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

1909
1910
showed that AO occurred in 325 of 1,341 patients
who had undergone third molar surgery without an-
tibiotic prophylaxis. In contrast, only 50 of 1,620
patients who received a single dose of penicillin be-
fore surgery had developed AO, signifying a reduction
in the incidence of AO from 24% to 3%. The effec-
tiveness of antibiotic prophylaxis was even more dra-
matic in patients with pericoronitis, where a single
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
third molar surgery. Although a number of subse-
quent clinical trials questioned the effectiveness of
antibiotic prophylaxis in third molar surgery,14-17
other studies supported the use of antibiotics before
or after the surgery.18-22 The conflicting conclusions
from randomized controlled clinical trials have caused
long-standing confusion in clinical practice, with ad-
vocates and opponents of antibiotic prophylaxis each
presenting their own supporting evidence.11,12 Al-
though the wisdom of routine antibiotic prophylaxis
has been questioned frequently due to its question-
able effectiveness, potential allergic and anaphylactic
reactions, and risk of inducing drug resistance, clini-
cians have not abandoned the practice of prescribing
antibiotics for prevention of postoperative complica-
tions after third molar surgery.11 Recent published
clinical trials only added to the confusion, with some
studies supporting the effectiveness of antibiotic pro-
phylaxis23-25 and others opposing it.26-28
Because postoperative AO and infection are accom-
panied by debilitating pain and severe functional im-
pairment, patients often experience diminished qual-
ity of life and lost productivity.29-32 Therefore, for
many years clinicians have sought an effective way to
prevent postoperative complications after third molar
surgery. Many randomized clinical trials were con-
ducted in the past to investigate the effectiveness of
antibiotic prophylaxis in reducing morbidity associ-
ated with third molar surgery, but these studies suf-
fered from a common flaw, that is, the lack of statis-
tical power to detect a meaningful difference
between the study groups. For example, if a reduc-
tion from 15% to 5% in postoperative complications is
considered effective and clinically significant, a clini-
cal trial with a sample size of 318 (159 in each group)
is required to detect such magnitude of difference
with 80% power at an alpha level of 0.05 for a 2-tailed
test (EpiInfo 3.3, Centers for Disease Control and
Prevention, Atlanta, GA). With few exceptions, pub-
lished clinical trials involved a much smaller sample
size that did not support a conclusive outcome anal-
ysis.
The purpose of this study was to conduct a syn-
thetic quantitative review of randomized controlled
clinical trials on the effectiveness of antibiotic pro-
ANTIBIOTIC PROPHYLAXIS IN THIRD MOLAR SURGERY
phylaxis in third molar surgery. The null hypothesis
was that antibiotic prophylaxis was not effective in
preventing postoperative complications including AO
and infections. The specific aims were to collect and
evaluate all randomized controlled clinical trials in
English and non-English literature, published or un-
published, and to test the hypothesis through meta-
analysis.
Materials and Methods
SEARCH STRATEGY
An initial search was conducted using Ovid Med-
line, PubMed, and the Cochrane Central Register of
Controlled Trials (CENTRAL) with a combination of
Medical Subject Headings (MeSH) of anti-bacterial
agents or antimicrobial agents, and third molar.
Both English and non-English articles were included
in the literature search. All abstracts were reviewed
and the articles described as a clinical trial were se-
lected. The reference lists of the selected articles
were searched and any relevant articles collected for
review. For non-English publications, the methods
and results sections were reviewed and translated by
2 dentists fluent in the original language. A separate
search was carried out to identify only review articles
and the reference lists of the review articles were
examined to look for additional clinical trials that
were not included in the above database or published
before 1966 when the database was established ini-
tially. We searched NLM Gateway (http://gateway.nlm.
nih.gov/gw/Cmd) to locate relevant meeting abstracts.
For those studies in which only an abstract was avail-
able, we attempted to contact the author to request
more detailed information. We also searched for unpub-
lished trials or theses through an Internet search engine
(Google). Worldwide clinical trial registration sites
(www.clinicaltrials.gov, www.controlled-trials.com,
and www.actr.org.au) were searched for on-going stud-
ies and the principle investigators of relevant clinical
trials were contacted to request trial and outcome infor-
mation, if available.
INCLUSION CRITERIA
Articles that meet the following criteria were re-
viewed and included in the meta-analysis:
1. Must involve surgical extraction of an impacted
mandibular third molar;
2. Must be described as a randomized clinical trial;
3. Must include a control group;
4. Must include systemic antibiotic prophylaxis as
intervention; and
5. Must include outcomes that are described as
postoperative inflammatory complications, such
REN AND MALMSTROM
as alveolar osteitis (dry socket, alveolitis, or
fibrinolytic alveolitis) or infection.
Studies that did not involve randomization, had no
control group or did not describe outcomes were not
included for review. Clinical trials that used topical
antimicrobial agents such as a mouthwash or socket
dressing were also excluded because our focus was
on systemic antibiotics that were given either enter-
ally or parenterally.
DATA EXTRACTION
A data extraction form was used to retrieve infor-
mation regarding study design, inclusion and exclu-
sion criteria, patient characteristics, intervention, and
outcomes.
The quality of the trial was evaluated based on the
rigor of the study design. All studies included in the
review were randomized and had a control group, but
a placebo was used only in some of the studies.
Investigator blinding was not described in some stud-
ies, which might negate the validity of the study.
Although all the selected clinical trials involved sys-
temic antibiotic prophylaxis, we recognized that large
variations existed in timing, type, route, and duration
of application. Timing of administration was divided
into preoperative (antibiotics were given at least 30
minutes before surgery) and postoperative (given af-
ter the completion of surgery). Type of antibiotics
was divided into wide-spectrum antibiotics (mostly
penicillin derivatives represented by amoxicillin) and
antianaerobic agents (represented by metronidazole).
Routes of administration included parenteral (by in-
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)
applications.
The primary outcome variable was postoperative
inflammatory complications including AO and surgi-
cal wound infection. Diagnostic criteria for AO and
infection was extracted from each study and recorded
in the data form. A diagnosis of AO was established if:
1) severe pain occurred 3 to 7 days after the extrac-
tion; or 2) there was a denuded extraction socket
with exposed osseous tissue. A diagnosis of surgical
wound infection was established if: 1) there was pu-
rulent discharge from the surgical site; or 2) there
were other signs of infection, such as fever, lymph-
adenopathy, or persistent swelling and pain that can-
not be explained by surgical trauma.
STATISTICAL ANALYSIS
The data from the studies were analyzed using a
meta-analytical program (Tecnopharma Meta-analysis
1.2.0) with a random-effect model. We determined
that a random effect model was more appropriate
1911
than a fixed effect model for this study because vari-
ations between different studies might be present
even if the 2 test for heterogeneity did not show
statistical significance. For the subgroup sensitivity
analysis, results for both the fixed-effect and random-
effect models were presented.
Sensitivity Analysis
Several sensitivity analyses for the primary outcome
were planned: 1) subgroup analysis according to dif-
ferent quality of study designs; 2) subgroup analysis
according to different types of antibiotics; and 3)
subgroup analysis according to timing and duration of
antibiotic use, including preoperative single dose,
preoperative plus postoperative multiple doses, and
postoperative multiple doses only.
Publication Bias Assessment
If the result of meta-analyses indicating antibiotic
prophylaxis was statistically more effective than the
control group, or vice versa, a publication bias assess-
ment (PBA) was carried out to analyze if the positive
finding was a function of publication bias. This assess-
ment was based on an estimation of the minimum
number of negative (or positive) studies required to
reverse the results of the meta-analysis to the level of
statistical non significance.33 The higher the number,
the less likely there is publication bias.
Number Needed to Treat
Number needed to treat (NnT) refers to the number
of patients needed to be treated with antibiotic pro-
phylaxis to prevent 1 postoperative AO or infection.
NnT was calculated as 1/pooled risk difference.
Results
Ovid Medline, PubMed, and CENTRAL search re-
sulted in 96 titles that potentially meet the inclusion
criteria. After reviewing all the abstracts, 23 clinical
trials involving systemic antibiotics were identified.
Further search of reference lists of published clinical
trials and review articles identified 14 more publica-
tions. Searching the NLM Gateway located 1 abstract
presented at an international conference. The primary
author in Barcelona, Spain was contacted and a manu-
script accepted for publication in English was re-
ceived. One ongoing clinical trial was found through
searching the online registration sites. The principle
investigator in the United States was contacted and a
manuscript accepted for publication was provided by
the principle investigator. Internet (Google) search
located 1 clinical trial described on a United States
dental school Web site involving antibiotic prophy-
laxis in smokers undergoing third molar surgery. The
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-
ceived systemic antibiotics, a frequency of 6.2%; and in
228 of 1,582 patients who received a placebo or no
treatment, a frequency of 14.4%. Meta-analysis indicated
that systemic antibiotic therapy was statistically signifi-
cant in reducing the risk of AO after mandibular third
molar surgery (OR, 2.175, 95% confidence interval [CI],
1.561 to 3.030) (Fig 2). There was no statistically signif-
icant heterogeneity among the studies (P .147). A
high PBA (96) indicated that the results were not asso-
ciated with publication bias. An NnT of 13 (95% CI, 9 to
26) indicated that on average 13 patients needed to be
treated with systemic antibiotics to prevent 1 case of
AO.
Subgroup Analysis: Quality of Study Design
The 16 clinical trials were classified into 3 quality
categories based on the rigor of the study design.
Category I (RBP) included 8 trials that had the highest
quality and were randomized, placebo controlled, and
1914
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
trials that were randomized, controlled and, to some
degree, investigator blinded. Category III (ROpen)
included 3 trials that were randomized, controlled but
no blinding was carried out. As shown in Figure 3,
subgroup analysis of Category I and II trials yielded
similar results as the overall meta-analysis. For the
Category III trials, the results were highly variable and
the effect of systemic antibiotics on the frequency of
AO was not statistically significant (OR, 3.927, 95%
CI, 0.934 to 16.512).
Subgroup Analysis: Types of Antibiotics
The 16 clinical trials were divided largely into 2 treat-
ment categories, ie, wide spectrum antimicrobials rep-
resented by amoxicillin (10 trials), and narrow spectrum
antianaerobics represented by metronidazole (6 trials).
The effect of different antibiotics on outcome of AO was
similar (Fig 4).
Subgroup Analysis: Timing of Antimicrobial
Dosing
Three dosing strategies were used in the 16 trials:
1) PreMultiday, first dose of antibiotics was given
ANTIBIOTIC PROPHYLAXIS IN THIRD MOLAR SURGERY
before surgery and the course of antibiotic therapy
lasted 2 to 7 days after surgery, with the exception of
Graziani et al,24 where a preoperative course was
given for 3 days but no postoperative course was
given; 2) PreSingleDose, a single dose of antibiotics
was given 30 to 90 minutes before surgery; and 3)
PostOp, first dose of antibiotics was given after the
surgery was completed and the course of therapy
lasted 4 to 5 days. Timing of antibiotic dosing had
significant effects on AO outcome (Fig 5). Preopera-
tive dosing (PreMultiday and PreSingleDose) were
more effective than postoperative dosing strategies.
Postoperative use of antibiotics had no statistically
significant effect on the frequency of AO (OR, 1.559,
95% CI, 0.862 to 2.823).
ANALYSIS OF CLINICAL TRIALS WITH WOUND
INFECTION AS THE OUTCOME MEASURE
A total of 2,396 patients were randomized to an
antibiotic or a placebo group in 12 clinical trials that
reported wound infection as an outcome. Wound
infection occurred in 44 of 1,110 patients who re-
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
on average 25 patients needed to be treated with
systemic antibiotics to prevent 1 case of extraction
wound infection.
Subgroup Analysis: Quality of Study Design
There were 8 Category I, 3 Category II trials, and 1
Category III trial. As shown in Figure 7 (with the
single Category III trial excluded), both Category I
and II trials indicated the effectiveness of antibiotics
for prevention of wound infection. The effect size and
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%
CI, 1.078 to 2.887).
Subgroup Analysis: Types of Antibiotics
Of 12 trials, 10 used wide spectrum antibiotics, 1 used
an antianaerobic agent, and 1 used both in 2 separate
treatment groups.7 Antianaerobic therapy was not effec-
tive in the prevention of wound infection (OR, 2.224,
95% CI, 0.265 to 18.667) (Fig 8).
Subgroup Analysis: Timing of Antimicrobial
Dosing
Timing of antibiotic dosing had significant effects on
wound infection outcomes (Fig 9). Systemic antibiotics
were effective only when dosing started preoperatively
and lasted for 2 to 7 days (OR, 2.594, 95% CI, 1.130 to
5.952). Preoperative single dosing and postoperative
dosing alone were not as effective for the prevention of
wound infection (OR, 2.867, 95% CI, 0.987 to 8.332;
and OR, 1.581, 95% CI, 0.869 to 2.877, respectively).
No subgroup analysis was done with regard to route
of antibiotic administration. Antibiotics were given by
mouth in 18 of 20 studies. For the remaining 2 studies,
one used an intravenous single dose of penicillin before
surgery,34 and the other used an intramuscular single
dose of penicillin before surgery followed by oral doses
for 4 days postoperatively.15 No meaningful subgroup
analysis could be carried out due to the limited sample
size.
Discussion
The results of this meta-analysis of randomized con-
trolled trials indicated that systemic antibiotics were
effective in reducing the frequencies of AO and wound
infection after surgical removal of impacted mandibular
third molars. On average, patients receiving systemic
antibiotics were 2.2 times less likely to develop AO and
1.8 times less likely to develop wound infection after
third molar surgery. The wide spectrum antibiotics, rep-
resented by various penicillin derivatives, and the nar-
row spectrum antianaerobics, represented by metroni-
dazole, were both effective in reducing the frequency of
AO, but the latter was not as effective as the former in
reducing postoperative wound infections. Dosing strat-
egies were found to be an important predictor of the
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
after the surgery. Antibiotics given after the surgery was
completed were not effective in reducing the frequency
of either AO or wound infection. It seemed that the
most effective dosing strategy was with the first dose
started 30 to 90 minutes before surgery and continuing
for 3 to 5 days after the surgery. A preoperative single
dose was nearly as effective as the multiday dosing
strategy.
Because oral surgery is always carried out in a clean-
contaminated environment where a large amount of
bacteria exist, and postoperative complications are usu-
ally associated with bacteria contamination and infec-
tions, it seems reasonable to prescribe antibiotics to
prevent and reduce the frequency of postoperative com-
plications. On the other hand, because the incidence of
postoperative complications is relatively low and usually
not life-threatening, and numerous underpowered clin-
ical trials have produced controversial evidence, there is
no consensus on if and how the antibiotics should be
used in third molar surgery. This quantitative review of
randomized controlled trials is aimed at gathering all
available evidence and providing guidance for antibiotic
prophylaxis in third molar surgery. Do the findings of
this meta-analysis provide a clearer guideline for antibi-
otic prophylaxis in third molar surgery? The clinical
implication of these findings is probably not as clear as
the statistical significance of the odds ratios. To prevent
1 case of AO, 13 patients need to receive antibiotic
therapy. Does the benefit of preventing AO outweigh
the risks associated with antibiotic therapy? There are
probably no clear cut answers to these questions. Be-
cause complications associated with third molar sur-
gery, especially AO, are very painful and disabling, the
sufferers quality of life and productivity are often im-
paired.29,35 The monetary costs associated with these
complications are certainly higher than the costs of
antibiotics prescribed commonly such as amoxicillin. It
may make sense to advocate prophylactic antibiotic
therapy in third molar surgery from a cost-effectiveness
perspective, but the risks of potential antimicrobial re-
sistance and severe adverse reactions are difficult to
estimate and cannot be entirely discounted in clinical
decision making.36,37 The decision to use antibiotic pro-
phylaxis in third molar surgery is ultimately the respon-
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-
tive complications and decide if the benefits of antibi-
otic therapy outweigh its risks. AO is not considered a
disease of bacterial infection but a healing disturbance
due to the loss of the blood clot in the extraction socket.
Bacteria invasion is most likely one of many factors
contributing to the blood clot disintegration and the
development of AO. Surgical trauma, age, and gender
are known risk factors for the development of AO and
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
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
judged to have increased risks of postoperative compli-
cations.
For the antibiotics to be effective in reducing the
surgical complications, the timing of its application is
very important. The antibiotic must be present in a
therapeutic amount when the first incision is made
and before surgery is completed to allow its effect on
microbes that contaminate the surgical wounds and
blood clots. This requires that the antibiotic be given
approximately 1 hour before surgery.41,42 The results
of the present study confirmed the effectiveness of
preoperative dosing and the ineffectiveness of post-
operative dosing of antibiotics for prevention of post-
operative complications. An antibiotic given 30 to 90
minutes before the first incision and continued 3 to 5
days after the surgery was a dosing strategy with the
most predictable effectiveness for the prevention of
AO and wound infections. A single dose of antibiotics
before surgery was also very effective in reducing the
frequency of AO, but less predictable in its effect on
postoperative wound infections. Because the fre-
quency of wound infection was low (6%) as com-
pared with that of AO (14%) in patients who did not
receive prophylactic antibiotics, a single dose of anti-
biotics given 1 hour before surgery may be the most
cost-effective strategy in third molar surgery.
Most of the reviewed clinical trials used 1 of 2
distinctive groups of antimicrobials: a wide spectrum
1919
antibiotic that is effective on both aerobic and anaer-
obic bacteria, and a narrow spectrum antibiotic that is
only effective on anaerobic bacteria. Although the
role of anaerobic bacteria has been emphasized in
postoperative complications,43,44 both types of bacte-
ria are present in the oral cavity and in association
with third molars.45 Amoxicillin and other penicillin
derivatives were shown to be highly effective on a
wide variety of aerobic and anaerobic bacteria in the
oral cavity. They might serve as the first choice for
antibiotic prophylaxis in third molar surgery.45,46 The
findings of this meta-analysis confirmed the effective-
ness of both wide spectrum antibiotics and narrow
spectrum antianaerobic agents in reducing the fre-
quency of AO. Antianaerobic agents seemed less ef-
fective in the prevention of wound infections, which
might indicate that anaerobic bacteria played a lesser
role in soft tissue wound infections than in intra-
socket AO. However, only 2 studies with relatively
small sample sizes reported the effects of antianaero-
bic agents on wound infections (Fig 8), which might
limit the validity of any conclusion regarding the ef-
fectiveness or ineffectiveness of this type of antibiot-
ics in the prevention of such complications.
As in any meta-analytic review, the quality of the
synthesized findings is to a large extent determined by
the quality of the original clinical studies. There were
significant discrepancies in study settings, case selec-
tions, surgical procedures, surgeon experiences, diag-
1920
nostic criteria, and scientific rigor in the conduct of
these original studies. We made efforts to use a ran-
dom effect model to increase the rigor of the statisti-
cal analysis and to use subgroup analysis to separate
the higher quality studies from the lower quality stud-
ies, but it cannot be stated with absolute certainty
that the outcome of this study should be used as a
rigid guideline in clinical practice concerning antibi-
otic prophylaxis in third molar surgery. Although the
findings of this study may represent the best available
evidence, a well-designed randomized and placebo-
controlled multicenter clinical trial is needed to reach
a definitive conclusion. Such definitive clinical trial
should take into consideration known risk factors
such as age, gender, and smoking, and have a clearly
defined criterion for case inclusion or exclusion, a
standardized procedure for surgical and antibiotic in-
terventions, and a sound protocol for outcome assess-
ments.
In summary, the findings of this meta-analysis sug-
gest that there is a role for systemic antibiotic pro-
phylaxis in third molar surgery. There is sufficient
evidence to recommend a single dose of penicillin or
its derivatives 1 hour before surgical removal of im-
pacted mandibular third molars. For patients who
have known risk factors for postoperative complica-
tions, such as smoking, poor oral hygiene, and older
age, a single dose before surgery followed by 2 to 5
days of penicillin after surgery should be considered.
It must be emphasized, however, that systemic anti-
biotics are not the only route for prevention of post-
operative complications. Topical applications of anti-
septics (eg, chlorhexidine) and antibiotics (eg,
tetracycline intrasocket dressing) are all viable alter-
natives. There are advantages and disadvantages for
each of these strategies in clinical practices, and the
clinicians are encouraged to carefully evaluate the
evidence for each choice and make an informed de-
cision for the best interests of their patients.
Acknowledgments
The authors thank Drs Michael Yunker and Thomas DeRosa for
their critical review and constructive comments during the prepa-
ration of this article.
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