Effectiveness of Antimicrobial

Prophylaxis in Preventing the Spread

of Infection as a Result of Oral
Procedures: A Systematic Review and
Meta-Analysis
Johana Alejandra Moreno-Drada, OD, MSc,* and
Herney Andr
es Garc
ıa-Perdomo, MD, MSc, EdD, PhDy
Purpose: To determine the effectiveness of prophylactic antibiotics for preventing localized infections
of the oral cavity, neck, and thoracic cavity in patients undergoing oral procedures.
Materials and Methods: A systematic review and meta-analysis was performed. A search strategy was
applied to the Medline database through Ovid, EMBASE, LILACS, the Cochrane Central Register of
Controlled Trials, and OpenGrey. Clinical trials were included, and studies in which patients underwent
procedures outside the oral cavity were excluded. Statistical analysis was performed using Stata 13 and
RevMan 5.3. A risk of bias assessment was performed according to Cochrane recommendations.
Results: For the primary results of oral cavity infection with antibiotic intervention versus placebo, 6
studies with a risk difference (RD) of 0.025 were included (95% confidence interval [CI], 0.043
to 0.007). For bacteremia with antibiotic intervention versus placebo, 7 studies with an RD of 0.278
were included (95% CI, 0.380 to 0.176); when an analysis of antibiotic versus antibiotic was performed,
6 studies with an RD 0.072 were included (95% CI, 0.255 to 0.112), favoring antibiotic prophylaxis.
There was no evidence of neck and thoracic cavity infection. For type of treatment, implant surgery with
placebo showed an RD of 0.021 (95% CI, 0.043 to 0.001), whereas an RD 0.245 was observed when
performing tooth extraction (95% CI, 0.337 to 0.154).
Conclusion: The incidence of infections in the oral cavity decreased with the use of antibiotic prophy-
laxis in patients undergoing tooth extraction. However, for implant surgery and endodontic surgery, pro-
phylactic antibiotic showed no differences compared with placebo. No infections in the neck or thoracic
cavity were reported. It is necessary to evaluate antibiotic prophylaxis in high-risk patients.
Ó 2016 American Association of Oral and Maxillofacial Surgeons
J Oral Maxillofac Surg 74:1313-1321, 2016

Odontogenic infections are the leading cause of consul-
tation in emergency departments and outpatient dental
practices. In addition, they are the reason for approxi-
mately 10% of antibiotic prescriptions written in Spain 1
and frequently result from dental caries, dentoalveolar
alterations, gingivitis, periodontitis, infections of
aponeurotic spaces, osteitis, and osteomyelitis.2,3
Moreover, the incidence of bacteremia has been well
documented after dental procedures.4,5 Bacteremia
has been observed in 100% of patients after dental
extraction, 70% after root planing, 55% after third
molar surgery, and 20% after endodontic treatment.6
Severe complications of odontogenic infections
have been reported as a result of bacteremia, induced
autoimmune response, diffusion through anatomic
planes, and paths of least resistance.7-9 Infections

*Department Head, Department of Dentistry and Oral and Received January 19 2016
Maxillofacial Surgery, Hospital San Juan de Dios, Cali, Colombia. Accepted March 8 2016
yProfessor, University of Valle; Academic Managing Director, Ó 2016 American Association of Oral and Maxillofacial Surgeons
Hospital Universitario del Valle, Cali, Colombia. 0278-2391/16/00340-2
Address correspondence and reprint requests to Ms Moreno-Drada: http://dx.doi.org/10.1016/j.joms.2016.03.006
Hospital de San Juan de Dios, Cali, Colombia; e-mail: johanita1420@
hotmail.com

1313
1314
occasionally can disseminate to different parts of the
body and can even lead to serious complications and
death.1,10 However, surgical wounds of the oral
cavity have been classified as clean-contaminated
wounds.11 Clean-contaminated wounds can be
managed with preoperative prophylactic antibiotics
if there are no other major risk factors.11
Dental procedures are considered high risk. Based
on expert opinions, it is recommended that prophy-
laxis be given to patients at high risk before manipula-
tion of the gingiva or periapical region of the teeth and
before perforation of the oral mucosa during dental
procedures.12
The decision of whether to use preoperative pro-
phylactic antibiotics is controversial. Some investiga-
tors have written that this decision is based on the
supposition that the patient has no major medical
risk factors that could affect the patient’s defense
mechanisms. Several risk factors include poorly
controlled diabetes, kidney disease, severe alcoholism,
immunosuppressive diseases (eg, leukemia, lym-
phoma, or advanced malignancy), and the use of
chemotherapeutic agents or other immunosuppres-
sive medications. In these patients, the health profes-
sional must be concerned about the prevention of
initial contamination and the possibility of reinfection
during the postoperative period.11
However, in most cases, the antibiotic prescription
refers to a series of factors that are not always well
defined. As a result, treatments might be inappropriate
and promote the development of bacterial resistance.2
The prescription of prophylactic antibiotics in cases in
which they might be unnecessary likewise could
result in an increased risk of adverse reactions. It has
been reported that approximately 3% of adverse reac-
tions to medications are caused by amoxicillin, the
antibiotic most widely prescribed for prophylaxis.13
Thus, the nature of dental procedures that cause
bacteremia, the determination of patients at risk, and
the effectiveness of antimicrobial prophylaxis remain
controversial; despite numerous studies, the discus-
sion continues.14
In the face of bacterial resistance, infections can
continue to disseminate through the anatomic planes
and pathways with lower resistance, leading to com-
plications, such as Ludwig angina, thoracic empyema,
mediastinal retinitis, necrotizing fasciitis, cavernous
sinus thrombosis, cerebral abscess, meningitis, septi-
cemia, and bacterial endocarditis. Maxillary sinusitis
and osteomyelitis, orbital abscess, abscess causing
compression of the airway, carotid sheath abscesses
and jugular thrombophlebitis, pleurisy, and other pro-
cesses related to bacteremia have been found.7
Therefore, it is very important to learn about antibi-
otic prophylaxis in oral procedures and the risk of
infectious dissemination, especially in the head,
ANTIMICROBIAL PROPHYLAXIS IN ORAL PROCEDURES
neck, and thorax, which can lead to severe complica-
tions and even death.
The objective of this study was to determine the
effectiveness of prophylactic antibiotics for preventing
localized infections of the oral cavity, neck, and thoracic
cavity in patients undergoing oral procedures.
Materials and Methods
This study was performed according to Cochrane
recommendations and Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA)
guidelines. The protocol was registered in PROSPERO
(registration number, CRD42016032985), an interna-
tional prospective register of systematic reviews.
Clinical trials were included without any restric-
tions on language. Articles included in this study con-
cerned only women and men older than 18 years who
underwent oral procedures and received a prophylac-
tic antibiotic (single preoperative dose) or another
intervention for the prevention of infection. Proce-
dures that were emphasized in the selected articles
were tooth extraction, oral implantation, and end-
odontic surgery. Similarly, interventions (compari-
sons) emphasized in the selected studies were
antibiotic versus placebo, antibiotic versus antibiotic,
and antibiotic versus no intervention.
Studies in which patients underwent procedures
outside the oral cavity and studies in which the effec-
tiveness of antibiotic prophylaxis or adverse events
was not described were excluded.
The primary outcome variables selected were infec-
tion of the oral cavity, infection of the neck, and infec-
tion of the thoracic cavity, and the secondary outcome
variables were the type of prophylactic antibiotic, anti-
biotic adverse effect, and bacteremia.
A search of clinical trials was performed using the
Medline database through Ovid, EMBASE, the Co-
chrane Central Registry of Controlled Trials (CEN-
TRAL), LILACS, and OpenGrey. A search for
additional studies was conducted in the reference lists
of selected articles. The results of the searches were
verified to eliminate duplicates. Study authors, confer-
ences, and topic experts were contacted to include un-
published literature (Appendix 1).
The studies were selected by blinded and indepen-
dent researchers. They were collected according to ti-
tles and abstracts to determine the possible usefulness
of the articles. The eligibility criteria were applied to
the complete articles in the final selection.
The data were collected using a standardized data
collection format that contained the study design, par-
ticipants, variables, interventions and comparisons,
and results. The authors confirmed the data entry
and checked it by double entry of the data for greater
accuracy.
MORENO-DRADA AND GARC
ıA-PERDOMO 1315

The risk of bias was evaluated according to Co-

chrane recommendations15 for sequence generation;
allocation concealment; blinding of participants,
personnel, and outcome assessors; incomplete
outcome data; selective outcome reporting; and other
sources of bias.
Statistical analysis was performed using Stata 13 (Sta-
taCorp, College Station, TX) and RevMan 5.3 (Cochrane
Informatics and Knowledge Management Department,
London, UK). The final outcome variables are reported
as risk difference (RD) and relative risk (RR). A random-
effects model was used in accordance with the hetero-
geneity found in the studies. The results are reported in
forest plots of the estimated effects of the included
studies with 95% confidence intervals (CIs).
Subgroup analyses were performed to investigate
heterogeneous results or answer specific questions
about different groups.15 Subgroup analysis for the
type of prophylactic antibiotic and the type of oral pro-
cedure was performed. No analysis was performed for
subgroups considered high risk, such as immunocom-
promised patients, patients with diabetes mellitus, pa-
tients with heart disease, and age, because this
information was not described in the study.
Heterogeneity was evaluated using the I2 test. For
interpretation, values of 25, 50, and 75% in the I2
test corresponded to low, medium, and high levels of
heterogeneity, respectively.15
An evaluation was conducted to identify reporting
or publication bias using the funnel plot.15

Results
Of 329 articles found, 14 were included in the
qualitative and quantitative analyses (Anitua et al16;
Halpern et al17; Esposito et al18; Lindeboom et al19;
Bezerra et al20; Nolan et al21; Duvall et al22; Diz Dios
et al23; Maharaj et al24; Vergis et al25; Josefsson
et al26; Lockhart et al27; Shanson et al28; Hall et al29)
after excluding duplicates and articles that did not
meet the inclusion criteria (Fig 1).
In total, 2,063 patients were included in the 14
studies; 6 studies evaluated oral infection as the
outcome of interest, and 8 evaluated bacteremia. FIGURE 1. Study selection diagram.
None measured the 2 outcomes. For type of procedure Moreno-Drada and Garc
ıa-Perdomo. Antimicrobial Prophylaxis
performed, the studies of Anitua et al, Esposito et al, in Oral Procedures. J Oral Maxillofac Surg 2016.
and Nolan et al examined the placement of dental
implants. The study of Lindeboom et al concerned penicillin derivatives as the principal intervention or
endodontic surgery, and the remaining studies investi- comparator (Table 1).
gated tooth extraction. Only 1 study reported on adverse effects,28 and no
For type of antibiotic, 11 studies used oral antibiotics. adverse effects were reported in 6 studies.16-19,25,26
Five studies compared another antibiotic with nonin- Only the studies by Anitua et al and Lindeboom et al
tervention23-26,28 and 8 studies compared antibiotic presented a ‘‘low’’ risk in their articles, whereas Vergis
with placebo. Only the studies by Lindeboom et al et al, Nolan et al, Hall et al, and Diz Dios et al showed
and Hall et al did not use penicillin derivatives, but an ‘‘unclear’’ risk in their articles. High risk of bias was
instead used lincosamide. The remaining studies used observed in the studies by Shanson et al and Josefsson
1316 ANTIMICROBIAL PROPHYLAXIS IN ORAL PROCEDURES

et al who acknowledged the risk for several of the used

No prophylaxis

No prophylaxis
No prophylaxis
Oral clindamycin Oral moxifloxacin No prophylaxis

No prophylaxis
Comparison
parameters (Fig 2).
The bias with higher evaluation of low risk involved
Placebo
Placebo
Placebo
Placebo
Placebo

Placebo

Placebo

Placebo
data with incomplete results. The bias of allocation
concealment and blinding of randomization presented
the highest proportion of evaluation, and unclear and
selective outcome reporting and other sources of bias
Antibiotic 3

presented the highest proportion of high risk of bias

(Fig 3).

INFECTION IN THE ORAL CAVITY

For antibiotic intervention versus placebo, 6 studies
Topical amoxicillin

were included,16-21 which showed an RR of 0.488

Oral erythromycin
Oral clindamycin

Oral clindamycin
(95% CI, 0.24-0.99; RD, 0.025; 95% CI, 0.043 to
Antibiotic 2

Amoxicillin IM 0.007) in the primary outcome (Fig 4).

BACTEREMIA
For antibiotic intervention versus placebo, 7 studies
were included,22-28 which showed an RR of 0.603
Oral amoxicillin and placebo rinse

(95% CI, 0.484-0.751; RD, 0.278; 95% CI, 0.380

Oral phenoxymethylpenicillin
Penicillin iv or clindamycin iv

to 0.176; Fig 4). For analysis of antibiotic versus anti-

biotic, 6 studies were included,23-26,28,29 which
Antibiotic 1

showed an RR of 0.847 (95% CI, 0.553-1.298; RD,

Moreno-Drada and Garc
ıa-Perdomo. Antimicrobial Prophylaxis in Oral Procedures. J Oral Maxillofac Surg 2016.

0.072; 95% CI, 0.255 to 0.112).

Oral erythromycin

Oral clindamycin
Oral amoxicillin
Oral amoxicillin
Oral amoxicillin

Oral amoxicillin

Oral amoxicillin

Oral amoxicillin
Oral amoxicillin

Oral amoxicillin

Teicoplanin iv

TYPE OF INTERVENTION IN THE ORAL CAVITY

For type of treatment with placebo, implant surgery
with placebo showed an RR of 0.587 (95% CI, 0.228-
1.510; RD, 0.021; 95% CI, 0.043 to 0.001), whereas
an RR of 0.591 was observed (95% CI, 0.473-0.737; RD,
Endodontic surgery

0.245; 95% CI, 0.337 to 0.154) when performing

Tooth extraction

Tooth extraction

Tooth extraction

Tooth extraction
Tooth extraction
Tooth extraction

Tooth extraction

Tooth extraction

Tooth extraction
Tooth extraction
Procedure

tooth extraction (Fig 5).

TYPE OF ANTIBIOTIC
Implant
Implant
Implant

For type of antibiotic used compared with placebo,

amoxicillin, the most widely used antibiotic, showed
an RR of 0.535 (95% CI, 0.384-0.744; RD, 0.210;
Year Oral Cavity Infection Bacteremia

95% CI, 0.334 to 0.085), followed by clindamycin,

Yes
Yes

Yes

Yes
Yes
Yes

Yes
Yes
No
No
No
No

No

No
Table 1. CHARACTERISTICS OF INCLUDED STUDIES

Abbreviations: IM, intramuscularly; IV, intravenously.

which showed an RR of 0.873 (95% CI, 0.773-0.985;

RD, 0.063; 95% CI, 0.146 to 0.019), and erythro-
mycin, which presented an RR of 0.667 (95% CI,
0.221-2.009; RD, 0.100; 95% CI, 0.367 to 0.167;
eFig 1).
Yes
Yes
Yes
Yes

Yes

Yes
No
No

No

No
No
No

No
No

For type of antibiotic used compared with another

antibiotic, amoxicillin showed an RR of 0.668 (95%
CI, 0.377-1.183; RD, 0.154; 95% CI, 0.393 to
0.084), clindamycin showed an RR of 1.497 (95% CI,
2009
2010
2014
2007
2013
2006
2011
2012
2001

2008
1987
1985
1996

2005

1.166-1.923; RD, 0.283; 95% CI, 0.124-0.442), and

erythromycin had an RR of 0.938 (95% CI, 0.692-
1.269; RD, 0.053; 95% CI, 0.299 to 0.193).
Lindeboom et al
Josefsson et al

Lockhart et al
Diz Dios et al
Esposito et al

No studies that compromised the results of the

Shanson et al
Halpern et al

Maharaj et al
Bezerra et al
Anitua et al

Duvall et al

Vergis et al
Nolan et al

meta-analysis in relation to its estimated weight within

Hall et al

the model were found in the sensitivity analysis.

Study

A funnel diagram was produced for each of the com-

parisons and outcomes. A heterogeneous distribution
MORENO-DRADA AND GARC
ıA-PERDOMO
FIGURE 2. Risk of bias within studies.
Moreno-Drada and Garc
ıa-Perdomo. Antimicrobial Prophylaxis
in Oral Procedures. J Oral Maxillofac Surg 2016.
was evident, leaving a gap with no evidence of studies
with a small sample and with an estimated effect on
risk of infection. However, given the search strategy
that was performed, it is clear that, despite the test re-
sults, little likelihood of bias was observed (eFig 2).
Discussion
Decreased risk was found when using a prophylac-
tic antibiotic before tooth extraction; this is consistent
with the systematic review of Susarla et al30 who re-
ported a decreased risk of infection using antibiotic
1317
prophylaxis after tooth extraction. However, no differ-
ences were found between the use of antibiotics and
the use of placebo for endodontic surgery and dental
implants; the latter data agree with systematic reviews
by Esposito et al31,32 who found no effect of antibiotic
prophylaxis on preventing postoperative infections.
Most studies had small samples, as presented in the
systematic review of Campos and Cooper,33 in which
the included studies did not support or refute the
use of prophylaxis after tooth extraction owing to
the small sample and low internal validity of the
studies. This suggested the need to produce higher-
quality research.
It is important to remember that the Committee for
the Prevention of Infective Endocarditis of the Amer-
ican Heart Association (AHA) recommends that pro-
phylaxis be considered for patients with a prosthetic
valve or prosthetic material,34,35 patients with
previous infective endocarditis,36 and patients with
congenital heart disease37 undergoing oral proce-
dures.12 These variables could not be measured
because the obtained data did not include patients
with these characteristics. On the contrary, within
the inclusion criteria of the clinical trials, patients
were generally in good health.
Subgroup analysis indicated that prophylactic anti-
biotic with amoxicillin was the most frequently used
and it showed a protective effect, which is in accor-
dance with expert opinions and the Committee for
the Prevention of Infective Endocarditis of
the AHA.12,38
According to Poveda-Roda et al,39 dental extraction
is undoubtedly the oral surgical procedure for which
most research on bacteremia has been performed.
Since the mid-20th century, a relation between dental
extraction and bacteremia has been established.
Although extraction is not the only example, only tooth
extraction procedures were reported as being related
to bacteremia in the articles reviewed in this study.
Prophylactic antibiotic use, especially amoxicillin,
was shown to favor the decrease of bacteremia, similar
to other studies that have confirmed the effectiveness
of amoxicillin in preventing bacteremia after dental
manipulation, as suggested by Tom
as Carmona
et al.40 Similarly, the study by Vergis et al reported a
decrease of almost 80% in the prevalence of postextrac-
tion bacteremia after prophylaxis with amoxicillin 3 g.
The experiments evaluated in this review were not
adequately described; thus, the risk bias might have
been overestimated. However, thus far, the Cochrane
risk of bias tool is the best and most consistent tool
for evaluating these types of studies15,41; therefore,
this tool was used.
The production of higher-quality research with
larger samples that permit an evaluation of the effec-
tiveness of antibiotic prophylaxis after oral
1318 ANTIMICROBIAL PROPHYLAXIS IN ORAL PROCEDURES

FIGURE 3. Risk of bias among studies.

Moreno-Drada and Garc
ıa-Perdomo. Antimicrobial Prophylaxis in Oral Procedures. J Oral Maxillofac Surg 2016.

procedures, highlighting clinical and bacteriologic as-
pects, is recommended. Most of the available evidence
regarding oral procedures involves tooth extraction.
Few studies on other procedures in the oral cavity
have been observed. Randomized controlled experi-
mental studies in patients at high risk for the dissemina-
tion of infection (advanced age, immunosuppression,
diabetes mellitus, and cardiovascular history) are sug-
gested to determine the most effective antibiotic for
preventing this outcome.
To conclude, the incidence of localized infections of
the oral cavity decreased with the use of antibiotic pro-
phylaxis compared with placebo in patients undergo-
ing tooth extraction. In contrast, no differences were
observed in prophylactic antibiotic use for implant
and endodontic surgeries compared with placebo.
Localized infections of the neck and thoracic cavity
were not reported with the use of antibiotic
prophylaxis.
The incidence of bacteremia decreased when using
antibiotic prophylaxis compared with placebo in pa-
tients undergoing tooth extraction. Tooth extraction
was the only procedure that was evaluated as having
such an outcome; thus, further studies evaluating

FIGURE 4. Infection in oral cavity and bacteremia. Antibiotic versus placebo: 0, oral infection; 3, bacteremia. CI, confidence interval; RD, risk
difference.
Moreno-Drada and Garc
ıa-Perdomo. Antimicrobial Prophylaxis in Oral Procedures. J Oral Maxillofac Surg 2016.
MORENO-DRADA AND GARC
ıA-PERDOMO
FIGURE 5. Antibiotic versus placebo. Type of treatment. CI, confidence interval; RD, risk difference.
Moreno-Drada and Garc
ıa-Perdomo. Antimicrobial Prophylaxis in Oral Procedures. J Oral Maxillofac Surg 2016.
bacteremia during other procedures in the oral cavity
are recommended.
Supplementary Data
Supplementary data associated with this article can
be found, in the online version, at http://dx.doi.org/
10.1016/j.joms.2016.03.006.
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Appendix 1. Search Strategy 14. or/

15. 6 AND 10 AND 16
LILACS
Medline (Ovid) 1. Control de infecci
on dental (Decs)
1. exp infection control, dental/ 2. Profilaxis Antibi
otica (Decs)
2. exp antibiotic prophylaxis/ 3. antibiotico (tw)
3. antibiotic$.mp. 4. or/
4. or/ 5. Procedimientos Quir
urgicos Orales (Decs)
5. exp oral surgical procedures/ 6. Cirug
ıa bucal (Decs)
6. exp surgery, oral/ 7. or/
7. (oral adj3 surg$ adj3 procedure$).mp. 8. Ensayo clinico (Decs)
8. or/ 9. Doble ciego (tw)
9. exp randomized controlled trial/ 10. Experimento clinico (Tw)
10. (randomi*ed adj3 controlled adj3 trial).mp. 11. or/
11. exp clinical trial/ 12. 4 AND 7 AND 11
12. (clinical adj3 trial).mp. CENTRAL
13. exp double-blind method/ 1. exp infection control, dental/
14. or/ 2. exp antibiotic prophylaxis/
15. 4 AND 8 AND 14 3. antibiotic next/3 proph*laxis:ti,ab,kw
Embase 4. antibiotic:ti,ab,kw
1. ‘infection control’/exp 5. or/
2. ‘antibiotic prophylaxis’/exp 6. exp oral surgical procedures/
3. (antibiotic next/3 proph*laxis):ti,ab 7. exp surgery, oral
4. antibiotic*:ti,ab 8. oral next/3 surg* next/3 procedure*:ti,ab,kw
5. or/ 9. or/
6. ‘surgery oral’/exp 10. exp randomized controlled trial/
7. (oral next/3 surg* next/3 procedure*):ti,ab 11. Randomi*ed next/3 controlled next/3
8. or/ trial:ti,ab,kw
9. ‘randomized controlled trials’/exp 12. exp clinical trial/
10. (randomi*ed NEXT/3 controlled NEXT/3 trial):ti,ab 13. clinical next/3 trial:ti,ab,kw
11. ‘clinical trials’/exp 14. exp double-blind method/
12. (clinical NEXT/3 trial):ti,ab 15. or/
13. ‘double blind procedure’/exp 16. 5 AND 9 AND 15