Accepted Manuscript

Bacteremia Associated with Oral Surgery: A Review

Beatriz González Navarro, Enric Jané Salas, Albert Estrugo Devesa, José López
López, Miguel Viñas

PII: S1532-3382(16)30170-1
DOI: 10.1016/j.jebdp.2016.12.001
Reference: YMED 1160

To appear in: The Journal of Evidence-Based Dental Practice

Received Date: 9 November 2016

Accepted Date: 2 December 2016

Please cite this article as: González Navarro B, Jané Salas E, Estrugo Devesa A, López López J, Viñas
M, Bacteremia Associated with Oral Surgery: A Review, The Journal of Evidence-Based Dental Practice
(2017), doi: 10.1016/j.jebdp.2016.12.001.

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 ACCEPTED MANUSCRIPT

Bacteremia Associated with Oral Surgery: A

Review

Beatriz González Navarro1, Enric Jané Salas1, Albert Estrugo Devesa1, José López López1,
Miguel Viñas2

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1OralHealth and Masticatory System Group. University of Barcelona. Section of Oral
Pathology. School of Dentistry. beatrizgonzaleznavarro@gmail.com //

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enjasa19734@gmail.com // albertestrugodevesa@gmail.com // 18575jll@gmail.com

2Department of Pathology and Experimental Therapeutics; University of Barcelona and

IDIBELL, Barcelona, Spain. CESPU, IINFACTS, Gandra, Portugal. mvinya@ub.edu

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(*) Corresponding author

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José López López

Bellvitge University Campus
Section of Oral Medicine, School of Dentistry
C/Feixa LLarga s/n
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08907 L'Hospitalet de Llobregat. Barcelona, Spain

18575jll@gmail.com Tel:0034-606-457-362
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ABSTRACT

OBJECTIVES: Bacterial (infective) endocarditis, a microbial infection of the endocardium

surfaces following bacteremia, causes significant morbidity and mortality. Recent
epidemiological studies have reported a prevalence of 2–8 cases per 100,000 individuals per
year, with the highest incidence in those 70–80 years of age and living in developed countries.
We systematically reviewed the literature on several critical aspects regarding the development

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of bacteremia following oral surgery. The purpose of this work is to assess the controversy
regarding antibiotic prophylaxis prior to oral surgery.

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MATERIALS AND METHODS: Publications between 1976 and 2015 were included.
Clinical studies focusing on oral surgery as the underlying cause were included.

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RESULTS: Among the 32 clinical studies reviewed, 3,564 cases, accounting for 12,839 blood
cultures, were evaluated. In 10 of these studies, amoxicillin usefulness was studied.

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Antimicrobial prophylaxis prior to an invasive dental procedure does not prevent bacteremia,
although it can decrease both its magnitude and its persistence.
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CONCLUSIONS: The highly conflicting data and conclusions of the analyzed work highlight
the need for new approaches to the study of bacteremia that would provide reliable evidence and
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thus appropriate prophylactic and therapeutic standards. Many reports have explored the
occurrence of bacteremia after dental procedures, but the results have been conflicting.
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Key words
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Amoxicillin, bacteremia, bacterial endocarditis, infective endocarditis, prophylaxis.

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INTRODUCTION

Bacterial endocarditis (BE) generally referred to as infective endocarditis (IE), is a bacterial

infection of the endocardium accounting for high morbidity and high mortality particularly

when done in compromised patients. Patients with prosthetic heart valves, congenital or

structural heart disease, intravenous drug users or being under invasive medical treatment are

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seen as high-risk patients.1-3 The etiology and demographics of IE has evolved within the last

two decades. In the past, IE was mostly found in young adults affected by rheumatic heart valve

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diseases, although nowadays it is most frequent among elderly people particularly after medical

procedures.1,4,5 Epidemiological data indicates annual prevalence of 2–8 cases per 100,000

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individuals.1,2,6,7 There is a much higher incidence in individuals being 70-80 years old.4,8 In

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most cases initial step of IE consists in a mass formed mainly by platelets and fibrin that

originally is microbial-free but susceptible to be colonized by microorganisms. Nevertheless,

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most of bacteremias are transient, self-limited and do not have systemic complications.3
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Gram positive cocci cause 85% of IE; Streptococcus are responsible of one half of cases,

whereas Staphylococcus and Enterococcus are the etiological agents of the remainder.1,3,8-13
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The most prevalent species are those of the viridans group (which comprises S. salivarius, S.
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mutans, S. mitis, S. bovis and S. anginosus)14 but also Gemella morbillorum is isolated

frequently. Among staphylococci, the species most frequently involved is S. aureu.s1,8,9,11

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Oral infections and bacteria colonizing the mouth seem to play a key role in such a
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pathology.3,15 Bacteremia can emerge not only after invasive procedures, but also after routine
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oral hygiene activities, such as teeth brushing and flossing, or even during chewing. These

temporary episodes of bacteremia have a short-term duration and bacterial load is as low as

between 1 and 300 colony forming units (CFU)/ml of blood, with an average of 1.7 CFU/ml,

and its duration less than 10 min. According to the American Heart Association (AHA), the

intensity of bacteremia originated after a tooth extraction is similar to the one induced by

routine oral care activities (bacterial load < 103 CFU/ml of blood). Thus, bacteremia tends to be

short and limited to the immediate postoperative period16. Nevertheless, bacteremia lasting up to
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1 h after completion of the procedure has been reported,17-24 being the most common duration

between 10 and 30 min.

Other studies have also found that aggressive procedures, such as tooth extractions, can be in

the origin of bacteremia.3,15 According to the literature, the incidence after tooth extraction

varies from 0 to 100%3,17,18,23,25-28 a such divergence of results has reinforced the idea that no

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relationship between IE and oral invasive procedures exists.1,29,30

Moreover, inoculum size needed to originate IE, is extremely difficult to be determined

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experimentally, although it has been shown that the number of bacteria required to trigger IE is

approximately 1 × 102 CFU/ml. Experiments in rats have shown that the inoculum size required

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to induce IE in 90% of animals is 5 × 103 CFU/animal.31,32 The volemia of a rat is 60-70 ml/Kg ,

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human volemia is quite similar. This means that minimal inoculum should be of an order of

magnitude of 1 x 105 CFU/ individual. Antibiotic prophylaxis can partially prevent bacteremia,33
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which may be influenced by the inoculum size, as shown in animal studies. In rats inoculated

(5×103 CFU/animal), the development of IE was completely prevented by teicoplanin (at 7

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mg/kg 30 min before operation) and significantly inhibited by vancomycin (at 15 mg/kg 30
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min). A 10-fold larger inoculum had identical infectivity but although teicoplanin still achieved
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100% protection, vancomycin failed in protecting a significant proportion of animals. When

using even larger inocula no antimicrobials resulted to be able to protect rats from IE.32 Taking
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into account the relationship between inoculum size and occurrence of antibiotic effectiveness

in protecting against IE, measures such as oral hygiene and preoperative disinfection acquire
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relevancy since they can contribute to the antibiotic prophylaxis in protecting patients at IE risk.
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Moreover, it should be taken into account that whether good disinfection practices can result in

a reduction of the inoculum size up to values lower than the minimal infective dose, the use of

antimicrobials can become superfluous. If this is so or not should be enforced by new research

and is in the basis of the lack of agreement between authors.

The 2007 AHA report recommended antibiotic prophylaxis in patients with implanted heart

valves, or with those having previous history of IE, as well as for patients with congenital heart

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diseases.16 Similar recommendations were made by the European Society of Cardiology1 and by

the British Society of Antimicrobial Chemotherapy.34 This recommendation was supported by

Glenny et al.35 In contrast, the 2008 recommendations of the National Institute of Clinical

Excellence36 did not recommended antimicrobial prophylaxis for any dental procedure

regardless of the patient’s history, although emphasized adequate patient education on oral

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hygiene, risk of invasive procedures, and recognition of the early symptoms of IE to ensure

early medical assistance (Table 1). This statement is nowadays under review, as it seems that

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there has been a significant increase of the incidence of bacterial endocarditis since 2008, thus,

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the NICE (The National Institute for Health and Care Excellence) has been invited to check up

this guide.37

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The controversy regarding the incidence, length, nature, and extent of bacteremia subsequent to
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dental procedures is partly due to the heterogeneity of the study designs. For these reasons we

set out to do this review.

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The purpose of this work was to assess the controversy regarding antibiotic prophylaxis prior to

oral surgery. Moreover we have used the PICO questions (Patient, (population or problem);
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Intervention, Comparison and Outcome). Thus the hypothesis could be formulated as “a careful
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literature analysis could support the usefulness of antibiotic prophylaxis to prevent IE”.
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MATERIALS AND METHODS

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A research restricted to the last 10 years was performed using PubMed, Medline, Scopus and

Cochrane based on the Keywords "bacterial endocarditis" AND "dental." A second set of

researches without time limits and restricted to clinical trials used the MESH terms

"bacteremia" AND “dental extraction;" "oral bacteremia” AND "surgery"; "bacteraemia” AND

"third molar surgery"; “bacteremia” AND “tooth extraction” and "bacteraemia” AND “dental

implants”.

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To perform this review, several procedures were used in order to do the selection of articles and

abstracts. Articles included in the review, were read by three blind reviewers (BGN, EJS, AED).

The differences in the results were solved following the criteria of the two senior authors (JLL

y MV).

Exclusion criteria of these articles were those that were not clinical trials, that were done in

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animals and that do not compare different types of antibiotic or antiseptics. Moreover, exclusion

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criteria were: papers in which bacteraemia after all types of surgery were studied (not

specifically referred to oral surgery) and articles referring orthodontics or conservatory dental

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treatments (Figure 1). The methodological quality of the trials was controlled by using the scale

of Jadad et al.38. Jadad scale is a procedure to independently assess the methodological quality

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of clinical trials. It consists in answering seven methodological questions assigning values of 1,
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0 or -1. It is based in seven questions. 1: Was the study described as randomized? (Yes: 1 point

/ No: 0 point); 2: The method of randomization was described? (Yes: 1 point / No: 0 point); 3:
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The method of randomization was appropriate? (Yes: 0 point / No -1point); 4: Was the study

described as double blind? (Yes: 1 point / No: 0 point); 5: The method of blinding was
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described? (Yes: 1 point / No: 0 point); 6: The method of blinding was appropriate? (Yes: 0
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point / No: -1 point); 7: Was there a description of withdrawals and dropouts? (Yes: 1 point /

No: 0 point). The score is from 0 to 5, being five the highest.

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RESULTS
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The first research identified 384 papers, 98 were selected for full review (full text); a second

selection resulted in the final inclusion of 25 reports whose topics were restricted to the field of

microbiology, microbiological methods, observational studies, and clinical cases.

Among the 80 articles identified in the second search, we selected 28 clinical trials focusing on

oral surgery. In addition four more papers17,39-41 were included during the review of the 28

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previously included (Table 2). This heterogeneous group consisted of six reports on single tooth

extraction,13,18,42-45 3 on third molar extraction,15,20,46 11 on multiple extractions,21,22,24,30,47-53 3

more studies on the extraction of third molars,54-56 one comparing a simple extraction with the

extraction of a third molar,17 another comparing single extraction, multiple extraction, and flap

lifting,26 2 in which extraction and teeth-brushing were discussed,7,12 one focusing on the

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relationship between extraction, teeth-brushing, and eating,39 two comparing extractions and

conservative treatments,19,40 one reporting on the follow-up of implant surgery57 and another

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focusing on extraction and the intra-ligament injection of anesthetics.41

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The included papers from the first and second searches reported on a total of 3,564 treated

patients and the results of 12,839 laboratory blood tests and cultures. Ten were randomized

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clinical trials (RCTs),12,13,18,21,22,24,26,49,52,57 11 were double-blind RCTs;7,15,19,43-46,48,50,51,56 and 3
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were single-blind studies.41,47,53 The remaining 8 clinical trials were non-

randomized.17,20,30,39,40,42,54,55 In 19 of the 32 studies, antibiotics were included. The most

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frequently used was amoxicillin. Other antibiotics assessed were clindamycin,13,21,44,51

erythromycin,43,44,48,50,51,54 teicoplanin,42,49 penicillin V,18 moxifloxacin,21 josamycin,43,50

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phenoxymethylpenicillin,54 cefuroxime,52 and cefaclor.45 Several studies also evaluated the

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benefits of oral antiseptics including chlorhexidine 0.2% or 0.12%,13,24,41,46,56,57 povidone

iodine41,46,47 and Lugol.47

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DISCUSSION
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We focused our analysis on the: i) occurrence of bacteremia, ii) extent of bacteremia after tooth

extraction or treatment, iii) duration of bacteremia and iv) relation between bacteremia and oral

health.

i) Occurrence of bacteremia

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Vergis et al53 found that post-extraction bacteremia take place in 10% of patients when

previously treated with 3 g of amoxicillin by systemic (oral) administration, but in as much as

60% of patients previously treated with topical amoxicillin and in 89% of untreated individuals.

These results suggested that systemic amoxicillin should be able to protect most patients

undergoing tooth extraction. Hall et al44 did a similar work in order to determine the

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prophylactic effectiveness of erythromycin and clindamycin when administered 1.5 h before

dental extraction. They found very high rates of intraoperative bacteremia: 79% of the

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erythromycin-treated (1 g) patients and 84% of the clindamycin-treated (600 mg) patients, 10

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min later values were reduced to 58% and 53% respectively.

Many articles reported failures of antibiotics in preventing post-extraction bacteremia, (in most

cases no significant differences with the placebo group were found). Duvall et al56 compared the

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effect of amoxicillin, chlorhexidine, and placebo; Sefton et al43 and Cannell et al50
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erythromycin, josamycin, and placebo; and Josefsson et al54 erythromycin and

phenoxymethylpenicillin. Penicillin V, amoxicillin, and placebo;18 cefaclor and placebo45 have

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been also compared; in all cases results were not conclusive. Thus, whether or not prophylactic
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antibiotics can prevent the bacteremia associated with dental procedures remains controversial.
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Lockhart et al19 explored the efficacy of amoxicillin (50 mg/kg) in children; bacteremia appears

1.5 min after the start of the extraction in 15% of the patients receiving amoxicillin but in 76%
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of the untreated patients. Moreover, positive blood cultures were obtained from 56% of the

patients orally administered amoxicillin (2g) and 80% in control.15 These data suggested that
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amoxicillin protects patients undergoing dental surgery from bacteremia better than
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chlorhexidine, which is better than no prophylaxis at all.

Both Sefton et al43 and Cannell et al50 compared the rates of streptococcal bacteremia

development following dental extraction and the protective effects of two macrolides,

erythromycin (1.5 g) and josamycin (1.5 g). The results of the two studies were identical: 60%

of the patients in the erythromycin group, 70% of those in the josamycin group, and 65% of

those in the placebo group developed bacteremia.

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Maskell et al42 and Shanson et al49 compared bacteremia after tooth extraction and effectiveness

of prophylactic teicoplanin and amoxicillin. Both undoubtedly concluded that teicoplanin was

as effective as amoxicillin in reducing incidence and extent of bacteremia. In the study of

Maskell et al42 bacteremia developed in 100% of the control group, in 60% of the teicoplanin-

treated group, and in 40% of the amoxicillin-treated group. Shanson et al49 restricted their study

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to determining the presence of S. viridans in blood samples. They found that teicoplanin reduces

the prevalence of S. viridans bacteremia.

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Other antimicrobial agents that have been tested include cefuroxime, which in the study of

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Wahlmann et al52 was shown to statistically lower bacteremia rates: within 10 min after the start

of surgery. Bacteremia developed in 79% of the control group vs. 23% of the antibiotic-treated

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group; at 40 min the respective percentages were 69% and 20%. Shanson et al48 show that 15%
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of the erythromycin-treated but 43% of the placebo group developed bacteremia. Aitken et al51

show that 45 % of clindamycin-treated (600 mg) patients and 60% of erythromycin-treated with
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1.5 g had streptococcal bacteremia.

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The relationship between the severity of the procedure and the occurrence of bacteremia is
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relevant; the prevalence of bacteremia after third molar extraction varies in literature reports

between 25% and 60%. It is also worthy of interest the eventual effectiveness of disinfectants.
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In the series of patients evaluated by Tuna et al46 bacteremia developed in 25% of those treated

with chlorhexidine, in 33% of those treated with povidone-iodine, and in 40% of the control-
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untreated patients. Similarly, Duvall et al56 when comparing antibiotics and disinfectants
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reported bacteremia in 45% of amoxicillin-treated patients, in 50% of the placebo group, and in

60% of the chlorhexidine group. Thus, neither antibiotic prophylaxis nor preoperative

disinfection appears in this case to be effective in preventing bacteremia. In other studies,

bacteremia developed in 40%,20 50%,55 and 55%17,54 of patients undergoing third molar

extractions. However, evidences supporting the effectiveness of antibiotics over disinfectants

have been published. Maharaj et al13 reported post-extraction bacteremia in 40% of

chlorhexidine-treated patients (0.2%), in 35% in the control group and in 20% (clindamycin)
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and 7.5% (amoxicillin). In this case amoxicillin resulted to be much more effective and yielded

statistically significant results when compared with either the chlorhexidine or control group.

Furthermore, Rahn et al41 showed that chlorhexidine appears as less effective than povidone-

iodine. Piñeiro et al57 evaluating the use of 0.2% chlorhexidine during the completion of

mucoperiosteal flap surgery performed in the setting of implant placement demonstrate that

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none of the chlorhexidine-treated patients but 6.7% of the control group developed bacteremia.

Another study surprisingly found slightly higher rates of bacteremia in chlorhexidine-treated

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patients than in control group.56

Sweet et al47 compared T-chloramine-based rinses with teeth-brushing using T-chloramine and

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irrigation of the gingival sulcus with Lugol. The prevalence of bacteremia in the T-chloramine-

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treated patients was 48% whereas in the Lugol and untreated control patients it was 80% and
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84%, respectively, thus supporting the use of chloramine disinfection.

Bacteremias frequent in children undergoing dental extraction, but not after conservative
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treatments (48.8% vs. 0%).40 Maharaj et al39 demonstrated that eating an apple do not increase

the risk of bacteremia whereas after tooth extraction and teeth brushing, 29.6% and 10.8%,
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respectively, of blood cultures were positive.

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The dispersion of the results can be due, at least in part, to the differences in the microbiological
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methods used. Benítez-Páez et al30 demonstrated that the traditional microbiological blood

culture methods used in hospital setting are more effective than 16S rRNA pyrosequencing in
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determining bacteremia. Thus, conventional microbiology rends more accurate results than
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molecular microbiological determinations.

ii) Extent of bacteremia after tooth extraction

Another interesting parameter is the extent of bacteremia. In the series of Duvall et al56 the

magnitude of bacteremia was quite similar in untreated (placebo) patients (3-7 × 103 CFU/L),

followed by those who were chlorhexidine-treated (2-4 x 103 CFU/L) and amoxicillin-treated

(0.6-1.3 x 103 CFU/L). Hall et al44 reported an average post-extraction bacteremia of 2 × 103
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CFU/L in erythromycin-treated patients and 0.72 × 103 CFU/ml in those receiving clindamycin.

The blood samples were taken 10 minutes after dental extraction and the average reduction of

bacteremia in the two groups of antibiotic-treated patients was essentially identical, 0.6 and 0.3

x 103 CFU/L. In samples from patients studied by Hall et al18 the average bacterial load during

the procedure and 10 minutes after was 8 x 102 CFU/L and 3 x 102 CFU/L, respectively, in

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untreated individuals vs. 6 x 102 CFU/L and 3.6 x 102 CFU/L, respectively, in the penicillin-V-

treated ones and 1.08 × 103 CFU/L and 2.4 × 102 CFU/L, respectively, in the amoxicillin-treated

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group. Patients who underwent third molar extraction had a bacterial load of 1.34 × 103

CFU/L.17 Lockhart et al15 were unable to detect bacteremia based on a threshold of 104 CFU/ml,

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this is consistent with previous results. Finally, Roberts et al22 in their pediatric study found

values 1 min and 15 min post-extraction of 2.73 × 103 and 0.32 × 103 CFU/L, respectively.

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Shanson et al48 did not detect significant differences in the bacterial load among four groups of

patients rinsing with chloramine, brushing with chloramine, or irrigating with Lugol, and
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without antiseptic use. It should be emphasized that these were medical rather than

microbiological studies. The methods used in the latter (culture on bacteriological media in Petri
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dishes) would have shown that the reported values, all of which were in the range of 103 CFU/L,
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were of negligible difference. The extent of bacteremia taking into account the data herein

revised suggest that the interesting parameter to be taken into account is the presence or absence
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of bacteria in blood (positive blood culture) since all of these bacterial populations are almost

identical and small differences seem to be due to the limitation of methods more than to a truly
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difference in bacterial population. Moreover the identity of microbes isolates should be

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explored, since there is not a knowledge of the relevance of false positives that in blood cultures

can be significant and strongly dependent on the expertise of the professional doing the blood

extraction.

iii) Duration of bacteremia of dental origin

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Bacteremia of dental origin is mainly transitory, with a maximum duration usually of up to15

min.16 This was confirmed by Roberts et al22 who reported an average of duration between 7.5

and 15 min in a group of more than 500 patients. Moreover, the duration depends upon the

nature and severity of the surgical procedure. Rajasuo et al20 found out that in patients

undergoing third molar extraction bacteremia persisted for at least 30 min. The eventual role of

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antibiotics in reducing duration of bacteremia has been also studied. Lockhart et al19 showed

that amoxicillin prophylaxis significantly reduced the duration of post-extraction bacteremia in

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children. None of the specimens obtained from those antibiotic-treated patients 30 and 45 min

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after the procedure contained cultivable bacteria. On the contrary, in the control group16% at 30

min cultures and 14% at 45 min were positive. Diz Dios et al21 reported similar results when

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they reported bacteremia at 15 min post-procedure confirmed in 64.2% of the control group but
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in only 10.7% of an amoxicillin-treated group; at 30 min the respective values had decreased to

20% and 3.7%. Another strategy to prevent bacteremia could be theoretically simply hygiene;
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one hour post-extraction 9% of subjects previously disinfected by brushing had bacteremia

whereas only 2% of the untreated patients gave positive blood culture. In an amoxicillin-treated
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group, none of the blood cultures were positive after 1 h, it was shown that brushing facilitates
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bacterial entry into the bloodstream; oral disinfection prior to extraction is better than brushing

since the rate of bacteremia is lower;19 finally in this case amoxicillin prophylaxis reduced the
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duration of bacteremia.

iv) Bacteremia and oral status

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The effect of oral status on bacteremia has been extensively addressed particularly in reference

to the oral microbiome structure and oral hygiene.3,17,26 S. viridans is the most frequently

isolated microorganism from blood after extraction of impacted lower third molars.46,55

Conventional extraction could have higher incidences of bacteremia than those in surgical

removal of unerupted third molars.17

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The incidence of bacteremia is higher in children than in adults.19 This has been attributed to the

higher number of teeth, a higher bacterial abundance, and greater bacterial diversity. In efficacy

of cefuroxime prophylaxis studies52 there is no significant relation between bacteremia, oral

hygiene and periodontal status. Nevertheless, it has been shown that after extraction without

antibiotic prophylaxis, 100% of patients with poor oral hygiene developed bacteremia whereas

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80% of patients with good oral hygiene had bacteremia. This is in agreement with Lockhart et

al7 when showing that the risk of developing IE is higher in patients with gingivitis and poor

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oral hygiene than in those with periodontal disease, probably because gram-positive

supragingival microbiota includes most of microbes responsible of IE. In contrast, Tomas et al55

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were unable to find evidence of association between the levels of oral health variables and the

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prevalence of bacteremia after wisdom teeth extraction.
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The nature of the surgical intervention should be taken into account in assessing the causes of

bacteremia following dental procedures. Roberts et al26 compared the development of

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bacteremia after single-tooth extraction, multiple extractions, and flap lifting. Bacteremia

percentages were higher in patients with multiple extractions than in the group with a flap lift
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(54.2% vs. 43.1%). Multiple extractions are usually performed to treat infection or pain, in
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which a high bacterial content can therefore be expected. By contrast, flap lifting is typically

performed in patients with better oral health who are undergoing orthodontic procedures. Unlike
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the relationship between upper vs. lower jaw procedures and bacteremia rates, the relationship

between inflammation, gingival bleeding and bacteremia was significant. This outcome can be
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explained by considering inflammation as an indicator of an established pathology that

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facilitates microbial access to the gingival sulcus and therefore bloodstream.

In summary, this literature review was based on articles dealing with IE, including the

conditions leading to its development and the strategies for its prevention. Despite the extense

disagreement regarding almost all aspects of bacteremia in patients undergoing dental

procedures, a broad agreement on some aspects should be emphasized: (1) The microbial

species most commonly found is S. viridans. (2) The prophylactic use of antimicrobials reduce
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the risk of bacteremia and therefore of IE. (3) High-dose amoxicillin administered 1 h before

surgery is effective. (4) Although antibiotic prophylaxis fails in fully preventing bacteremia, it

reduces duration and subsequently clinical risks.

The research involving antibiotic use has frequently significant bias. This has to be particularly

taken into account when articles recommend the use of some particular drug. One can find in

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the literature consensus statements recommending the use of a particular pharmaceutical to fight

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oral infections or to prevent infections based on actually weak scientific evidences. Moreover as

it happens in many other fields of biomedical sciences, the successful research is published

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much easier than negative or inconclusive results. This bias comes from both editors and

authors. Moreover it has been shown that in some cases grey literature may be of great interest.

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This is the case of antimicrobial resistance topic in which comprehensive and up-to-date data
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concerning antibiotic resistance are found mainly in the grey literature, whereas only a few are

published in peer-reviewed journals. The grey literature, therefore, may be a very valuable
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source of information 58. In the case of antibiotics use and misuse, it has been extensively shown

that the public (and sometimes practitioners) have poor understanding of antibiotic resistance
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and many misperceptions59 on the basis of scientific literature. However it was lateron pointed
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out that it is convenient to add information coming from grey literature 60.
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Given the disparity of the results, new studies and approaches using standardized methods that

allow direct comparisons of the results and conclusions are needed to fully understand the
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relationship between bacteremia, IE, and risk of both due to dental invasive procedures.
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Contribution:

Beatriz González Navarro: contributed to conception, design and data interpretation, drafted and
critically revised the manuscript

Enric Jané Salas: contributed to data acquisition and interpretation, drafted and critically revised
the manuscript

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Albert Estrugo Devesa: contributed to data interpretation, drafted and critically revised the
manuscript

José López López: contributed to conception, design and data interpretation, drafted and
critically revised the manuscript

Miguel Viñas: contributed to conception in microbiology, data acquisition, analysis and

interpretation, critically revised the manuscript

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Funding Sources

This research did not receive any specific grant from funding agencies in the public,

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commercial, or not-for-profit sectors.

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40. Peterson LJ, Peacock R. The incidence of bacteremia in pediatric patients following tooth

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49. Shanson DC, Shehata A, Tadayon M, Harris M. Comparison of intravenous teicoplanin with

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53. Vergis EN, Demas PN, Vaccarello SJ, Yu VL. Topical antibiotic prophylaxis for bacteremia
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58. Hoffmann K, Wagner G, Apfalter P, Maier M. Antibiotic resistance in primary care in

Austria - a systematic review of scientific and grey literature. BMC Infectious Diseases2011;

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Jan;71(1):27-33. doi: 10.1093/jac/dkv310

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60. McCullough AR, Parekh S, Rathbone J, Del Mar CB, Hoffmann TC. A systematic review

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Chemother. 2016 Aug;71(8):2366

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TABLES AND FIGURES
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One figure:

Figure 1: Flow chart summarizing the final article selection.

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Two tables:
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Table 1: Main features of protocols referred to antibiotic prophylaxis, based on the criteria
adopted tor the different societies. AHA (American Heart Association)16, ESC
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(European Society of Cardiology)1, BASC (British Society of Antimicrobial

Chemotherapy)34 and NICE (National Institute of Clinical Excellence)36.
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Table 2: List of different studies that have analyzed bacteremia after dental procedures and
the most significant conclusions. The type of study, its JADAD38 value and the "N"
used is also indicated. IM: Intramuscular injection; IV: intravenous; IV: endovenous
injection. Times indicate time before the operation starts.

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 ACCEPTED MANUSCRIPT
AHA (2007) - BSAC (2006) - ESC (2009) NICE (2008)
Patients with high risk of IE: They do not recommend antibiotic prophylaxis in
-Carriers of prosthetic valves any procedure or patient.
-Patients with previous IE.
-Patients with congenital heart disease.
(Most risky procedures: gingival or periapical

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manipulation or perforation of oral mucosa)
Antibiotic instructions: The professional must inform patient about
-Amoxicillin/Ampicillin 2g (ov/iv) prevention, including:

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-Clindamycin (for allergics to penicillin): 600mg -Benefits and risks of the antibiotic prophylaxis
(ov/iv). -Give information concerning the reasons why

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-Cephalexin/Cefazolin/ceftriaxone (If antibiotic prophylaxis is not performed
intolerance ov): Cephalexin 2g (iv), Cefazolin or -Importance of maintaining good oral health.

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Ceftriaxone 1g (iv). -symptoms that may denote the occurrence of IE
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in order to request medical assistance.

Table 1: Main features of protocols referred to antibiotic prophylaxis, based on the criteria
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adopted tor the different societies. AHA (American Heart Association) [16], ESC
(European Society of Cardiology) [1], BASC (British Society of Antimicrobial
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Chemotherapy) [34] and NICE (National Institute of Clinical Excellence) [36].

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 ACCEPTED MANUSCRIPT

STUDY JADAD MOST FREQUENT

AUTHOR N BLOOD DRAWNS PROCEDURES MOST RELEVANT CONCLUSIONS
TYPE VALUE BACTERIAl species
Compare post extraction bacteremia. Suggests the maintenance of a good oral hygiene

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Lockhart et al, RCT double Placebo group and brushing. (43,8%) trigger lower IE incidence.
194 1164 4
2009 (7) blind S. viridans No bacteremia 20 minutes after operation or after
brushing.

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Compare Streptococcus spp was the most prevalent
-bacteremia. after brushing, -post tooth Using BACTEC instead lysis filtration higher recover
Bahrani-

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extraction with Amoxicillin prophylaxis of anaerobic, even some non-cultivable species.
Mougeot et RCT 290 1740 4 Streptococcus 20%, 9% and 6% of bacteremia at 20 min, 40 and
(2g) 1h before) and
al, 2008 (12) 60 min. respectively. Antibiotic prophylaxis reduces
-post tooth extraction with placebo
streptococcal bacteremia, but It appears to have

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bacteremia little influence on the Proteobacterial bacteremia
Compares protection by bacteremia. Significant differences:

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Maharaj et al, Amoxicillin 3 g 1h before, Clindamycin (24,39%) -between control and amoxicillin
RCT* 160 160 2 -between chlorhexidine and amoxicillin bacteremia
2012 (13) (600mg) 1h before, Chlorhexidine group S. viridans
0,2% and placebo group was not fully prevented

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Compare Amoxicillin significantly reduced incidence of
-bacteremia after brushing, positive cultures at 1.5 minutes, 5 minutes and 20

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Lockhart et al, RCT double -bacteremia post tooth extraction with (43%) minutes after starting extraction.
290 1740 4
2008 (15) blind Amoxicillin ((2g) 1h), S. viridans Viridans

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-bacteremia post tooth extraction with
Placebo.
Heimdahl et Compare bacteremia after simple Higher bacteremia incidence after simple
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CT 40 120 0 (85%) S. viridans
al, 1990 (17) extractions and third molar extraction. extraction
Compare post extraction bacteremia. Penicillin V or amoxicillin failed in reducing
Hall et al, S. intermedius (S.
RCT 60 180 1 with prophylaxis (Penicillin V (2g) 1h), incidence, type or magnitude.
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1993 (18) viridans group)

and (Amoxicilline (3g) 1h ) and placebo
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Compare bacteremia after teeth Bacteremia in the amoxicillin group had significant
Lockhart et al, RCT double extractions or conservative treatment. lower incidence. Significant reduction of duration
100 800 4 S. viridans
2004 (19) blind with prophylaxis Amoxicillin (50mg/kg 1
h) and without
Rajasuo et al, Gingival culture and bacteremia after Any species found in the blood was also isolated
CT 16 96 0 N.S.
2004 (20) extraction of inferior partly erupted third from the mouth, from 93% of the pericoronal
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molars. pockets and from 43% of the extraction sockets.

Compare bacteremia after teeth It was statistically significant the administration of
extractions. Amoxicillin and Moxifloxacin versus control group
(63,1%)

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Diz Dios et al, -Amoxicillin group ((2g) 1-2h) and Clindamycin group to reduce post extraction
RCT 221 884 2 Streptococcus
2006 (21) Clindamycin group ((600mg) 1-2h) bacteremia after 30 seconds, 15 minutes and 1
(mostly viridans)
-Moxifloxacin group ((400mg) 1-2h) and hour.

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control.
Compare bacteremia along the period of Bacteremia lasts a 7,5-15 min Aprox.
Roberts et al,

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RCT 500 1000 2 time after dental extraction. N.S.*** Greater intensity of bacteremia is one minute after
2006 (22)
extraction
Compare bacteremia after dental Routinely rinse with 0.2% chlorhexidine reduce the
Tomas et al, (57,7%) S. viridans

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RCT 106 424 2 extractions with and without prevalence and duration of post extraction
2007 (24) (34%) S. mitis
Chlorhexidine 0,2% prophylaxis bacteremia.

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Compare bacteremias Bacteremia of dental origin occurs after minimal
-After one extraction surgical procedures in children, and is higher in the
Roberts et al,
RCT 207 207 2 -Multiple extractions N.S. group of patients with multiple extractions
1998 (26)

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-Flap
-Control
Benítez-Paez Bacteremia detection after teeth (87%) S. viridans, Conventional culture techniques gave higher

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et al, 2013 CT** 8 24 0 extractions (50%) S. mitis and prevalence than RNA 16S pyrosequentiation

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(30) (22%) S. salivarius
Compare bacteremia. Positive cultures in
(79,9%)
-Post extraction 30% of patients after extraction
Maharaj et al, Streptococcus
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CT 214 1072 0 -, brushing group 11% of patients after brushing,
2012 (39) (S. viridans most
- eating an Apple 0 % after eating an apple. Bacteremia was
founded)
unrelated with oral health status
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Compare bacteremia. (29%) No positive cultures after conservative treatment ,

Peterson et al,
CT 107 107 0 -extraction after conservative treatment. α-hemolytic
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1976 (40)
streptococci
Compare bacteremia after molar Povidone iodine sulcus Irrigation significantly
Rahn et al, RCT simple extraction or after intra-ligament reduces rates of bacteremia.
120 480 1 S. viridans
1995 (41) blind injection.
-Povidone iodine 10%,
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-Clorhexidine 0,2%
-Control
Compare bacteremia They analyzed only Teicoplanin (easy to be administered and lacking

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-Teicoplanin (200mg) (IM) Sreptococcus, secondary effects) may be a good alternative for
Maskell et al,
CT 30 30 0 Amoxicillin group ((3g) 1h) without allergics to penicillin.
1986 (42)
differentiating S.

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viridans
Compare bacteremia Josamycin is more effective in reducing bacteremia
Sefton et al, RCT double They analyzed only

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60 60 4 - Erythromycin ((1,5g) 1.5h)_ Josamycin than erythromycin.
1990 (43) blind Sreptococcus spp.,
group ((1,5g) 1,5h) - placebo.
Compare bacteremia No statistically significant differences erythromycin
Hall et al, RCT double (25,31%)

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38 114 2 -Erythromycin ((1gr) 1.5h) or clindamycin.
1996 (44) blind S. viridans
-Clindamycin ((600mg) 1,5h before).

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Hall et al, RCT double Compare bacteremia - Cefaclor ((1g) 1 h)- S. viridans (S. Cefaclor do not diminish incidence neither
39 117 2
1996 (45) blind placebo. intermedius) magnitude
Compare bacteremia after impacted No significant differences.

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Tuna et al, RCT double third molar extraction. - Povidone iodine (38%)
34 102 4
2012 (46) blind 7,5%, -Chlorhexidine 0,2% S. viridans

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-placebo group.
Compare bacteremia. The incidence of bacteremia is significantly

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-Mouthwash T-Chloramine, reduced by topical application 1 % T-Chloramine
Sweet et al, RCT simple
100 600 1 -brushing with T-Chloramine,
1978 (47) blind
-sulcus irrigation with Lugol,
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-control group
Compare bacteremia Erythromycin reduces the prevalence of
Shanson et al, RCT double restricted to
82 82 4 -Erythromycin ((1,5g) 1 h) postextraction streptococcal bacteremia.
1985 (48) blind
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S. viridans
-Placebo
Compare bacteremia Teicoplanin reduces prevalence of S.viridans
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Shanson et al, -Teicoplanin (400mg) IM 5-10 min They only analyzed bacteremia. Teicoplanin is be recommended to
RCT 120 360 2
1987 (49) -Amoxicillin (1g) IM 20-30 min S. viridans replace intravenous Vancomycin
-Control group
Cannell et al, RCT double Compare bacteremia S. mitis and S. Erythromycin and josamycin candidates for
60 120 3
1991 (50) blind -Erythromycin (1,5g 1.5 H), sanguis prophylaxis for patients at risk or allergic to
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-Josamicin (1,5g 1.5 h) penicillin

-Placebo 1-1,5h.
Compare bacteremia Clindamycin more effective than erythromycin and
Aitken et al, RCT double Restricted to S.

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40 80 3 -Clindamycin (600mg) shortened the positive period
1995 (51) blind viridans
-Erythromycin (1,5g)
Compare Cefuroxime is safer in terms of allergic reactions

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Wahlmann et –Cefuroxime (1,5g) IV (intravenous)(IV) and prevents bacteremia.
RCT 59 118 1 S. viridans
al, 1999 (52) 10 min

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-Placebo.
Compare bacteremia The use of topical antibiotics do not significantly
RCT a -Amoxicillin (3g) in mouth washing rinse reduce rates of bacteremia
Vergis et al, (61%)

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simple 29 108 2 (topical),
2001 (53) S. viridans
blind -Amoxicillin group 3g in oral

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administration and control group.
Compare bacteremia- The study shows that the Phenoxymethylpenicillin
Josefsson et phenoxymethylpenicillin )(2g, 1-1.5h) , more effective against anaerobes than

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CT 60 180 0 S. viridans
al, 1985 (54) -Erythromycin (500mg, 1.5-2.5h) Erythromycin
-Control

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They analyzed if there is bacteremia after None of the variables of oral health nor the extent
Tomas et al, third molar extractions related with (87,8%) of surgery are significantly associated with the
CT 100 300 0

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2008 (55) different oral parameters and surgical S. viridans prevalence of bacteremia after wisdom teeth
strategies extraction.
Compare bacteremia after third molar Neither the incidence nor the magnitude of
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extractions. bacteremia were significantly different
Duvall et al, RCT double (21%)
30 120 5 - Amoxicillin ((2g) 1h), Clorhexidine
2013 (56) blind S. viridans
(0,12% 15 min)
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-Placebo
Compare bacteremia after implant No statistically significant differences in prevalence
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Piñeiro et al, surgery. S.mitis and duration of bacteremia

RCT 50 150 1
2010 (57) -Clorhexidine 0,2% (S. viridans)
-Control group
TOTAL 3564 12839
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*RCT: Randomized clinical trial; **CT: Clinical trial ***N.S.: No specified;

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Table 2: List of different studies that have analyzed bacteremia after dental procedures and the most significant conclusions. The type of study, its JADAD

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(37) value and the "N " used is also indicated. IM Intramuscular injection. IV intravenous IV endovenous injection. Times indicate time before the
operation starts.

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