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Efficacy of antibiotic prophylaxis on postoperative inflammatory complications in Chinese patients having impacted mandibular third molars removed: a split-mouth, double-blind, self-controlled, clinical trial
YBJOM-4445; No. of Pages 5
ARTICLE IN PRESS Available online at www.sciencedirect.com
British Journal of Oral and Maxillofacial Surgery xxx (2015) xxx–xxx
Efficacy of antibiotic prophylaxis on postoperative inflammatory complications in Chinese patients having impacted mandibular third molars removed: a split-mouth, double-blind, self-controlled, clinical trial P. Xue, J. Wang, B. Wu, Y. Ma, F. Wu, R. Hou ∗ State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, Fourth Military Medical University, Xi’an 710032, China Accepted 1 February 2015
Abstract We investigated the effect of antibiotic prophylaxis on postoperative inflammatory complications after operations for impacted mandibular third molars in Chinese patients. A total of 207 patients had their bilateral third molars removed in a split-mouth, double-blind, self-controlled, clinical trial in two visits. For one side amoxicillin (or clindamycin) was given (antibiotic group) from one hour before operation until 3 days postoperatively. For the other side a placebo was given (placebo group) at the same time. The outcome, including alveolar osteitis, surgical wound infection, prebuccal infection, and infection of the anterior isthmus of fauces, was assessed 2 and 10 days postoperatively. A total of 192 patients completed the study, and there was no difference between the groups in the incidence of inflammatory complications. In the treatment group, there were 4 cases of alveolar osteitis (2%), 2 infections of the wound (1%), and 14 other reactions (gastrointestinal (n = 4), bleeding (n = 2), ulcer (n = 2), and fever (n = 6)). In the placebo group, there were 6 cases of alveolar osteitis (3%), 2 wound infections (1%), and 22 other reactions (bleeding (n = 6), ulcer (n = 2) and fever (n = 14)). There was no significant difference in the extraction time and postoperative reactions, except the pain score on day 10 (p = 0.005). Prophylactic amoxicillin (or clindamycin) is not effective for the prevention or reduction of postoperative inflammatory complications after the removal of impacted mandibular third molars in Chinese patients. © 2015 Published by Elsevier Ltd. on behalf of The British Association of Oral and Maxillofacial Surgeons.
Keywords: Impacted mandibular third molar surgery; Inflammatory complications; Antibiotic treatment ;
Introduction The removal of impacted mandibular third molars is a common procedure in oral and maxillofacial surgery, and is often followed by pain, swelling, trismus, alveolar osteitis, and infections of the wound, prebuccal site, and anterior isthmus of the fauces.1 The most common is alveolar osteitis, which ∗
Corresponding author. Tel.: +86 29 84776102; fax: +86 29 83223047. E-mail address: [email protected] (R. Hou).
affects 25%–30% of patients.2 Infection of the wound is also common, ranging from 2% to 12%.3,4 The other two severe infections, those of the prebuccal site and the anterior isthmus of the fauces, are seldomly reported.5 Infections of the prebuccal site take longer to develop postoperatively, and infection of the anterior isthmus of the fauces is characterised by obvious difficulty in opening the mouth (less than one finger’s width), swelling, tenderness on the anteromedial area of mandibular angle, pharyngeal pain, and difficulty in swallowing.
http://dx.doi.org/10.1016/j.bjoms.2015.02.001 0266-4356/© 2015 Published by Elsevier Ltd. on behalf of The British Association of Oral and Maxillofacial Surgeons.
Please cite this article in press as: Xue P, et al. Efficacy of antibiotic prophylaxis on postoperative inflammatory complications in Chinese patients having impacted mandibular third molars removed: a split-mouth, double-blind, self-controlled, clinical trial. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.02.001
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ARTICLE IN PRESS P. Xue et al. / British Journal of Oral and Maxillofacial Surgery xxx (2015) xxx–xxx
The efficacy of antibiotic prophylaxis in preventing complications after removal of lower third molars has long been controversial. Some authors say that it is effective, others say that it is not, despite the fact that antibiotic prophylaxis against postoperative wound infections accounts for 30% of prescriptions for antibiotics in general hospitals,6 and that the excessive and inappropriate use of antibiotics may lead to bacterial resistance and increase the economic burden of healthcare. We have evaluated the efficacy of antibiotic prophylaxis in a split-mouth, double-blind, self-controlled clinical trial over two visits after the removal of impacted mandibular third molars in a Chinese stomatology hospital.
Material and methods The study was designed as a split-mouth, randomised, double-blind, self-controlled, crossover trail and the Hospital Ethics Committee approved the design (No. IRB-REV2013005). Patients were all American Society of Anesthesiologists (ASA) class I or II and between the ages of 18 and 60. Clinical and radiological assessments were made to ensure that the degree of impaction and surgical difficulty were comparable on both sides. Gingival incision, creation of a flap, excision of bone with a cutting burr, sectioning of teeth, and suturing were all essential to the success of the extraction. The patient had had no antibiotics or local anaesthetic during in the week before extraction. A full verbal and written explanation of the study was given to each patient and a consent form was signed. Patients were excluded if they had any contraindications to removal of the teeth, as were patients who were pregnant or lactating, those who had any serious coexisting medical conditions, and those who smoked. By the use of computer-generated random numbers, the patients were assigned to receive antibiotics (even number) or placebo (odd number) at their first appointment. The other treatment was used when they had the second third molar removed 10–14 days later. All operations were done by the same oral surgeon. Impacted teeth were defined as being in position A, B, or C according to the Pell and Gregory classification.7 They were also classified as vertical, mesioangular, distoangular, horizontal, inverted, buccal and lingual impaction according to the Winter classification.8 Patients in the treatment group took amoxicillin 0.5 g (Zhuhai United Laboratories Co., Ltd.) one hour preoperatively, or clindamycin hydrochloride 0.3 g (Hunan Yada Pharmaceutical Co., Ltd.) if they were allergic to amoxicillin. Postoperatively they took the same dose three times a day for three days. Patients in the placebo group took a placebo with the same shape and dose on the same times before and after operation.
Table 1 Pell Gregory classification (n = 192). Group
Position A
Position B
Position C
Treatment Placebo
12 14
88 96
92 82
kappa = 0.852.
Surgical technique After the local anaesthesia with 2% lignocaine (Shanxi Jincheng Pharmaceutical Co., Ltd.), a buccal mucoperiosteal flap was raised. The bone was then removed with burs to expose the impacted tooth, which was sectioned. After the tooth had been removed the flap was closed with absorbable sutures. The teeth on the opposite side of the mouth were extracted 10–14 days later. A cold compress was applied immediately postoperatively, and patients took loxoprofen sodium (Shandong Disha Pharmaceutical Group Co., Ltd.) before or after operation as necessary. We recorded the extraction time for each single impacted mandibular third molar, together with any signs of postoperative inflammation, including specific infections, on postoperative days 2 and 10. Adverse reactions and other postoperative complications were also recorded on postoperative days 2 and 10. Severity of pain after extraction and swallowing were measured on Visual Analogue Scales (VAS). Facial swelling was measured as the difference between the distance (mm) between the lower earlobe and the mesomentum on the extraction side. Mouth opening was measured as the distance between upper and lower incisors (mm). Statistical analysis We used SPSS for Windows (version 17.0, SPSS Inc., Chicago, IL, USA) for statistical analysis. The kappa consistency test was made on different impaction sites, impaction position, and extraction time for both groups. The chi square test was used to compare the proportions of inflammatory complications between the groups. The Wilcoxon signed rank test was used to compare the extraction time, the pain score, amount of swelling, and mouth opening between the groups.
Results Two hundred and seven patients complied with the study protocol from January to December 2013, and 15 were excluded. All analyses refer to the remaining 192 patients (74 men (39%) and 118 women (61%), mean age 33 years, range 18–60) who had extractions of bilaterally symmetrical impacted teeth during two visits. Tables 1 and 2 showed the classifications of impacted position and direction in the two groups. The kappa values of the Pell Gregory and Winter classifications are 0.852 and 0.734,
Please cite this article in press as: Xue P, et al. Efficacy of antibiotic prophylaxis on postoperative inflammatory complications in Chinese patients having impacted mandibular third molars removed: a split-mouth, double-blind, self-controlled, clinical trial. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.02.001
ARTICLE IN PRESS
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P. Xue et al. / British Journal of Oral and Maxillofacial Surgery xxx (2015) xxx–xxx
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Fig. 1. Postoperative reactions and other complications in 192 cases. There were no significant differences between the groups. Blue = treated group and red = placebo group. Table 2 Winter classification (n = 192).
Discussion
Type of impaction
Treatment group
Placebo
Vertical Mesioangular Horizontal Distoangular Buccoangular Lingoangular Inverted
60 68 50 10 2 2 0
58 74 46 10 2 2 0
kappa = 0.734.
respectively, which indicated that the two groups had a good degree of consistency. There was no significant difference between the two groups in the extraction time (Z = −1.826 (negative rank), p = 0.068). There were only 4 cases (2%) of alveolar osteitis and 2 cases (1%) of wound infection among the treated group, and 6 cases of alveolar osteitis (3%) and 2 cases (1%) of wound infection in the placebo group. The total numbers of patients with alveolar osteitis and wound infection were 10 (3%) and 4 (1%), respectively. Fig. 1 and Table 3 show the postoperative reactions and other complications in the two groups. There was no significant difference between the two groups except for the pain score on postoperative day 10 (p = 0.005).
Extraction of an impacted mandibular third molar of the mandible is a clean-contaminated operation. As the oral cavity is colonised by more than 400 species of aerobic and anaerobic bacteria, antibiotics have often been used to prevent and reduce postoperative infection. However, whether antibiotics must be used has been disputed for a long time, and reports on the use of antibiotics during the extraction of impacted mandibular third molars have differed from each other on three questions. First, can the use of antibiotics prevent or decrease the incidence of postoperative inflammatory complications? In the 1960s, Kay9 showed that alveolar osteitis occurred in 325 of 1341 patients who had had third molars extracted without antibiotic prophylaxis. In contrast, only 50 of 1620 patients given a single preoperative dose of penicillin had developed it, which strongly supports the use of antibiotics for extraction of third molars. Another review concluded that systemic antibiotics were effective in reducing the incidence of alveolar osteitis and wound infection after extraction of third molars in a total of 2932 patients randomised in 16 clinical trials.10 However, some clinical trials raised doubts of effectiveness of antibiotics. Siddiqi et al.11 showed that prophylactic antibiotics made no significant difference to the incidence of postoperative infections after extraction of third molars. In a
Table 3 Postoperative reactions and other complications (n = 192). Variable
2 days Z
Pain after extraction Swallowing pain Swelling (mm) Trisums (mm) a b
−1.893a −0.738a −1.600a −0.260a
10 days p value
Z
p value
0.058 0.461 0.110 0.795
−2.793a
0.005 0.102 1.000 0.317
−1.633a 0.000b −1.000a
Positive rank. Sum of positive rank = sum of negative rank.
Please cite this article in press as: Xue P, et al. Efficacy of antibiotic prophylaxis on postoperative inflammatory complications in Chinese patients having impacted mandibular third molars removed: a split-mouth, double-blind, self-controlled, clinical trial. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.02.001
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double-blind, randomised study of 71 patients, Adde et al.12 found no significant difference in the duration of operation, dose of antibiotic, VAS, interincisal distance, and oedema between amoxicillin, clindamycin, and no medication, and concluded that antibiotics were not indicated in all clinical conditions. Pasupathy and Alexander13 also failed to show any advantage in the routine use of prophylactic antibiotics. Because we knew of few if any standard clinical trials on this topic in China, we designed this split-mouth, double-blind, self-controlled, clinical trial to identify whether antibiotics have an effect on postoperative inflammatory complications after extraction of impacted mandibular third molars in Chinese patients, similar to that of Mehrabi et al.14 The second question was which antibiotics could be used to prevent and reduce the incidence of postoperative inflammatory complications? The ideal antibiotic for a particular clinical application should be non-toxic and easy to use, and as anaerobic bacteria do not lead to many infections in impacted mandibular third molars,10 amoxicillin and other penicillin derivatives with their extended coverage are suitable.11,15–17 Delilbasi et al.18 found that it would be more beneficial to use chlorhexidine solution with a -lactamase inhibitor that contained antibiotic to prevent alveolar osteitis. Graziani et al.19 found that a macrolide antibiotic may reduce the influence of piroxicam on postoperative inflammation. Kupfer20 showed that clindamycin was remarkably effective in reducing the incidence of dry socket. Because amoxicillin is the most commonlyprescribed antibiotic in our hospital, we chose to use it in this trial. The third question was when should we give the antibiotic so that it reduces the incidence of postoperative inflammatory complications? A randomised trial by Olusanya et al.21 found no difference between the preoperative and postoperative groups in respect of postoperative pain, swelling, trismus, wound infection, and alveolar osteitis. They also showed that the use of a single bolus dose of antibiotic before the operation helped to reduce the cost of treatment in developing countries. The study by Luaces-Rey et al.16 also showed no significant postoperative differences between the preoperative and postoperative groups in the variables that they recorded. In contrast, López-Cedrún et al.15 showed that the best results were obtained by using the drug postoperatively, and Yoshii et al.,22 indicated that lenampicillin for one day may be recommended as prophylaxis for prophylaxis in extraction of mandibular third molars in medically healthy patients. We chose to use the antibiotic one hour before, and 3 days after, this clean-contaminated oral operation to make sure that serum concentrations were higher for longer. Our results have shown that there was good consistency on positions and heights of impacted teeth with 192 cases in the same condition. The moderate-to-good consistency further showed that the difficulty of extraction of the third molars was similar on both sides, which guaranteed
the impartiality on the study of postoperative inflammatory complications. We found that the number of cases of alveolar osteitis in the treatment group was lower than that in the placebo group, but not significantly so (p = 0.5). In addition, the only two cases of wound infection in both groups were from the same two patients. This indicates that perioperative antibiotics had no significant effect in preventing postoperative inflammatory complications. We also found that extraction time, other complications, and postoperative reactions in the two groups did not differ significantly (Table 3), except for the VAS for pain on day 10 (p = 0.005), which may related to the different times and use of painkillers. Patients who did develop infections recovered well after symptomatic treatment. The Cochrane Collaborative Review by Lodi et al. on antibiotics in the prevention of complications after tooth extractions from 18 double-blind placebo-controlled trials with a total of 2456 participants,23 showed that antibiotics were associated with an increase in generally mild and transient adverse effects compared with placebo, which means that for every 21 people (range 8–200) who are given antibiotics, an adverse effect is likely. Although there is evidence that prophylactic antibiotics reduce the risk of infection, dry socket, and pain after extraction of third molars, and result in an increase in adverse effects, the authors suggested that clinicians should carefully consider whether treating 12 healthy patients with antibiotics to prevent one infection is likely to do more harm than good because of the increased prevalence of bacteria that are resistant to treatment by currently available antibiotics. Like the papers in that review,23 our study included only healthy people (ASA class I or II), the mean extraction time was no longer than 30 min, and there were no apparent intraoperative complications in any case. We therefore need to study further whether the results would be similar in patients with systemic diseases, when the extraction is difficult, the extraction time is much longer, and when there are intraoperative complications. In conclusion, oral prophylactic antibiotics in the removal of lower third molars do not contribute to better wound healing, less pain, or increased mouth opening, and do not prevent postoperative inflammatory complications. We therefore do not recommend them for routine use, which will benefit patients and reduce the economic burden on society.
Conflict of interest We have no conflict of interest.
Ethics statement/confirmation of patients’ permission We obtained approval from the Hospital Ethics Committee (No. IRB-REV-2013005), and written informed consent from all patients.
Please cite this article in press as: Xue P, et al. Efficacy of antibiotic prophylaxis on postoperative inflammatory complications in Chinese patients having impacted mandibular third molars removed: a split-mouth, double-blind, self-controlled, clinical trial. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.02.001
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References 1. Clauser B, Barone R, Briccoli L, et al. Complications in surgical removal of mandibular third molars. Minerva Stomatol 2009;58:359–66. 2. Blum IR. Contemporary views on dry socket (alveolar osteitis): a clinical appraisal of standardization, aetiopathogenesis and management: a critical review. Int J Oral Maxillofac Surg 2002;31:309–17. 3. Chiapasco M, De Cicco L, Marrone G. Side effects and complications associated with third molar surgery. Oral Surg Oral Med Oral Pathol 1993;76:412–20. 4. Osborn TP, Frederickson Jr G, Small IA, et al. A prospective study of complications related to mandibular third molar surgery. J Oral Maxillofac Surg 1985;43:767–9. 5. Kruger GO. Textbook of oral and maxillofacial surgery. 6th ed. St. Louis: Mosby; 1984. 6. Alerany C, Campany D, Monterde J, et al. Impact of local guidelines and an integrated dispensing system on antibiotic prophylaxis quality in a surgical centre. J Hosp Infect 2005;60:111–7. 7. Winter GB. Impacted mandibular third molars. St. Louis: American Medical Book Co.; 1926. p. 241–79. 8. Pell GJ, Gregory BT. Impacted mandibular third molars: classification and modified techniques for removal. Dent Digest 1933;39:330–8. 9. Kay LW. Investigations into the nature of pericoronitis II. Br J Oral Surg 1966;4:52–78. 10. 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;65:1909–21. 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;39:107–14. 12. 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)):S26–31. 13. Pasupathy S, Alexander M. Antibiotic prophylaxis in third molar surgery. J Craniofac Surg 2011;22:551–3.
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14. Mehrabi M, Allen JM, Roser SM. Therapeutic agents in perioperative third molar surgical procedures. Oral Maxillofac Surg Clin North Am 2007;19:69–84. 15. López-Cedrún JL, Pijoan JI, Fernández S, et al. Efficacy of amoxicillin treatment in preventing postoperative complications in patients undergoing third molar surgery: a prospective, randomized, double-blind controlled study. J Oral Maxillofac Surg 2011;69:e5–14. 16. Luaces-Rey R, Arenaz-Búa J, Lopez-Cedrun-Cembranos JL, et al. 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: e633–8. 17. Monaco G, Tavernese L, Agostini R, et al. Evaluation of antibiotic prophylaxis in reducing postoperative infection after mandibular third molar extraction in young patients. J Oral Maxillofac Surg 2009;67:1467–72. 18. Delilbasi C, Saracoglu U, Keskin A. Effects of 0.2% chlorhexidinegluconate and amoxicillin plus clavulanic acid on the prevention of alveolar osteitis following mandibular third molar extractions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;94:301–4. 19. 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;52:485–90. 20. Kupfer SR. Prevention of dry socket with clindamycin. A retrospective study. N Y State Dent J 1995;61:30–3. 21. Olusanya AA, Arotiba JT, Fasola OA, et al. Prophylaxis versus preemptive antibiotics in third molar surgery: a randomized control study. Niger Postgrad Med J 2011;18:105–10. 22. Yoshii T, Hamamoto Y, Muraoka S, et al. Differences in postoperative morbidity rates, including infection and dry socket, and differences in the healing process after mandibular third molar surgery in patients receiving 1-day or 3-day prophylaxis with lenampicillin. J Infect Chemother 2002;8:87–93. 23. Lodi G, Figini L, Sardella A, et al. Antibiotics to prevent complications following tooth extractions. Cochrane Database Syst Rev 2012;(11). Article Number CD003811.
Please cite this article in press as: Xue P, et al. Efficacy of antibiotic prophylaxis on postoperative inflammatory complications in Chinese patients having impacted mandibular third molars removed: a split-mouth, double-blind, self-controlled, clinical trial. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.02.001
ARTICLE IN PRESS Available online at www.sciencedirect.com
British Journal of Oral and Maxillofacial Surgery xxx (2015) xxx–xxx
Efficacy of antibiotic prophylaxis on postoperative inflammatory complications in Chinese patients having impacted mandibular third molars removed: a split-mouth, double-blind, self-controlled, clinical trial P. Xue, J. Wang, B. Wu, Y. Ma, F. Wu, R. Hou ∗ State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, Fourth Military Medical University, Xi’an 710032, China Accepted 1 February 2015
Abstract We investigated the effect of antibiotic prophylaxis on postoperative inflammatory complications after operations for impacted mandibular third molars in Chinese patients. A total of 207 patients had their bilateral third molars removed in a split-mouth, double-blind, self-controlled, clinical trial in two visits. For one side amoxicillin (or clindamycin) was given (antibiotic group) from one hour before operation until 3 days postoperatively. For the other side a placebo was given (placebo group) at the same time. The outcome, including alveolar osteitis, surgical wound infection, prebuccal infection, and infection of the anterior isthmus of fauces, was assessed 2 and 10 days postoperatively. A total of 192 patients completed the study, and there was no difference between the groups in the incidence of inflammatory complications. In the treatment group, there were 4 cases of alveolar osteitis (2%), 2 infections of the wound (1%), and 14 other reactions (gastrointestinal (n = 4), bleeding (n = 2), ulcer (n = 2), and fever (n = 6)). In the placebo group, there were 6 cases of alveolar osteitis (3%), 2 wound infections (1%), and 22 other reactions (bleeding (n = 6), ulcer (n = 2) and fever (n = 14)). There was no significant difference in the extraction time and postoperative reactions, except the pain score on day 10 (p = 0.005). Prophylactic amoxicillin (or clindamycin) is not effective for the prevention or reduction of postoperative inflammatory complications after the removal of impacted mandibular third molars in Chinese patients. © 2015 Published by Elsevier Ltd. on behalf of The British Association of Oral and Maxillofacial Surgeons.
Keywords: Impacted mandibular third molar surgery; Inflammatory complications; Antibiotic treatment ;
Introduction The removal of impacted mandibular third molars is a common procedure in oral and maxillofacial surgery, and is often followed by pain, swelling, trismus, alveolar osteitis, and infections of the wound, prebuccal site, and anterior isthmus of the fauces.1 The most common is alveolar osteitis, which ∗
Corresponding author. Tel.: +86 29 84776102; fax: +86 29 83223047. E-mail address: [email protected] (R. Hou).
affects 25%–30% of patients.2 Infection of the wound is also common, ranging from 2% to 12%.3,4 The other two severe infections, those of the prebuccal site and the anterior isthmus of the fauces, are seldomly reported.5 Infections of the prebuccal site take longer to develop postoperatively, and infection of the anterior isthmus of the fauces is characterised by obvious difficulty in opening the mouth (less than one finger’s width), swelling, tenderness on the anteromedial area of mandibular angle, pharyngeal pain, and difficulty in swallowing.
http://dx.doi.org/10.1016/j.bjoms.2015.02.001 0266-4356/© 2015 Published by Elsevier Ltd. on behalf of The British Association of Oral and Maxillofacial Surgeons.
Please cite this article in press as: Xue P, et al. Efficacy of antibiotic prophylaxis on postoperative inflammatory complications in Chinese patients having impacted mandibular third molars removed: a split-mouth, double-blind, self-controlled, clinical trial. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.02.001
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The efficacy of antibiotic prophylaxis in preventing complications after removal of lower third molars has long been controversial. Some authors say that it is effective, others say that it is not, despite the fact that antibiotic prophylaxis against postoperative wound infections accounts for 30% of prescriptions for antibiotics in general hospitals,6 and that the excessive and inappropriate use of antibiotics may lead to bacterial resistance and increase the economic burden of healthcare. We have evaluated the efficacy of antibiotic prophylaxis in a split-mouth, double-blind, self-controlled clinical trial over two visits after the removal of impacted mandibular third molars in a Chinese stomatology hospital.
Material and methods The study was designed as a split-mouth, randomised, double-blind, self-controlled, crossover trail and the Hospital Ethics Committee approved the design (No. IRB-REV2013005). Patients were all American Society of Anesthesiologists (ASA) class I or II and between the ages of 18 and 60. Clinical and radiological assessments were made to ensure that the degree of impaction and surgical difficulty were comparable on both sides. Gingival incision, creation of a flap, excision of bone with a cutting burr, sectioning of teeth, and suturing were all essential to the success of the extraction. The patient had had no antibiotics or local anaesthetic during in the week before extraction. A full verbal and written explanation of the study was given to each patient and a consent form was signed. Patients were excluded if they had any contraindications to removal of the teeth, as were patients who were pregnant or lactating, those who had any serious coexisting medical conditions, and those who smoked. By the use of computer-generated random numbers, the patients were assigned to receive antibiotics (even number) or placebo (odd number) at their first appointment. The other treatment was used when they had the second third molar removed 10–14 days later. All operations were done by the same oral surgeon. Impacted teeth were defined as being in position A, B, or C according to the Pell and Gregory classification.7 They were also classified as vertical, mesioangular, distoangular, horizontal, inverted, buccal and lingual impaction according to the Winter classification.8 Patients in the treatment group took amoxicillin 0.5 g (Zhuhai United Laboratories Co., Ltd.) one hour preoperatively, or clindamycin hydrochloride 0.3 g (Hunan Yada Pharmaceutical Co., Ltd.) if they were allergic to amoxicillin. Postoperatively they took the same dose three times a day for three days. Patients in the placebo group took a placebo with the same shape and dose on the same times before and after operation.
Table 1 Pell Gregory classification (n = 192). Group
Position A
Position B
Position C
Treatment Placebo
12 14
88 96
92 82
kappa = 0.852.
Surgical technique After the local anaesthesia with 2% lignocaine (Shanxi Jincheng Pharmaceutical Co., Ltd.), a buccal mucoperiosteal flap was raised. The bone was then removed with burs to expose the impacted tooth, which was sectioned. After the tooth had been removed the flap was closed with absorbable sutures. The teeth on the opposite side of the mouth were extracted 10–14 days later. A cold compress was applied immediately postoperatively, and patients took loxoprofen sodium (Shandong Disha Pharmaceutical Group Co., Ltd.) before or after operation as necessary. We recorded the extraction time for each single impacted mandibular third molar, together with any signs of postoperative inflammation, including specific infections, on postoperative days 2 and 10. Adverse reactions and other postoperative complications were also recorded on postoperative days 2 and 10. Severity of pain after extraction and swallowing were measured on Visual Analogue Scales (VAS). Facial swelling was measured as the difference between the distance (mm) between the lower earlobe and the mesomentum on the extraction side. Mouth opening was measured as the distance between upper and lower incisors (mm). Statistical analysis We used SPSS for Windows (version 17.0, SPSS Inc., Chicago, IL, USA) for statistical analysis. The kappa consistency test was made on different impaction sites, impaction position, and extraction time for both groups. The chi square test was used to compare the proportions of inflammatory complications between the groups. The Wilcoxon signed rank test was used to compare the extraction time, the pain score, amount of swelling, and mouth opening between the groups.
Results Two hundred and seven patients complied with the study protocol from January to December 2013, and 15 were excluded. All analyses refer to the remaining 192 patients (74 men (39%) and 118 women (61%), mean age 33 years, range 18–60) who had extractions of bilaterally symmetrical impacted teeth during two visits. Tables 1 and 2 showed the classifications of impacted position and direction in the two groups. The kappa values of the Pell Gregory and Winter classifications are 0.852 and 0.734,
Please cite this article in press as: Xue P, et al. Efficacy of antibiotic prophylaxis on postoperative inflammatory complications in Chinese patients having impacted mandibular third molars removed: a split-mouth, double-blind, self-controlled, clinical trial. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.02.001
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P. Xue et al. / British Journal of Oral and Maxillofacial Surgery xxx (2015) xxx–xxx
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Fig. 1. Postoperative reactions and other complications in 192 cases. There were no significant differences between the groups. Blue = treated group and red = placebo group. Table 2 Winter classification (n = 192).
Discussion
Type of impaction
Treatment group
Placebo
Vertical Mesioangular Horizontal Distoangular Buccoangular Lingoangular Inverted
60 68 50 10 2 2 0
58 74 46 10 2 2 0
kappa = 0.734.
respectively, which indicated that the two groups had a good degree of consistency. There was no significant difference between the two groups in the extraction time (Z = −1.826 (negative rank), p = 0.068). There were only 4 cases (2%) of alveolar osteitis and 2 cases (1%) of wound infection among the treated group, and 6 cases of alveolar osteitis (3%) and 2 cases (1%) of wound infection in the placebo group. The total numbers of patients with alveolar osteitis and wound infection were 10 (3%) and 4 (1%), respectively. Fig. 1 and Table 3 show the postoperative reactions and other complications in the two groups. There was no significant difference between the two groups except for the pain score on postoperative day 10 (p = 0.005).
Extraction of an impacted mandibular third molar of the mandible is a clean-contaminated operation. As the oral cavity is colonised by more than 400 species of aerobic and anaerobic bacteria, antibiotics have often been used to prevent and reduce postoperative infection. However, whether antibiotics must be used has been disputed for a long time, and reports on the use of antibiotics during the extraction of impacted mandibular third molars have differed from each other on three questions. First, can the use of antibiotics prevent or decrease the incidence of postoperative inflammatory complications? In the 1960s, Kay9 showed that alveolar osteitis occurred in 325 of 1341 patients who had had third molars extracted without antibiotic prophylaxis. In contrast, only 50 of 1620 patients given a single preoperative dose of penicillin had developed it, which strongly supports the use of antibiotics for extraction of third molars. Another review concluded that systemic antibiotics were effective in reducing the incidence of alveolar osteitis and wound infection after extraction of third molars in a total of 2932 patients randomised in 16 clinical trials.10 However, some clinical trials raised doubts of effectiveness of antibiotics. Siddiqi et al.11 showed that prophylactic antibiotics made no significant difference to the incidence of postoperative infections after extraction of third molars. In a
Table 3 Postoperative reactions and other complications (n = 192). Variable
2 days Z
Pain after extraction Swallowing pain Swelling (mm) Trisums (mm) a b
−1.893a −0.738a −1.600a −0.260a
10 days p value
Z
p value
0.058 0.461 0.110 0.795
−2.793a
0.005 0.102 1.000 0.317
−1.633a 0.000b −1.000a
Positive rank. Sum of positive rank = sum of negative rank.
Please cite this article in press as: Xue P, et al. Efficacy of antibiotic prophylaxis on postoperative inflammatory complications in Chinese patients having impacted mandibular third molars removed: a split-mouth, double-blind, self-controlled, clinical trial. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.02.001
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double-blind, randomised study of 71 patients, Adde et al.12 found no significant difference in the duration of operation, dose of antibiotic, VAS, interincisal distance, and oedema between amoxicillin, clindamycin, and no medication, and concluded that antibiotics were not indicated in all clinical conditions. Pasupathy and Alexander13 also failed to show any advantage in the routine use of prophylactic antibiotics. Because we knew of few if any standard clinical trials on this topic in China, we designed this split-mouth, double-blind, self-controlled, clinical trial to identify whether antibiotics have an effect on postoperative inflammatory complications after extraction of impacted mandibular third molars in Chinese patients, similar to that of Mehrabi et al.14 The second question was which antibiotics could be used to prevent and reduce the incidence of postoperative inflammatory complications? The ideal antibiotic for a particular clinical application should be non-toxic and easy to use, and as anaerobic bacteria do not lead to many infections in impacted mandibular third molars,10 amoxicillin and other penicillin derivatives with their extended coverage are suitable.11,15–17 Delilbasi et al.18 found that it would be more beneficial to use chlorhexidine solution with a -lactamase inhibitor that contained antibiotic to prevent alveolar osteitis. Graziani et al.19 found that a macrolide antibiotic may reduce the influence of piroxicam on postoperative inflammation. Kupfer20 showed that clindamycin was remarkably effective in reducing the incidence of dry socket. Because amoxicillin is the most commonlyprescribed antibiotic in our hospital, we chose to use it in this trial. The third question was when should we give the antibiotic so that it reduces the incidence of postoperative inflammatory complications? A randomised trial by Olusanya et al.21 found no difference between the preoperative and postoperative groups in respect of postoperative pain, swelling, trismus, wound infection, and alveolar osteitis. They also showed that the use of a single bolus dose of antibiotic before the operation helped to reduce the cost of treatment in developing countries. The study by Luaces-Rey et al.16 also showed no significant postoperative differences between the preoperative and postoperative groups in the variables that they recorded. In contrast, López-Cedrún et al.15 showed that the best results were obtained by using the drug postoperatively, and Yoshii et al.,22 indicated that lenampicillin for one day may be recommended as prophylaxis for prophylaxis in extraction of mandibular third molars in medically healthy patients. We chose to use the antibiotic one hour before, and 3 days after, this clean-contaminated oral operation to make sure that serum concentrations were higher for longer. Our results have shown that there was good consistency on positions and heights of impacted teeth with 192 cases in the same condition. The moderate-to-good consistency further showed that the difficulty of extraction of the third molars was similar on both sides, which guaranteed
the impartiality on the study of postoperative inflammatory complications. We found that the number of cases of alveolar osteitis in the treatment group was lower than that in the placebo group, but not significantly so (p = 0.5). In addition, the only two cases of wound infection in both groups were from the same two patients. This indicates that perioperative antibiotics had no significant effect in preventing postoperative inflammatory complications. We also found that extraction time, other complications, and postoperative reactions in the two groups did not differ significantly (Table 3), except for the VAS for pain on day 10 (p = 0.005), which may related to the different times and use of painkillers. Patients who did develop infections recovered well after symptomatic treatment. The Cochrane Collaborative Review by Lodi et al. on antibiotics in the prevention of complications after tooth extractions from 18 double-blind placebo-controlled trials with a total of 2456 participants,23 showed that antibiotics were associated with an increase in generally mild and transient adverse effects compared with placebo, which means that for every 21 people (range 8–200) who are given antibiotics, an adverse effect is likely. Although there is evidence that prophylactic antibiotics reduce the risk of infection, dry socket, and pain after extraction of third molars, and result in an increase in adverse effects, the authors suggested that clinicians should carefully consider whether treating 12 healthy patients with antibiotics to prevent one infection is likely to do more harm than good because of the increased prevalence of bacteria that are resistant to treatment by currently available antibiotics. Like the papers in that review,23 our study included only healthy people (ASA class I or II), the mean extraction time was no longer than 30 min, and there were no apparent intraoperative complications in any case. We therefore need to study further whether the results would be similar in patients with systemic diseases, when the extraction is difficult, the extraction time is much longer, and when there are intraoperative complications. In conclusion, oral prophylactic antibiotics in the removal of lower third molars do not contribute to better wound healing, less pain, or increased mouth opening, and do not prevent postoperative inflammatory complications. We therefore do not recommend them for routine use, which will benefit patients and reduce the economic burden on society.
Conflict of interest We have no conflict of interest.
Ethics statement/confirmation of patients’ permission We obtained approval from the Hospital Ethics Committee (No. IRB-REV-2013005), and written informed consent from all patients.
Please cite this article in press as: Xue P, et al. Efficacy of antibiotic prophylaxis on postoperative inflammatory complications in Chinese patients having impacted mandibular third molars removed: a split-mouth, double-blind, self-controlled, clinical trial. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.02.001
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Please cite this article in press as: Xue P, et al. Efficacy of antibiotic prophylaxis on postoperative inflammatory complications in Chinese patients having impacted mandibular third molars removed: a split-mouth, double-blind, self-controlled, clinical trial. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.02.001