Journal of

Oral Rehabilitation

Journal of Oral Rehabilitation 2014 41; 941--956

Review

Prophylactic antibiotic regimen and dental implant failure: a meta-analysis B. R. CHRCANOVIC*, T. ALBREKTSSON*† & A. WENNERBERG* dontics, Faculty of Odontology, Malm€o University, Malm€o,

*Department of Prostho-

Sweden and †Department of Biomaterials, G€oteborg University, G€oteborg,

Sweden

SUMMARY The aim of this meta-analysis was to investigate whether there are any positive effects of prophylactic antibiotic regimen on implant failure rates and post-operative infection when performing dental implant treatment in healthy individuals. An electronic search without time or language restrictions was undertaken in March 2014. Eligibility criteria included clinical human studies, either randomised or not. The search strategy resulted in 14 publications. The I2 statistic was used to express the percentage of the total variation across studies due to heterogeneity. The inverse variance method was used with a fixed- or random-effects model, depending on the heterogeneity. The estimates of relative effect were expressed in risk ratio (RR) with 95% confidence interval. Six studies were judged to be at high risk of bias, whereas one study was considered at moderate risk, and six studies were considered at low risk of bias. The test for overall effect showed that the difference between the procedures (use

Introduction The risk of infection in any dental implant surgical procedure depends on several patient factors, management procedures during implant placement and the care of the surgical team in maintaining the basic principles of surgery and asepsis (1). Although many surgeons believe that antibiotic coverage for implant placement is not necessary, they continue to use them to protect against claims of malpractice (2). However, the benefits of antibiotic prophylaxis in © 2014 John Wiley & Sons Ltd

versus non-use of antibiotics) significantly affected the implant failure rates (P = 0
0002), with a RR of 0
55 (95% CI 0
41–0
75). The number needed to treat (NNT) to prevent one patient having an implant failure was 50 (95% CI 33–100). There were no apparent significant effects of prophylactic antibiotics on the occurrence of post-operative infections in healthy patients receiving implants (P = 0
520). A sensitivity analysis did not reveal difference when studies judged as having high risk of bias were not considered. The results have to be interpreted with caution due to the presence of several confounding factors in the included studies. KEYWORDS: dental implants, antibiotic prophylaxis, implant failure rate, post-operative infection, meta-analysis Accepted for publication 15 June 2014

healthy patients undergoing routine surgical procedures, such as the placement of endosseous dental implants, are still a controversial issue (3), even for the placement of implants into infected sites (4). Moreover, there is a general trend of providing inappropriate antibiotic prescriptions in dental practice, usually in excess, in both therapeutic and prophylactic use (5). Among the possible disadvantages of routine antibiotic prophylaxis is the risk of drug-related complications (such as hypersensitivity and anaphylaxis), doi: 10.1111/joor.12211

942

B . R . C H R C A N O V I C et al. which may be greater than the risk of post-operative infection occurring with that particular operation, and the possibility that its use may lead to lax surgical techniques and actually increase the complication rate (3). In addition, in view of the growing concerns that healthcare professionals have regarding the potential for an increase in new antibiotic-resistant bacteria, antibiotic prophylaxis guidelines are being reviewed and modified by healthcare professionals (2). The indiscriminate use of antibiotics may produce unwanted adverse effects in patients, cause unnecessary economic waste and add to the increasing emergence of resistant bacterial strains. The recent increase in resistant bacteria observed in the healthcare environments represents a major concern that requires all healthcare professionals to closely examine each procedure in which prophylactic antibiotics are frequently used to determine their true effectiveness (6). Even though oral surgeons often prescribe antibiotics routinely following implant surgery, the usefulness of pre- and post-operative antibiotics in reducing the failure rates of endosseous implants remained unclear and unsubstantiated for several years (7). Most of the conclusions about the use of prophylactic antibiotic regimen in implant dentistry come from retrospective analyses, with multiple operators, different antibiotic prescriptions and different regimens. Despite the widespread use of oral implants in dentistry, we are still lacking a clear guideline on if, when and how to prescribe antibiotics for this type of surgery (8). For approximately the last 15 years, researchers have been trying to evaluate whether the use of antibiotics may or may not influence the survival of dental implants. A review (9) on the subject concluded that a single dose of pre-operative antibiotic therapy may slightly decrease the failure rate of dental implants. However, as the philosophies of treatment alter over time, a periodic review of the different concepts is necessary to refine techniques and eliminate unnecessary procedures. Having said this, we conducted a meta-analysis of clinical studies to investigate whether there are any positive effects of prophylactic antibiotic regimen on implant failure rates and post-operative infection when performing dental implant treatment in healthy individuals. This study presents a more detailed and profound analysis of the influence of prophylactic antibiotics on the implant failure rates, previously assessed in a published systematic review (7).

Materials and methods This study followed the PRISMA Statement guidelines (10). A review protocol does not exist. Objective The purpose of this review was to test the null hypothesis of no difference in the implant failure rates and post-operative infection in patients receiving or not receiving prophylactic antibiotic for dental implant treatment against the alternative hypothesis of a difference. Search strategies An electronic search without time or language restrictions was undertaken in March 2014 in the following databases: PubMed, Web of Science and the Cochrane Oral Health Group Trials Register. The following terms were used in the search strategy on PubMed: {Subject AND Adjective} {Subject: (dental implant OR dental implant failure OR dental implant survival OR dental implant success [text words]) AND Adjective: (antibiotic prophylaxis [text words])} The following terms were used in the search strategy on Web of Science: {Subject AND Adjective} {Subject: (dental implant failure OR dental implant survival OR dental implant success [title]) AND Adjective: (antibiotic prophylaxis [title])} The following terms were used in the search strategy on the Cochrane Oral Health Group Trials Register: (dental implant OR dental implant failure OR dental implant survival OR dental implant success AND (antibiotic prophylaxis)) A manual search of dental implant-related journals, including British Journal of Oral and Maxillofacial Surgery, Clinical Implant Dentistry and Related Research, Clinical Oral Implants Research, European Journal of Oral Implantology, Implant Dentistry, International Journal of Oral and Maxillofacial Implants, International Journal of Oral and Maxillofacial Surgery, International Journal of Periodontics and Restorative Dentistry, International Journal of Prosthodontics, Journal of Clinical Peri© 2014 John Wiley & Sons Ltd

ANTIBIOTICS AND IMPLANTS: META-ANALYSIS odontology, Journal of Dental Research, Journal of Oral Implantology, Journal of Craniofacial Surgery, Journal of Cranio-Maxillofacial Surgery, and Journal of Maxillofacial and Oral Surgery, Journal of Oral and Maxillofacial Surgery, Journal of Oral Rehabilitation, Journal of Periodontology and Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology, was also performed. The reference list of the identified studies and the relevant reviews on the subject were also scanned for possible additional studies. Moreover, online databases providing information about clinical trials in progress were checked (clinicaltrials.gov; www.centerwatch. com/clinicaltrials; www.clinicalconnection.com).

of random assignments by preventing foreknowledge of the forthcoming allocations), incomplete outcome data (clear explanation of withdrawals and exclusions) and blinding (measures to blind study participants and personnel from knowledge of which intervention a participant received). The incomplete outcome data will also be considered addressed when there are no withdrawals and/or exclusions. A study that met all the criteria mentioned above was classified as having a low risk of bias, and a study that did not meet one of these criteria was classified as having a moderate risk of bias. When two or more criteria were not met, the study was considered to have a high risk of bias.

Inclusion and exclusion criteria Eligibility criteria included clinical human studies, either randomised or not, comparing the implant failure/survival rates in any group of patients receiving versus not receiving antibiotic prophylactic regimen for the placement of implants. For this review, implant failure represents the complete loss of the implant. Exclusion criteria were case reports, technical reports, animal studies, in vitro studies and reviews papers. The use of grafts in the patients was not an exclusion criterion for the studies. Study selection The titles and abstracts of all reports identified through the electronic searches were read independently by the three authors. For studies appearing to meet the inclusion criteria, or for which there were insufficient data in the title and abstract to make a clear decision, the full report was obtained. Disagreements were resolved by discussion between the authors. Studies rejected at this or subsequent stages were recorded, together with the reason for the exclusion. Quality assessment The quality assessment was performed using the recommended approach for assessing risk of bias in studies included in Cochrane reviews (11). The classification of the risk of bias potential for each study was based on the four following criteria: sequence generation (random selection in the population), allocation concealment (steps that must be taken to secure strict implementation of the schedule © 2014 John Wiley & Sons Ltd

Data extraction and meta-analysis From the studies included in the final analysis, the following data were extracted (when available): year of publication, study design, unicentre or multicentre study, number of patients, patients’ age, follow-up, pre-operative antibiotics, post-operative antibiotics, mouth rinse, failed and placed implants, post-operative infection, implant surface modification, use of grafting procedures and presence of smokers in the study. Contact with authors for possible missing data was performed. Implant failure and post-operative infection were the outcome measures evaluated, both dichotomous outcomes. The statistical unit for ‘implant failure’ was the implant and for ‘post-operative infection’ was the patient. Whenever outcomes of interest were not clearly stated, the data were not used for analysis. The I2 statistic was used to express the percentage of the total variation across studies due to heterogeneity, with 25% corresponding to low heterogeneity, 50% to moderate and 75% to high. The inverse variance method was used for random-effects or fixed-effects model. Where statistically significant (P < 0
10) heterogeneity was detected, a random-effects model was used to assess the significance of treatment effects. Where no statistically significant heterogeneity was found, analysis was performed using a fixed-effects model (12). The estimates of relative effect were expressed in risk ratio (RR) with 95% confidence interval (CI). Only if there were studies with similar comparisons reporting the same outcome measures was meta-analysis to be attempted. Here, all patients receiving antibiotics were considered in the group

943

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B . R . C H R C A N O V I C et al. ‘use of antibiotics’, to increase the sample size of individual trials, as the variation of the regimens (antibiotic type, dosage, time of administration) used by each study could limit the number of included studies in case any specific regimen was chosen as an inclusion criterion. A funnel plot (plot of effect size versus standard error) will be drawn. Asymmetry of the funnel plot may indicate publication bias and other biases related to sample size, although the asymmetry may also represent a true relationship between trial size and effect size. The data were analysed using the statistical software Review Manager (version 5.2.8, The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark, 2014).

Results

papers; 13 were cited in more than one research of terms. The full-text reports of the remaining 15 articles led to the exclusion of 4 because they did not meet the inclusion criteria: two articles (13, 14) did not inform of the number of failed implants in each group, one article (15) did not clearly inform of the number of implants in each group, and one article (16) did not evaluate implant failures. Orenstein et al. (15) informed of the number of implants placed and the number of failed implants in patients taking preand post-operative antibiotics separately. However, it was not informed whether, for example, some patients who did not take antibiotics pre-operatively made use of antibiotics post-operatively. Thus, it was not possible to clearly define the groups. Additional hand searching of the reference lists of selected studies yielded three additional papers. Thus, a total of 14 publications were included in the review.

Literature search

Description of the studies

The study selection process is summarised in Fig. 1. The search strategy resulted in 311 papers. The three reviewers independently screened the abstracts for those articles related to the focus question. The initial screening of titles and abstracts resulted in 28 full-text

Detailed data of the 14 included studies are listed in Table 1. Eight RCTs (8, 17–23), four CCTs (2, 3, 24, 25) and two retrospective studies (26, 27) were included in the meta-analysis. In seven studies (8, 18–23), both patients and operators/outcome assessors were blinded to the tested intervention. Nine studies (8, 19–23) had short follow-ups, six of them with a follow-up up to 4 months, whereas one study (18) with 5 months and two (17, 25) with a 6-month follow-up. Four articles (2, 3, 17, 24) did not provide any kind of information about the patients’ age, and two (2, 17) did not inform of the number of patients in the study. All studies with available data of patients’ age included only adult patients. Seven studies (19–24, 27) did not use post-operative antibiotics in all patients, and four (2, 3, 8, 17) made use of several different regimens of antibiotic prophylaxis. One study only informed that the patients were receiving antibiotics ‘pre- or immediately after implant surgery’ (25). Seven studies (8, 18–23) chose amoxicillin as the only antibiotic used. Four studies (2, 17, 25, 27) did not mention whether the patients performed antimicrobial mouth rinses. In all other ten studies, the patients rinsed with antimicrobial solutions at least pre-operatively. All articles provided information about the number of failed implants. However, one recent study (22) did

Fig. 1. Study screening process.

© 2014 John Wiley & Sons Ltd

CCT (multicentre)

CCT (multicentre)

1998

2000

2000

Gynther et al. (26)

© 2014 John Wiley & Sons Ltd

Laskin et al. (3) Morris et al. (24)

Zinser et al. (27)

RCT (multicentre)

RCT (multicentre)

2010

2011

RA (unicentre)

RCT (multicentre)

2009

2013

RCT (multicentre)

2008

CCT (unicentre)

2008

Esposito et al. (19) Anitua et al. (20) Esposito et al. (21) Caiazzo et al. (8)

RCT (unicentre)

2008

Abu-Ta’a et al. (18) Alsaadi et al. (25)

CCT (multicentre)

2004

Morris et al. (2)

RA (unicentre)

RCT (multicentre)

1997

Dent et al. (17)

Study design

Published

Authors

Table 1. Detailed data of the included studies

18–85 (49; G1) 18–86 (48; G2P) NM (42–52*, G1) NM (43, G2)

35–81 (56
1)

224 (NM)‡

18–78 (48; G1) 19–76 (48; G2P) 18–73 (48)

27–82 (60; G1) 26–88 (57; G2) 18–86 (56
2)

NM

NM

NM

18–86 (53; G1) 22–81 (58; G2)

NM

Patients’ age range (mean) (years)

316 (158, G1; 158, G2P) 105 (52, G1; 53, G2P) 506 (252, G1; 254, G2P) 100 (75 G1; 25 G2)

80 (40, G1; 40, G2) 283 (NM)

NM

702 (387, G1; 315, G2) 663 (NM)

279 (147, G1; 132, G2)

NM

Patients (n) (number per group)

1, 3, and 6 months after the reconstructive procedure; at 1, 3 and 6

1 and 2 weeks 4 months 3 and 10 days 1 and 3 months 1 and 2 weeks 4 months 1, 2, 4, and 8 weeks 3 months

3–5 years (depending on the research centre) 7–10 days 2 and 5 months 6 months

36 months

Until uncovering surgery (maxilla: 6 months; mandible: 4 months) 1–6 years (mean 3; G1) 1–5 years (mean 3; G2) 36 months

Follow-up visits (or range)

1 g phenoxymethylpenicillin, 39/day for 10 days

1 g phenoxymethy lpenicillin, 1 h before

(1) ampicillin/ sulbactam 3 9 3 g, 1 h before

1 g amoxicillin, 1 h before ‘pre- or immediately after implant surgery’ 2 g amoxicillin, 1 h before 2 g amoxicillin, 1 h before 2 g amoxicillin, 1 h before (1) 2 g amoxicillin (2) 2 g amoxicillin (3) NP†

(1) NP (2) 1 g amoxicillin, 29/day for 7 days (3) 1 g amoxicillin, 29/day for 7 days† (1) ampicillin/ sulbactam 3 9 374 mg,

NP

NP

NP

500 mg amoxicillin, 49/day for 2 days ‘pre- or immediately after implant surgery’

Several different regimens

NP

Several different regimens

Several different regimens

Several different regimens

Several different regimens Used, but details were not informed Several different regimens

Post-operative antibiotics (G1)

Pre-operative antibiotics (G1)

ANTIBIOTICS AND IMPLANTS: META-ANALYSIS 945

2014

Mouth rinse

NM

Tan et al. (23)

Authors

Dent

et al. (24)

Morris

et al. (3)

Laskin

et al. (26)

Gynther

(n = 1615)

(chlorhexidine)

were not informed

Used, but details

(chlorhexidine)

following surgery

For 2 weeks

solution)

123/1254 (G2)

77/1663 (G1)

128/1287 (G2)

56/1293 (G1)

34/664 (G2)

49/790 (G1)

48/1193 (G2)

21/1448 (G1)

implants (n)

9
81 (G2)

4
63 (G1)

9
9 (G2)

4
3 (G1)

5
1 (G2)

6
2 (G1)

4
0 (G2)

1
5 (G1)

rate (%)

failure

Implant

329 (249, G1; 80, G2)

55 (27, G1; 28 G2P)

NM

10 cigarettes/day;

but no details

some patients,

36, G1; 28, G2P), 45 heavy smokers

(≤10 cigarettes/day;

64 light smokers operators’

Performed in

NP

in fresh extraction

implants inserted

left to the individual

Several: ‘Choice was

implants in diabetics, 9

smokers, 26

95 implants in

were provided

but no details

were smokers,

Some patients

NM

Observations

G€ oteborg, Sweden)

NM

NM

NM

Grafting

TiUnite, Nobel Biocare,

Oxidised (Mk III,

NM

Mannheim, Germany)

Dentsply-Friadent,

etched (Ankylos,

Sandblasted and acid-

Encino, USA)

DBA Paragon Company,

modification (brand)

Implant surface

ANTIBIOTICS AND IMPLANTS: META-ANALYSIS 947

et al. (22)

Nolan

et al. (27)

Zinser

et al. (8)

Caiazzo

2 (G2P)

0 (G1)

NM

0 (G2)

0 (G1)

7 (G2P)

3 (G1)

infection

0
49

NM

NM

infection)

operative

(for post-

Biomet3i, Palm Beach

Acid-etched (Osseotite,

NM

NM

operators’

left to the individual

Several: ‘Choice was

modification (brand)

Implant surface

Switzerland)

SLA, Straumann, Basel,

Mannheim, Germany;

Dentsply-Friadent,

etched (Ankylos,

sandblasted and acid-

G€ oteborg, Sweden),

(TiUnite, Nobel Biocare,

0
0515

0
19

§

rate)

operative

P-value

(chlorhexidine)

(G2P)

¶

(G1)

¶

12
9 (G2)

8
4 (G1)

6
9 (G2)

0 (G1)

2
7 (G2P)

1
4 (G1)

rate (%)

(for failure

failure

Post-

Gardens, USA), anodised

5/¶ (G2P)

0/¶ (G1)

8/62 (G2)†

40/478 (G1)

2/29 (G2)

0/119 (G1)

13/483 (G2P)

7/489 (G1)

implants (n)

Failed / placed

P-value

Implant

for 7 days

and 4–59/day

Before surgery

NM

(chlorhexidine)

15 days

and 29/day for

Before surgery

(chlorhexidine)

7 days

and 29/day for

Before surgery

Esposito

et al. (21)

Mouth rinse

Authors

Table 1. (continued)

60, G1; 76, G2

NP

implants, 470 were

(7, G1; 6 G2)

13 smokers

unknown)

antibiotics is

using vs. not using

implants in smokers

(the number of

inserted in smokers

In the total of 1045 sinus

Only in maxilla

-

extraction sockets:

inserted in fresh

28, G2P), implants

day; 26, G1;

(>10 cigarettes/

heavy smokers

60, G2P), 54

day; 55, G1;

(≤10 cigarettes/

115 light smokers

Observations

grafted maxillary

All patients had

NM

Grafting

948

B . R . C H R C A N O V I C et al.

© 2014 John Wiley & Sons Ltd

© 2014 John Wiley & Sons Ltd

Before surgery

Tan 1/80 (G2P)

0/249 (G1)

implants (n)

Failed / placed

NM

0 (G1) 1
25 (G2P)

rate)

(for failure

P-value

rate (%)

failure

Implant

0 (G2P)

2 (G1)

infection

operative

Post-

NM

infection)

operative

(for post-

P-value

of the patients were

smoker (1
5%)

day; 9
1%) or

(