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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 12  |  Issue : 3  |  Page : 189-196

Triple antibiotic paste––Challenging intracanal medicament: A systematic review


School of Dental Sciences, Health Campus Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia

Date of Submission22-Aug-2019
Date of Decision13-Jan-2020
Date of Acceptance06-Feb-2020
Date of Web Publication02-Jun-2020

Correspondence Address:
Dr. Saleem D Makandar
School of Dental Sciences, Health Campus Universiti Sains Malaysia 16150, Kubang Kerian, Kelantan.
Malaysia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JIOH.JIOH_213_19

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  Abstract 

Aim: To evaluate and compare the performance of triple antibiotic paste (TAP) as intracanal medicaments during the root canal treatment. Materials and Methods: Search strategy included the in vivo studies, in vitro studies, and clinical trials from the databases of PubMed Central, Cochrane, EBSCO, and MEDLINE from January 1981 to August 2019. A total of 223 articles were searched, of which 39 articles were relevant to our study. The searched articles were clinical trials, case reports, and original studies that met with inclusion criteria. Of which, 13 articles were used for quantitative synthesis. A systematic review was performed for TAPs, antibacterial efficiency, effect on mechanical properties, discoloration effect, and cytotoxicity on stem cells. Results: In the included studies, the systematic review articles, the evidence of antibacterial efficiency of TAP is significantly more efficient compared to other medicaments techniques. The mechanical properties has been evaluated, there is a mild reduction in the mechanical properties of the dentin. TAP plays a significant role in reducing the chronic periapical infections. It shows minimal discoloration effect and minimal cytotoxicity to dental pulp stem cell (DPSC) as compared to calcium hydroxide and Ledermix. Conclusion: This systematic review of available data and evidences reveals that TAP is significantly more efficient than the other intracanal medicaments because of its minimal discoloration effect on teeth and less toxic nature to the DPSCs.

Keywords: Minocycline Discoloration, Periapical Lesion, Regenerative Endodontics, Stem Cells, Triple Antibiotic Paste


How to cite this article:
Makandar SD, Noorani TY. Triple antibiotic paste––Challenging intracanal medicament: A systematic review. J Int Oral Health 2020;12:189-96

How to cite this URL:
Makandar SD, Noorani TY. Triple antibiotic paste––Challenging intracanal medicament: A systematic review. J Int Oral Health [serial online] 2020 [cited 2020 Sep 20];12:189-96. Available from: http://www.jioh.org/text.asp?2020/12/3/189/285568




  Introduction Top


It has been clinically indicated that the pulpal and periapical infection is established by the presence of bacteria, and the success is directly related to the decrease in the bacterial colonization pulp system and periapical area.[1] Several studies have investigated the microflora of root canal system infections. In primary root canal infections, necrotic pulp tissue has revealed polymicrobial flora with gram negative species of different kinds of obligatory anaerobic bacteria, which comprises of 90% of all bacteria.[2],[3]

The most prevalent organisms among the samples of secondary root canal infections are Enterococcus faecalis that are more prevalent organisms in the failed root canals.[4] The root canal infection occurs as a result of multiple microorganisms, of which, E. faecalis dominates along with polymicrobial anaerobic species. In reinfection, the E. faecalis are more prevalent. Appropriate medicaments are required to obtain microbial-free environment of root canal system to achieve success.[5]

The prevalence of complex root canal system results in sheltering the microorganisms from the effect of medicaments. A single antibiotic is insufficient to eradicate all polymicrobial flora; hence, triple antibiotic paste (TAP) is used to achieve complete disinfection. The combination that appears to be most promising consists of metronidazole, ciprofloxacin, and minocycline.[5],[6] A significant reduction was observed in microbial growth following the irrigation protocol and antibiotic paste application. In total, 90% of the bacteria remained positive following irrigation with 10mL 1.25% sodium hypochlorite (NaOCl). However, this percentage dropped to 20% following the application of TAP.[6] TAP is most commonly used for root canal treatment. Nowadays, it has been most successful in achieving complete disinfection. However, discoloration of crown was reported with the use of minocycline,[7] and hence the modified TAP (MTAP) was used. Minocycline was replaced with clindamycin and was found to be most successful in achieving disinfection in root canal system.[8]

The aim of this review was to evaluate the efficiency and demerits of TAP used as intracanal medicaments. Does the TAP is a efficient antibacterial?, Does it interfere with the mechanical properties of dentin?, Does it discolors the dentin?, Is TAP toxic to the stem cells? It has been hypothesized that the TAP is an efficient antibacterial agent with minimal toxicity and less effect on strength as other intracanal medicaments.


  Materials and Methods Top


Study design

It is a systematic review. The records were identified by the electronic database search, through PubMed, PubMed Central, ScienceDirect, and Cochrane Central Register of Controlled Trials. The search was specifically performed for the following keywords: TAP as an efficient antibacterial, effect on mechanical properties of teeth, discoloration of teeth, and toxic effect on stem cells.

Inclusion criteria

The inclusion criteria of the study consisted the following:

Clinical questions:

  1. Teeth with infected root canals: Is TAP more effective than other intracanal medicaments?

    • Population: Infected root canals


    • Intervention: TAP


    • Compared with: Other intracanal medicaments, NaOCl, calcium hydroxide [Ca(OH)2], and double antibiotic pastes


    • Outcome of interest: Disinfection of TAP has been evaluated


  2. Does the TAP have any effect on mechanical properties of dentin and does it have discoloration effect?

    • Population: Infected root canals requiring intracanal medicaments


    • Intervention: TAP


    • Compared with: Other medicaments Ca(OH)2


    • Outcome: Strength of dentin and discoloration


  3. Does the TAP have toxic effects on dental pulp stem cells (DPSCs)?

    • Population: DPSCs


    • Intervention: TAP


    • Compared with: Ca(OH)2


    • Outcome of interest: Toxicity


Depending on these questions and criteria, the included articles were the clinical trials, original studies, and case reports.

Exclusion criteria

The exclusion criteria of the study included the following:

  • Articles that are irrelevant as compared to TAP intracanal medicaments.


  • Search strategy

    Published literature on TAP as intracanal medicaments and comparative studies, which included original articles and research papers in databases such as PubMed Central, ScienceDirect, and Cochrane Central Register of Controlled Trials, were taken for review. A total of 223 abstracts appeared with these combinations, of these 39 articles were relevant to the study and 13 articles met the inclusion criteria [Figure 1]. Two independent reviewers screened the search results by title and abstract, then by full-text assessment to determine included studies.
    Figure 1: Search strategy layout

    Click here to view


    Data collection

    Independent articles were extracted depending on the keywords used. The data which are more relevant which included as antibacterial efficiency whether in vivo, in vitro, clinical trials selected. The articles used were of quantitative analysis, which have meaningful information about the keywords, used for the reviewing process.

    Statistical analysis

    Summary measures and data synthesis: Original studies with infected root canals were chosen as a unit of analysis. For dichotomous outcome, risk ratio and its 95% confidence interval (CI) were used as a measure for the effect size. For the continuous outcome, mean difference and its 95% CI were used as a measure for the effect size. Meta-analysis was not possible due to studies assessing different outcomes and could not be combined. The data were statistically analyzed with the Kruskal–Wallis H and Dunn’s post hoc tests to assess the differences in antibacterial efficacy between groups (P < 0.05).[12]

    Data were collected and analyzed by using Statistical Package for the Social Sciences (SPSS) software program, version 22.0 (IBM, Chicago, Illinois) via Wilcoxon signed-rank test.[38]

    Analysis of variance (ANOVA) and post hoc test were used to compare the differences in antimicrobial efficacy between all groups (P ≤0.001)[39],[40] [Table 1].
    Table 1: First-day antibacterial efficacy of triple antibiotic paste

    Click here to view



      Results Top


    The search yielded 223 articles, and 39 articles were independently assessed. Following removal of duplicates, the articles were assessed for eligibility and included in the review [Figure 1]. The TAP is an effective antibacterial compared to NaOCl. TAP reduces 70% of the bacterial culture, whereas NaOCl reduces only 10% of the bacterial culture.

    The TAP was compared with DAP at various dilutions 0.125, 0.25, 0.5, 1, and 10mg/mL. TAP with concentration of 0.125mg/mL showed an efficient antibacterial and less cytotoxicity to the stem cells.

    TAP in the chronic lesions showed the efficient decrease in the lesions.

    The TAP reduces the microhardness of dentin, anyhow the concentration 0.1mg/mL of TAP reduces the microhardness of dentin and which is far less than the effect of 1g/mL of TAP. TAP showed the best antimicrobial efficacy as compared to Ca(OH)2. It affects the microhardness of dentin but it is very minimal. TAP has shown very less toxicity to the stem cells and it is more biocompatible intracanal medicament [Table 1] and [Table 2].
    Table 2: Triple antibiotic paste as intracanal medicaments and comparative studies

    Click here to view



      Discussion Top


    The systematic administrations of antibiotic requires the bioabsorption and biomodulation in the liver and circulated in the circular system this brings the biomodulated drug via circulatory system to the infected area in the root canal system. In the infected root canal system and necrotic pulp there is hampered blood supply and the biomodulated drug also get hampered at the infected site and hence the drug will be no longer effective in the enclosed canals, therefore local application of drugs is more effective and it depends on the type of drugs and mode of local drug delivery system.[9]

    The suppression of microbial content in the root canal is the key success feature. Endodontic instrumentation alone cannot achieve the microbial-free environment alongside the instrumentation during root canal treatment. The combined chemical treatment, for example, irrigation protocol and the intracanal medicaments, play a pivotal role in endodontics. The medicaments are key factors in achieving the success in microbial-free environment. The traditional medicaments used are the Ca(OH)2. Some more efficient medicaments are also used, of which the most recent is the TAP (the combination of ciprofloxacin, minocycline, and metronidazole), which acts as microbicidal and biocompatible for the stem cells that are present in the periapical area as compared with the traditional Ca(OH)2, which is toxic to the stem cells. TAP containing medicaments is used in lesion healing. Regenerative procedures are considered as ideal medicaments with optimum concentrations for these procedures.[10],[13],[36]

    Composition and preparation

    According to Hoshino et al.[40]

    Antibiotic 3 mix––ratio is 1:1:1

  • Ciprofloxacin 200mg, metronidazole 400mg, and minocycline 100 mg


  • Carrier (MP)––ratio 1:1

  • Macrogol ointment and propylene glycol


  • 3Mix is incorporated into NO using the following:

  • 1:5 (MP:3Mix)


  • This standard mix has the potential of healing the periapical lesion.


  • Preparation of triple antibiotic paste

    3Mix MP: It is prepared using metronidazole 33%, minocycline 34%, and ciprofloxacin 33% with a macrogol and propylene glycol (MP) paste.

    3Mix NO alternate with iodoform: It is prepared using metronidazole 30%, clindamycin 30%, ciprofloxacin 30%, iodoform 10% with a macrogol and propylene glycol (MP) paste. This mixture is MTAP as clindamycin instead of minocycline for effective results; iodoform is used for the radio-opacity of the paste.

    Disinfection of root canals

    The microbiota of root canal is polymicrobial, which includes aerobic and anaerobic bacteria, actinomyces, and other bacteria resistant to single antibiotic. As resistance to single antibiotic most common and hence required multiple antibiotics to overcome the resistance and disinfection with all the polymicrobes.[10] To date, the most effective combined drug to overcome the resistance of bacterial strains is TAP. Pai et al.[11] studied the effect of Ca(OH)2 and TAP. They found that 3 of 20 patients with 15% Ca(OH)2 developed inter-appointment flare-ups. However, with respect to the TAP none of them developed inter-appointment flare-ups.[11] In another study, it was found that the TAP showed better disinfection properties as compared to the Ca(OH)2.[12],[38],[39] In this study, in a comparison between TAP, Ca(OH)2 paste, and photo-activated disinfections (PAD) on disinfecting the root canal, 15% failure for Ca(OH)2, 5% failure for TAP, and no failure for PAD were observed, which concludes that the combination of PAD with TAP may give promising results in disinfecting the root canal.[13]

    In another study, they evaluated the efficacy of TAP with the combination of other antibiotics such as amoxicillin + metronidazole, amoxicillin clavulanic acid + metronidazole, amoxicillin clavulanic acid + metronodazole, amoxicillin + cloxacillin + metronodazole. They found that the TAP showed the maximum bacterial inhibition zone among other formulations.[14] The antibacterial efficacy on E. faecalis of combination of TAP and Ca(OH)2 with 2% chlorhexidine was studied. They found that combination of Ca(OH)2 with 2% chlorhexidine is more potent than the TAP against E. faecalis. TAP could eliminate bacteria to the depth of 400 µm, while Ca(OH)2 could eliminate bacteria from only 200 µm depth of dentin.[15],[37] Metronidazole is a nitroimidazole compound that shows broad spectrum of activities against protozoa and anaerobic bacteria. It has clinical activity against anaerobic gram-negative cocci and anaerobic gram-positive bacilli.[16]

    Use in regeneration and revascularization techniques

    The revascularization is the process of inducing bleeding from PA area into the root canal that carries the stem cells from the periapical area, which is suitable for the root lengthening and regeneration of pulp. The TAP is less toxic to stem cells as compared to Ca(OH)2 when used in an appropriate concentration. Use of lower concentrations of TAP (1, 0.1, and 0.01mg/mL) has the ability to eradicate all E. faecalis with least side effects on apical papilla stem cells as compared to higher concentrations of TAP (10 and 100mg/mL).[17] TAP is used in regenerative endodontics to eradicate the complete microbes and preserve the stem cells at periapical area and also to heal the large periapical lesion. In one study, we found that concentration of 0.125mg/mL of TAP has no cytotoxic effect on stem cells. The lowest concentrations of TAP should be used in eradicating the E. faecalis and in preservation of stem cells during regeneration.[18],[36]

    Lesion healing

    Large periapical cyst-like lesion can be healed by using TAP as medicament, even the larger lesion can be healed using TAP.[19] In one study, the efficiency of TAP has been checked in primary teeth. They evaluated the clinical and radiographic success of pulpectomized primary teeth with chronic infection using a mixture of metronidazole, ciprofloxacin, and minocycline (3Mix)-MP as an intracanal medicament before the obturation. They treated Group A with TAP and Group B with routine pulpectomy procedure. High success rate was observed in Group A in both clinical and radiographic results.[20] Thus, TAP (3Mix) was preferred as an intracanal medicament in the treatment of the large periapical lesion.

    Effect on dentinal structure

    However, the effect of TAP as chemical structure of dentin and the mechanical properties have been evaluated by the Prather et al. In his work he found that the TAP and MTAP currently used in regenerative endodontics caused significant reduction in the microhardness of dentin, he explained it may be the demineralizing effect of this antibiotic mixture on dentin. Use of TAP has resulted in etching of dentin and results mild eroding of dentinal structure, which results in decrease in mechanical properties of dentin, hence tooth brittleness increases and it tends to fractures.

    When used at higher concentration, the 1g/mL TAP treatment causes a significant reduction in microhardness at 500 µm from the pulp dentin complex as compared with MTAP at the same concentration. This could be explained by the minocycline causing the chelation of calcium from the dentin and demineralize the dentinal structure. Showed that methyl cellulose based 0.1mg / ml of TAP and MTAP caused significantly lower reduction in microhardness of dentin when compared with 1g/mL concentration of same antibiotics.[21]

    Effect on stem cells

    The TAP is most commonly used in regenerative endodontics. The Ca(OH)2 dressing, which is used most commonly for disinfection of root canal, is more toxic on apical papilla stem cells, and hence the TAP is used as it has shown more promising results. The TAP preserves the apical papilla stem cells and sling side to achieve the disinfection of root canal.[22] It acts as the microbicidal and is biocompatible for the stem cells, which are present in the periapical area, as compared with the traditional Ca(OH)2 that is toxic to the stem cells.[23] However, the highest concentration used in regenerative endodontics is 1g/mL, but it has shown some toxicity to stem cells from the apical papilla. Hence, the recommended concentration is in the range 0.1–2mg/mL to overcome the negative cytotoxicity effect.[24],[25] The combination of TAP and Ledermix medicaments decreased the viability of DPSCs, although Ledermix was more toxic.[22],[36]

    Discoloration of tooth

    The most important drawback is the tooth discoloration after treatment studies, which indicated that TAP was associated with the highest amount of discoloration as compared to other medicaments and control group, which was related to of minocycline. Different medicament replacements, such as amoxicillin and Cefaclor (a member of the second-generation cephalosporins), have been used to prevent the problem.[26] In addition to avoid the discoloration dentin bonding agent (resin) is used to avoid penetration of minocycline and to avoid discoloration,[27] tooth bleaching procedure is used to reverse the discoloration.[28],[29] Al Saeed et al.[30] carried out a study to find the antibacterial efficacy and discoloration activity of TAP, Augmentin, and tigecycline. They concluded that the TAP, augmentin, and tigecycline reduced bacterial growth significantly with minimal discoloration.[30] Jagdale et al.[31] evaluated the discoloration induced by two TAPs (TAP 1 [metronidazole + ciprofloxacin + cefaclor] and TAP 2 [metronidazole + ciprofloxacin + minocycline]) when used at different depth levels. TAP 1 and TAP 2 both showed an increased discoloration, whereas greater discoloration was seen with TAP 2, containing minocycline. At greater depths, where the more thick temporary restoration was used, had shown less discoloration.[31]

    Triple antibiotic paste removal

    The ideal technique for TAP removal is to remove with irrigation and instrumentation technique, and complete removal may not be achieved by this photon-induced acoustic streaming (EndoActivator and photo-initiator photoacoustic streaming technique on removal of DAP and TAP). Ultrasonic activation has given effective results in the removal of TAP from the root canals.[32]

    The TAP removal a challenge: The irrigation techniques such as EndoActivator (Dentsply, Tulsa, Oklahoma), EndoVac (SybronEndo, Coppell, Texas), and a syringe/Max-i-Probe needle (Dentsply Rinn, Elgin, Illinois) were used to remove the medicaments. Approximately 88% of the TAP was retained in the root canal system regardless of irrigation technique used, evaluated by radioactivity technique. Further, approximately 50% of radiolabel TAP was present in up to 359 µm within dentin. Conversely, up to 98% of the radiolabeled intracanal Ca(OH)2 was removed, and most residual medicament was only found in 50 µm of dentinal tubules. TAP cannot be effectively removed by the current irrigation techniques, because of its binding capacity with dentin.[33]

    In another study, they evaluated the efficiency of different irrigation protocol in the removal of TAP from root canals. They used peracetic acid as irrigant, 1-hydroxyethylidene-1,1-bisphosphonate (HEBP) + NaOCl, EDTA + NaOCl. The irrigating solution EDTA gave more promising results than PAA, HEBP solutions.[34],[37]

    Triple antibiotic paste in other materials

    The incorporation of 1.5% TAP into glass ionomer cement (GIC) has resulted in optimal antibacterial effect without altering the physical, mechanical, and chemical properties of GIC. TAP is also used along with gutta-percha, which is known as medicated gutta-percha with TAP.[35]

    The limitations are related to the discoloration of coronal tooth structure. Following adequate concentrations of TAP helps in obtaining promising results in endodontics.


      Conclusion Top


    The review evaluated the efficiency of TAP as compared to the conventional intracanal medicaments such as Ca(OH)2 and other local medication. It has been found that the TAP is more efficient as bactericidal, has minimal effect on dentinal mechanical properties, has very minimal discoloration effect, and helps in preserving the stem cells at periapical area in the regenerative endodontics.

    Ethical policy and institutional review board statement

    All 13 included randomized clinical trials, in vitro studies, were approved and registered by their corresponding institutional ethics committees and institutional review boards.

    Data availability statement

    The data set presented within this manuscript has been obtained from the 3 included clinical trials and 10 original articles. The data were readily available within the articles.

    Acknowledgement

    We thank Richard Kirumbakaran, research scientist (biostatistics) Cochrane South Asia, and the peer referees for their contribution in conducting the original systematic review and meta-analysis. We also thank the contribution of the departmental staff members and colleagues.

    Financial support and sponsorship

    Nil.

    Conflicts of interest

    There are no conflicts of interest.



     
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