mg (8/8 h for 4 days)
Topical administration of intra-alveolar tetracycline did not affect the incidence of alveolitis, but reduced pain and trismus although the differences were not statistically significant.
Arteagoitia et al19
Clinical, prospective, single center, randomized, double-blind, placebo-controlled
n = 490 patients; 200 M3 extracted; 40% male; follow-up 8 weeks; 0.12% chlorhexidine mouthwash
G1: amoxicillin/clavulanic acid (500 mg/125 mg OR, 3 × day for 4 days). CG: placebo in the same dosage
The authors question the systematic use of prophylactic antibiotics. Prescription only for specific cases. Take into consideration the age and the difficulty degree of surgery.
Graziani et al12
Clinical, prospective, comparative, single center, randomized
n = 30 patients; 30 M3 extracted; 50% male; follow-up 1 week
G1: piroxicam (20 mg sublingual, once daily, for 3 days) before surgery. G2: azithromycin (500 mg once daily, for 3 days); G3: azithromycin (500 mg once daily, for 3 days) + piroxicam (20 mg/day, sublingual, for 3 days)
Azithromycin administered 3 days before surgery reduces incidence of infections. Concomitant use with piroxicam reduces its anti-inflammatory capacity.
Ishihama et al9
Clinical, retrospective, singlecenter, not controlled
n = 45 patients; 45 M3 extracted; 28.89 % male; follow-up 2 weeks; mean age: 28.8 years
Azithromycin (500 mg OR, 1 × day, for 3 days) after surgery
Authors do not agree with routine use of prophylactic antibiotic. However, if there is indication, they suggest the strategy of rotational use of antimicrobials to prevent the development of drug resistant and cross-resistant bacteria.
Stavropoulos et al27
Clinical, prospective, multicenter, controlled
n = 123 patients; 492 M3 extracted; 38% male; follow-up 2 weeks; mean age: 20–21 years
Slow-release microspheres containing 1.0 mg of minocycline applied topically in the alveolus
The intra-alveolar topical administration of minocycline reduced the incidence of late clinical recovery. Indicated only for cases with high risk of complications.
van Eeden and Bütow36
Clinical, prospective, comparative, single center, blinded, controlled, splitmouth
n = 19 patients; 38 M3 extracted; follow-up 1 week
Medicated hand: insert covomycin-D socket (compound containing chloramphenicol, neomycin, and dexamethasone). Side control: no topical medication
Intra-alveolar topical administration of the compound covomycin-D reduced the incidence of postoperative complications in a statistically significant way.
Halpern and Dodson13
Clinical, prospective, single center, double-blind, randomized, placebo-controlled
n = 118 patients; 425 M3 extracted; 47% male; follow-up: 1 week; mean age: 25.4 years
GT: penicillin (15,000 units/kg IV) or clindamycin (300 mg IV). CG: 0.9% saline solution
Antibiotics reduce the incidence of surgical site infections.
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Study
Study design
Sample/follow-up
Antibiotic and dosage
Conclusions
Hedström and Sjögren6
Systematic review
32 randomized controlled trials, but only 8 associated with antibiotic regimens in the prevention of dry alveolitis
Kaczmarzyk et al21
Clinical, prospective, single center, double-blind, randomized, placebo-controlled
n = 86 patients; 86 M3 extracted; 27% male; follow-up 1 week; mean age: 23.5 years
G1: clindamycin (600 mg / single dose OR). G2: clindamycin (300 mg OR, 3 × day for 5 days). CG: placebo (300 mg OR, 3 × day for 5 days)
The systemic use of clindamycin was not effective in preventing postoperative complications.
Lacasa et al3
Clinical, prospective, comparative, phase III, single center, doubleblind, randomized, placebocontrolled
n = 225 patients; 100 M3 extracted; 43% male; follow-up 15 days; mean age: 29 years
G1: amoxicillin/clavulanic acid (2000 mg/125 mg OR, single dose). G2: amoxicillin/clavulanic acid (2000 mg/125 mg OR, 1 hour before surgery and 1 × daily, for 5 more days). CG: placebo tablets with the same aspect
Preemptive therapy reduces the rate of infections subsequent to cases of osteotomy. The authors recommend prophylactic antibiotics even in the simplest cases.
Ren and Malmstrom2
Systematic review and meta-analysis
Total n = 2,932 patients in 20 randomized trials
Ataoğlu et al20
Clinical, prospective, single center, double-blind, randomized, placebo-controlled
n = 150 patients; 150 M3 extracted; 17% male; follow-up 1 week; mean age: 23 years; 0.12% chlorhexidine mouthwash
Wilson et al10
Systematic review (AHA Guideline)
Systematic review of all articles indexed by MEDLINE until 2007
Al-Asfour30
Clinical retrospective single-center
n = 90 patients; 110 M3 extracted; 34.45 % male; follow-up 1 week; mean age: 25.2 years
No systemic antibiotics were administered or prescribed before or after the surgeries
Authors do not recommend routinely antibiotic prescription for dento-alveolar surgery, due to the low incidence of postoperative infection evidenced by the study.
Limeres et al14
Clinical, prospective, single center, double-blind, randomized, controlled
n = 100 patients; 100 M3 extracted; follow-up 1 week; age: 18-45 years; 0.12% chlorhexidine mouthwash
G1: moxifloxacin (400 mg OR × 1 capsule daily for 5 days). G2: amoxicillin/clavulanic acid (500 mg/125 mg OR, 3 × day for 5 days)
The use of moxifloxacin shortens the recovery period after surgery and should be used mainly in allergic to β-lactams.
Monaco et al15
Clinical, prospective, comparative, single center, randomized, controlled
n = 59 patients; 59 M3 extracted; 45.7% male; follow-up 1 week; mean age: 15 years; chlorhexidine 0.12%
G1: amoxicillin (2000 mg OR 1 hour before the surgery). CG: no antibiotic
For the age group 12–19 years old, antibiotic prophylaxis is recommended to reduce the psychologic impact of this type of surgery.
Luaces-Rey et al34
Clinical, prospective, comparative, single center, double-blind, randomized, placebo-controlled
n = 160 patients; 160 M3 extracted; 33.1% male; follow-up 1 week; mean age: 27 years; 0.12% chlorhexidine mouthwash
G1: amoxicillin (2000 mg OR), 1 hour before surgery plus 1000 mg 6 hours after surgery. Every 8 hours placebo for 4 days. G2: amoxicillin (1000 mg OR) 6 hours after surgery and another 1000 mg OR, every 8 hours for 4 days.
Authors recommend the use of prophylactic antibiotic. Continued use of amoxicillin postoperatively is not justified. It is not yet clear to which group of patients antibiotic prophylaxis would be more beneficial.
Local treatment with tetracycline, and also with chlorhexidine 0.12%, pre- and postoperatively, seem to have a significant preventive effect on alveolar osteitis.
Systemic antibiotics given before surgery are effective in preventing postoperative complications, especially in patients at higher risk for potential complications. G1 (postoperative): amoxicillin/clavulanic acid (1000 mg/250 mg OR, 2 × daily for 5 days). G2 (preoperative): same dose but starting 5 days before surgery. G3: placebo
Authors do not recommend antibiotic prophylaxis or preemptive for healthy patients.
Antibiotic prophylaxis is indicated only in cases of very restricted high risk of infective endocarditis.
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Study
Study design
Sample/follow-up
Antibiotic and dosage
Conclusions
Siddiqi et al11
Clinical, prospective, comparative, single center, double-blind, randomized, placebo-controlled, split-mouth technique
n = 100 patients; 380 M3 extracted; 33% male; follow-up 3 weeks; mean age: 26 years; 0.12% chlorhexidine mouthwash
G1: amoxicillin (1000 mg OR), single dose, 1 hour before stage-one surgery; in stagetwo surgery the patient received only one placebo containing glucose, or vice versa. G2: amoxicillin (1000 mg OR), a single dose, 1 hour before stage-one surgery and 500 mg OR, 8/8 hour for 2 days; in the stage-two surgery, the patient received only one placebo containing glucose or vice versa
Prophylactic antibiotics do not reduce the risk of infection in a statistically significant way. The authors do not recommend antibiotic prophylaxis for healthy patients.
Bezerra et al26
Clinical, prospective, single center, double-blind, randomized, placebo-controlled, split-mouth
n = 34 patients; 136 M3 extracted; 22.4% male; follow-up 2 weeks; mean age: 24 years; 0.12% chlorhexidine mouthwash
Amoxicillin (1000 mg OR), a single dose, 1 hour before surgery in the first procedure and placebo in the second procedure or vice versa
Authors do not recommend antibiotic prophylaxis for healthy patients.
Gelesko et al16
Clinical, multicenter, exploratory, comparative, controlled
n = 206 patients; 824 M3 extracted; 43% male; follow-up 2 weeks; mean age: 21 years
G1: cryotherapy + analgesic. G2: slow release microspheres containing 1.0 mg of minocycline applied topically in the alveolus + analgesic. CG: only analgesic
Authors suggest that the local deposition of antibiotic and the cryotherapy reduce the level of pain after surgery
LópezCedrún et al28
Clinical, prospective, single center, double-blind, randomized, placebo-controlled
n = 123 patients; 123 M3 extracted; 26.8% male; follow-up 1 week; mean age: 23 years
G1: amoxicillin (2000 mg OR), single dose, 2 hours prior to surgery and 500 mg of placebo, OR, every 8 h, for 5 days. G2: placebo (2000 mg OR), single dose, 2 hours prior to surgery and 500 mg of placebo, OR, every 8 h, for 5 days. G3: placebo (2000 mg OR), single dose, 2 hours prior to surgery and 500 mg amoxicillin, OR, every 8h, for 5 days
Amoxicillin appears to be effective in preventing postoperative complications. The best results were obtained with the postsurgical administration protocol.
Olusanya et al17
Clinical, comparative, prospective, single center, double-blind, randomized
n = 79 patients; 79 M3 extracted; 36.8% male; follow-up 1 week; mean age: 25 years
G1: amoxicillin (2000 mg OR) plus metronidazole (1000 mg OR) single dose 1 hour before surgery. G2: amoxicillin (500 mg OR) plus metronidazole (400 mg OR), 3 × day for 5 days
Antibiotic in a single dose is sufficient to prevent postoperative complications. Can reduce treatment costs in developing countries. If the risk of infection is high, 5-day dose.
Pasupathy and Alexander31
Clinical, prospective, single center, double-blind, randomized, placebo-controlled
n = 89 patients; 89 M3 extracted; 53.9% male; follow-up 1 week; mean age: 28.7 years
G1: placebo (1000 mg OR), a single dose, 1 hour before surgery. G2: amoxicillin (1000 mg OR), single dose, 1 hour before surgery. G3: metronidazole (800 mg OR) single dose, 1 hour before surgery
There is no advantage in routine antibiotic prophylaxis for healthy individuals.
Susarla et al5
Systematic review
12 clinical studies, placebo-controlled, doubleblind, randomized; n = 2,396 patients
Adde et al29
Clinical, prospective, single center, double-blind, randomized, controlled
n = 71 patients; 71 M3 extracted; 69.01% male; follow-up 1 week; mean age: 27.1 years; 0.12% chlorhexidine mouthwash
G1 (postoperative): amoxicillin (500 mg OR, 3 × daily for 7 days). G2 (postoperative): clindamycin (300 mg OR, 4 × daily for 7 days). G3: no antibiotic
Antibiotic prophylaxis should not be indicated in all cases of third molar surgery, but only for those cases where there is systemic impairment, contamination, or difficulties extending the time of surgery.
Calvo et al33
Clinical, prospective, single center, randomized, controlled
n = 110 patients; 150 M3 extracted; 39.09% male; follow-up 1 week; mean age: 22.7 years
No systemic or local antibiotics were prescribed or administered before or after the surgeries
This study suggests that antibiotic prescriptions are unnecessary before or after M3 removal in healthy patients.
Antibiotic prophylaxis is recommended for multiple M3 extractions on an outpatient basis.
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Study
Study design
Sample/follow-up
Daly et al
Systematic review
18 randomized controlled trials, but only with local interventions for the prevention of dry socket; n = 2,376 patients
The only local intervention that prevents alveolitis in a statistically significant way is the irrigation with chlorhexidine (0.12% and 0.2%) or deposition of chlorhexidine gel (0.2%) in dental alveoli.
Lodi et al7
Systematic review
18 clinical studies, placebo-controlled, doubleblind, randomized; n = 2,456 patients
Prophylactic antibiotics may reduce the risk of infection, dry socket, and pain, but result in an increase in mild and transient adverse effects. The use in healthy patients is questionable.
Oomens and Forouzanfar23
Systematic review
23 clinical studies, placebo-controlled, doubleblind, randomized; 15 “low-quality” and 8 “high-quality”
There is no evidence that justifies the routine antibiotic prophylaxis in cases of third molar surgery.
Sisalli et al18
Clinical, comparative, prospective, single center, not controlled
n = 107 patients; 107 M3 extracted; 38% male; follow-up 1 week; mean age: 23 years
G1: amoxicillin (2000 mg OR), single dose, 2 hours prior to surgery and 500 mg amoxicillin OR, every 8 h, for 5 days. G2: ceftazidime (1000 mg IM) 2 hours before surgery and another 1000 mg IM, every 24 hours, for 4 more days
There was no statistical difference between the two groups to justify the indication of a second choice intramuscular antibiotic.
Bortoluzzi et al22
Clinical, prospective, single center, double-blind, randomized, placebo-controlled
n = 50 patients; 50 M3 extracted; 26% male; follow-up 1 week; mean age: 22.5 years
G1: amoxicillin (2 g OR) + dexamethasone (8 mg OR), single dose before surgery. G2: amoxicillin (2 g OR) + placebo (8 mg OR), single dose. G3: placebo (2g OR) + dexamethasone (8 mg OR), single dose. G4: placebo (2 g OR) + placebo (8 mg OR), single dose
The authors recommend that antibiotic and corticoid prophylaxis should not be administered routinely in single dose when third molars are removed in healthy and young patients since it did not produce any clear benefit.
Sane et al32
Open, clinical trial, prospective, single center, not controlled
n = 50 patients; 50 M3 extracted; 46% male; follow-up 10 days; mean age: 32 years
All patients received a single dose of azithromycin 500 mg OR, 1 hour prior to the procedure
Single dose of azithromycin administered 1 hour before surgery seems to reduce the incidence of surgical site infections.
Busa et al37
Clinical, prospective, single center, double-blind, randomized, controlled
n = 40 patients; 80 M3 extracted; 40% male; follow-up 14 days; mean age: 31.5 years
G1: amoxicillin/clavulanic acid (2,000 mg OR before surgery + 1,000 mg 2 × day for 5 days). G2: chloramphenicol (local deposition). G3: amoxicillin/clavulanic acid (2,000 mg OR before surgery + 1,000 mg 2 × day for 5 days) and chloramphenicol (local deposition). CG: no antibiotic
The study failed in finding significant differences regarding bacterial growth rate. Local administration of antibiotics is a viable option for M3 extraction surgery.
Crincoli et al35
Clinical, prospective, single center, comparative, double-blind, randomized, not controlled, splitmouth
n = 24 patients; 48 M3 extracted; follow-up 1 week; mean age: 27.5 years; 0.12% chlorhexidine mouthwash
Amoxicillin + clavulanic acid (1 g OR every 12 h for 5 days) after the first surgery and sodium cefazolin (1 g IM, 2 × a day for 5 days) after the second surgery or vice versa
Both therapies proved effective in preventing IC. However, the higher cost and the minor compliance of the patient do not justify routine antibiotic IM therapy.
Lee et al4
Clinical, retrospective, single center, comparative, controlled, not randomized
n = 890 patients; 1,222 M3 extracted; follow-up 1 week; mean age: 28 years
G1: cefditoren pivoxil (100 mg OR, 3 × day, for 1 week). G2: no antibiotic
Results provide further evidence that antibiotic prophylaxis to prevent postoperative inflammatory complications is unnecessary in extraction of mandibular M3.
38
Antibiotic and dosage
Conclusions
CG, control group; G1, group 1; G2, group 2; IM, intramuscular; IV, intravenous; M3, third molar; OR, oral route.
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Fig 3 Image of a dry socket in the region of the maxillary left second premolar in a healthy patient.
life postoperatively.3 A careful surgical technique can limit the damage, but not eliminate it.11 In order to ensure a better quality of life for patients and faster return to normal activities, additional measures such as the use of preemptive anti-inflammatories, cryotherapy, and even antibiotic prophylaxis, are applied.16 The mechanical disruption of the biofilm adhered to the extracted tooth or surrounding alveolar mucosa releases bacteria and toxins in the surgical site. The presence of these microorganisms eventually contributes to clot dissolution and the manifestation of an inflammatory process called localized alveolar osteitis or dry socket (Fig 3).2,26 Depending on immunologic factors, conditions of the oral environment, quality of the microbiota, and the tissue exposure time, localized infection can develop and slow down the process of surgical wound repair. The inflammatory clinical status can degrade, with the manifestation of dysphagia and fever.26 For some authors the best way to prevent such postoperative complications is the strict control of surgical asepsis and proper conditioning of patients.1,26 However, approximately 50% of clinicians routinely prescribe the use of prophylactic antibiotics for this purpose.14,26,28,29 The main focus of the present study was the lack of consensus regarding the prescription of antibiotics to healthy patients submitted to M3 extractions. Thirty
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clinical studies and 8 systematic reviews published in the last 10 years were raised to check whether there is scientific support for such conduct. The methodologic heterogeneity of the studies evaluated meant it was exceedingly difficult to compare their results and extract consistent scientific evidence. There was no standardization of drugs or associations used in antibiotic prophylaxis, route of administration, or dosage. Great variation in the amplitude of the samples was observed (19 to 890 patients). It is known that very small samples represent a higher risk of type II error, or false negative, which consists of not rejecting the null hypothesis when it is actually false.24 For example, if a reduction of 15% to 5% in postoperative complications is considered effective and clinically significant, a clinical trial with a sample of 318 patients (159 in each group) would be needed to detect the magnitude of such difference, with 80% energy an alpha level of 0.05.2,24 With few exceptions, published clinical trials involved a sample so reduced that a conclusive analysis of results was not possible. According to data shown in Table 1, the conclusions of 15 authors signaled that prophylactic or preemptive antibiotics administration reduced, in a statistically significant way, the incidence of IC related to third molar extraction. However, five of these authors only assessed the topical use of the drug with the deposition inside the alveolus. There were 17 studies whose authors concluded unfavorably regarding the prescription of prophylactic antibiotics and, in another four studies, the recommendation was their use only in cases where the risk of infection is increased. Although all studies involved the concomitant prescription of anti-inflammatory and/or analgesics and antibiotics, only one study considered the interference of the antibiotic on the absorption and efficacy of these drugs. The effects of local preventive methods, such as using chlorhexidine-based solution or cryotherapy, on the final results were discussed only in three studies, although these were used in almost all patients. To enhance the internal validity of a study it is necessary to use appropriate control groups, blinding of patients and professionals involved, and randomization
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of individuals in the samples.24 In almost all of the trials there were errors in at least one of these aspects, which may lead to exacerbation of the treatment effects. External validity indicates how much the results can be extrapolated to a population outside the experimental situation, and this was a significant problem. For example, studies have been completed on subjects who have M3 extracted either one at a time or as unilateral extractions, which is significantly dissimilar to those of contemporary oral surgical practice; usually, multiple M3s are extracted in a single-visit.5 Samples of multicenter studies tend to be more representative of reality and, therefore, the data become more valid. There were only three multicenter studies in which results were favorable regarding antibiotic prophylaxis, but just one of them evaluated systemic administration; the other two assessed local application. Rates of IC presented in the articles selected for this study ranged between 3.5% and 12% in the control group and 0% and 9% in the groups treated with antibiotics. There are innumerable determining factors for such discrepancies. For example, authors do not use standard criteria for diagnosis of complications (infection/inflammation) after M3 extraction. A well-established guideline was discussed by Arteagoitia et al,19 but only six authors applied this in the evaluation of their results. Another aspect to consider is the followup period after surgery, which should be extended to prevent loss of complications that manifest at a late stage.13 One group of authors showed that approximately 60% of IC expressed in the antibiotic group appeared after 1 week of evaluation,19 suggesting that patient monitoring should include longer periods. In the present review, there were just 12 studies in which the follow-up period was greater than 7 days. Therefore, in studies that included only 1 week of follow-up, the IC incidence results in groups treated with antibiotics may have been underestimated.19 The literature also shows that the incidence of postoperative infection in oral surgery varies between 1% and 5.8%, and most are mild infections.1,5,11,30-32 Specifically, for the surgical removal of impacted M3, the rate of infection is expected, on average, to be less than
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1%.3,29 Progression to severe cellulitis of the fascial spaces does not manifest in more than 1% of patients.2 One research group found that from 380 impactions, only six alveoli (2%) became infected,11 the same incidence (2%) observed by Sane et al.32 In another study, no sign of infection was detected after extraction of 150 M3s in 110 distinctive patients evaluated over a week.33 Another group found an incidence of dry socket and drainage of purulent material close to 7.35%,26 but according to the authors, these cases were related to impaired oral hygiene or poor blood supply to the surgical site. Considering all these aspects, the prescription of prophylactic antibiotics for M3 extractions in healthy patients becomes questionable. Approximately 30% of antibiotic prescriptions by physicians or dentists have preventive purpose;11 An alarming number, considering that risks of indiscriminate prescription of antimicrobials include the manifestation of allergic reactions, secondary infection, toxicity, and the development of resistant microorganisms.5,7,20,30 It is estimated that 6% to 7% of patients receiving antibiotics have some type of adverse reaction.20 In a careful study that included 52 patients who received amoxicillin in combination with clavulanic acid after M3 surgery, nine individuals had nausea, and 21 had diarrhea.14 The problem of multiresistant bacterial strains is not restricted to the hospital environment, but society as a whole,21,30 and dentists should carefully evaluate whether treating healthy patients with antibiotics to prevent an infection presents a good cost-effective treatment.7 One important reason for excessive prescription of antibiotics, both quantitatively and qualitatively, is that every surgeon fears that an eventual inflammatory or infectious complication may denote professional negligence and raise doubts about competence.1 Acknowledging the significant potential risks of antibiotic overuse, the guidelines for endocarditis prophylaxis have been recently revised by the AHA.10 The main aspects considered to be predisposing to postoperative complications are: history of previous infections, teeth located on a lower level to the occlusal plane, and need for osteotomy.8 The incidence of delayed healing in patients with symptoms prior to
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Fig 4 Panoramic radiograph showing the mandibular third molars in unfavorable positions for extraction surgery implying greater need for osteotomy and odontosection.
extraction is significantly (P < .01) higher.27 In patients who frequently have pericoronitis, the alveolar bone usually exhibits sclerotic change around the third molar. Patient age could be linked with disadvantages for bone remodeling and regeneration, and proximity of the third molar to the inferior alveolar nerve canal could be related to the degree of bony exposed area.9 Patients at increased risk of infection should benefit most from the use of prophylactic antibiotics, since in such cases complications may be more difficult to treat.7 The possibility of postoperative complications in patients without antibiotic is 10% at 20 years of age, and above 30% at 40 years. Therefore, the risk of IC presents an increase of 1.08 per year of age.19 These authors claim that in cases of M3 extractions vertical or submucosal antibiotic seems unnecessary.19 The medication would be more effective to M3s partially covered by bone and those with a more horizontal position.3 The depth and angle of the molar determine the need for odontosection or ostectomy, and most traumatic procedures that extend the operating time (Fig 4).3,4 Another factor that may increase the time of intervention and therefore the chance of infection is reduced experience of the professional operative.12,33 If the criterion to administer antibiotics only to patients at high risk of complications were clinically applied as a guideline, less than 50% of young adult
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patients with M3s removed would be eligible to receive antibiotics prior to the surgical procedure.27 In cases where the prediction of occurrence of postoperative infectious complications is not possible, the decision to use antibiotics must be taken after surgery.13 However, if systemic prophylactic antibiotics are considered, it is important to remember that they provide adequate protection only when effective blood levels are present at the moment of bacterial dissemination.11,31 Amoxicillin and other penicillin derivatives are effective against both aerobic and anaerobic bacteria in the oral cavity and exhibit good bioavailability with minimal side effects. Therefore, they should be the first choice if antibiotic prophylaxis is used.2 Indeed, among the 30 clinical studies included in this literature review, 21 involved penicillin or some derivative. Nowadays, amoxicillin/clavulanic acid is the most widely used option in dentoalveolar surgery, and there is some evidence of advantage from the use of this combination for prophylactic purposes.3,14 Its coverage extended spectrum allows activity against penicillinresistant viridans streptococci and, at the same time, against anaerobic bacteria, including beta-lactamaseproducing strains.3 One study supports that there are no indications for use of a second choice antibiotic to prevent IC.18 Other classes such as lincosamides (clindamycin) or azalides (azithromycin) should be
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given only in cases of allergies to first choice antibiotics.8,13,21 Nevertheless, both azithromycin and clindamycin have an antimicrobial spectrum covering oral endogenous flora, high tissue penetration, and long persistence of concentration, and could be good alternatives for rotational use of antibiotics.9,32 In fact, the AHA has recommended azithromycin for infective endocarditis prophylaxis in its most recent guidelines.10 Cycling of homogenous antimicrobial exposure should be avoided in order to prevent multidrug resistance and development of cross-resistant bacteria.9 Regarding anaerobic agents, only two studies,17,31 with relatively small sample sizes, reported the effects of metronidazole in wound infections, which may limit the validity of any conclusion about the effectiveness or ineffectiveness of this type of antibiotic for the prevention of such complications. Considering the studies evaluated herein, multiple dosing strategies were used for antibiotic prophylaxis: single-dose preoperative administration, multidose preoperative, perioperative or pre-emptive dosing (preoperative and postoperative continuous dosing), and multiday postoperative dosing only. Some authors have claimed a significant reduction in the incidence of IC with a single loading dose of the drug, equivalent to twice the usual recommended therapeutic dose.3,15,17 Evidence suggests that a single dose of systemic antibiotic, equal to the usual therapeutic dose, administered 1 hour before surgery, would be sufficient.8,12,13 Available data from a well-designed systematic review suggest that systemic antibiotics should be administered only preoperatively.5 By testing two different amoxicillin administration protocols, one research group concluded that the continued use of antibiotics in the postoperative period is not justified.34 These data are corroborated by a recent meta-analysis in which a preoperative single dose was nearly as effective as the multiday dosing strategy.2 Particularly in cases where more complex and aggressive procedures are performed (eg, osteotomy) and the surgery is lengthy, the concept of continuing antibiotic therapy for a few days (pre-emptive therapy) after an initial dose becomes relevant, because these are known risk factors for infection.3
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Regarding antibiotic administration, literature findings highlight almost the same effectiveness of intravenous, intramuscular, and oral systemic route in preventing postoperative complications in dental surgery. Some authors recommend using treatment that is less costly and less invasive.13 Poor patient compliance and the higher cost does not justify routine antibiotic intramuscular or intravenous therapy, reserving it for patients with gastrointestinal disorders.35 Alternative local delivery of antibiotics by either topical administration or by a delivery device may enable the maintenance of a high local antibiotic concentration for an extended duration of release. This may be advantageous with regard to changes in the commensal flora and the manifestation of systemic adverse effects.6,16,27 A recent meta-analysis studied the evidence for the effectiveness of this administration route.2 The antibiotic would be incorporated into the clot formed within the alveoli, which should facilitate its action on bacteria.27,36 In fact, local treatment with tetracycline seems to have a significant and clinically relevant preventive effect on localized alveolar osteitis.6 It has been demonstrated that topical use of both minocycline and chloramphenicol reduces, with statistical significance, the incidence of late clinical recovery in those patients in whom complications were predicted,27,37 and reduces the level of pain postoperatively.16,37 Special care should be taken in circumstances where there is exposure of the inferior alveolar nerve because topical antibiotics of the tetracycline group and its derivatives can cause neurosensorial injury. In these cases, if indicated, systemic antibiotics should be chosen.28 However, according to a systematic review, the only local method that provides statistically significant benefit in the prevention of alveolitis is irrigation with chlorhexidine (0.12% and 0.2%) or deposition of chlorhexidine gel (0.2%) in the alveoli following extraction.38 It appears that intraoperative alveolar irrigation and the use of chlorhexidine 0.12% for 5 days have a significant and clinically relevant effect in the prevention of alveolar osteitis.6
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CONCLUSIONS There is no consistent scientific evidence that may support the use of prophylactic antibiotic (local or systemic) for all surgical extraction of M3 in healthy patients. Only in very specific situations should such conduct be considered: • patients with previous symptomatology • unfavorable position of the third molar implying greater need for ostectomy and/or odontosection with consequent extension of surgical time • standard oral hygiene deficiency • elderly people. The best way to prevent inflammatory and infectious complications remains the strict control of the aseptic chain and a refined surgical technique. However, if there is indication for systemic antibiotic prophylaxis, the administration of a single dose 1 to 2 hours before surgery, equal to the minimum necessary to reach an effective plasmatic concentration, seems more rational. Amoxicilin/clavulanic acid continues to be the first option, but in cases requiring multiple interventions, antibiotic alternation in different sessions would be of interest to avoid the development of bacterial resistance. Clindamycin and azithromycin are good options for this purpose. Due to the lower cost and greater patient acceptance, the oral route is preferable for antibiotic administration. The development of high-quality randomized clinical trials, with larger and better selected samples, considering known risk factors and taking into account clinical outcomes, is recommended to reach a final consensus on the efficacy of antibiotic prophylaxis. Research into alternative antibacterial therapies would also be relevant.
REFERENCES 1. Poeschl PW, Eckel D, Poeschl E. Postoperative prophylactic antibiotic treatment in third molar surgery: a necessity? J Oral Maxillofac Surg 2004;62:3–8. 2. Ren YF, Malmstrom HS. Effectiveness of antibiotic prophylaxis in third molar surgery: a meta-analysis of randomized controlled clinical trials. J Oral Maxillofac Surg 2007;65:1909–1921.
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3. Lacasa JM, Jiménez JA, Ferrás V, et al. Prophylaxis versus pre-emptive treatment for infective and inflammatory complications of surgical third molar removal: a randomized, double-blind, placebo-controlled, clinical trial with sustained release amoxicillin/clavulanic acid (1000/62.5 mg). Int J Oral Maxillofac Surg 2007;36:321–327. 4. Lee JY, Do HS, Lim JH, et al. Correlation of antibiotic prophylaxis and difficulty of extraction with postoperative inflammatory complications in the lower third molar surgery. Br J Oral Maxillofac Surg 2014;52:54–57. 5. Susarla SM, Sharaf B, Dodson, TB. Do antibiotics reduce the frequency of surgical site infections after impacted mandibular third molar surgery? Oral Maxillofacial Surg Clin N Am 2011;23:541–546. 6. Hedström L, Sjögren P. Effect estimates and methodological quality of randomized controlled trials about prevention of alveolar osteitis following tooth extraction: a systematic review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:8–15. 7. Lodi G, Figini L, Sardella A, Carrassi A, Del Fabbro M, Furness S. Antibiotics to prevent complications following tooth extractions. Cochrane Database Syst Rev 2012;11:CD003811. 8. Foy SP, Shugars DA, Phillips C, Marciani RD, Conrad SM, White RP Jr. The impact of intravenous antibiotics on health-related quality of life outcomes and clinical recovery after third molar surgery. J Oral Maxillofac Surg 2004;62:15–21. 9. Ishihama K, Kimura T, Yasui Y, Komaki M, Ota Y. Azithromycin as prophylaxis for the prevention of postoperative infection in impacted mandibular thirdmolar surgery. J Infect Chemother 2006;12:31–35. 10. Wilson W, Taubert K, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association Rheumatic fever, Endocarditis, and Kawasaki Disease Committee. Council on Cardiovascular Disease in the Young, and the Council on Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of care and outcomes Research Interdisciplinary Working Group. Circulation 2007:277:1794–1801. 11. Siddiqi A, Morkel JA, Zafar S. Antibiotic prophylaxis in third molar surgery: A randomized double-blind placebo-controlled clinical trial using split-mouth technique. Int J Oral Maxillofac Surg 2010;39:107–114. 12. Graziani F, Corsi L, Fornai M, et al. Clinical evaluation of piroxicam-FDDF and azithromycin in the prevention of complications associated with impacted lower third molar extraction. Pharmacol Res 2005;52:485–490. 13. Halpern LR, Dodson TB. Does prophylactic administration of systemic antibiotics prevent postoperative inflammatory complications after third molar surgery? J Oral Maxillofac Surg 2007;65:177–185. 14. Limeres J, Sanromán JF, Tomás I, Diz P. Patients’ perception of recovery after third molar surgery following postoperative treatment with moxifloxacin versus amoxicillin and clavulanic acid: a randomized, double-blind, controlled study. J Oral Maxillofac Surg 2009;67:286–291. 15. Monaco G, Tavernese L, Agostini R, Marchetti C. Evaluation of antibiotic prophylaxis in reducing postoperative infection after mandibular third molar extraction in young patients. J Oral Maxillofac Surg 2009;67:1467–1472. 16. Gelesko S, Long L, Faulk J, Phillips C, Dicus C, White RP Jr. Cryotherapy and topical minocycline as adjunctive measures to control pain after third molar surgery: an exploratory study. J Oral Maxillofac Surg 2011;69:e324–e332. 17. Olusanya AA, Arotiba JT, Fasola OA, Akadiri AO. Prophylaxis versus pre-emptive antibiotics in third molar surgery: a randomized control study. Niger Postgrad Med J 2011;18:105–110. 18. Sisalli U, Lalli C, Cerone L, et al. Amoxicillin and clavulanic acid vs ceftazidime in the surgical extraction of impacted third molar: a comparative study. Int J Immunopathol Pharmacol 2012;25:771–774. 19. Arteagoitia I, Diez A, Barbier L, Santamaría G, Santamaría J. Efficacy of amoxicillin/clavulanic acid in preventing infectious and inflammatory complications following impacted mandibular third molar extraction. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;100:e11–e18. 20. Ataoğlu H, Oz GY, Candirli C, Kiziloğlu D. Routine antibiotic prophylaxis is not necessary during operations to remove third molars. Br J Oral Maxillofac Surg 2008;46:133–135.
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21. Kaczmarzyk T, Wichlinski J, Stypulkowska J, Zaleska M, Panas M, Woron J. Single-dose and multi-dose clindamycin therapy fails to demonstrate efficacy in preventing infectious and inflammatory complications in third molar surgery. Int J Oral Maxillofac Surg 2007;36:417–422. 22. Bortoluzzi MC, Capella DL, Barbieri T, Pagliarini M, Cavalieri T, Manfro R. A single dose of amoxicillin and dexamethasone for prevention of postoperative complications in third molar surgery: a randomized, double-blind, placebo controlled clinical trial. J Clin Med Res 2013;5:26–33. 23. Oomens MA, Forouzanfar T. Antibiotic prophylaxis in third molar surgery: a review. Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e5–e12. 24. Olivo SA, Macedo LG, Gadotti IC, Fuentes J, Stanton T, Magee DJ. Scales to assess the quality of randomized controlled trials: a systematic review. Phys Ther 2008;88:156–175. 25. Sanchis JM, Sáez U, Peñarrocha M, Gay C. Tetracycline compound placement to prevent dry socket: a postoperative study of 200 impacted mandibular third molars. J Oral Maxillofac Surg 2004;62:587–591. 26. Bezerra TP, Studart-Soares EC, Scaparo HC, Pita-Neto IC, Batista SH, Fonteles CS. Prophylaxis versus placebo treatment for infective and inflammatory complications of surgical third molar removal: a split-mouth, double-blind, controlled, clinical trial with amoxicillin (500 mg). J Oral Maxillofac Surg 2011;69:e333–e339. 27. Stavropoulos MF, Shugars DA, Phillips C, Conrad SM, Fleuchaus PT, White RP Jr. Impact of topical minocycline with third molar surgery on clinical recovery and health-related quality of life outcomes. J Oral Maxillofac Surg 2006;64:1059–1065. 28. López-Cedrún JL, Pijoan JI, Fernández S, Santamaria J, Hernandez G. Efficacy of amoxicillin treatment in preventing postoperative complications in patients undergoing third molar surgery: a prospective, randomized, doubleblind controlled study. J Oral Maxillofac Surg 2011;69:e5–e14. 29. Adde CA, Soares MS, Romano MM, et al. Clinical and surgical evaluation of the indication of postoperative antibiotic prescription in third molar surgery. Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114(Suppl 5):S26–S31.
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30. Al-Asfour A. Postoperative infection after surgical removal of impacted mandibular third molars: an analysis of 110 consecutive procedures. Med Princ Pract 2009;18:48–52. 31. Pasupathy S, Alexander M. Antibiotic prophylaxis in third molar surgery. J Craniofac Surg 2011;22:551–553. 32. Sane VD, Gadre KS, Chandan S, Ramanojam S, Singh V, Halli R. Efficacy of single dose azithromycin as prophylactic antibiotic in surgical removal of mandibular third molars: a clinical study. J Maxillofac Oral Surg 2013;12:382–386. 33. Calvo AM, Brozoski DT, Giglio FP, et al. Are antibiotics necessary after lower third molar removal? Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114(Suppl 5):S199–S208. 34. Luaces-Rey R, Arenaz-Búa J, Lopez-Cedrun-Cembranos JL, Martínez-Roca C, Pértega-Díaz S, Sironvalle-Soliva S. Efficacy and safety comparison of two amoxicillin administration schedules after third molar removal. A randomized, double-blind and controlled clinical trial. Med Oral Patol Oral Cir Bucal 2010;15:e633–e638. 35. Crincoli V, Di Comite M, Di Bisceglie MB, et al. Which route of antibiotic administration should be used for third molar surgery? A split-mouth study to compare intramuscular and oral intake. Clin Ter 2014;165:e12–e16. 36. van Eeden SP, Bütow K. Post-operative sequelae of lower third molar removal: a literature review and pilot study on the effect of Covomycin D. SADJ 2006;61:154–159. 37. Busa A, Parrini S, Chisci G, Pozzi T, Burgassi S, Capuano A. Local versus systemic antibiotics effectiveness: a comparative study of postoperative oral disability in lower third molar surgery. J Craniofac Surg 2014;25:708–709. 38. Daly B, Sharif MO, Newton T, Jones K, Worthington HV. Local interventions for the management of alveolar osteitis (dry socket). Cochrane Database Syst Rev 2012;12:CD006968.
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ORAL SURGERY
Willian Caetano Rodrigues
Antibiotic prophylaxis for third molar extraction in healthy patients: Current scientific evidence Willian Caetano Rodrigues, DDS, MSc1/Roberta Okamoto, DDS, MSc, PhD2/Eduardo Piza Pellizzer, DDS, MSc, PhD3/ Ana Cláudia Nazareno dos Anjos Carrijo, MD4/Rafael Santiago de Almeida, DDS5/Willian Morais de Melo, DDS, MSc6 Third molar extraction is one of the most frequently performed procedures in the dental clinic, and it is associated with innumerable trans- and postoperative complications, such as pain, trismus, edema, localized alveolar osteitis, and surgical site infection. Some authors advocate the use of local or systemic antibiotics to reduce the incidence of these postoperative complications. However, several studies have revealed an insignifi-
cant gain after using antibiotics. Despite the risks of allergic reactions, toxicity, and the development of resistant microorganisms, about 50% of dentists routinely prescribe the use of prophylactic antibiotics for this purpose. The goal of this paper is to evaluate the scientific evidence that justifies antibiotic prescription to healthy patients undergoing third molar extraction. (Quintessence Int 2015;46:149–161; doi: 10.3290/j.qi.a32825)
Key words: antibiotics, prophylaxis, therapeutics, third molar
Surgery for third molar (M3) extraction is one of the most frequently performed procedures in the dental clinic,1,2 whether by specialists or by general practitioners, and is associated with innumerable trans- and postoperative complications, such as pain, jaw fracture, injury to other teeth, temporomandibular joint dysfunction, trismus, swelling, bleeding, localized alveolar 1
Specialist in Implantology and Orthodontics, Surgery & Integrated Clinic Department, Araçatuba Dental School, São Paulo State University (FOA - UNESP), São Paulo, Brazil.
2
Professor, Surgery & Integrated Clinic Department, Araçatuba Dental School, São Paulo State University (FOA - UNESP), São Paulo, Brazil.
3
Professor, Dental Materials and Prosthodontics, Araçatuba Dental School, São Paulo State University (FOA - UNESP), São Paulo, Brazil.
4
Specialist in Internal Medicine, Private Practice, São Paulo, Brazil.
5
Specialist in Orthodontics, Surgery & Integrated Clinic Department, Araçatuba Dental School, São Paulo State University (FOA - UNESP), São Paulo, Brazil.
6
PhD Student, Surgery & Integrated Clinic Department, Araçatuba Dental School, São Paulo State University (FOA - UNESP), São Paulo, Brazil.
Correspondence: Dr Willian Caetano Rodrigues, Rua Pres. Bernardes, 482, apto 12, Ed. Imperial, Vila Santo Antônio, Araçatuba, CEP 16015353, São Paulo, Brazil. Email: [email protected]
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osteitis (painful dry socket), lost workdays, and nerve damage.3,4 Surgical site infection is the greatest cause for concern because if left untreated, it can progress to cellulitis and abscesses of the fascial spaces (Figs 1 and 2) that eventually lead the patient to hospitalization and further serious consequences.5 M3 extraction is usually considered clean-contaminated surgery, but the organisms involved are part of the normal oral flora, and therefore are not a usual source of postextraction infection. Nevertheless, many professionals recommend preventive use of antibiotics for minor oral surgeries even if the patient does not present any prior symptomatology or comorbidity.6,7 The presumption of this practice is that antibiotics will prevent the occurrence of delayed healing after surgery.8 For patients more susceptible to infections, such as diabetics or chronic corticosteroid users, and especially those at increased risk of endocarditis, antibiotic prophylaxis is already consolidated in the scientific litera-
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Fig 1 Side view of swelling related to cellulitis and fascial abscess caused by complications after extraction of the mandibular right third molar. Penrose drain installed after extra oral drainage under general anesthesia.
Fig 2 Intraoral drainage of abscess caused by complications after extraction of the mandibular right third molar.
ture.1,9,10 Controversy exists regarding healthy patients who are subject to minor oral surgery such as mandibular M3 extraction.11 Some authors allege that the use of local or systemic antibiotics reduces the incidence of inflammatory and infectious postoperative complications associated with this type of procedure.2,3,8,12-18 Others are opposed to this practice, as the results of their studies did not demonstrate statistically significant reduction in the incidence of such problems by the administration of antibiotics to non-immunocompromised patients.1,4,10,19-22,23 The subject is of interest to both maxillofacial surgeons and general clinicians, and the intent of this literature review is to present scientific evidence regarding the effectiveness of antibiotics in preventing infectious and inflammatory complications (IC) after surgery for extraction of M3s in healthy patients.
and “prophylaxis or therapy or prophylactic or therapeutics or therapeutic” and “third molar or third molars”. By limiting the search to articles written only in English, 124 references were found. After this preliminary survey of potentially relevant publications, three authors (WCR, ACC, and RA) independently assessed the abstracts and selected only those that fully fitted the inclusion criteria proposed for this literature review: • discuss use of local or systemic prophylactic antibiotics for the extraction of M3s • involve only healthy patients (American Society of Anesthesiologists’ Classes I and II) • fall within the following types of study: systematic literature reviews, meta-analyses, randomized clinical trials, retrospective and prospective epidemiologic studies, cross-sectional and prospective comparative studies.
METHOD AND MATERIALS The strategy for identification of the studies used in this literature review was searching the database PubMed/ MEDLINE in the period from 1 January 2003 to 30 April 2014, with the descriptors: “antibiotic or antibiotics”
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The following exclusion criteria were applied: • papers published in any language other than English • animal model experiments • in vitro studies
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• • • • •
case reports case series without control groups literature reviews interviews or personal commentaries by renowned authors studies involving unhealthy patients (ASA III and IV).
After the reading the selected papers, the reference lists were studied for additional relevant references.
RESULTS The search in PubMed/MEDLINE according to the period, descriptors, applied limits, and inclusion/exclusion criteria allowed the selection of 36 references. The full texts were obtained, carefully evaluated, and their references lists checked. This allowed the inclusion of two further relevant articles: the American Heart Association (AHA) guide,10 for information on endocarditis prophylaxis, and a meta-analysis24 that provided guidelines for assessing the methodologic quality of the studies, with regard to internal validity, external validity, and statistical analysis. In total, 38 publications were obtained: 8 systematic reviews, 20 randomized controlled clinical trials, and 10 nonrandomized comparative controlled studies. Among the 30 clinical studies, only three multicenter and 11 placebo-controlled studies were found. Other authors had used the split-mouth technique (4) or control groups with no medication. Patients and professionals were double-blind in 20 clinical studies, and in four studies only patients were blind. In quantitative terms, the clinical studies included between 19 and 890 patients. Considering the criteria proposed by Olivo et al,24 the majority of clinical studies (23) used appropriate statistical analysis. There were eight papers in which the sample was less than desirable for a level of more substantial evidence. Qualitatively there was also a widely variety with respect to age, single or multiple extractions of M3s, and non-randomized distribution in relation to the gender of the patients (Table 1). Most of the clinical studies evaluated the efficacy of antibiotics’ systemic action (25), and amoxicillin was
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used in 11 studies, followed by amoxicillin/clavulanic acid (7), clindamycin (5), azithromycin (3), metronidazole (3), penicillin (2), ampicillin (1), moxifloxacin (1), cefazolin (1), ceftazidime (1), and cefeditoren pivoxil (1). The oral route of administration was preferred by the authors (23), and the parenteral route was chosen in just four studies. In nine cases the oral administration occurred at 1 hour in advance, and in three studies the medication was started 2 hours before surgery; in other cases, the use of antibiotics was started immediately after the procedure. In eight studies the systemic antibiotic coverage was extended for 5 days postoperatively, and in 11 studies by only 3 or 4 days. An intraalveolar topical antibiotic was found in five clinical trials, and the following active principles were evaluated: tetracycline (2), minocycline (2), and chloramphenicol (1). In all clinical studies evaluated, both anti-inflammatory and analgesic were prescribed in the postoperative period, but the possible consequences of drug interaction among antibiotic and these medications were evaluated in only one study.12 The implications of local interventions such as methods of oral hygiene and the use of intraoral antiseptics with chlorhexidine were discussed in only two clinical studies.25,26 Only one of the systematic reviews highlighted these aspects.6 Table 1 lists some of these aspects and also the conclusions of several authors on the recommendation or not to use antibiotics to prevent or minimize the incidence of postoperative infection and/or inflammatory complications after third molar extraction.
DISCUSSION The greater the depth of the M3 to be extracted in relation to the occlusal plane, the greater the need for osteotomy and the more extensive the surgical procedure.8,27 Consequently, there is greater trauma to the surrounding tissues and an intensification of the inflammatory process, with pronounced discomfort to the patient.26 The intensity of pain, swelling, and trismus are related to mechanical and biochemical factors inherent to the procedure, and may affect the patient’s quality of
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Table 1
Studies arranged in chronological order, with brief information of their characteristics, sample size, follow-up period, and the main conclusions of the authors
Study
Study design
Sample/follow-up
Antibiotic and dosage
Conclusions
Foy et al
Clinical, prospective, multicenter, comparative
n = 116 patients; 464 M3 extracted; 43% male; follow-up 2 weeks
G1: ampicillin (1.0 g IV) or clindamycin (300 mg IV) for allergic to β-lactams just before surgery. CG: no antibiotic
Systemic (IV) antibiotic should be used just in in patients with higher risk for complications after third molar surgery because it can improve clinical recovery.
Poeschl et al1
Clinical, prospective, single center, randomized controlled
n = 288 patients; 528 M3 extracted; follow-up 4 weeks; 0.2% chlorhexidine mouthwash
G1: amoxicillin/clavulanic acid (1000 mg/250 mg OR, 2 × day for 5 days). G2: clindamycin (300 mg OR, 3 × day for 5 days). CG: no antibiotic
There was no reduction in the rates of complications and the authors do not recommend the routine use of preemptive antibiotics.
Sanchis et al25
Clinical comparative, single center
n = 200 patients; 200 M3 extracted; 32 % male; follow-up 1 week; oral hygiene control
G1: (n = 100) paste containing 4% (9 mg) tetracycline + 500 mg amoxicillin (8/8 h for 4 days). CG: (n = 100) no medicine in the alveolus + amoxicillin 500 mg (8/8 h for 4 days)
Topical administration of intra-alveolar tetracycline did not affect the incidence of alveolitis, but reduced pain and trismus although the differences were not statistically significant.
Arteagoitia et al19
Clinical, prospective, single center, randomized, double-blind, placebo-controlled
n = 490 patients; 200 M3 extracted; 40% male; follow-up 8 weeks; 0.12% chlorhexidine mouthwash
G1: amoxicillin/clavulanic acid (500 mg/125 mg OR, 3 × day for 4 days). CG: placebo in the same dosage
The authors question the systematic use of prophylactic antibiotics. Prescription only for specific cases. Take into consideration the age and the difficulty degree of surgery.
Graziani et al12
Clinical, prospective, comparative, single center, randomized
n = 30 patients; 30 M3 extracted; 50% male; follow-up 1 week
G1: piroxicam (20 mg sublingual, once daily, for 3 days) before surgery. G2: azithromycin (500 mg once daily, for 3 days); G3: azithromycin (500 mg once daily, for 3 days) + piroxicam (20 mg/day, sublingual, for 3 days)
Azithromycin administered 3 days before surgery reduces incidence of infections. Concomitant use with piroxicam reduces its anti-inflammatory capacity.
Ishihama et al9
Clinical, retrospective, singlecenter, not controlled
n = 45 patients; 45 M3 extracted; 28.89 % male; follow-up 2 weeks; mean age: 28.8 years
Azithromycin (500 mg OR, 1 × day, for 3 days) after surgery
Authors do not agree with routine use of prophylactic antibiotic. However, if there is indication, they suggest the strategy of rotational use of antimicrobials to prevent the development of drug resistant and cross-resistant bacteria.
Stavropoulos et al27
Clinical, prospective, multicenter, controlled
n = 123 patients; 492 M3 extracted; 38% male; follow-up 2 weeks; mean age: 20–21 years
Slow-release microspheres containing 1.0 mg of minocycline applied topically in the alveolus
The intra-alveolar topical administration of minocycline reduced the incidence of late clinical recovery. Indicated only for cases with high risk of complications.
van Eeden and Bütow36
Clinical, prospective, comparative, single center, blinded, controlled, splitmouth
n = 19 patients; 38 M3 extracted; follow-up 1 week
Medicated hand: insert covomycin-D socket (compound containing chloramphenicol, neomycin, and dexamethasone). Side control: no topical medication
Intra-alveolar topical administration of the compound covomycin-D reduced the incidence of postoperative complications in a statistically significant way.
Halpern and Dodson13
Clinical, prospective, single center, double-blind, randomized, placebo-controlled
n = 118 patients; 425 M3 extracted; 47% male; follow-up: 1 week; mean age: 25.4 years
GT: penicillin (15,000 units/kg IV) or clindamycin (300 mg IV). CG: 0.9% saline solution
Antibiotics reduce the incidence of surgical site infections.
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Study
Study design
Sample/follow-up
Antibiotic and dosage
Conclusions
Hedström and Sjögren6
Systematic review
32 randomized controlled trials, but only 8 associated with antibiotic regimens in the prevention of dry alveolitis
Kaczmarzyk et al21
Clinical, prospective, single center, double-blind, randomized, placebo-controlled
n = 86 patients; 86 M3 extracted; 27% male; follow-up 1 week; mean age: 23.5 years
G1: clindamycin (600 mg / single dose OR). G2: clindamycin (300 mg OR, 3 × day for 5 days). CG: placebo (300 mg OR, 3 × day for 5 days)
The systemic use of clindamycin was not effective in preventing postoperative complications.
Lacasa et al3
Clinical, prospective, comparative, phase III, single center, doubleblind, randomized, placebocontrolled
n = 225 patients; 100 M3 extracted; 43% male; follow-up 15 days; mean age: 29 years
G1: amoxicillin/clavulanic acid (2000 mg/125 mg OR, single dose). G2: amoxicillin/clavulanic acid (2000 mg/125 mg OR, 1 hour before surgery and 1 × daily, for 5 more days). CG: placebo tablets with the same aspect
Preemptive therapy reduces the rate of infections subsequent to cases of osteotomy. The authors recommend prophylactic antibiotics even in the simplest cases.
Ren and Malmstrom2
Systematic review and meta-analysis
Total n = 2,932 patients in 20 randomized trials
Ataoğlu et al20
Clinical, prospective, single center, double-blind, randomized, placebo-controlled
n = 150 patients; 150 M3 extracted; 17% male; follow-up 1 week; mean age: 23 years; 0.12% chlorhexidine mouthwash
Wilson et al10
Systematic review (AHA Guideline)
Systematic review of all articles indexed by MEDLINE until 2007
Al-Asfour30
Clinical retrospective single-center
n = 90 patients; 110 M3 extracted; 34.45 % male; follow-up 1 week; mean age: 25.2 years
No systemic antibiotics were administered or prescribed before or after the surgeries
Authors do not recommend routinely antibiotic prescription for dento-alveolar surgery, due to the low incidence of postoperative infection evidenced by the study.
Limeres et al14
Clinical, prospective, single center, double-blind, randomized, controlled
n = 100 patients; 100 M3 extracted; follow-up 1 week; age: 18-45 years; 0.12% chlorhexidine mouthwash
G1: moxifloxacin (400 mg OR × 1 capsule daily for 5 days). G2: amoxicillin/clavulanic acid (500 mg/125 mg OR, 3 × day for 5 days)
The use of moxifloxacin shortens the recovery period after surgery and should be used mainly in allergic to β-lactams.
Monaco et al15
Clinical, prospective, comparative, single center, randomized, controlled
n = 59 patients; 59 M3 extracted; 45.7% male; follow-up 1 week; mean age: 15 years; chlorhexidine 0.12%
G1: amoxicillin (2000 mg OR 1 hour before the surgery). CG: no antibiotic
For the age group 12–19 years old, antibiotic prophylaxis is recommended to reduce the psychologic impact of this type of surgery.
Luaces-Rey et al34
Clinical, prospective, comparative, single center, double-blind, randomized, placebo-controlled
n = 160 patients; 160 M3 extracted; 33.1% male; follow-up 1 week; mean age: 27 years; 0.12% chlorhexidine mouthwash
G1: amoxicillin (2000 mg OR), 1 hour before surgery plus 1000 mg 6 hours after surgery. Every 8 hours placebo for 4 days. G2: amoxicillin (1000 mg OR) 6 hours after surgery and another 1000 mg OR, every 8 hours for 4 days.
Authors recommend the use of prophylactic antibiotic. Continued use of amoxicillin postoperatively is not justified. It is not yet clear to which group of patients antibiotic prophylaxis would be more beneficial.
Local treatment with tetracycline, and also with chlorhexidine 0.12%, pre- and postoperatively, seem to have a significant preventive effect on alveolar osteitis.
Systemic antibiotics given before surgery are effective in preventing postoperative complications, especially in patients at higher risk for potential complications. G1 (postoperative): amoxicillin/clavulanic acid (1000 mg/250 mg OR, 2 × daily for 5 days). G2 (preoperative): same dose but starting 5 days before surgery. G3: placebo
Authors do not recommend antibiotic prophylaxis or preemptive for healthy patients.
Antibiotic prophylaxis is indicated only in cases of very restricted high risk of infective endocarditis.
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Study design
Sample/follow-up
Antibiotic and dosage
Conclusions
Siddiqi et al11
Clinical, prospective, comparative, single center, double-blind, randomized, placebo-controlled, split-mouth technique
n = 100 patients; 380 M3 extracted; 33% male; follow-up 3 weeks; mean age: 26 years; 0.12% chlorhexidine mouthwash
G1: amoxicillin (1000 mg OR), single dose, 1 hour before stage-one surgery; in stagetwo surgery the patient received only one placebo containing glucose, or vice versa. G2: amoxicillin (1000 mg OR), a single dose, 1 hour before stage-one surgery and 500 mg OR, 8/8 hour for 2 days; in the stage-two surgery, the patient received only one placebo containing glucose or vice versa
Prophylactic antibiotics do not reduce the risk of infection in a statistically significant way. The authors do not recommend antibiotic prophylaxis for healthy patients.
Bezerra et al26
Clinical, prospective, single center, double-blind, randomized, placebo-controlled, split-mouth
n = 34 patients; 136 M3 extracted; 22.4% male; follow-up 2 weeks; mean age: 24 years; 0.12% chlorhexidine mouthwash
Amoxicillin (1000 mg OR), a single dose, 1 hour before surgery in the first procedure and placebo in the second procedure or vice versa
Authors do not recommend antibiotic prophylaxis for healthy patients.
Gelesko et al16
Clinical, multicenter, exploratory, comparative, controlled
n = 206 patients; 824 M3 extracted; 43% male; follow-up 2 weeks; mean age: 21 years
G1: cryotherapy + analgesic. G2: slow release microspheres containing 1.0 mg of minocycline applied topically in the alveolus + analgesic. CG: only analgesic
Authors suggest that the local deposition of antibiotic and the cryotherapy reduce the level of pain after surgery
LópezCedrún et al28
Clinical, prospective, single center, double-blind, randomized, placebo-controlled
n = 123 patients; 123 M3 extracted; 26.8% male; follow-up 1 week; mean age: 23 years
G1: amoxicillin (2000 mg OR), single dose, 2 hours prior to surgery and 500 mg of placebo, OR, every 8 h, for 5 days. G2: placebo (2000 mg OR), single dose, 2 hours prior to surgery and 500 mg of placebo, OR, every 8 h, for 5 days. G3: placebo (2000 mg OR), single dose, 2 hours prior to surgery and 500 mg amoxicillin, OR, every 8h, for 5 days
Amoxicillin appears to be effective in preventing postoperative complications. The best results were obtained with the postsurgical administration protocol.
Olusanya et al17
Clinical, comparative, prospective, single center, double-blind, randomized
n = 79 patients; 79 M3 extracted; 36.8% male; follow-up 1 week; mean age: 25 years
G1: amoxicillin (2000 mg OR) plus metronidazole (1000 mg OR) single dose 1 hour before surgery. G2: amoxicillin (500 mg OR) plus metronidazole (400 mg OR), 3 × day for 5 days
Antibiotic in a single dose is sufficient to prevent postoperative complications. Can reduce treatment costs in developing countries. If the risk of infection is high, 5-day dose.
Pasupathy and Alexander31
Clinical, prospective, single center, double-blind, randomized, placebo-controlled
n = 89 patients; 89 M3 extracted; 53.9% male; follow-up 1 week; mean age: 28.7 years
G1: placebo (1000 mg OR), a single dose, 1 hour before surgery. G2: amoxicillin (1000 mg OR), single dose, 1 hour before surgery. G3: metronidazole (800 mg OR) single dose, 1 hour before surgery
There is no advantage in routine antibiotic prophylaxis for healthy individuals.
Susarla et al5
Systematic review
12 clinical studies, placebo-controlled, doubleblind, randomized; n = 2,396 patients
Adde et al29
Clinical, prospective, single center, double-blind, randomized, controlled
n = 71 patients; 71 M3 extracted; 69.01% male; follow-up 1 week; mean age: 27.1 years; 0.12% chlorhexidine mouthwash
G1 (postoperative): amoxicillin (500 mg OR, 3 × daily for 7 days). G2 (postoperative): clindamycin (300 mg OR, 4 × daily for 7 days). G3: no antibiotic
Antibiotic prophylaxis should not be indicated in all cases of third molar surgery, but only for those cases where there is systemic impairment, contamination, or difficulties extending the time of surgery.
Calvo et al33
Clinical, prospective, single center, randomized, controlled
n = 110 patients; 150 M3 extracted; 39.09% male; follow-up 1 week; mean age: 22.7 years
No systemic or local antibiotics were prescribed or administered before or after the surgeries
This study suggests that antibiotic prescriptions are unnecessary before or after M3 removal in healthy patients.
Antibiotic prophylaxis is recommended for multiple M3 extractions on an outpatient basis.
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Study design
Sample/follow-up
Daly et al
Systematic review
18 randomized controlled trials, but only with local interventions for the prevention of dry socket; n = 2,376 patients
The only local intervention that prevents alveolitis in a statistically significant way is the irrigation with chlorhexidine (0.12% and 0.2%) or deposition of chlorhexidine gel (0.2%) in dental alveoli.
Lodi et al7
Systematic review
18 clinical studies, placebo-controlled, doubleblind, randomized; n = 2,456 patients
Prophylactic antibiotics may reduce the risk of infection, dry socket, and pain, but result in an increase in mild and transient adverse effects. The use in healthy patients is questionable.
Oomens and Forouzanfar23
Systematic review
23 clinical studies, placebo-controlled, doubleblind, randomized; 15 “low-quality” and 8 “high-quality”
There is no evidence that justifies the routine antibiotic prophylaxis in cases of third molar surgery.
Sisalli et al18
Clinical, comparative, prospective, single center, not controlled
n = 107 patients; 107 M3 extracted; 38% male; follow-up 1 week; mean age: 23 years
G1: amoxicillin (2000 mg OR), single dose, 2 hours prior to surgery and 500 mg amoxicillin OR, every 8 h, for 5 days. G2: ceftazidime (1000 mg IM) 2 hours before surgery and another 1000 mg IM, every 24 hours, for 4 more days
There was no statistical difference between the two groups to justify the indication of a second choice intramuscular antibiotic.
Bortoluzzi et al22
Clinical, prospective, single center, double-blind, randomized, placebo-controlled
n = 50 patients; 50 M3 extracted; 26% male; follow-up 1 week; mean age: 22.5 years
G1: amoxicillin (2 g OR) + dexamethasone (8 mg OR), single dose before surgery. G2: amoxicillin (2 g OR) + placebo (8 mg OR), single dose. G3: placebo (2g OR) + dexamethasone (8 mg OR), single dose. G4: placebo (2 g OR) + placebo (8 mg OR), single dose
The authors recommend that antibiotic and corticoid prophylaxis should not be administered routinely in single dose when third molars are removed in healthy and young patients since it did not produce any clear benefit.
Sane et al32
Open, clinical trial, prospective, single center, not controlled
n = 50 patients; 50 M3 extracted; 46% male; follow-up 10 days; mean age: 32 years
All patients received a single dose of azithromycin 500 mg OR, 1 hour prior to the procedure
Single dose of azithromycin administered 1 hour before surgery seems to reduce the incidence of surgical site infections.
Busa et al37
Clinical, prospective, single center, double-blind, randomized, controlled
n = 40 patients; 80 M3 extracted; 40% male; follow-up 14 days; mean age: 31.5 years
G1: amoxicillin/clavulanic acid (2,000 mg OR before surgery + 1,000 mg 2 × day for 5 days). G2: chloramphenicol (local deposition). G3: amoxicillin/clavulanic acid (2,000 mg OR before surgery + 1,000 mg 2 × day for 5 days) and chloramphenicol (local deposition). CG: no antibiotic
The study failed in finding significant differences regarding bacterial growth rate. Local administration of antibiotics is a viable option for M3 extraction surgery.
Crincoli et al35
Clinical, prospective, single center, comparative, double-blind, randomized, not controlled, splitmouth
n = 24 patients; 48 M3 extracted; follow-up 1 week; mean age: 27.5 years; 0.12% chlorhexidine mouthwash
Amoxicillin + clavulanic acid (1 g OR every 12 h for 5 days) after the first surgery and sodium cefazolin (1 g IM, 2 × a day for 5 days) after the second surgery or vice versa
Both therapies proved effective in preventing IC. However, the higher cost and the minor compliance of the patient do not justify routine antibiotic IM therapy.
Lee et al4
Clinical, retrospective, single center, comparative, controlled, not randomized
n = 890 patients; 1,222 M3 extracted; follow-up 1 week; mean age: 28 years
G1: cefditoren pivoxil (100 mg OR, 3 × day, for 1 week). G2: no antibiotic
Results provide further evidence that antibiotic prophylaxis to prevent postoperative inflammatory complications is unnecessary in extraction of mandibular M3.
38
Antibiotic and dosage
Conclusions
CG, control group; G1, group 1; G2, group 2; IM, intramuscular; IV, intravenous; M3, third molar; OR, oral route.
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Fig 3 Image of a dry socket in the region of the maxillary left second premolar in a healthy patient.
life postoperatively.3 A careful surgical technique can limit the damage, but not eliminate it.11 In order to ensure a better quality of life for patients and faster return to normal activities, additional measures such as the use of preemptive anti-inflammatories, cryotherapy, and even antibiotic prophylaxis, are applied.16 The mechanical disruption of the biofilm adhered to the extracted tooth or surrounding alveolar mucosa releases bacteria and toxins in the surgical site. The presence of these microorganisms eventually contributes to clot dissolution and the manifestation of an inflammatory process called localized alveolar osteitis or dry socket (Fig 3).2,26 Depending on immunologic factors, conditions of the oral environment, quality of the microbiota, and the tissue exposure time, localized infection can develop and slow down the process of surgical wound repair. The inflammatory clinical status can degrade, with the manifestation of dysphagia and fever.26 For some authors the best way to prevent such postoperative complications is the strict control of surgical asepsis and proper conditioning of patients.1,26 However, approximately 50% of clinicians routinely prescribe the use of prophylactic antibiotics for this purpose.14,26,28,29 The main focus of the present study was the lack of consensus regarding the prescription of antibiotics to healthy patients submitted to M3 extractions. Thirty
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clinical studies and 8 systematic reviews published in the last 10 years were raised to check whether there is scientific support for such conduct. The methodologic heterogeneity of the studies evaluated meant it was exceedingly difficult to compare their results and extract consistent scientific evidence. There was no standardization of drugs or associations used in antibiotic prophylaxis, route of administration, or dosage. Great variation in the amplitude of the samples was observed (19 to 890 patients). It is known that very small samples represent a higher risk of type II error, or false negative, which consists of not rejecting the null hypothesis when it is actually false.24 For example, if a reduction of 15% to 5% in postoperative complications is considered effective and clinically significant, a clinical trial with a sample of 318 patients (159 in each group) would be needed to detect the magnitude of such difference, with 80% energy an alpha level of 0.05.2,24 With few exceptions, published clinical trials involved a sample so reduced that a conclusive analysis of results was not possible. According to data shown in Table 1, the conclusions of 15 authors signaled that prophylactic or preemptive antibiotics administration reduced, in a statistically significant way, the incidence of IC related to third molar extraction. However, five of these authors only assessed the topical use of the drug with the deposition inside the alveolus. There were 17 studies whose authors concluded unfavorably regarding the prescription of prophylactic antibiotics and, in another four studies, the recommendation was their use only in cases where the risk of infection is increased. Although all studies involved the concomitant prescription of anti-inflammatory and/or analgesics and antibiotics, only one study considered the interference of the antibiotic on the absorption and efficacy of these drugs. The effects of local preventive methods, such as using chlorhexidine-based solution or cryotherapy, on the final results were discussed only in three studies, although these were used in almost all patients. To enhance the internal validity of a study it is necessary to use appropriate control groups, blinding of patients and professionals involved, and randomization
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of individuals in the samples.24 In almost all of the trials there were errors in at least one of these aspects, which may lead to exacerbation of the treatment effects. External validity indicates how much the results can be extrapolated to a population outside the experimental situation, and this was a significant problem. For example, studies have been completed on subjects who have M3 extracted either one at a time or as unilateral extractions, which is significantly dissimilar to those of contemporary oral surgical practice; usually, multiple M3s are extracted in a single-visit.5 Samples of multicenter studies tend to be more representative of reality and, therefore, the data become more valid. There were only three multicenter studies in which results were favorable regarding antibiotic prophylaxis, but just one of them evaluated systemic administration; the other two assessed local application. Rates of IC presented in the articles selected for this study ranged between 3.5% and 12% in the control group and 0% and 9% in the groups treated with antibiotics. There are innumerable determining factors for such discrepancies. For example, authors do not use standard criteria for diagnosis of complications (infection/inflammation) after M3 extraction. A well-established guideline was discussed by Arteagoitia et al,19 but only six authors applied this in the evaluation of their results. Another aspect to consider is the followup period after surgery, which should be extended to prevent loss of complications that manifest at a late stage.13 One group of authors showed that approximately 60% of IC expressed in the antibiotic group appeared after 1 week of evaluation,19 suggesting that patient monitoring should include longer periods. In the present review, there were just 12 studies in which the follow-up period was greater than 7 days. Therefore, in studies that included only 1 week of follow-up, the IC incidence results in groups treated with antibiotics may have been underestimated.19 The literature also shows that the incidence of postoperative infection in oral surgery varies between 1% and 5.8%, and most are mild infections.1,5,11,30-32 Specifically, for the surgical removal of impacted M3, the rate of infection is expected, on average, to be less than
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1%.3,29 Progression to severe cellulitis of the fascial spaces does not manifest in more than 1% of patients.2 One research group found that from 380 impactions, only six alveoli (2%) became infected,11 the same incidence (2%) observed by Sane et al.32 In another study, no sign of infection was detected after extraction of 150 M3s in 110 distinctive patients evaluated over a week.33 Another group found an incidence of dry socket and drainage of purulent material close to 7.35%,26 but according to the authors, these cases were related to impaired oral hygiene or poor blood supply to the surgical site. Considering all these aspects, the prescription of prophylactic antibiotics for M3 extractions in healthy patients becomes questionable. Approximately 30% of antibiotic prescriptions by physicians or dentists have preventive purpose;11 An alarming number, considering that risks of indiscriminate prescription of antimicrobials include the manifestation of allergic reactions, secondary infection, toxicity, and the development of resistant microorganisms.5,7,20,30 It is estimated that 6% to 7% of patients receiving antibiotics have some type of adverse reaction.20 In a careful study that included 52 patients who received amoxicillin in combination with clavulanic acid after M3 surgery, nine individuals had nausea, and 21 had diarrhea.14 The problem of multiresistant bacterial strains is not restricted to the hospital environment, but society as a whole,21,30 and dentists should carefully evaluate whether treating healthy patients with antibiotics to prevent an infection presents a good cost-effective treatment.7 One important reason for excessive prescription of antibiotics, both quantitatively and qualitatively, is that every surgeon fears that an eventual inflammatory or infectious complication may denote professional negligence and raise doubts about competence.1 Acknowledging the significant potential risks of antibiotic overuse, the guidelines for endocarditis prophylaxis have been recently revised by the AHA.10 The main aspects considered to be predisposing to postoperative complications are: history of previous infections, teeth located on a lower level to the occlusal plane, and need for osteotomy.8 The incidence of delayed healing in patients with symptoms prior to
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Fig 4 Panoramic radiograph showing the mandibular third molars in unfavorable positions for extraction surgery implying greater need for osteotomy and odontosection.
extraction is significantly (P < .01) higher.27 In patients who frequently have pericoronitis, the alveolar bone usually exhibits sclerotic change around the third molar. Patient age could be linked with disadvantages for bone remodeling and regeneration, and proximity of the third molar to the inferior alveolar nerve canal could be related to the degree of bony exposed area.9 Patients at increased risk of infection should benefit most from the use of prophylactic antibiotics, since in such cases complications may be more difficult to treat.7 The possibility of postoperative complications in patients without antibiotic is 10% at 20 years of age, and above 30% at 40 years. Therefore, the risk of IC presents an increase of 1.08 per year of age.19 These authors claim that in cases of M3 extractions vertical or submucosal antibiotic seems unnecessary.19 The medication would be more effective to M3s partially covered by bone and those with a more horizontal position.3 The depth and angle of the molar determine the need for odontosection or ostectomy, and most traumatic procedures that extend the operating time (Fig 4).3,4 Another factor that may increase the time of intervention and therefore the chance of infection is reduced experience of the professional operative.12,33 If the criterion to administer antibiotics only to patients at high risk of complications were clinically applied as a guideline, less than 50% of young adult
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patients with M3s removed would be eligible to receive antibiotics prior to the surgical procedure.27 In cases where the prediction of occurrence of postoperative infectious complications is not possible, the decision to use antibiotics must be taken after surgery.13 However, if systemic prophylactic antibiotics are considered, it is important to remember that they provide adequate protection only when effective blood levels are present at the moment of bacterial dissemination.11,31 Amoxicillin and other penicillin derivatives are effective against both aerobic and anaerobic bacteria in the oral cavity and exhibit good bioavailability with minimal side effects. Therefore, they should be the first choice if antibiotic prophylaxis is used.2 Indeed, among the 30 clinical studies included in this literature review, 21 involved penicillin or some derivative. Nowadays, amoxicillin/clavulanic acid is the most widely used option in dentoalveolar surgery, and there is some evidence of advantage from the use of this combination for prophylactic purposes.3,14 Its coverage extended spectrum allows activity against penicillinresistant viridans streptococci and, at the same time, against anaerobic bacteria, including beta-lactamaseproducing strains.3 One study supports that there are no indications for use of a second choice antibiotic to prevent IC.18 Other classes such as lincosamides (clindamycin) or azalides (azithromycin) should be
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given only in cases of allergies to first choice antibiotics.8,13,21 Nevertheless, both azithromycin and clindamycin have an antimicrobial spectrum covering oral endogenous flora, high tissue penetration, and long persistence of concentration, and could be good alternatives for rotational use of antibiotics.9,32 In fact, the AHA has recommended azithromycin for infective endocarditis prophylaxis in its most recent guidelines.10 Cycling of homogenous antimicrobial exposure should be avoided in order to prevent multidrug resistance and development of cross-resistant bacteria.9 Regarding anaerobic agents, only two studies,17,31 with relatively small sample sizes, reported the effects of metronidazole in wound infections, which may limit the validity of any conclusion about the effectiveness or ineffectiveness of this type of antibiotic for the prevention of such complications. Considering the studies evaluated herein, multiple dosing strategies were used for antibiotic prophylaxis: single-dose preoperative administration, multidose preoperative, perioperative or pre-emptive dosing (preoperative and postoperative continuous dosing), and multiday postoperative dosing only. Some authors have claimed a significant reduction in the incidence of IC with a single loading dose of the drug, equivalent to twice the usual recommended therapeutic dose.3,15,17 Evidence suggests that a single dose of systemic antibiotic, equal to the usual therapeutic dose, administered 1 hour before surgery, would be sufficient.8,12,13 Available data from a well-designed systematic review suggest that systemic antibiotics should be administered only preoperatively.5 By testing two different amoxicillin administration protocols, one research group concluded that the continued use of antibiotics in the postoperative period is not justified.34 These data are corroborated by a recent meta-analysis in which a preoperative single dose was nearly as effective as the multiday dosing strategy.2 Particularly in cases where more complex and aggressive procedures are performed (eg, osteotomy) and the surgery is lengthy, the concept of continuing antibiotic therapy for a few days (pre-emptive therapy) after an initial dose becomes relevant, because these are known risk factors for infection.3
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Regarding antibiotic administration, literature findings highlight almost the same effectiveness of intravenous, intramuscular, and oral systemic route in preventing postoperative complications in dental surgery. Some authors recommend using treatment that is less costly and less invasive.13 Poor patient compliance and the higher cost does not justify routine antibiotic intramuscular or intravenous therapy, reserving it for patients with gastrointestinal disorders.35 Alternative local delivery of antibiotics by either topical administration or by a delivery device may enable the maintenance of a high local antibiotic concentration for an extended duration of release. This may be advantageous with regard to changes in the commensal flora and the manifestation of systemic adverse effects.6,16,27 A recent meta-analysis studied the evidence for the effectiveness of this administration route.2 The antibiotic would be incorporated into the clot formed within the alveoli, which should facilitate its action on bacteria.27,36 In fact, local treatment with tetracycline seems to have a significant and clinically relevant preventive effect on localized alveolar osteitis.6 It has been demonstrated that topical use of both minocycline and chloramphenicol reduces, with statistical significance, the incidence of late clinical recovery in those patients in whom complications were predicted,27,37 and reduces the level of pain postoperatively.16,37 Special care should be taken in circumstances where there is exposure of the inferior alveolar nerve because topical antibiotics of the tetracycline group and its derivatives can cause neurosensorial injury. In these cases, if indicated, systemic antibiotics should be chosen.28 However, according to a systematic review, the only local method that provides statistically significant benefit in the prevention of alveolitis is irrigation with chlorhexidine (0.12% and 0.2%) or deposition of chlorhexidine gel (0.2%) in the alveoli following extraction.38 It appears that intraoperative alveolar irrigation and the use of chlorhexidine 0.12% for 5 days have a significant and clinically relevant effect in the prevention of alveolar osteitis.6
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CONCLUSIONS There is no consistent scientific evidence that may support the use of prophylactic antibiotic (local or systemic) for all surgical extraction of M3 in healthy patients. Only in very specific situations should such conduct be considered: • patients with previous symptomatology • unfavorable position of the third molar implying greater need for ostectomy and/or odontosection with consequent extension of surgical time • standard oral hygiene deficiency • elderly people. The best way to prevent inflammatory and infectious complications remains the strict control of the aseptic chain and a refined surgical technique. However, if there is indication for systemic antibiotic prophylaxis, the administration of a single dose 1 to 2 hours before surgery, equal to the minimum necessary to reach an effective plasmatic concentration, seems more rational. Amoxicilin/clavulanic acid continues to be the first option, but in cases requiring multiple interventions, antibiotic alternation in different sessions would be of interest to avoid the development of bacterial resistance. Clindamycin and azithromycin are good options for this purpose. Due to the lower cost and greater patient acceptance, the oral route is preferable for antibiotic administration. The development of high-quality randomized clinical trials, with larger and better selected samples, considering known risk factors and taking into account clinical outcomes, is recommended to reach a final consensus on the efficacy of antibiotic prophylaxis. Research into alternative antibacterial therapies would also be relevant.
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