Triple antibiotic paste

Triple antibiotic paste DEFAULT

Triple Antibiotic Paste (TAP)

Triple antibiotic paste is an endodontic preparation that is ideal for treating primary teeth with a pulpotomy to avoid tooth extraction. This procedure using a mix of antibiotics minimizes instrumentation and is referred to as an endodontic regenerative procedure (ERP). The treatment technique is sometimes called Lesion Sterilization and Tissue Repair (LSTR). With LSTR, damaged tissues can be repaired through the disinfection of lesions achieved with triple antibiotic paste. This method has been demonstrated to produce a greater increase in dentin wall thickness and improved functional development of the pulp-dentin complex.

Three Effective Antibiotics in One

There are a variety of bacteria that can be present in an infection and some may be resistant to certain antibiotics. A single antibiotic used alone is not likely to provide complete sterilization. By combining three different antibiotics together for LSTR, the multiple types of bacteria that may be present in a root canal infection can be eliminated. The MP paste made with macrogol and propylene glycol is an excellent vehicle to carry the antibiotics into the dentin to kill the bacterial lesions.

Triple Antibiotic Paste Formulations

There are two formulations for triple antibiotic paste that we make that are both effective. The 3Mix MP is the “original” formulation but we now offer an alternate formulation based on requests from dentists who use the product. Each order of triple antibiotic paste comes packaged in two luer-lock syringes for mixing the antibiotic powder and the MP paste.


Triple antibiotic paste in root canal therapy

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

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

Saleem D Makandar, Tahir Y Noorani
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.
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JIOH.JIOH_213_19

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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 2021 Oct 14];12:189-96. Available from:

  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?

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

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

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:

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.

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].

  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

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  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

Carrier (MP)––ratio 1:1

3Mix is incorporated into NO using the following:

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.


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


Conflicts of interest

There are no conflicts of interest.

  References Top

Murray RR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH. Manual of Clinical Microbiology. 7th ed. Washington, DC: ASM Press; 1999. p. 264-82, 283-305.  Back to cited text no. 1
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  [Figure 1]

  [Table 1], [Table 2]

This article has been cited by
Kavimalar Kavimalar,Sonia Khatri,Sylvia Mathew,Nithin Shetty
[Pubmed] | [DOI]

Intra-canal Medicaments

Efficiency of Triple Antibiotic Mixture and Propolis as Intracanal Medication in Revascularization process in immature apex: A clinical study


In the last 10 years, numerous published cases and case series described the revascularization or regenerative endodontics. Revascularization is a conservative method for inducing maturogenesis in necrotic immature teeth [1]. The favorable outcomes of regenerative endodontics are largely dependent on the adequate disinfection of the root canal [1]. These canals with compromised fragile underdeveloped dentinal walls represent a contraindication for mechanical instrumentation; thus, chemical debridement remains the main form of disinfection [1]. A mixture of ciprofloxacin, metronidazole, and minocycline, known as the triple antibiotic paste (TAP), has been shown to be very effective in eliminating endodontic pathogens in vitro and in situ [1,3-5]. However, TAP has an adverse effect on stem cell survival [6]. Discoloration of the tooth is a problem mostly related to the use of minocycline in TAP [7]. Moreover, TAP can demineralize dentin resulting in reduced microhardness and fracture resistance [8]. Propolis, a flavonoid-rich resinous product of honeybees, is ten times less cytotoxic than calcium hydroxide and has a well-known antibacterial effect [9]. Therefore, creating alternatives to the TAP for disinfecting the root canal of necrotic teeth during the process of pulp revascularization is thought to be of value. The null hypothesis in the current study stated that there is no difference between the tested intracanal medications on the outcome of the revascularization process in immature teeth.

Materials and Methods

Forty patients with immature, non-vital maxillary incisors were included in this study from the outpatient clinic of the Faculty of Dentistry, Ain Shams University, Cairo, Egypt. A detailed medical and dental history was obtained from each patient’s parents or guardians. Only medically free patients were included in this research. The clinical and radiographic exclusion criteria were teeth with vertical fractures, periodontally involved teeth, and nonrestorable teeth. All procedures were performed after obtaining proper institutional review board approval based on the regulations of the Ethical Committee of the Faculty of Dentistry, Ain Shams University (FDASU-RECID011508). Intraoral periapical radiographs revealed immature apices. The age of the patients ranged between 8 and 18 years. Informed consent was signed for each case by the patient’s parents or guardians including the proposed treatment and possible outcomes or complications.

Cases were divided randomly and equally into 4 groups according to the intracanal medicament (10 patients for each group):

TAP group: was treated with Triple Antibiotic Paste

CP group: was treated with Ciprofloxacin + Propolis paste

CM group: was treated with Ciprofloxacin + Metronidazole paste

PM group: was treated with Propolis + Metronidazole paste

1). Triple Antibiotic Paste (TAP): It consisted of Ciprofloxacin (Ciprocin 250 mg tablets; EPICO, Cairo, Egypt), Metronidazole (Flagyl 500 mg tablets; Sanofi Aventis Pharma, Cairo, Egypt), Doxycycline (Vibramycin 100 mg capsules; Pfizer, Cairo, Egypt). One Doxycycline capsule content was evacuated in a sterile mortar, one tablet of metronidazole and one tablet of ciprofloxacin were crushed and ground in the same mortar using a pestle into homogenous powder. Saline drops (Otrivin baby saline; Novartis, Cairo, Egypt) were added and mixed using the pestle until a creamy paste was achieved [4,10].

2). Ciprofloxacin + Propolis Paste: Ethanol extract of raw propolis (EEP; ElEzaby Co. Labs, Cairo, Egypt.) was prepared by adding 10 gm of propolis (Imtinan, Cairo, Egypt) to 40 gm of 70% ethanol (ElGomhorya Co., Cairo, Egypt) (for 20% tincture) in a dark container to prevent reduction of propolis. The container was sealed and placed at room temperature for a period of three weeks. The sealed container was manually shaken every 2 days to ensure proper mixing. After 3 weeks, the container was opened and ethanol extract of propolis was obtained. Ethanol-free EEP was made by evaporating the ethanol in a water bath [11,12]. EEP was then mixed with Ciprofloxacin powder in the ratio 1:1. Saline drops were added and mixed using the pestle until a creamy paste was achieved.

3) Ciprofloxacin + Metronidazole Paste: Ciprofloxacin powder was mixed with Metronidazole powder in the ratio 1:1. Saline drops were added and mixed using the pestle until a creamy paste was achieved.

4) Propolis + Metronidazole paste: EEP was mixed with Metronidazole powder in the ratio 1:1. Saline drops were added and mixed using the pestle until a creamy paste was achieved.

A preoperative radiograph was taken using the standardized paralleling technique by the Rinn XCP alignment system (Rinn Corporation Elgin, Illinois, USA) and Fona ScaNeo intra-oral digital imaging system (FONA Dental, Bratislava, Slovak Republic). Patients were treated as follows: Caries was excavated; access cavity was prepared. The rubber dam was then applied and working length was determined with a periapical radiograph taken with a file inserted into the canal. Canal space was debrided using K file size #80. Canal space was irrigated using 40 cc of NaOCl 2.6% solution and final flush of saline. Canal space was dried using paper points. The antibiotic paste was prepared as previously described. One cubic centimeter of the prepared paste was injected into the canals using a sterile plastic syringe with 20” gauge needle. Care was taken to avoid apical extrusion and to minimize placement in the coronal portion of the tooth. The access cavity was then sealed using temporary restoration (Coltosol F; Coltene Whaledent, Altstatten, Switzerland) over plain cotton. Coltosol F is a long-term temporary restoration. After the 3 weeks, under the same aseptic conditions, anesthesia without vasoconstrictor (Mepecaine, Alexandria Co., Alexandria, Egypt) was administrated. The tooth was re-entered, the antibiotic paste was removed and the canal was irrigated using a sterile saline and dried using paper points [4,13].

Sterile hand file size #25 was introduced into the root canal and placed at 2 mm beyond the working length to induce bleeding into the canal. The bleeding was allowed to reach a 3-mm level below the cemento-enamel junction, and teeth were left at rest for 5 minutes so that a blood clot could be formed [14]. Next, a 3-mm plug of MTA (Angelus; Londrina, Brazil) was inserted into the canals using a suitable-sized amalgam carrier to seal the root canal at the cervical level. The MTA plug was verified radiographically. The MTA plug was then covered by moist cotton and temporary filling. After one week, MTA setting was confirmed clinically, adhesive composite resin (Z250 Restorative; 3M ESPE, St Paul, Minnesota, USA) was used to seal the access cavity [15-17] Figure 1.

Figure 1:Photographs showing the clinical steps of pulp revascularization; A) after cleaning and irrigation with NaOCl solution, B) after intracanal application of TAP or CM, C) after intracanal application of CP or PM, D) dry clean canals after removal of intracanal medication, E) blood clot induced up to the level of canal orifice, F) MTA orifice plug.


Patients were recalled for follow up at 3, 6, 9, 12, and 18 months. Follow-up included the clinical assessment of pain and/or swelling, and standardized radiographic assessment for:

1. An increase in root length

2. An increase in root thickness

3. A decrease in apical diameter

4. A change in periapical bone density

All follow-up radiographs were standardized using the Rinn XCP alignment system and Fona ScaNeo intra-oral digital imaging system. All radiographic measures were collected by the same investigator. All radiographic measurements were repeated after 1 week, and the mean of the 2 sets was considered as the final value.

Increase in root length: A measuring scale was set in the Image-J software (Image-J v1.44, US National Institutes of Health, Bethesda, MD) by measuring a known clinical dimension to its radiographic dimension. The scale was calculated as number of measured pixels per mm length. Root length was measured as a straight line from the cemento- enamel junction to the radiographic apex of the tooth [4,18] in millimeters. Pre and follow-up root lengths were measured using Image-J analysis software. Difference in length was calculated. Percentage of increase in length was calculated as follows: percentage of increase in length = [(postoperative length – preoperative length) / preoperative length] x 100.

Increase in root thickness: Using the preset measurement scale, the level of the apical third was determined and fixed from the cemento-enamel junction. The root thickness and the pulp width were measured mesiodistally at this level in millimeters. Mesiodistal dentin thickness was measured by subtraction of the pulp space from the whole root thickness. Pre and follow-up root thicknesses were measured. Measurements were done pre and post operatively at the same fixed level [18]. Difference in dentin thickness was calculated. Percentage of increase in dentin thickness was calculated as follows: percentage of increase in dentin thickness = [(postoperative thickness – preoperative thickness) / preoperative thickness] x 100.

Decrease in apical diameter: Using the preset measurement scale, the mesiodistal diameter of the apical foramen was measured in millimeters [4]. Measurements were done pre and postoperatively. Percentage of apical closure was calculated as follows: percentage of apical closure = [(preoperative apical diameter – postoperative apical diameter) / preoperative apical diameter] x 100.

Periapical bone density: Periapical bone density was estimated using Image-J software as follows: periapical area was located and analyzed for bone density. Average area density was measured in scale from 0 (black) to 255 (white) and recorded for each radiograph. The same area was then measured in subsequent radiographs and average densities were recorded for the follow up radiographs [4]. The difference between densities was calculated between subsequent radiographs [4,5]. Percentage of change in density was calculated from the original pre-operative radiograph density as follows: percentage of change in density = [(postoperative bone density - preoperative bone density)/preoperative bone density] x 100.

Data were collected, tabulated and statistically analyzed using statistical analysis software SPSS (Statistical Packages for the Social Sciences 19.0, IBM, Armonk, NY). Two-way analysis of variance was performed. The Tukey post hoc test was used in case of significance.


A total of five cases were dropped out from the study, four of which was excluded due to poor patient compliance. Clinical and radiographic examination during the follow-up period showed signs and symptoms of failure in 1 case, which was re-evaluated, and the treatment plan was shifted to MTA apexification. Clinical outcomes are presented in Table 1.

Table 1: The percentage of cases which presented clinical signs and symptoms after the revascularization visit.
Intracanal medicationPostoperative pain/ discomfortSwellingSensitivity to percussionSensitivity to palpation+ve response to thermal testFunctional asymptomatic tooth
(Group 1)
40 %0 %0 %0 %0 %100 %
(Group 2)
20 %0 %0 %0 %0 %100 %
(Group 3)
20 %0 %0 %0 %0 %100 %
(Group 4)
30 %0 %0 %0 %0 %100 %

Radiographic changes:

I. Increase in root length: Figure 2

Figure 2:Representative case in TAP; A: preoperative radiograph, B: 6 month follow up radiograph, C: 12 month follow up radiograph, D: 18 month follow up radiograph. Note the increase in root length from (a-b) in the preoperative radiograph to (a-c) in the postoperative radiograph after 18 months of follow up.

 Effect of type of intracanal medication:

Statistical analysis revealed significant effect of time on increase in root length. However, no statistically significant difference was found between 3 months and 6 months, nor between 6 months and 9 months, nor between 9 months and 12 months (P > 0.05) Table 2

Table 2: The mean percentage of increase in root length ± SD of the four groups among the five evaluation periods.
 Group I
Group II
Group III
Group IV
3 months4.8±3.1 % Ab4.1±2.3 % Ab3.6±2.1 % Ab3.3±2.8 % Ab3.9±2.6 %
6 months6.4±2.4 % Abc5.9±2.1 % Abc6.4±3.3 % Abc5.6±4.8 % Abc6.1±3.2 %
9 months9.7±2.5 % Acd7.2±1.4 % Acd8.5±4.2 % Acd7.5±6 %
8.2±3.9 %
12 months11±2.6 %
9.5±1.3 % Ad12.8±7.2 % Ad10.3±6.3 % Ad10.9±5 %
18 months15.9±5.7 % Ae12.3±1 % Ae20±12.7 % Ae14.8±6.5 % Ae15.7±7.9 %
Mean9.5±5.2 % 7.8±3.3 % 10.3±8.7 % 8.3±6.6 %  
Significant at p≤0.05
Different capital letters indicate significant difference between groups within the same follow-up period
Similar small letter indicates insignificant difference between periods within the same group

 Effect of time:

Statistical analysis revealed significant effect of time on increase in root length. However, no statistically significant difference was found between 3 months and 6 months, nor between 6 months and 9 months, nor between 9 months and 12 months (P > 0.05) Table 2.

II. Increase in root thickness: Figure 3

Figure 3:Representative case in group CP; A: preoperative radiograph, B: 6 month follow up radiograph, C: 12 month follow up radiograph, D: 18 month follow up radiograph. Note the increase in root thickness indicated by narrowing of pulp space from (a) in the preoperative radiograph to (b) in the postoperative radiograph after 18 months of follow up.

 Effect of type of intracanal medication:

Statistical analysis showed that there was no statistically significant difference between all groups through the whole follow up period (P > 0.05) Table 3.Effect of time:

No statistically significant difference was found between 6 months and 9 months (P > 0.05). However, statistically significant difference was found among other follow up periods Table 3.

Table 3: The mean percentage of increase in root thickness ± SD of the four groups among the five evaluation periods.
 Group I
Group II
Group III
Group IV
3 months3±1.9 % Ab2.7±1.9 % Ab4.9±1.2 % Ab2.9±1.5 % Ab3.4±1.8 %
6 months5.5±2.9 % Ac5.8±2.5 % Ac5.5±1.3 % Ac6.1±2.6 % Ac5.7±2.3 %
9 months7±2.9 % Ac6.9±2.5 % Ac6.6±1.3 % Ac7.7±2.8 % Ac7.1±2.4 %
12 months9.5±3.4 % Ad9±2.4 % Ad8.3±1.2 % Ad10.3±3.7 % Ad9.3±2.8 %
18 months14.1±5.8 % Ae12.9±3.9 % Ae14.1±2 %
15.4±3.6 % Ae14.1±4 %
Mean7.8±5.2 % 7.5±4.3 % 7.9±3.6 % 8.5±5.1 %  
Significant at p≤0.05
Different capital letters indicate significant difference between groups within the same follow-up period
Different small letters indicate significant difference between periods within the same group

III. Decrease in apical diameter: Figure 4

Figure 4:Representative case in group CM; A: preoperative radiograph, B: 6 month follow up radiograph, C: 12 month follow up radiograph, D: 18 month follow up radiograph. Note the decrease in apical diameter from (a) in the preoperative radiograph to (b) in the postoperative radiograph after 18 months of follow up.

 Effect of type of intracanal medication:

Statistical analysis showed that there was no statistically significant difference between all groups through the whole follow up period (P > 0.05) Table 4. Effect of time:

Statistically significant difference was found among all follow up periods Table 4.

Table 4: The mean percentage of decrease in apical diameter ± SD of the four groups among the five evaluation periods.
 Group I
Group II
Group III
Group IV
3 months7.1±5.4 % Ab5.1±0.5 % Ab10.8±6.8 % Ab7.1±2.6 %
7.5±4.8 %
6 months15.9±2.6 % Ac14.6±1.1 % Ac22.3±11.3 % Ac12.6±4.1 % Ac16.3±7 %
9 months23.3±0.3 % Ad23.2±0.3 % Ad26.1±10.6 % Ad19.9±6.3 % Ad23.1±6.3 %
12 months32.3±7.6 % Ae30.9±1.2 % Ae32.1±8.9 %
30.8±11.7 % Ae31.5±8 %
18 months46.3±12 % Af50.1±0.3 % Af48.7±10.2 % Af54.5±6.9 % Af49.9±8.8 %
Mean25±15.2 % 24.8±15.5 % 28±15.7 % 25±18.2 %  
Significant at p≤0.05
Different capital letters indicate significant difference between groups within the same follow-up period
Different small letters indicate significant difference between periods within the same group

IV. Periapical bone density: Figure 5

Table 5: The mean percentage of increase in periapical bone density ± SD of the four groups among the five evaluation periods.
 Group I
Group II
Group III
Group IV
3 months6.1±1.5 % Ab6±1.2 %
6.2±1.2 % Ab5.8±1.4 % Ab6±1.3 %
6 months9.3±1.5 % Ac9.6±1.5 % Ac9.5±1.7 % Ac9.7±2.1 % Ac9.5±1.7 %
9 months10.4±2.4 % Ad11.1±2.1 % Ad10.8±2.5 % Ad11.2±2.3 % Ad10.9±2.3 %
12 months12.7±1.8 % Ae13±2 % Ae12.8±2.2 % Ae13.3±2.5 % Ae12.9±2.1 %
18 months17.8±1.9 % Af18.6±1.6 % Af18.6±1.3 % Af18.1±1.7 % Af18.3±1.6 %
Mean11.3±4.3 %11.7±4.5 %11.6±4.5 %11.6±4.5 % 
Significant at p≤0.05
Different capital letters indicate significant difference between groups within the same follow-up period
Different small letters indicate significant difference between periods within the same group
Figure 5:Representative case in group PM; A: preoperative radiograph, B: 6 month follow up radiograph, C: 12 month follow up radiograph, D: 18 month follow up radiograph. Note the increase in periapical bone density from (a) in the preoperative radiograph to (b) in the postoperative radiograph after 18 months of follow up.

 Effect of type of intracanal medication:

Statistical analysis showed that there was no statistically significant difference between all groups through the whole follow up period (P > 0.05) Table 5.

 Effect of time:

Statistically significant difference was found among all follow up periods. Significant improvement in bone density was found after 9 months of follow up in each group Table 5.


Triple antibiotic paste (TAP) has been found to have antimicrobial properties and to be biocompatible [19]. Ciprofloxacin inhibits DNA gyrase synthesis, metronidazole inhibits DNA synthesis, and minocycline inhibits protein synthesis of microbes [15]. Because case reports have shown that minocycline causes visible crown discoloration [20,21]. In our study, Saline drops were added and mixed with the antibiotic combination until a creamy paste was achieved. This is consistent with most case reports, in which there was no attempt to deliberately deliver a specific concentration of the drugs. Instead, drugs were mixed until a certain physical consistency was achieved that was deemed suitable by clinicians [4].

Propolis was used as an intra-canal irrigant and has been found to be effective in reducing endotoxins and inhibiting E. faecalis, Streptococcus aureus, Candida albicans and E. coli [22]. Also, the co-adjuvant activity of propolis in antimicrobial therapy was confirmed [23]. In vitro experiments have shown that propolis presents a high level of artepillin-C, inhibiting the cyclo-oxygenase pathway and eicosanoid synthesis [24]. In addition, studies have observed that propolis promotes regeneration of dental pulp [25].

Immature permanent teeth with necrotic pulp and an apical opening that measures 1 mm or larger were selected because they are considered suitable candidates for treatment [26,27]. Mechanical instrumentation is contraindicated, not only to avoid further weakening the thin root canal walls, but also to protect the vitality of stem cells of apical tissues [2]. However, Lin et al. 2014 published a failed clinical case of regenerative endodontic therapy due to the bacterial biofilms that remained firmly attached to the apical canal walls because of the lack of mechanical debridement [28]. Therefore, there is a trend for even slightly mechanical instrumentation in recent publications [4,29], which was made in our study.

Our clinical observations are in agreement with Paryani and Kim [30]. Our clinical results are also in full agreement with a retrospective study, which demonstrated 100% survival rate of teeth after regenerative treatment [31]. In a retrospective study of 30 cases, followed for up to 1 year, only two cases had complications, which were restricted to discomfort or discoloration [17], which is consistent with our study.

The bone density results in our study showed an increase in the radio-opacity of previously rarefacted areas. This indicates a favorable healing response to the treatment. In the majority of our cases, improvement or resolution of the apical lesion was evident in approximately 6 months. Root elongation and apical closure, with thickening of the root canal walls, was evident after 12-16 months postoperatively.

Our findings concerning the increase in length and thickness were in agreement with many authors [5,19,26,32]. Our findings were also in agreement with other authors [33,34], who reported an increase in length and thickness without quantitative measurements. The results of our study are in disagreement with Lin et al., [28], where the failure was attributed to inadequate root canal disinfection without mechanical removal of biofilm and bacteria in dentinal tubules.

All of groups, except group 3 (DAP-2, Ciprofloxacin+Metronidazole), have shown cervical discoloration, which can be due to using minocycline or propolis in the intracanal medicament [35,36]. There are reports that white MTA may also discolor the tooth structure [7,37,38].


All tested intracanal medicaments paved the way for successful pulp revascularization process in immature permanent anterior teeth, which was evident by continued root growth and resolution of periapical radiolucency. Thereofore, the null hypothesis was accepted.


Follow up visits should be scheduled every 6 months, rather than 3 months, to observe root changes after pulp revascularization procedure. Longer follow up period (>18 months) is needed for monitoring of complete root maturogenesis.


Paste triple antibiotic

Evaluation of Triple Antibiotic Paste Pulp Therapy Compared to Vitapex in Primary Molars.

Brief Summary:

The aim of the study was to compare the clinical and radiographic success of triple antibiotic paste (TAP) which includes (metronidazole, ciprofloxacin, and minocycline) and Vitapex (calcium hydroxide/iodoform paste) for root canal treatment of pulpally involved teeth.

Dental Pulp CavityDrug: triple antibiotic paste (TAP)Drug: Vitapex (calcium hydroxide/iodoform paste)Phase 3

Detailed Description:

This study evaluated and compared the clinical and radiographic efficacy of non-instrumentation triple antibiotic paste pulp therapy (TAP) versus Vitapex pulpectomy in non-vital primary molars. Healthy 5 to 9 years old children with at least one non-vital primary molar were included in the study. molars were divided based on the subject's cooperation level and parental preference into two groups. In the first group, molars received TAP and in the second group, they received Vitapex pulpectomy followed by a stainless-steel crown. The TAP was freshly prepared and proportioned in equal parts by volume (metronidazole, minocycline, and ciprofloxacin=1:1:1) before the scheduled treatment appointment. The clinical and radiographic examination was performed by two calibrated and trained pediatric dentists at the pre-operative baseline and at the six- and 12-months follow-up visits.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment :54 participants
Intervention Model:Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title:Clinical and Radiographic Evaluation of Triple Antibiotic Paste Pulp Therapy Compared to Vitapex Pulpectomy in Non-vital Primary Molars.
Actual Study Start Date :June 1, 2017
Actual Primary Completion Date :December 1, 2018
Actual Study Completion Date :December 30, 2018

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