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Systematic Review

Effectiveness of triple antibiotic paste as an intra-canal medication for the root canal treatment of non-vital teeth with apical periodontitis: A systematic review

[version 1; peer review: 1 approved, 1 approved with reservations]
PUBLISHED 11 Oct 2018
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Abstract

Background: This is a systematic review to assess and provide a pooled effect estimate, if possible, for the effects of triple antibiotic paste as an intra-canal medication for root canal treatment of mature permanent non-vital teeth with apical periodontitis. This review will assess post-operative pain, flare-up incidence, and clinical and radiographic healing.
Methods: Nine electronic databases (Pubmed, CENTRAL, VHL, Scopus, EBSCOhost, Web of Science, Trip, OpenGrey, Proquest) were searched along with two major clinical trial registries. Conference proceedings, reference lists and citations of the included studies were also searched. A total of 537 records were identified and 392 were obtained after duplicate removal. Six records were identified after screening and three studies were included after full text eligibility assessment.
Results:  Three comparators were reported in the included studies: calcium hydroxide paste, 2% chlorhexidine gel and ledermix paste.  There was no statistically significant difference between triple antibiotic paste and calcium hydroxide regarding postoperative pain, and clinical and radiographic healing of periapical lesions. There was no difference between triple antibiotic paste and chlorhexidine regarding flare-up incidence. However, triple antibiotic paste reduced the level of post-operative pain more than ledermix, which was statistically significant.
Conclusions:  The evidence is still insufficient surrounding the use of triple antibiotic paste; therefore more clinical investigations with high levels of evidence and rigorous methodologies are needed.

Keywords

Root canal therapy, postoperative pain, nonvital tooth

Introduction

Pulpal tissue infection initiates inflammation of periapical tissues and results in apical periodontitis1. Root canal treatment aims to prevent or manage apical periodontitis by decreasing the intra-canal microbial load2. The anatomy of the root canal system makes it almost impossible to completely eliminate the bacteria using conventional mechanical and chemical techniques, even with the highest technical standards3. Therefore, an effective intra-canal medication in the root canal is required to kill any remaining bacteria4, thereby reducing postoperative pain and inducing periapical healing5. Calcium hydroxide has been considered the gold standard for optimally disinfecting root canals; however, it had been reported that Enterococcus faecalis the dominant bacteria in resistant endodontic infections, is resistant to calcium hydroxide6. Recently, triple antibiotic paste (a mixture of ciprofloxacin, metronidazole and minocycline) has been used as an intra-canal medication for root canal disinfection7. It had been shown that triple antibiotic paste could kill any remaining bacteria in the root canal system8.

To the best of our knowledge, the effectiveness of triple antibiotic paste as an intra-canal medication in the treatment of non-vital permanent teeth with apical periodontitis hasn’t yet been subjected to systematic review. Thus, the purpose of this study is to systematically review and provide a pooled effect estimate, if possible, for the effects of triple antibiotic paste as an intra-canal medication for root canal treatment of mature permanent non-vital teeth with apical periodontitis. This review will assess post-operative pain, flare-up incidence, and clinical and radiographic healing.

Methods

This systematic review was reported according to PRISMA Statement9. Supplementary File 1 contains the completed PRISMA checklist. The protocol was registered in PROSPERO database, registration number: CRD42018106518.

Eligibility criteria

Population: adult patients who had non-vital permanent mature teeth with apical periodontitis or previously root canal-treated teeth with apical periodontitis, undergoing root canal treatment in multiple visits. Primary teeth, immature, vital teeth and single visit root canal treatment were excluded.

Intervention: triple antibiotic paste, which is a mixture of ciprofloxacin, metronidazole and minocycline.

Comparators: placebo, no intra-canal medication or any other intra-canal medication other than the intervention.

Outcome measures: primary outcomes were post-operative pain and flare-up incidence after the first visit as defined by the trial authors. Secondary outcome was clinical and radiographic healing as defined by the trial authors with at least one year follow-up.

Study designs: randomized and quasi randomized controlled clinical trials were included. Non-randomized clinical trials, observational, in vitro or animal studies were excluded.

Other: there were no restrictions on language, timing or settings.

Information sources

The following electronic databases were searched: CENTRAL, Medline via Pubmed, Virtual Health Library, Trip, Scopus, Web of Science, EBSCOhost, OpenGrey, ProQuest thesis and dissertation. Ongoing clinical trial registries were searched: ICTRP and ClinicalTrials.gov. The search was conducted until 5/7/2018. Other sources included searching reference lists of included studies and relevant systematic reviews10,11, citation searching of included studies done in Google Scholar and searching conference proceedings of International Association of Dental Research (IADR), European Society of Endodontology (ESE) and American Association of Endodontists (AAE).

Search strategy was conducted using free text terms and controlled terms (MeSH) regarding the population and intervention. A sensitivity and precision filter maximizing randomized clinical trials was used in PubMed to help identify randomized clinical trials as recommended by Cochrane handbook12. The full search strategy for CENTRAL database is shown in Table 1.

Table 1. Full search strategy used for CENTRAL database.

IDSearchNumber of hits
#1triple antibiotic paste 57
#2tri antibiotic paste 12
#3tri-antibiotic paste 1
#4triantibiotic paste 1
#5TAP 1786
#6antibiotic paste 153
#7antibiotic mix 124
#8{or #1-#7} 2042
#9MeSH descriptor: [Root Canal
Therapy] explode all trees
1051
#10endodontic 1178
#11endodontic therapy 569
#12endodontic treatment 701
#13endodontic filling 311
#14endodontically treated teeth 228
#15root canal therapy 926
#16root canal treatment 909
#17root canal filling 671
#18{or #9-#17} 2225
#19intracanal medication 60
#20intra-canal medication 7
#21root canal medication 138
#22intra-canal medicament 1
#23intracanal medicament 43
#24root canal medicament 61
#25intra-canal dressing 4
#26intracanal dressing 42
#27root canal dressing 75
#28intracanal disinfectant 4
#29intra-canal disinfectant 0
#30root canal disinfictant 0
#31{or #19-#30} 242
#32#8 and #31 and #18 19

Study selection

After searching the electronic sources 534 records were identified, and an additional three records were identified through searching other sources. After duplicate removal by Endnote X7 reference manager software, 392 records were identified. Two independent reviewers (EAH, AMI) screened the search results by title and abstract then by full text assessment to determine included studies.

Data collection process

A data extraction sheet was written according to the main data extraction items recommended by the Cochrane handbook12.

Data items

The following items were extracted from each included study: methods - study design, setting and country; participants - selection criteria, tooth type, tooth condition, diagnostic criteria, gender/age, number randomized/analyzed and unit of randomization/analysis; interventions - groups, cleaning and shaping technique, irrigation method, intra-canal medication placement technique and period; outcomes - outcome domain, outcome measurement, time points and the outcome assessor.

Risk of bias

To assess the risk of bias in the included randomized clinical trials, the revised RoB 2.0 domain-based tool was used13 to assess the risk of bias in the included randomized clinical trials. Studies were judged to be of “low risk”, “some concerns of risk” or “high risk” based on these domains: bias arising from the randomization process, bias due to deviation from intended interventions, bias due to missing outcome data, bias in measurement of the outcome and bias in selection of the reported results. The individually randomized, parallel group trials template of the RoB 2.0 tool was used on the outcome level for each study.

Summary measures and data synthesis

Single tooth or a patient with a single tooth was chosen as a unit of analysis. For dichotomous outcome, risk ratio and its 95% CI was used as a measure for the effect size. For the continuous outcome, mean difference and its 95% CI was used as a measure for the effect size. Meta-analysis was not possible due to studies assessing different outcomes and could not be combined. A qualitative synthesis was done instead.

Results

Study selection

After screening 392 records by title and abstract; 386 records were irrelevant, Six records were identified for full text eligibility assessment: one study14 was excluded due to using another combination of antibiotics (metronidazole, ciprofloxacin and clindamycin); two studies were awaiting assessment due to unavailable full text15 and no separate results for non-vital teeth16 (the authors of these previous two studies were contacted to obtain the missing data with no response). Therefore, three studies1719 were included in this systematic review (Figure 1).

2be9957c-91dc-4225-b982-5305856a2114_figure1.gif

Figure 1. PRISMA flow chart showing identification and selection process of articles included.

Study characteristics

Characteristics of the included studies are presented in Table 2. All the included studies were randomized parallel multi-arm clinical trials conducted in a single center. The settings of the included studies were done in university or dental college hospitals. There were two studies17,18 in India and one study in Turkey19. A total of 171 patients with 174 teeth were enrolled in the three included studies and 167 teeth were analyzed. All types of teeth were included, either single or multiple rooted teeth.

Table 2. Characteristics of the included studies.

Study IDStudy
design
ParticipantsAge
(years)
Number of
patients
GroupsCleaning/
shaping
Period
of ICM
placement
Outcome
domain
Tool of
measurement
Time
points
Johns
et al. 201412
RCTPatients
who had
periapical
lesions in
the maxillary
anterior
region
15–30 60Ca(OH)2
TAP
PAD
Step back
with K files
and 1%
NaOCL
solution
Not
mentioned
Treatment
success
and failure
Clinical and
radiographic
assessment
3,6,12,18
months
Sinhal et al.
201715
RCTDiabetic
patients
with primary
endodontic
lesion
≥ 20 36Ca(OH)2
TAP
CHX
Crown
down
technique
and 2.5%
NaOCL
solution
2 weeksIncidence
of inter-
appointment
flare-up
VRS 1,2,3,7,14
days
Uyan et al.
201816
RCTFailed
asymptomatic
root-canal-
treated
permanent
maxillary and
mandibular
multi-rooted
teeth with a
periapical
lesion 2–5 mm
18–45 75 patients
(78 teeth),
single visit
Ledermix
TAP
Ca(OH)2
Protaper
retreatment
kit with no
solvents,
2.5%
NaOCL
solution
1 weekPost-
operative
pain
intensity
Heft parker
VAS 0–170 mm
6,12,24,48
hours

RCT, randomized clinical trial; Ca (OH)2, calcium hydroxide paste; TAP, triple antibiotic paste; PAD, Photo activated disinfection; CHX, chlorhexidine; ICM, intra-canal medication; VRS, verbal rating scale; VAS, visual analogue scale.

The intervention of interest was a combination of three antibiotics (metronidazole, ciprofloxacin and minocycline) mixed with inert vehicles to form a paste. In the included studies, three comparators were reported - either calcium hydroxide paste, 2% chlorhexidine gel or ledermix paste.

Johns et al. 201417 evaluated clinical and radiographic healing of periapical lesions in which treatment success was based on either strict criteria (absence of clinical signs and symptoms with complete radiographic healing) or loose criteria (absence of clinical signs and symptoms with complete healing or reduction of lesion size). Uyan et al. 201819 evaluated postoperative pain after root canal retreatment. Sinhal et al. 201718 evaluated incidence of interappointment flare up in diabetic patients in which flare-up incidence was defined as score 4 and 5 of the verbal rating scale.

Risk of bias assessment

Risk of bias summary is presented in Table 3. Two studies17,18 had overall high risk of bias due to high risk of bias in domains regarding bias in selection of the reported results and bias in the measurement of the outcome. One study18 reported the results of flare-up incidence with no time points, while the other study17 reported only the results of clinical and radiographic healing for one time point and did not mention any data about the blinding of the outcome assessors.

Table 3. Risk of bias summary.

Study IDBias arising from
randomization
Bias due to deviation
from intended
interventions
Bias due to
missing data
Bias in measurement
of the outcome
Bias in the selection
of reported results
Overall bias
Post-operative pain
Uyan et al.
201816
Low riskLow riskLow riskLow riskLow riskLow risk
Flare up incidence
Uyan et al.
201816
Low riskLow riskLow riskLow riskLow riskLow risk
Sinhal et al.
201715
Some concernsLow riskSome
concerns
Low riskHigh riskHigh risk
Radiographic healing
Johns et al.
201412
Low riskLow riskLow riskHigh riskHigh riskHigh risk

Results of individual studies

It was not possible to combine the results of the studies in a meta-analysis, due to different outcomes being assessed with different time points and one study was reported in each outcome. A narrative synthesis was done for each study separately.

Triple antibiotic paste VS calcium hydroxide. Regarding post-operative pain, Uyan et al. 201819 found that at six hours, the mean and standard deviation values for pain intensity were 24.44 ± 3.13 in the triple antibiotic paste group and were 19.77 ± 3.18 for calcium hydroxide (mean difference = 4.67, 95% CI 2.72-6.63). At 12 hours, the mean and standard deviation values for pain intensity were 40.15 ± 3.54 in the triple antibiotic paste group and were 28.38 ± 3.59 for calcium hydroxide (mean difference = 11.77, 95% CI 9.56-13.98). At 24 hours, the mean and standard deviation values for pain intensity were 44.95 ± 3.51 in the triple antibiotic paste group and were 36.92 ± 3.56 for calcium hydroxide (mean difference = 8.04, 95% CI 5.85-10.23). At 48 hours, the mean and standard deviation values for pain intensity were 36.82 ± 3.14 in the triple antibiotic paste group and were 38.75 ± 3.19 for calcium hydroxide (mean difference = -1.93, 95% CI -3.89-0.03) after first visit of treatment.

Calcium hydroxide decreased the level of post-operative pain more than triple antibiotic paste in a statistically significant way at 6, 12 and 24 hours. There was no statistically significant difference at 48 hours.

Regarding flare-up incidence, Sinhal et al. 201718 reported that 40% of patients in calcium hydroxide group experienced interappointment flare-up, with no flare-up seen in triple antibiotic paste group. However, the presented data in this study was insufficient to calculate the effect size and its 95% confidence intervals. Uyan et al. 201819 reported no flare-up incidence with either calcium hydroxide or triple antibiotic paste groups.

Regarding clinical and radiographic healing, Johns et al. 201417 presented data only at 18 months follow-up. Based on the strict criteria of success, 13 out of 20 participants were healed in the triple antibiotic paste group and 7 out of 20 participants were healed in calcium hydroxide group (RR 1.86, 95% CI 0.94-3.66). Based on the loose criteria of success, 19 out of 20 participants were healed in triple antibiotic paste group and 17 out of 20 participants were healed in calcium hydroxide group (RR 1.12, 95% CI 0.91-1.38). There was no statistically significant difference between the two groups at 18 months follow-up based on either of the criteria of success.

Triple antibiotic paste VS 2% chlorhexidine gel. Only flare-up incidence was evaluated by Sinhal et al. 201718, who reported no flare-up incidence in either chlorhexidine or triple antibiotic paste groups. However, the presented data in this study was insufficient to calculate the effect size and its 95% confidence intervals.

Triple antibiotic paste VS ledermix paste. Regarding post-operative pain, Uyan et al. 201819 found that at six hours, the mean and standard deviation values for pain intensity were 24.44 ± 3.13 for triple antibiotic paste and were 54.89 ± 3.31 for ledermix (mean difference = -30.45, 95% CI -32.47 to -28.43). At 12 hours, the mean and standard deviation values for pain intensity were 40.15 ± 3.54 in the triple antibiotic paste group and were 64.27 ± 3.74 for ledermix (mean difference = -24.12, 95% CI -26.41 to -21.83). At 24 hours, the mean and standard deviation values for pain intensity were 44.95 ± 3.51 in the triple antibiotic paste group and were 61.77 ± 3.71 for ledermix (MD -16.82, 95% CI -19.09 to -14.55). At 48 hours, the mean and standard deviation values for pain intensity were 36.82 ± 3.14 in the triple antibiotic paste group and were 44.32 ± 3.32 for ledermix (mean difference = -7.50, 95% CI -9.53 to -5.47) after first visit of treatment. Triple antibiotic paste reduced the level of post-operative pain more than ledermix in a statistically significant way at all time points. Regarding flare-up incidence, Uyan et al. 201819 reported no flare-up incidence with either triple antibiotic paste or ledermix groups.

Discussion

Use of antibiotics agents had been suggested by various authors for the eradication of bacteria associated with persistent endodontic infections20. Due to side effects of systemic application, and ineffectiveness in necrotic teeth, local application of antibiotics would be more effective in endodontics21. Research showed that a combination of metronidazole, ciprofloxacin and minocycline could destroy any bacteria in the infected root canal dentin and periapical lesions8. The purpose of this systematic review was to assess the effectiveness of triple antibiotic paste as an intra-canal medication for endodontic treatment of non-vital teeth with apical periodontitis in terms of post-operative pain, flare-up incidence, clinical and radiographic healing.

The search strategy in this systematic review was comprehensive to identify all published and unpublished articles. Seven electronic databases were searched along with two clinical trial registries. Also, grey literature, conference proceedings, backward and forward searches were included in the search strategy to identify all relevant articles. Risk of bias was assessed using the revised RoB 2.0 tool13, which had some advantages over the originally developed tool in the Cochrane handbook12. The RoB 2.0 tool assessed risk of bias on outcome level for each study and provided templates for different study designs at which the overall risk of bias assessment was easier to reach.

Regarding post-operative pain, the evidence could be regarded as insufficient since only one study19 provided data for this outcome. Also, this study suffered from some limitations such as: adding new patients to replace the ones that were lost to follow-up, excluding patients from the analysis after treatment and unclear unit of randomization and analysis, since the number of teeth exceeded the number of patients with no mention if they were randomized an equal number of times. Therefore, this study had a unit of analysis issue22.

Regarding flare-up incidence, the evidence could be regarded as insufficient since only one study18 that had high risk of bias reported data for this outcome, which was insufficient to calculate the effect size and its 95% confidence intervals.

Regarding clinical and radiographic healing, the evidence could be regarded as insufficient since it was provided by one study17 that had high risk of bias.

One of the limitations of this review is the low numbers of studies that were identified despite the comprehensive search strategy conducted. Also, there were two studies awaiting assessment15,16, which, if they were available, might have changed the results of this review. Most of the studies suffered from high risk of bias so that the results of the included studies should be interpreted with caution.

It could be concluded that, the evidence of effectiveness of triple antibiotic paste is insufficient regarding post-operative pain, flare-up incidence, and clinical and radiographic healing. The number of randomized clinical studies assessing triple antibiotic paste effectiveness as an intra-canal medication is few. Consequently, we recommend conducting clearly reported, well designed, high quality, large randomized clinical trials to assess the effectiveness of triple antibiotic paste as an intra-canal medication in endodontic treatment of non-vital teeth with apical periodontitis or failed cases concerning relevant patient outcomes.

Data availability

All data underlying the results are available as part of the article and no additional source data are required.

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Abdel Hamid E, Abdel Aziz S, Sadek HS and Ibrahim AM. Effectiveness of triple antibiotic paste as an intra-canal medication for the root canal treatment of non-vital teeth with apical periodontitis: A systematic review [version 1; peer review: 1 approved, 1 approved with reservations]. F1000Research 2018, 7:1627 (https://doi.org/10.12688/f1000research.16423.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Key to Reviewer Statuses VIEW
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
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Reviewer Report 29 Jul 2021
Vivek Aggarwal, Department of Conservative Dentistry and Endodontics, Faculty of Dentistry, Jamia Millia Islamia, New Delhi, Delhi, India 
Approved
VIEWS 3
The authors have presented a systematic review evaluating the efficacy of triple antibiotic paste (vs other medications) in patients with apical periodontitis. The study has been initially published on 11-Oct-2018. This is an invited review (invitation by the Editorial Team, ... Continue reading
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Aggarwal V. Reviewer Report For: Effectiveness of triple antibiotic paste as an intra-canal medication for the root canal treatment of non-vital teeth with apical periodontitis: A systematic review [version 1; peer review: 1 approved, 1 approved with reservations]. F1000Research 2018, 7:1627 (https://doi.org/10.5256/f1000research.17944.r90674)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Reviewer Report 23 May 2019
A. R. Vivekananda Pai, Department of Conservative Dentistry and Endodontics, Faculty of Dentistry, Melaka-Manipal Medical College (Manipal Academy of Higher Education [MAHE]), Malacca City, Malaysia 
Sumanth Kumbargere Nagraj, Department of Oral Medicine and Oral Radiology, Faculty of Dentistry, Melaka-Manipal Medical College (Manipal Academy of Higher Education [MAHE]), Malacca City, Malaysia 
Approved with Reservations
VIEWS 16
Introduction:
  1. No comments. 
     
Methods:
  1. The authors have to mention if the data was extracted in duplicate or not. If so, who were those authors?
... Continue reading
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Pai ARV and Kumbargere Nagraj S. Reviewer Report For: Effectiveness of triple antibiotic paste as an intra-canal medication for the root canal treatment of non-vital teeth with apical periodontitis: A systematic review [version 1; peer review: 1 approved, 1 approved with reservations]. F1000Research 2018, 7:1627 (https://doi.org/10.5256/f1000research.17944.r45204)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.

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Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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