Prevention of Postdental Procedure Bacteremia: A Network Meta-

Analysis

Running title: Prevention of Bacteremia: NMA

Bing-Syuan Zeng, MD a,1 Shih-Ying Lin, DDSb,1, Yu-Kang Tu, DDS, PhD c,d, Yi-Cheng Wu,

MD e, Brendon Stubbs, MD, PhD f,g,h, Chih-Sung Liang, MD i,j, Ta-Chuan Yeh, MD k, Tien-

Yu Chen, MD k,l, Pao-Yen Lin, MD, PhD m,n, Wei-Te Lei, MD o, Chih-Wei Hsu, MD m, Yen-

Wen Chen, MD p, Ping-Tao Tseng, MD p,q,*, Chang-Hua Chen, MD r,s,t,*

a Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan

b Department of Dentistry, MacKay Memorial Hospital, Taipei, Taiwan

c Institute of Epidemiology & Preventive Medicine, College of Public Health, National

Taiwan University, Taipei, Taiwan

d Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan

e Department of Sports Medicine, Landseed International Hospital, Taoyuan, Taiwan

f Physiotherapy Department, South London and Maudsley NHS Foundation Trust,

London, UK

g Department of Psychological Medicine, Institute of Psychiatry, Psychology and

Neuroscience (IoPPN), King's College London, De Crespigny Park, London, UK

h Positive Ageing Research Institute (PARI), Faculty of Health, Social Care and

Education, Anglia Ruskin University, Chelmsford, UK

1

i Department of Psychiatry, Beitou Branch, Tri-Service General Hospital; School of

Medicine, National Defense Medical Center, Taipei, Taiwan

j Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei,

Taiwan

k Department of Psychiatry, Tri-Service General Hospital; School of Medicine,

National Defense Medical Center, Taipei, Taiwan

l Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan

m Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang

Gung University College of Medicine, Kaohsiung, Taiwan

n Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung

Memorial Hospital

o Division of Allergy, Immunology, Rheumatology Disease, Department of Pediatrics,

Mackay Memorial Hospital, Hsinchu, Taiwan

p Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung City, Taiwan

q WinShine Clinics in Specialty of Psychiatry, Kaohsiung City, Taiwan

r Program in Translational Medicine, National Chung Hsing University, Taichung City,

Taiwan

s Rong Hsing Research Center For Translational Medicine, National Chung Hsing

University, Taichung City, Taiwan

t Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan

2

1: contributed equally as first author

*: contributed equally as corresponding author

Correspondence to:

Ping-Tao Tseng. WinShine Clinics in Specialty of Psychiatry, Kaohsiung City, Taiwan.

No.68, Nantai Road, Xinxing District, Kaohsiung City 800, Taiwan. Telephone number:

+886-7-2850119. E-mail: ducktseng@gmail.com

OR

Chang-Hua Chen. Department of Internal Medicine, Changhua Christian Hospital,

Changhua, Taiwan. No. 135, Nanxiao Street, Changhua City, Changhua County 500,

Taiwan. Telephone number: +886-4-7238595. E-mail:

chenchanghuachad@gmail.com

Word count: 3143; Abstract Word count: 224 words

3

Abstract

Postdental procedure bacteremia is common and troublesome. The comparative

efficacy of multiple prophylactic interventions is unclear. We compared the efficacy of

interventions for the prevention of postdental procedure bacteremia. We conducted

a review of ClinicalKey, Cochrane CENTRAL, Embase, ProQuest, PubMed,

ScienceDirect, Web of Science, and ClinicalTrials.gov from inception to December

04th, 2018. Randomized controlled trials (RCTs) that evaluated prophylactic

interventions for the prevention of postdental procedure bacteremia were eligible.

The primary outcome was the incidence of postdental procedure bacteremia. A total

of 24 RCTs were included with a total of 2147 participants. Our network meta-

analysis (NMA) demonstrated that intravenous administration of 1000/200mg of

amoxicillin/clavulanate (IVAmox/Clav) provided the least incidence of postdental

procedure bacteremia among all the prophylactic interventions [odds ratio

(OR)=0.03, 95% confidence intervals (CIs)=0.00 to 0.63] compared to the

placebo/controls. The oral 3g amoxicillin (o3Amox) had the least incidence of

postdental procedure bacteremia among all oral or topical forms of prophylactic

interventions (OR=0.10, 95% CIs=0.02 to 0.44) compared to the placebo/controls. No

serious adverse events, such as anaphylactic shock, mortality, and the development

of antibiotic-resistant bacteria, were reported. None of the included subjects were of

high risk of infectious endocarditis. Our NMA demonstrates that the IVAmox/Clav

and o3Amox might be the best prophylactic interventions in preventing postdental

procedure bacteremia among all the oral/topical forms of interventions for the

overall populations.

Keywords: prophylaxis; network meta-analysis; bacteremia; prevention; dental

procedure

4

Abbreviation: chlorhexidine: rinse chlorhexidine; CI: confidence interval; ES: effect

size; IE: infectious endocarditis; IV: intravenous; IVAmox/Clav : intravenous

administration of 1000/200mg of amoxicillin/clavulanate; NMA: network meta-

analysis; o2Amox: oral 2g amoxicillin; o3Amox: oral 3g amoxicillin; o400Moxif: oral

400mg moxifloxacin; o500Azith: oral 500mg azithromycin; OR: odds ratio; RCT:

Randomized controlled trial; SUCRA: surface under the cumulative ranking curve

5

Introduction:

Postdental procedure bacteremia is a highly prevalent condition ranging from

58% to 100% in adult and 30% to 76% in children, respectively (Tomas and Alvarez

2012). Several frequent sources of bacteremia, such as viridans streptococci , and

Streptococcus spp., have been detected in the bloodstream after the dental

procedure in nearly half of the patients (Horliana et al. 2014; Mang-de la Rosa et al.

2014). The presence of odontogenic bacteremia has been associated with the risk of

infectious endocarditis (IE) in high-risk patients, such as in patients with prosthetic

heart valves (Tubiana et al. 2017), and odontogenic bacteremia accounts for 10% to

15% of episodes of IE’s pathogenesis (Barbosa et al. 2015). As a consequence of IE,

the in-hospital mortality rate of IE was as high as nearly 20% (Slipczuk et al. 2013).

Despite the potential link between the odontogenic bacteremia and IE, the role

of prophylaxis in patients receiving dental procedure has received much debate.

Some guidelines that recommended prophylaxis, especially using antibiotics, citing

the high risk of mortality and complication of IE related to odontogenic bacteremia

(Gould et al. 2006; Wilson et al. 2007; Habib et al. 2015; Nishimura et al. 2017).

However, other guidelines oppose antibiotic prophylaxis citing the increased risk of

anaphylactic shock related to antibiotics or the development of antibiotic-resistant

bacteria after a wide and long-term use of prophylactic antibiotics (Gould et al. 2006;

Wilson et al. 2007; NICE 2008; Nishimura et al. 2017). However, the cessation of

prophylactic antibiotics in line with the aforementioned guidelines has caused

concerns about the potential risks in the dramatic increase in IE incidence. A recent

report in England found that, following the dropping-down prescription rate of

prophylactic antibiotics, the incidence of IE had increased to 35 more cases per

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month on March 2013 above the projected historical trend (Dayer et al. 2015).

However, although the prophylactic antibiotics in patients with high risk of IE had

been admitted to be important by some guideline (Gould et al. 2006; Wilson et al.

2007; Habib et al. 2015; Nishimura et al. 2017), it is difficult to conduct well-designed

randomized controlled trials (RCT) directly investigating the benefit and preventive

effect of the prophylactic antibiotics to the postdental procedure IE due to low

incidence of the postdental procedure IE. Therefore, the investigation of the benefit

and preventive effect of bacteremia by individual prophylactic interventions in

general population is of high relevance for clinicians.

There has also been inconsistent results from systematic reviews and traditional

pair-wise meta-analyses, hence there lack of clarity to informed clinical care and

data. For instance, a recent review article indicated that antimicrobial prophylaxis

before an invasive dental procedure does not prevent bacteremia (Gonzalez Navarro

et al. 2017). Furthermore, although the traditional meta-analyses have demonstrated

the association of the decreased bacteremia with the prophylactic chlorhexidine

(Arteagoitia et al. 2018) or overall prophylactic antibiotics (Moreno-Drada and

Garcia-Perdomo 2016; Cahill et al. 2017), these meta-analyses could not provide

further information about the superiority of individual different prophylactic

antibiotics. Nevertheless, other review articles provided inconclusive findings. A

network meta-analysis (NMA) is a method that enables indirect comparisons of

efficacy between different prophylactic agents and can assess and evaluate the

comparative efficacies of the different agents.

Given the aforementioned rationale, we conducted an NMA of RCTs, which

investigated various antimicrobial prophylactic agents used to prevent postdental

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procedure bacteremia in the participants receiving dental procedure.

8

Methods

Search Strategy and Selection Criteria

We conducted a systematic review of ClinicalKey, Cochrane CENTRAL, Embase,

ProQuest, PubMed, ScienceDirect, Web of Science, and ClinicalTrials.gov from

inception to December 04th, 2018. We applied the keywords as “prevention”,

“bacteremia” and “dental procedure”. No language restriction was put in place. We

also conducted manual searches for those potentially eligible articles from the

reference lists.

We only included RCTs, either in placebo-controlled or active-controlled design,

in participants, either adult or pediatric, in published articles. The active controls

included different prophylactic interventions. For topical antiseptics, we followed the

rationale of previous meta-analysis (Arteagoitia et al. 2018), which analyzed the

efficacy of topical antiseptics at any dosage or duration of rinsing as overall one

group. The exclusion criteria included the following: (1) lack adequate control group,

(2) no related dental procedures, and (3) no define bacteremia according to the

blood culture result. In case of duplicated usage of data, we only included the report

with the most informative and largest sample sizes.

Outcome Measures

The primary outcome was the incidence of postdental procedure bacteremia,

which was determined by the positive blood culture from the recruited participants

after dental procedure. If one study provided several data of incidence rate of

bacteremia in different time period, we chose the most near dental procedure one.

The secondary outcome was the incidence of minor or serious adverse events, such

9

as anaphylactic shock, mortality, and development of antibiotic-resistant bacteria.

Two authors independently screened the studies, extracted the relevant data from

the manuscripts, and completed an assessment of the risk of bias among the

included studies. In cases of a discrepancy, the corresponding author was involved. If

there was lack of eligible data from the manuscripts, we contacted the corresponding

authors or coauthors to obtain the original data.

Two independent authors evaluated the risk of bias for each domain described

in the Cochrane risk of bias tool (Higgins and Green 2009).

Data Synthesis and Analysis

Based upon assumption of consistency and transitivity (Tonin et al. 2017), we

performed the NMA with Stata version 14.0 with Network package. For categorical

data, we estimated the summary of ORs with 95% CIs. We used random-effect

models in our pairwise meta-analysis and frequentist models in our NMA to compare

the effect sizes (ESs) between studies with the same interventions. The

heterogeneity among the included studies was evaluated using the tau value, which

is the estimated standard deviation of the treatment effect across the included

studies. A mixed treatment comparison with generalized linear mixed models was

used to analyze the direct and indirect comparisons among the NMAs. We calculated

the relative ranking probabilities between the treatment effects of all interventions

for the target outcomes. In brief, the surface under the cumulative ranking curve

(SUCRA) reflected the percentage of effectiveness each intervention can achieve

relative to an imaginary intervention that was the best without uncertainty. And, we

evaluated the potential local inconsistency using the loop-specific approach and the

side-splitting method and the design-by-treatment interaction model to evaluate the

10

global inconsistency.

Finally, we evaluated the quality of evidence according to Cochrane Handbook

for GRADE ratings (Schunemann et al. 2013) for quality assessment.

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Results

A total of 101 articles were considered for full text review (Figure 1) and 77

articles were excluded for various reasons (eTable 2). In brief, total 24 articles with a

total of 2147 participants (mean age=32.4 year, mean female proportion=48.9%)

were included in the current study (to see detailed characteristics of the included

studies, adverse events reported in each study, and information of dental procedure

applied in each study, please refer the appendix eTable 3,4,5 respectively). The

whole geometric distribution of the treatment arms is provided in eFigure 1A. The

time of blood drawn for blood culture after dental procedure ranged from 2 minutes

to 7 days (median=15 minutes, 25–75% quantile=9–60 minutes). The overall

incidence rate of bacteremia was 30.8% (24.8% in the active intervention groups and

41.2% in the placebo/control groups). None of the participants finally developed IE

among all the included RCTs. Although we did not set any limitations on the

participants’ characteristics in order to include both participants with high risk of IE

and those without definite risk factors during our literature selection stage, none of

the included studies recruited participants with high risk of IE (i.e., prosthetic cardiac

valves, pregnancy, immunodeficiency, past history of IE, rheumatic heart disease,

congenital heart disease). Therefore, we could not perform further subgroup analysis

of participants with high risk of IE.

Primary outcome: the incidence of postdental procedure bacteremia

In our NMA, the incidence of postdental procedure bacteremia by preventive

administration of oral 3g amoxicillin (o3Amox), oral 2g amoxicillin (o2Amox),

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intravenous (IV) 50mg/kg of amoxicillin in children, IV 400mg teicoplanin,

intravenous administration of 1000/200mg of amoxicillin/clavulanate (IVAmox/Clav),

and IV 1.5g cefuroxime was statistically significantly less than those of the

placebo/control groups (eTable 6A and Figure 2). According to the SUCRA, the

IVAmox/Clav provided the least incidence of postdental procedure bacteremia.

Among the oral/topical forms of preventive administration, o3Amox provided the

least incidence of postdental procedure bacteremia.

Subgroup analysis

In the subgroup analysis of the incidence of postdental extraction bacteremia

and postdental procedure bacteremia in adult participants, the main findings of our

NMA revealed similar findings with that observed in overall dental procedures (the

whole result of subgroup analysis please refer to eTable 6B-6E, Figure 3-5, eFigure

1B-1E, and eFigure 2). However, in the subgroup analysis of the incidence of

postdental procedure bacteremia in local/ general anesthesia, that had different

findings from the overall dental procedures. In local anesthesia, the incidence of

postdental procedure bacteremia by preventive oral 500mg azithromycin

(o500Azith) and rinsed povidone-iodine solution was also statistically significantly

less than those of the placebo/control groups. The SUCRA revealed that the

o500Azith and the o3Amox both provided the least incidence of postdental

procedure bacteremia. In general anesthesia, the incidence of postdental procedure

bacteremia by the preventive administration of rinsed chlorhexidine and the oral

400mg moxifloxacin (o400Moxif) was also significantly less compared to that of the

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placebo/control groups. The SUCRA revealed that the IVAmox/Clav provided the

least incidence of postdental procedure bacteremia.

Adverse events: minor or serious

Only three studies reported data considering minor adverse events, including

the bitter taste of povidone-iodine solution, gastrointestinal discomfort, mild

diarrhea, skin rash, nausea, and pain in the injection site. None of the studies

addressed the following serious adverse events: anaphylactic shock, mortality, and

development of antibiotic-resistant bacteria.

Risk of bias and publication bias

We found that 44.8%, 44.2%, and 11.0% in our studies had an overall low,

unclear, and high risk of bias, respectively. Funnel plots and the Egger’s test revealed

no significant publication bias among the articles included in our NMA. In general,

NMAs did not demonstrate inconsistency. The results of GRADE evaluation had been

listed in the appendix.

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Discussion

To the best of our knowledge, this is the first NMA addressing the preventive

effect of individual prophylactic interventions to the prevention of postdental

procedure bacteremia. Among all the prophylactic interventions, the IVAmox/Clav

provided the least incidence of bacteremia. Among the oral/topical forms of

preventive administration, the o3Amox provided the least incidence of bacteremia.

None of the topical antiseptic management was superior to the placebo/controls in

our NMA. The main results would not change in the subgroups of dental extraction

or in the subgroups of adult-only trials. In case of general anesthesia, the

IVAmox/Clav provided the least incidence of postdental procedure bacteremia;

similarly, in case of local anesthesia, the o500Azith and the o3Amox both provided

the least incidence of postdental procedure bacteremia. Finally, only three studies

addressed the minor adverse events, and none of the included studies reported

serious adverse events, such as anaphylactic shock, mortality, and development of

antibiotic-resistant bacteria.

The main finding of our current NMA was that the IVAmox/Clav (IV infusion after

anesthetic induction) provided the least incidence of postdental procedure

bacteremia among all the investigated interventions. Evidence had suggested that

the antimicrobial activity of penicillin against certain odontogenic bacteria would

decrease due to the presence of resistant bacteria, such as viridans streptococci or

some other Gram-negative anaerobic bacteria (Kuriyama et al. 2007; Limeres Posse

et al. 2016). Furthermore, the previous report based on bacterial culture from skin

scrapings and saliva samples found that Staphylococcus aureus and viridans

15

streptococci were highly resistant to amoxicillin (53% and 17%, respectively) but

were sensitive to amoxicillin and clavulanate (only 13% and 7% resistant,

respectively) (Groppo et al. 2005). Additionally, the amoxicillin/clavulanate

combination strategy had two advantages, that is, the combination strategy

produces not only synergistic antibacterial effect but also enhanced effect through

immune-mediated mechanisms, to deal with these two odontogenic species (Finlay

et al. 2003; Limeres Posse et al. 2016). Therefore, based on the rationale mentioned

above and the result of overall NMA, the IVAmox/Clav would be considered as one

of the effective prophylactic interventions in preventing postdental procedure

bacteremia.

Another important finding of our current NMA was that o3Amox and o2Amox

(one dose, 1–3 hours before the procedure) provided the least incidence of

postdental procedure bacteremia among all the oral/topical forms of preventive

administration. The prophylactic effect of the o3Amox in our current NMA was

consistent with the results of the previous RCTs (Vergis et al. 2001; Maharaj et al.

2012). Similarly, the BSAC guidelines in the prevention of postdental procedure

bacteremia/IE recommended o3Amox to be the drug of choice in adult general

population (Gould et al. 2006). According to the AHA guidelines, o2Amox was also

recommended as the drug of choice in adult general population to prevent

postdental procedure bacteremia/IE after dental procedure (Wilson et al. 2007).

Therefore, o3Amox would be the prophylactic antibiotic of choice to prevent

postdental procedure bacteremia among all oral or topical forms of prophylactic

interventions.

On the other hand, if patients are allergic to amoxicillin, our current NMA

16

revealed that the o400Moxif (one dose, 1–2 hours before the procedure) provided

the least incidence of postdental procedure bacteremia among all the oral/topical

forms of preventive management. In the previous two guidelines by the BSAC or by

the AHA, clindamycin (Gould et al. 2006) and cephalexin/clindamycin/azithromycin

(Wilson et al. 2007) were recommended to be prescribed in cases of allergy to

amoxicillin. Moxifloxacin, in vitro, had been proven to fight odontogenic pathogens

(Limeres et al. 2005) and could contribute to a low minimum inhibitory

concentration to all the streptococci species from iatrogenic bacteremia of oral

origin (Tomas et al. 2004). Therefore, these evidences would support the rationale of

o400Moxif as the prophylactic antibiotic of choice in case of allergy to amoxicillin.

The fourth important finding of our current NMA was that the o500Azith and the

o3Amox were both considered as the best prophylactic interventions in case of local

anesthesia, respectively. In clinical practice, most patients who needed dental

procedure are not required to receive general anesthesia; therefore, setting up an IV

line for prophylactic antibiotics is unnecessary. The AHA guidelines also suggested

that initially prophylactic antibiotics should be administered orally and not

intravenously and commented that IV antibiotics should only be administered in

patients who are unable to tolerate or absorb oral medications (Wilson et al. 2007).

Therefore, the oral form of o500Azith and o3Amox would be potential choice.

However, the evidence of o500Azith was derived from only one RCT (Morozumi et al.

2010), which evaluated the efficacy of o500Azith in subjects with dental scaling.

Therefore, the clinician should be careful when apply o500Azith to the other dental

procedure.

Finally, our NMA demonstrated that all the topical antiseptic interventions were

17

not superior to that of the placebo/controls in preventing postdental procedure

bacteremia in the overall group. These findings were similar to most of the previous

RCTs investigating the preventive effects of topical antiseptic interventions (Vergis et

al. 2001; Maharaj et al. 2012). These insufficient preventive effects could be due to

the poor penetration of these antiseptic medications, such as antimicrobial rinses

and irrigations, into the gingival sulcus deeper than 3mm, where the dental bacteria

enter into the systemic circulation (Lockhart and Schmidtke 1994). Additionally, the

suctioning and irrigation with water during the dental procedure would also result in

the removal of any retained topical antiseptic agents, thereby diminishing the

agents’ effect (Vergis et al. 2001). Therefore, the current evidences could not

support the role of topical antiseptic medications in preventing postdental

procedure bacteremia.

Several limitations of our current NMA merit further discussion. First, some of

the analyses in this study were limited by underpowered statistics, including

heterogeneity in the characteristics of the participants (e.g., comorbid diseases, the

complexity of the dental health status, age, gender distribution, the environment of

blood culture medium used in each trial, and trial duration), the small trial numbers

for some treatment arms, and heterogeneity in dental extraction (e.g., single or

multiple). Second, although we quantified the individual dosage of oral or

IV/intramuscular antibiotics in our current NMA, we could not make further

quantitative investigation to those topical antiseptic medications, in the aspect of

duration or intensity, because of the lack of sufficient data. Third, none of the

included studies had focused on participants with high risk of IE, although we tried to

include such participants by not setting any limitation on their end during our

literature selection stage. In such participants with high risk of IE, some of them

18

would regularly take prophylactic antibiotics to prevent IE in the long term, which

might increase the possibility of developing resistance to antibiotics. Therefore,

clinicians should pay special attention when our result is being applied in participants

with high risk of IE because of the high risk of antibiotic resistance. Furthermore,

none of the included RCTs reported the development of IE in the recruited

participants, indicating the absolute risk of IE after dental procedures being very

small in general population. Forth, only two trials consisted of “both child and adult”

or “child only.” Among them, only one trial has focused on participants less than 18

years old (Lockhart et al. 2004). Therefore, we could not make further analysis

focusing on such patients. Fifth, some of the treatment (i.e. IVAmox/Clav and

o500Azith) arms were consisted of few RCTs so that the application of the general

results to clinical application should be careful. In addition, because the NMA was a

new technique under development, there would be a controversy regarding its

application. Sixth, in the current NMA, we followed the rationale to pool the topical

antiseptics at any dosage or any rinsing duration into one overall group, which might

not be able to distinguish the potentially different efficacy of such topical antiseptics

(i.e. chlorhexidine) in different dosage or different rinsing duration. Finally, some of

the network structures of our current NMA were poorly connected; hence, no

sufficient indirect evidences were available to support these findings.

19

Conclusion and implication for research

The main finding of our current NMA revealed that the IVAmox/Clav provided

the least incidence of postdental procedure bacteremia. If focusing on the

oral/topical forms of preventive administration, the o3Amox provided the least

incidence of postdental procedure bacteremia. The IVAmox/Clav and the o500Azith

were considered the best prophylactic interventions in case of general anesthesia

and local anesthesia, respectively. However, because some of the intervention arms

were based upon few RCTs, the clinical indications should be selected carefully to

avoid “one-size-fits-all” treatment to all the clinical condition. The results of current

NMA should not be interpreted as evidence to support prescribe prophylactic agents

to prevent IE in general population receiving dental procedures. Future large-scale

RCTs investigating the preventive effect between the prophylactic antibiotics and

incidence of IE related to postdental procedure bacteremia in high risk patients

should be warranted.

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Acknowledgement

There were no any funding sources associated with the current work. The

authors declared of no potential conflicts of interest with respect to the authorship

and/or publication of this article.

Brendon Stubbs is supported by a Clinical Lectureship (ICA-CL-2017-03-001)

jointly funded by Health Education England (HEE) and the National Institute for

Health Research (NIHR). Brendon Stubbs is part funded by the NIHR Biomedical

Research Centre at South London and Maudsley NHS Foundation Trust. Brendon

Stubbs is also supported by the Maudsley Charity, King’s College London and the

NIHR South London Collaboration for Leadership in Applied Health Research and

Care (CLAHRC) funding. This paper presents independent research. The views

expressed in this publication are those of the authors and not necessarily those of

the acknowledged institutions.

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Figure Legends

1. The flowchart of the current network meta-analysis

2. Forest plot of network meta-analysis of incidence of bacteremia after overall

dental procedure

3. Forest plot of network meta-analysis of incidence of bacteremia after dental

extraction

4. Forest plot of network meta-analysis of incidence of bacteremia after dental

procedure in adult participants only

5. Forest plot of network meta-analysis of incidence of bacteremia after dental

procedure in situation of local anesthesia

Figure 1 depicted the whole flowchart of current network meta-analysis

Figure 2-5 indicated that, when ES < 1, it meant less incidence of bacteremia

by preventive management than placebo/control groups did.

Abbreviation: chlorhexidine: rinse chlorhexidine; CI: confidence interval; control:

control/placebo; essentialoil: rinse essential oil–containing antiseptic; i15cefuroxime:

IV 1.5g cefuroxime; i1amoxycillin: IM 1g amoxycillin; i4teicoplanin: IV 400mg

teicoplanin; i5amoxicillin: IV 50mg/kg amoxicillin in children; iamclavulanate: IV

1000/200mg amoxicillin/clavulanate; IM: intramuscular; IV: intravenous;

27

o15erythromycin: oral 1.5g erythromycin; o1cefaclor: oral 1g cefaclor;

o1erythromycin: oral 1g erythromycin; o2amoxicillin: oral 2g amoxicillin; o2penicillin:

oral 2g penicillin; o3amoxicillin: oral 3g amoxicillin; o4moxifloxacin: oral 400mg

moxifloxacin; o5azithromycin: oral 500mg azithromycin; o6clindamycin: oral 600mg

clindamycin; ojosamycin: oral 1.5g josamycin; povidone: rinse povidone-iodine

solution; topamoxicillin: rinse amoxicillin suspension

28