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BASIC AND PATIENT-ORIENTED RESEARCH

J Oral Maxillofac Surg


65:1909-1921, 2007

Effectiveness of Antibiotic Prophylaxis in


Third Molar Surgery: A Meta-Analysis of
Randomized Controlled Clinical Trials
Yan-Fang Ren, DDS, PhD, MPH* and
Hans S. Malmstrom, DDS

Purpose: We conducted a synthetic quantitative review of the published clinical trials on the effec-
tiveness of antibiotic prophylaxis in third molar surgery.
Materials and Methods: Electronic databases were searched for randomized controlled trials. The
primary outcome variables included alveolar osteitis (AO) and surgical wound infection. The extracted
data were analyzed using a meta-analytical program with a random-effect model. Number needed to treat
(NnT) was calculated.
Results: A total of 2,932 patients randomized in 16 clinical trials reported AO as an outcome. AO
occurred in 84 of 1,350 patients in the treatment group, a frequency of 6.2%; and in 228 of 1,582 patients
in the control group, a frequency of 14.4%. Systemic antibiotic therapy was effective in reducing the risk
of AO (odds ratio [OR], 2.175) with an NnT of 13. A total of 2,396 patients randomized in 12 clinical trials
reported wound infection as an outcome. Wound infection occurred in 44 of 1,110 patients in the
treatment group, a frequency of 4%; and in 78 of 1,286 patients in the control group, a frequency of 6.1%.
Systemic antibiotic therapy was effective in reducing the risk of wound infection (OR, 1.794) with an
NnT of 25. Antibiotics reduced the risk of AO and wound infection only when first dose was given before
surgery.
Conclusions: Systemic antibiotics given before the surgery were effective in reducing the frequencies
of AO and wound infection after third molar surgery.
2007 American Association of Oral and Maxillofacial Surgeons
J Oral Maxillofac Surg 65:1909-1921, 2007

Surgical extraction of impacted third molars is the removal of impacted mandibular third molars.2 Al-
procedure carried out most commonly in oral surgery though AO is generally considered an inflammatory
and general dental practices around the world.1 Ow- response of the alveolar bone to traumatic stimulus
ing to the nature and environment of the surgery, rather than a bacterial infection, its etiology is associ-
inflammation and infection associated with bacterial ated closely with bacterial contamination and fibri-
contamination are the most common complications nolysis of the socket blood clot.2-4 Postoperative in-
after third molar surgery. Alveolar osteitis (AO), or dry fection is a more severe complication but less
socket, is the sequela reported most frequently and frequent than AO, occurring in approximately 2% to
may involve 25% to 30% of the patients undergoing 12% of patients.5-8 Severe fascial space cellulitis that
requires hospitalization may occur in about 1% of
Received from Eastman Dental Center, University of Rochester, patients after mandibular third molar surgery.9 Al-
Rochester, NY. though such severe infections are not common, the
*Assistant Professor. consequences of these infections are disabling and
Associate Professor. costly.10
This study is supported in part by NIDCR (DE16917). Antibiotic prophylaxis in third molar surgery has
Address correspondence and reprint requests to Dr Ren: Uni- long been an issue of controversy in clinical prac-
versity of Rochester, Eastman Dental Center, 625 Elmwood Ave, tices.11,12 In his comprehensive investigation into the
Rochester, NY 14620; e-mail: yanfang_ren@urmc.rochester.edu nature of pericoronitis and complications after third
2007 American Association of Oral and Maxillofacial Surgeons molar removal in the 1960s, Kay13 provided seem-
0278-2391/07/6510-0002$32.00/0 ingly overwhelming evidence about the need for an-
doi:10.1016/j.joms.2007.03.004 tibiotic prophylaxis for third molar surgery. He

1909
1910 ANTIBIOTIC PROPHYLAXIS IN THIRD MOLAR SURGERY

showed that AO occurred in 325 of 1,341 patients phylaxis in third molar surgery. The null hypothesis
who had undergone third molar surgery without an- was that antibiotic prophylaxis was not effective in
tibiotic prophylaxis. In contrast, only 50 of 1,620 preventing postoperative complications including AO
patients who received a single dose of penicillin be- and infections. The specific aims were to collect and
fore surgery had developed AO, signifying a reduction evaluate all randomized controlled clinical trials in
in the incidence of AO from 24% to 3%. The effec- English and non-English literature, published or un-
tiveness of antibiotic prophylaxis was even more dra- published, and to test the hypothesis through meta-
matic in patients with pericoronitis, where a single analysis.
dose of penicillin reduced the incidence of AO from
71% to 8%. This report has served as the impetus for
widespread antibiotic prescriptions associated with Materials and Methods
third molar surgery. Although a number of subse-
SEARCH STRATEGY
quent clinical trials questioned the effectiveness of
antibiotic prophylaxis in third molar surgery,14-17 An initial search was conducted using Ovid Med-
other studies supported the use of antibiotics before line, PubMed, and the Cochrane Central Register of
or after the surgery.18-22 The conflicting conclusions Controlled Trials (CENTRAL) with a combination of
from randomized controlled clinical trials have caused Medical Subject Headings (MeSH) of anti-bacterial
long-standing confusion in clinical practice, with ad- agents or antimicrobial agents, and third molar.
vocates and opponents of antibiotic prophylaxis each Both English and non-English articles were included
presenting their own supporting evidence.11,12 Al- in the literature search. All abstracts were reviewed
though the wisdom of routine antibiotic prophylaxis and the articles described as a clinical trial were se-
has been questioned frequently due to its question- lected. The reference lists of the selected articles
able effectiveness, potential allergic and anaphylactic were searched and any relevant articles collected for
reactions, and risk of inducing drug resistance, clini- review. For non-English publications, the methods
cians have not abandoned the practice of prescribing and results sections were reviewed and translated by
antibiotics for prevention of postoperative complica- 2 dentists fluent in the original language. A separate
tions after third molar surgery.11 Recent published search was carried out to identify only review articles
clinical trials only added to the confusion, with some and the reference lists of the review articles were
studies supporting the effectiveness of antibiotic pro- examined to look for additional clinical trials that
phylaxis23-25 and others opposing it.26-28 were not included in the above database or published
Because postoperative AO and infection are accom- before 1966 when the database was established ini-
panied by debilitating pain and severe functional im- tially. We searched NLM Gateway (http://gateway.nlm.
pairment, patients often experience diminished qual- nih.gov/gw/Cmd) to locate relevant meeting abstracts.
ity of life and lost productivity.29-32 Therefore, for For those studies in which only an abstract was avail-
many years clinicians have sought an effective way to able, we attempted to contact the author to request
prevent postoperative complications after third molar more detailed information. We also searched for unpub-
surgery. Many randomized clinical trials were con- lished trials or theses through an Internet search engine
ducted in the past to investigate the effectiveness of (Google). Worldwide clinical trial registration sites
antibiotic prophylaxis in reducing morbidity associ- (www.clinicaltrials.gov, www.controlled-trials.com,
ated with third molar surgery, but these studies suf- and www.actr.org.au) were searched for on-going stud-
fered from a common flaw, that is, the lack of statis- ies and the principle investigators of relevant clinical
tical power to detect a meaningful difference trials were contacted to request trial and outcome infor-
between the study groups. For example, if a reduc- mation, if available.
tion from 15% to 5% in postoperative complications is
considered effective and clinically significant, a clini- INCLUSION CRITERIA
cal trial with a sample size of 318 (159 in each group) Articles that meet the following criteria were re-
is required to detect such magnitude of difference viewed and included in the meta-analysis:
with 80% power at an alpha level of 0.05 for a 2-tailed
test (EpiInfo 3.3, Centers for Disease Control and 1. Must involve surgical extraction of an impacted
Prevention, Atlanta, GA). With few exceptions, pub- mandibular third molar;
lished clinical trials involved a much smaller sample 2. Must be described as a randomized clinical trial;
size that did not support a conclusive outcome anal- 3. Must include a control group;
ysis. 4. Must include systemic antibiotic prophylaxis as
The purpose of this study was to conduct a syn- intervention; and
thetic quantitative review of randomized controlled 5. Must include outcomes that are described as
clinical trials on the effectiveness of antibiotic pro- postoperative inflammatory complications, such
REN AND MALMSTROM 1911

as alveolar osteitis (dry socket, alveolitis, or than a fixed effect model for this study because vari-
fibrinolytic alveolitis) or infection. ations between different studies might be present
even if the 2 test for heterogeneity did not show
Studies that did not involve randomization, had no statistical significance. For the subgroup sensitivity
control group or did not describe outcomes were not analysis, results for both the fixed-effect and random-
included for review. Clinical trials that used topical effect models were presented.
antimicrobial agents such as a mouthwash or socket
dressing were also excluded because our focus was Sensitivity Analysis
on systemic antibiotics that were given either enter- Several sensitivity analyses for the primary outcome
ally or parenterally. were planned: 1) subgroup analysis according to dif-
ferent quality of study designs; 2) subgroup analysis
DATA EXTRACTION according to different types of antibiotics; and 3)
A data extraction form was used to retrieve infor- subgroup analysis according to timing and duration of
mation regarding study design, inclusion and exclu- antibiotic use, including preoperative single dose,
sion criteria, patient characteristics, intervention, and preoperative plus postoperative multiple doses, and
outcomes. postoperative multiple doses only.
The quality of the trial was evaluated based on the
Publication Bias Assessment
rigor of the study design. All studies included in the
If the result of meta-analyses indicating antibiotic
review were randomized and had a control group, but
prophylaxis was statistically more effective than the
a placebo was used only in some of the studies.
control group, or vice versa, a publication bias assess-
Investigator blinding was not described in some stud-
ment (PBA) was carried out to analyze if the positive
ies, which might negate the validity of the study.
finding was a function of publication bias. This assess-
Although all the selected clinical trials involved sys-
ment was based on an estimation of the minimum
temic antibiotic prophylaxis, we recognized that large
number of negative (or positive) studies required to
variations existed in timing, type, route, and duration
reverse the results of the meta-analysis to the level of
of application. Timing of administration was divided
statistical non significance.33 The higher the number,
into preoperative (antibiotics were given at least 30
the less likely there is publication bias.
minutes before surgery) and postoperative (given af-
ter the completion of surgery). Type of antibiotics Number Needed to Treat
was divided into wide-spectrum antibiotics (mostly Number needed to treat (NnT) refers to the number
penicillin derivatives represented by amoxicillin) and of patients needed to be treated with antibiotic pro-
antianaerobic agents (represented by metronidazole). phylaxis to prevent 1 postoperative AO or infection.
Routes of administration included parenteral (by in- NnT was calculated as 1/pooled risk difference.
tramuscular or intravenous injection) and enteral (by
mouth). Duration of administration was described as
single dose or multiday (3 to 5 days in most studies)
Results
applications.
The primary outcome variable was postoperative Ovid Medline, PubMed, and CENTRAL search re-
inflammatory complications including AO and surgi- sulted in 96 titles that potentially meet the inclusion
cal wound infection. Diagnostic criteria for AO and criteria. After reviewing all the abstracts, 23 clinical
infection was extracted from each study and recorded trials involving systemic antibiotics were identified.
in the data form. A diagnosis of AO was established if: Further search of reference lists of published clinical
1) severe pain occurred 3 to 7 days after the extrac- trials and review articles identified 14 more publica-
tion; or 2) there was a denuded extraction socket tions. Searching the NLM Gateway located 1 abstract
with exposed osseous tissue. A diagnosis of surgical presented at an international conference. The primary
wound infection was established if: 1) there was pu- author in Barcelona, Spain was contacted and a manu-
rulent discharge from the surgical site; or 2) there script accepted for publication in English was re-
were other signs of infection, such as fever, lymph- ceived. One ongoing clinical trial was found through
adenopathy, or persistent swelling and pain that can- searching the online registration sites. The principle
not be explained by surgical trauma. investigator in the United States was contacted and a
manuscript accepted for publication was provided by
STATISTICAL ANALYSIS the principle investigator. Internet (Google) search
The data from the studies were analyzed using a located 1 clinical trial described on a United States
meta-analytical program (Tecnopharma Meta-analysis dental school Web site involving antibiotic prophy-
1.2.0) with a random-effect model. We determined laxis in smokers undergoing third molar surgery. The
that a random effect model was more appropriate principle investigator was contacted but no reply had
1912 ANTIBIOTIC PROPHYLAXIS IN THIRD MOLAR SURGERY

96 potentially relevant studies been received to the date when this article was sub-
identified by Medline, PubMed
and CENTRAL search and 4 review articles mitted for publication.
identified and
abstracts reviewed
references examined The above search strategy yielded 39 full-length
articles that were subjected to further review (Fig 1).
23 clinical trials Of 39 studies, 37 were published in English, 1 in
retrieved for full review
Swedish, and 1 in Spanish. Two authors reviewed the
1 study identified from NLM 14 potentially relevant studies
articles and extracted the data independently. After
Gateway conference site identified from reference lists of the review and data extraction, it was agreed by the 2
and received full paper 23 original and 4 review articles
from author authors that 19 studies did not meet the inclusion
criteria and they were excluded from the final analy-
1 study identified from
clinicaltrials.gov and sis. The reasons for exclusion of these studies are
received full paper from
author
presented in Table 1.
Twenty studies were included in the meta-analysis
1 study identified from a (Table 2). Of 20 studies, 8 studies reported both AO and
dental school website but
received no reply from infections outcomes, 8 reported AO only, and 4 re-
author
ported wound infections only. Therefore, 16 studies
were included in the final analysis with AO as an out-
39 studies collected for come, and 12 studies in a separate analysis with wound
detailed evaluation and
data extraction infection as an outcome.

ANALYSIS OF CLINICAL TRIALS WITH AO AS THE


19 studies did not meet the
predetermined inclusion OUTCOME MEASURE
criteria (see Table 1 for
reasons for exclusion) A total of 3,050 patients were randomized to an anti-
biotic or a control group in 17 clinical trials that re-
ported AO as an outcome. An incidence of zero was
20 studies included in the reported in both the antibiotic and the control groups in
final meta-analytic review
1 study involving 118 patients.34 This study was ex-
cluded because the meta-analysis software automatically
FIGURE 1. Studies included in the final meta-analytic review.
eliminates studies that report a value of zero in both the
Ren and Malmstrom. Antibiotic Prophylaxis in Third Molar Sur- study and the control groups. Therefore, 2,932 patients
gery. J Oral Maxillofac Surg 2007.
from 16 clinical trials were included in the final analysis

Table 1. STUDIES NOT INCLUDED IN THE META-ANALYSIS

Study Reasons for Exclusion


29
Foy et al Not randomized, no concurrent control
Yoshii et al47 No control group
Sekhar et al28 Large and unexplained dropout in 1 treatment group (23%), questionable
randomization*
Kupfer48 Not a clinical trial, only retrospective data reported
Capuzzi et al49 No relevant outcomes reported
Lloyd and Earl50 No control group
Chapnick and Diamond51 No control group, all subjects received systemic antibiotics
Goker and Guvener52 No relevant outcomes reported
Schatz et al53 No systemic antibiotics were used
Mitchell and Morris21 No control group
Krekmanov and Nordenram54 Not randomized
Kaziro55 No relevant outcomes reported
MacGregor and Addy56 No relevant outcomes reported
Rood and Murgatroyd57 Not a randomized, but a cross-over study
MacGregor and Hutchinson58 No systemic antibiotics were used
Hellem and Nordenram59 No relevant outcomes reported
Laird et al60 No control group
Paterson et al61 Not for third molar extraction
Kay13 Not randomized
*Number of subjects randomized into each group varied from 37 to 61 and dropouts ranged from 8% to 23%. Large numbers of subjects
in the control group were apparently excluded without explanation.
Ren and Malmstrom. Antibiotic Prophylaxis in Third Molar Surgery. J Oral Maxillofac Surg 2007.
REN AND MALMSTROM 1913

Table 2. TREATMENTS AND OUTCOMES OF CLINICAL TRIALS INCLUDED IN THE META-ANALYSIS

Study Interventions* n AO Infection

1 Halpern and Dodson34 Penicillin 15 KU/kg single dose iv preop 59 0 0


Placebo 59 0 5
2 Graziani et al24 Azithromycin 500 mg po 3 days preop 20 0 0
Control 10 1 1
3 Arteagoitia et al23 Augmentin 500/125 mg po 4 days postop 231 0 5
Placebo 259 2 11
4 Bergdahl and Hedstrom26 Metronidazole 1,600 mg po preop 59 10
Placebo 60 13
5 Poeschl et al27 Augmentin 500/125 mg po 5 days postop 176 8 6
Clindamycin 300 mg po 5 days postop 180 7 8
Control 172 8 7
6 Martinez-Lacasa et al25 Augmentin 2,000/125 mg po preop 75 4
Augmentin 2,000/125 mg po 5 days postop 75 2
Placebo 75 12
7 Delilbasi et al62 Augmentin 500/125 mg po 5 days postop 56 6
Control 62 13
8 Bulut et al63 Amoxicillin 500 mg po 4 days pre-postop 30 2
Placebo 30 2
9 Monaco et al16 Amoxicillin 2,000 mg po 5 days postop 66 2 2
Control 75 4 8
10 Ritzau et al17 Metronidazole 1,000 mg po preop 135 6
Placebo 135 7
11 Lyall20 Metronidazole 400 mg po 2 days pre-postop 70 9
Control 70 23
12 Happonen et al7 Pen VK 660 mg po 5 days pre-postop 44 6
Tinidazole 500 mg po 5 days pre-postop 47 5
Placebo 45 5
13 Hedstrom22 Metronidazole 400 mg po preop 40 6
Placebo 40 15
14 Lombardia-Garcia et al64 Amoxicillin 500 mg po preop 44 6 1
Control 441 73 11
15 Barclay14 Metronidazole 400 mg po 3 days pre-postop 45 8
Placebo 50 17
16 Mitchell65 Tinidazole 2,000 mg po preop 25 4 0
Placebo 25 14 4
17 Krekmanov18 Penicillin 800 mg po preop 50 2
Control 48 15
18 Krekmanov and Hallander19 Penicillin 800 mg po preop 40 2
Control 40 13
19 Bystedt et al66 Antibiotic groups 80 3 2
Placebo 60 5 8
20 Curran et al15 Penicillin G 1 million IU im/250 mg po 4 days pre-postop 33 5 0
Control 35 5 3
Abbreviations: im, intramuscular; iv, intravenous; po, per oral; postop, dosing started after surgery; preop, single dosing before surgery;
pre-postop, dosing started before surgery and continued after surgery.
*Placebo, the control group received a placebo. Control, the control group received no treatment.
Azidocillin (750 mg), erythromycin (500/250 mg); clindamycin (300/150 mg), and doxycycline (200/100 mg) po for 7 days pre-postop.
Ren and Malmstrom. Antibiotic Prophylaxis in Third Molar Surgery. J Oral Maxillofac Surg 2007.

(Fig 2). AO occurred in 84 of 1,350 patients who re- ciated with publication bias. An NnT of 13 (95% CI, 9 to
ceived systemic antibiotics, a frequency of 6.2%; and in 26) indicated that on average 13 patients needed to be
228 of 1,582 patients who received a placebo or no treated with systemic antibiotics to prevent 1 case of
treatment, a frequency of 14.4%. Meta-analysis indicated AO.
that systemic antibiotic therapy was statistically signifi-
cant in reducing the risk of AO after mandibular third Subgroup Analysis: Quality of Study Design
molar surgery (OR, 2.175, 95% confidence interval [CI], The 16 clinical trials were classified into 3 quality
1.561 to 3.030) (Fig 2). There was no statistically signif- categories based on the rigor of the study design.
icant heterogeneity among the studies (P .147). A Category I (RBP) included 8 trials that had the highest
high PBA (96) indicated that the results were not asso- quality and were randomized, placebo controlled, and
1914 ANTIBIOTIC PROPHYLAXIS IN THIRD MOLAR SURGERY

FIGURE 2. Meta-analysis of clinical trials of systemic antibiotics with alveolar osteitis (AO) as the outcome measure. Het, heterogeneity test; NnT,
number needed to treat; OR, odds ratio calculated from a random effect model; PBA, publication bias assessment.
Ren and Malmstrom. Antibiotic Prophylaxis in Third Molar Surgery. J Oral Maxillofac Surg 2007.

investigator blinded. Category II (RBC) included 5 before surgery and the course of antibiotic therapy
trials that were randomized, controlled and, to some lasted 2 to 7 days after surgery, with the exception of
degree, investigator blinded. Category III (ROpen) Graziani et al,24 where a preoperative course was
included 3 trials that were randomized, controlled but given for 3 days but no postoperative course was
no blinding was carried out. As shown in Figure 3, given; 2) PreSingleDose, a single dose of antibiotics
subgroup analysis of Category I and II trials yielded was given 30 to 90 minutes before surgery; and 3)
similar results as the overall meta-analysis. For the PostOp, first dose of antibiotics was given after the
Category III trials, the results were highly variable and surgery was completed and the course of therapy
the effect of systemic antibiotics on the frequency of lasted 4 to 5 days. Timing of antibiotic dosing had
AO was not statistically significant (OR, 3.927, 95% significant effects on AO outcome (Fig 5). Preopera-
CI, 0.934 to 16.512). tive dosing (PreMultiday and PreSingleDose) were
more effective than postoperative dosing strategies.
Subgroup Analysis: Types of Antibiotics
Postoperative use of antibiotics had no statistically
The 16 clinical trials were divided largely into 2 treat-
significant effect on the frequency of AO (OR, 1.559,
ment categories, ie, wide spectrum antimicrobials rep-
95% CI, 0.862 to 2.823).
resented by amoxicillin (10 trials), and narrow spectrum
antianaerobics represented by metronidazole (6 trials). ANALYSIS OF CLINICAL TRIALS WITH WOUND
The effect of different antibiotics on outcome of AO was INFECTION AS THE OUTCOME MEASURE
similar (Fig 4).
A total of 2,396 patients were randomized to an
Subgroup Analysis: Timing of Antimicrobial antibiotic or a placebo group in 12 clinical trials that
Dosing reported wound infection as an outcome. Wound
Three dosing strategies were used in the 16 trials: infection occurred in 44 of 1,110 patients who re-
1) PreMultiday, first dose of antibiotics was given ceived systemic antibiotics, a frequency of 4.0%; and
REN AND MALMSTROM 1915

FIGURE 3. Subgroup analysis of AO outcomes in clinical trials of different quality of study design. FEM, fixed effect model; RBC, randomized,
blinded, and controlled; RBP, randomized, double blind, and placebo controlled; REM, random effect model; R Open, randomized and controlled.
Ren and Malmstrom. Antibiotic Prophylaxis in Third Molar Surgery. J Oral Maxillofac Surg 2007.

in 78 of 1,286 patients who received a placebo or no after mandibular third molar surgery (OR, 1.794, 95%
treatment, a frequency of 6.1%. Meta-analysis indi- CI, 1.199 to 2.684) (Fig 6). There was no statistically
cated that systemic antibiotic therapy was statistically significant heterogeneity among the studies (P .263).
significant in reducing the risk of wound infection A PBA of 13 indicated a low probability of publication

FIGURE 4. Subgroup analysis of AO outcomes in clinical trials using different types of antimicrobials. FEM, fixed effect model; REM, random effect model.
Ren and Malmstrom. Antibiotic Prophylaxis in Third Molar Surgery. J Oral Maxillofac Surg 2007.
1916 ANTIBIOTIC PROPHYLAXIS IN THIRD MOLAR SURGERY

FIGURE 5. Subgroup analysis of AO outcomes in clinical trials using different dosing strategies. FEM, fixed effect model; PostOp, initial dose given
after surgery followed by 3- to 5-day dosing; PreMultiDay, initial dose given before surgery followed by 3- to 5-day dosing; PreSingleDose, single
dose before surgery; REM, random effect model.
Ren and Malmstrom. Antibiotic Prophylaxis in Third Molar Surgery. J Oral Maxillofac Surg 2007.

bias. An NnT of 25 (95% CI, 15 to 73) indicated that wound infection (OR, 2.867, 95% CI, 0.987 to 8.332;
on average 25 patients needed to be treated with and OR, 1.581, 95% CI, 0.869 to 2.877, respectively).
systemic antibiotics to prevent 1 case of extraction No subgroup analysis was done with regard to route
wound infection. of antibiotic administration. Antibiotics were given by
mouth in 18 of 20 studies. For the remaining 2 studies,
Subgroup Analysis: Quality of Study Design
one used an intravenous single dose of penicillin before
There were 8 Category I, 3 Category II trials, and 1
surgery,34 and the other used an intramuscular single
Category III trial. As shown in Figure 7 (with the
dose of penicillin before surgery followed by oral doses
single Category III trial excluded), both Category I
for 4 days postoperatively.15 No meaningful subgroup
and II trials indicated the effectiveness of antibiotics
analysis could be carried out due to the limited sample
for prevention of wound infection. The effect size and
size.
variation in treatment effect were more pronounced
in Category II trials (OR, 3.300, 95% CI, 1.094 to
9.952) than that in Category I trials (OR, 1.764, 95%
Discussion
CI, 1.078 to 2.887).
The results of this meta-analysis of randomized con-
Subgroup Analysis: Types of Antibiotics
trolled trials indicated that systemic antibiotics were
Of 12 trials, 10 used wide spectrum antibiotics, 1 used
effective in reducing the frequencies of AO and wound
an antianaerobic agent, and 1 used both in 2 separate
infection after surgical removal of impacted mandibular
treatment groups.7 Antianaerobic therapy was not effec-
third molars. On average, patients receiving systemic
tive in the prevention of wound infection (OR, 2.224,
antibiotics were 2.2 times less likely to develop AO and
95% CI, 0.265 to 18.667) (Fig 8).
1.8 times less likely to develop wound infection after
Subgroup Analysis: Timing of Antimicrobial third molar surgery. The wide spectrum antibiotics, rep-
Dosing resented by various penicillin derivatives, and the nar-
Timing of antibiotic dosing had significant effects on row spectrum antianaerobics, represented by metroni-
wound infection outcomes (Fig 9). Systemic antibiotics dazole, were both effective in reducing the frequency of
were effective only when dosing started preoperatively AO, but the latter was not as effective as the former in
and lasted for 2 to 7 days (OR, 2.594, 95% CI, 1.130 to reducing postoperative wound infections. Dosing strat-
5.952). Preoperative single dosing and postoperative egies were found to be an important predictor of the
dosing alone were not as effective for the prevention of effectiveness of the antibiotics, with dosing started be-
REN AND MALMSTROM 1917

FIGURE 6. Meta-analysis of clinical trials of systemic antibiotics with wound infection as the outcome measure. Het, heterogeneity test; NnT, number
needed to treat; OR, odds ratio calculated from a random effect model; PBA, publication bias assessment.
Ren and Malmstrom. Antibiotic Prophylaxis in Third Molar Surgery. J Oral Maxillofac Surg 2007.

fore surgery being more effective than dosing started prophylaxis in third molar surgery. Do the findings of
after the surgery. Antibiotics given after the surgery was this meta-analysis provide a clearer guideline for antibi-
completed were not effective in reducing the frequency otic prophylaxis in third molar surgery? The clinical
of either AO or wound infection. It seemed that the implication of these findings is probably not as clear as
most effective dosing strategy was with the first dose the statistical significance of the odds ratios. To prevent
started 30 to 90 minutes before surgery and continuing 1 case of AO, 13 patients need to receive antibiotic
for 3 to 5 days after the surgery. A preoperative single therapy. Does the benefit of preventing AO outweigh
dose was nearly as effective as the multiday dosing the risks associated with antibiotic therapy? There are
strategy. probably no clear cut answers to these questions. Be-
Because oral surgery is always carried out in a clean- cause complications associated with third molar sur-
contaminated environment where a large amount of gery, especially AO, are very painful and disabling, the
bacteria exist, and postoperative complications are usu- sufferers quality of life and productivity are often im-
ally associated with bacteria contamination and infec- paired.29,35 The monetary costs associated with these
tions, it seems reasonable to prescribe antibiotics to complications are certainly higher than the costs of
prevent and reduce the frequency of postoperative com- antibiotics prescribed commonly such as amoxicillin. It
plications. On the other hand, because the incidence of may make sense to advocate prophylactic antibiotic
postoperative complications is relatively low and usually therapy in third molar surgery from a cost-effectiveness
not life-threatening, and numerous underpowered clin- perspective, but the risks of potential antimicrobial re-
ical trials have produced controversial evidence, there is sistance and severe adverse reactions are difficult to
no consensus on if and how the antibiotics should be estimate and cannot be entirely discounted in clinical
used in third molar surgery. This quantitative review of decision making.36,37 The decision to use antibiotic pro-
randomized controlled trials is aimed at gathering all phylaxis in third molar surgery is ultimately the respon-
available evidence and providing guidance for antibiotic sibility of the surgeon. He or she must consider all
1918 ANTIBIOTIC PROPHYLAXIS IN THIRD MOLAR SURGERY

FIGURE 7. Subgroup analysis of wound infection outcomes in clinical trials of different quality of study design. FEM, fixed effect model; RBC,
randomized, blinded, and controlled; RBP, randomized, double blind, and placebo controlled; REM, random effect model.
Ren and Malmstrom. Antibiotic Prophylaxis in Third Molar Surgery. J Oral Maxillofac Surg 2007.

potential factors that may contribute to the postopera- Bacteria invasion is most likely one of many factors
tive complications and decide if the benefits of antibi- contributing to the blood clot disintegration and the
otic therapy outweigh its risks. AO is not considered a development of AO. Surgical trauma, age, and gender
disease of bacterial infection but a healing disturbance are known risk factors for the development of AO and
due to the loss of the blood clot in the extraction socket. other postoperative complications.38-40 It may be pru-

FIGURE 8. Subgroup analysis of wound infection outcomes in clinical trials using different types of antimicrobials. FEM, fixed effect model; REM,
random effect model.
Ren and Malmstrom. Antibiotic Prophylaxis in Third Molar Surgery. J Oral Maxillofac Surg 2007.
REN AND MALMSTROM 1919

FIGURE 9. Subgroup analysis of wound infection outcomes in clinical trials using different dosing strategies. FEM, fixed effect model; PostOp, initial
dose given after surgery followed by 3- to 5-day dosing; PreMultiDay, initial dose given before surgery followed by 3- to 5-day dosing;
PreSingleDose, single dose before surgery; REM, random effect model.
Ren and Malmstrom. Antibiotic Prophylaxis in Third Molar Surgery. J Oral Maxillofac Surg 2007.

dent to use antibiotic prophylaxis only in patients antibiotic that is effective on both aerobic and anaer-
judged to have increased risks of postoperative compli- obic bacteria, and a narrow spectrum antibiotic that is
cations. only effective on anaerobic bacteria. Although the
For the antibiotics to be effective in reducing the role of anaerobic bacteria has been emphasized in
surgical complications, the timing of its application is postoperative complications,43,44 both types of bacte-
very important. The antibiotic must be present in a ria are present in the oral cavity and in association
therapeutic amount when the first incision is made with third molars.45 Amoxicillin and other penicillin
and before surgery is completed to allow its effect on derivatives were shown to be highly effective on a
microbes that contaminate the surgical wounds and wide variety of aerobic and anaerobic bacteria in the
blood clots. This requires that the antibiotic be given oral cavity. They might serve as the first choice for
approximately 1 hour before surgery.41,42 The results antibiotic prophylaxis in third molar surgery.45,46 The
of the present study confirmed the effectiveness of findings of this meta-analysis confirmed the effective-
preoperative dosing and the ineffectiveness of post- ness of both wide spectrum antibiotics and narrow
operative dosing of antibiotics for prevention of post- spectrum antianaerobic agents in reducing the fre-
operative complications. An antibiotic given 30 to 90 quency of AO. Antianaerobic agents seemed less ef-
minutes before the first incision and continued 3 to 5 fective in the prevention of wound infections, which
days after the surgery was a dosing strategy with the might indicate that anaerobic bacteria played a lesser
most predictable effectiveness for the prevention of role in soft tissue wound infections than in intra-
AO and wound infections. A single dose of antibiotics socket AO. However, only 2 studies with relatively
before surgery was also very effective in reducing the small sample sizes reported the effects of antianaero-
frequency of AO, but less predictable in its effect on bic agents on wound infections (Fig 8), which might
postoperative wound infections. Because the fre- limit the validity of any conclusion regarding the ef-
quency of wound infection was low (6%) as com- fectiveness or ineffectiveness of this type of antibiot-
pared with that of AO (14%) in patients who did not ics in the prevention of such complications.
receive prophylactic antibiotics, a single dose of anti- As in any meta-analytic review, the quality of the
biotics given 1 hour before surgery may be the most synthesized findings is to a large extent determined by
cost-effective strategy in third molar surgery. the quality of the original clinical studies. There were
Most of the reviewed clinical trials used 1 of 2 significant discrepancies in study settings, case selec-
distinctive groups of antimicrobials: a wide spectrum tions, surgical procedures, surgeon experiences, diag-
1920 ANTIBIOTIC PROPHYLAXIS IN THIRD MOLAR SURGERY

nostic criteria, and scientific rigor in the conduct of 5. Chiapasco M, De Cicco L, Marrone G: Side effects and compli-
cations associated with third molar surgery. Oral Surg Oral Med
these original studies. We made efforts to use a ran-
Oral Pathol 76:412, 1993
dom effect model to increase the rigor of the statisti- 6. Goldberg MH, Nemarich AN, Marco WP 2nd: Complications
cal analysis and to use subgroup analysis to separate after mandibular third molar surgery: A statistical analysis of
the higher quality studies from the lower quality stud- 500 consecutive procedures in private practice. J Am Dent
Assoc 111:277, 1985
ies, but it cannot be stated with absolute certainty 7. Happonen RP, Backstrom AC, Ylipaavalniemi P: Prophylactic
that the outcome of this study should be used as a use of phenoxymethylpenicillin and tinidazole in mandibular
rigid guideline in clinical practice concerning antibi- third molar surgery, a comparative placebo controlled clinical
trial. Br J Oral Maxillofac Surg 28:12, 1990
otic prophylaxis in third molar surgery. Although the
8. Osborn TP, Frederickson G Jr, Small IA, et al: A prospective
findings of this study may represent the best available study of complications related to mandibular third molar sur-
evidence, a well-designed randomized and placebo- gery. J Oral Maxillofac Surg 43:767, 1985
controlled multicenter clinical trial is needed to reach 9. Yoshii T, Hamamoto Y, Muraoka S, et al: Incidence of deep
fascial space infection after surgical removal of the mandibular
a definitive conclusion. Such definitive clinical trial third molars. J Infect Chemother 7:55, 2001
should take into consideration known risk factors 10. Kunkel M, Morbach T, Kleis W, et al: Third molar complica-
such as age, gender, and smoking, and have a clearly tions requiring hospitalization. Oral Surg Oral Med Oral Pathol
Oral Radiol Endodont 102:300, 2006
defined criterion for case inclusion or exclusion, a 11. Piecuch JF, Arzadon J, Lieblich SE: Prophylactic antibiotics for
standardized procedure for surgical and antibiotic in- third molar surgery: A supportive opinion. J Oral Maxillofac
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dissenting opinion. J Oral Maxillofac Surg 53:61, 1995
In summary, the findings of this meta-analysis sug- 13. Kay LW: Investigations into the nature of pericoronitisII. Br J
gest that there is a role for systemic antibiotic pro- Oral Surg 4:52, 1966
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tions, such as smoking, poor oral hygiene, and older impacted third molar surgery. Eur J Oral Sci 107:437, 1999
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biotics are not the only route for prevention of post- in the mandible. Int J Oral Surg 10:173, 1981
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clavulanic acid in preventing infectious and inflammatory com-
The authors thank Drs Michael Yunker and Thomas DeRosa for plications following impacted mandibular third molar extrac-
their critical review and constructive comments during the prepa- tion. Oral Surg Oral Med Oral Pathol Oral Radiol Endodont
ration of this article. 100:e11, 2005
24. Graziani F, Corsi L, Fornai M, et al: Clinical evaluation of
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