Triple antibiotic paste in root canal therapy.

The success of the endodontic treatment depends on the microbial suppression in the root canal and periapical region. Endodontic instrumentation alone cannot achieve a sterile condition. With the advent of non-instrumentation endodontic treatment and lesion sterilization and tissue repair, local application of antibiotics has been investigated. Triple antibiotic paste (TAP) containing metronidazole, ciprofloxacin, and minocycline has been reported to be a successful regimen in controlling the root canal pathogen and in managing non-vital young permanent tooth. This paper reviews the existing literature on biocompatibility, efficiency, drawbacks of TAP in endodontic therapy and pulp revascularization.

The role of microorganisms in the development and perpetuation of pulp and periapical diseases has clearly been demonstrated in animal models and human studies.[1] The development and progression of endodontically induced periapical lesion is clearly associated with the presence of microorganisms in the root canal system.[2] Bacteria in infected root canals and periradicular tissues are capable of invading and residing deeply within dentin and in cementum around the periapex. Endodontic therapy is aimed at elimination of bacteria from the infected root canal and at the prevention of infection.[3] The infection of the root canal system is considered to be a polymicrobial infection, consisting of both aerobic and anaerobic bacteria. Because of the complexity of the root canal infection, it is unlikely that any single antibiotic could result in effective sterilization of the canal. More likely, a combination would be needed to address the diverse flora encountered. The combination that appears to be most promising consists of metronidazole, ciprofloxacin, and minocycline.[4] Majority of bacteria in the infected root canal dentin are obligate anaerobes. Hence, metronidazole was selected as the first choice among antibacterial drugs. Even at a high concentration, it cannot kill all the bacteria, indicating the necessity for combination of other drugs. Propylene glycol can be used as a vehicle for the delivery of this paste.[3] The triple-antibiotics regimen was first tested by Sato et al.[5] Teeth with immature root development, necrotic pulps, and apical periodontitis present multiple challenges for successful treatment.[6]

Recently, the concept of revascularization of necrotic pulps regained interest and became an alternative conservative treatment option for young permanent teeth with immature roots.[7] “Lesion sterilization and tissue repair (LSTR) therapy” employs the use of a combination of antibacterial drugs (metronidazole, ciprofloxacin, and minocycline) for the disinfection of oral infectious lesions, including dentinal, pulpal, and periradicular lesions.[8] Traditionally, the treatment of immature permanent teeth with necrotic pulps involves long-term application of calcium hydroxide to induce apexification at the root apex. Recently, mineral trioxide aggregate (MTA) has been used in one-step apexification procedures to create an artificial apical barrier on which the obturation material can be compacted. Although clinically successful for treatment of apical periodontitis, these techniques do not help strengthen the root, and in the absence of continued development of the root, the roots remain thin and fragile.[9] Hoshino et al. performed an in vitro study testing the antibacterial efficacy of these drugs alone and in combination against the bacteria of infected dentin, infected pulps, and periapical lesions. Alone, none of the drugs resulted in complete elimination of bacteria. However, in combination, these drugs were able to consistently sterilize all samples.[10] Metronidazole is a nitroimidazole compound that exhibits a broad spectrum of activity against protozoa and anaerobic bacteria. Minocycline is a semisynthetic derivative of tetracycline with a similar spectrum of activity. Ciprofloxacin, a synthetic fluoroquinolone, has a bactericidal mode of action.[4]

The endodontic regenerative procedure (ERP), an alternative clinical approach to apexification, has received great attention in recent years. This treatment protocol involves the use of a triple antibiotic paste (TAP) consisting of metronidazole, minocycline, and ciprofloxacin as a dressing and the induction of bleeding to create a matrix for the ingrowth of new vital tissue in the pulp canal space.[10]

A gentle treatment regimen (minimal or no instrumentation and an intracanal medication with TAP) before ERP may conserve any viable tissue that may remain in the canal (stem cells in the apical papilla (SCAP) and dental pulp stem cells in the pulp).[10] Many clinical investigations have reported an increase in root thickness and length, resembling normal maturation of the root after TAP therapy.[11-13]

With the increase in non-surgical approach, the goal of this study is to perform a literature search on TAP in endodontics No attempt is made to undertake additional statistical analysis.

Materials and Methods

A PubMed, Medine search was carried out with the key words: “non-vital”, “young permanent tooth”, and “triple antibiotic paste.” Articles were selected after reading the title and abstract. References from the selected articles were also considered for review. Case reports, and in vitro, in vivo animal studies and investigations on TAP were included for review.

Discussion

Modern concept of medicine emphasizes prevention and reversal of the diseases. Only when these attempts fail, we would take on the unfavorable approaches, i.e., surgical intervention and restoration with artificial prostheses.[14] The success of non-surgical endodontic treatment method is based on appropriate cleaning, shaping, asepsis, and filling of the root canal.[2] Several case reports have been published on non-surgical management of tooth with a non-vital pulp and persisting sinus tract using TAP. TAP was successful in promoting the healing and repair of the periapical tissue.[215] The systemic administration of antibiotics relies on patient compliance with the dosing regimens followed by absorption through the gastrointestinal tract and distribution via the circulatory system to bring the drug to the infected site. Hence, the infected area requires a normal blood supply which is no longer the case for teeth with necrotic pulps and for teeth without pulp tissue. Therefore, local application of antibiotics within the root canal system may be a more effective mode for delivering the drug.[15]

Microorganisms in dentinal tubules may constitute a reservoir from which root canal and surrounding tissue infection and re-infection may occur.[16] Portenier et al. demonstrated that dentin itself can have an inhibitory effect on the bactericidal activity of intracanal medicaments like calcium hydroxide.[17]

William Windley observed a statistically significant reduction in bacteria, following the irrigation and antibiotic paste protocol. 90% of the bacteria remained positive following irrigation with 10 ml 1.25% sodium hypochlorite. However, this dropped to 30% following the application of the TAP for 2 weeks.[4]

Dental trauma may tear the apical neurovascular bundle and cause pulp necrosis, resulting in arrested root formation in immature teeth.[18] The traditional approach for treating cases of a necrotic immature permanent tooth was apexification with calcium hydroxide or MTA, but it does not lead to a further thickening of dentinal walls or an increased root length.[19] It is difficult to get an appropriate apical seal in teeth with open apices by using the conventional endodontic treatment methods. Long-term use of calcium hydroxide has several disadvantages such as multiple treatment appointments, probable recontamination of the root canal system during treatment period, and increased brittleness of root dentin which increases the risk of future cervical root fractures.[20] An alternative material of choice for apexification is MTA[21] and it has shown high success rates.[22-24] Regenerative endodontics is an emerging field focusing on replacing traumatized and diseased pulp tissue in these teeth.[25] Utilization of stem cells to regenerate the lost tissues may reverse tissues to their normal state. Regenerative endodontics deals with the healing of impaired dental tissues, including dentin, pulp, cementum, and periodontal tissues.[14]

Regeneration can occur from vital pulp cells remaining at the apical end of the root canal,[19] the multipotent dental pulp stem cells,[26] the stem cells in the periodontal ligament,[27] and stem cells from apical papilla or in bone marrow. The blood clot itself is a rich source of growth factors.[27] Revascularization of the pulp space in a tooth with necrotic infected pulp tissue and apical periodontitis has been thought to be impossible.[4] Nygaard-Ostby and Hjortdal successfully regenerated pulps after vital pulp removal in immature teeth, but were unsuccessful when the pulp space was infected. Thus, if the canal is effectively disinfected, revascularization should occur similar to that in an avulsed immature tooth.[4] Once the canal infection is controlled, it resembles the avulsed tooth that has a necrotic but sterile pulp space. The blood clot is then introduced so as to mimic the scaffold that is in place with the ischemic necrotic pulp in the avulsed tooth.[7] In this situation, the necrotic uninfected pulp acts as a scaffold for the ingrowth of new tissue from the periapical area. The absence of bacteria is critical for successful revascularization because the new tissue will stop at the level at which it meets bacteria in the canal space. The clinical effectiveness of the TAP in the disinfection of immature teeth with apical periodontitis has been reported.[7] Calcium hydroxide can cause necrosis of the surrounding tissue, destroying remnant vital tissues that have the potential to differentiate into new pulp.[28]

When the canal is properly disinfected, the inflammatory process reverses and the tissues may proliferate. Revascularization of immature teeth with apical periodontitis depends mainly on: (a) disinfection of the canal; (b) placement of a matrix in the canal for tissue ingrowth; and (c) a bacterial tight seal of the access opening. Since the infection of the root canal system is considered to be polymicrobial, a combination of drugs would be needed to treat the diverse flora. Thus, the recommended protocol combines the use of metronidazole, ciprofloxacin, and minocycline.[7]

Raison Bose compared TAP, calcium hydroxide, and formocresol as intracanal medicaments in non-vital young permanent tooth. The triple antibiotic group showed the highest percentage increase in the dentin wall thickness compared with the other two groups. TAP can help promote functional development of the pulp–dentin complex.[9] Reynolds et al. achieved revascularization of a necrotic bicuspid using TAP.[7] TAP contains both bactericidal (metronidazole, ciprofloxacin) and bacteriostatic (minocycline) agents to allow for successful revascularization.[29]

In apexification, the canal is temporarily filled until a hard tissue barrier forms at the apex. Because the canal space is filled, there is no space available for vital tissue to proliferate into the root canal and the possibility of revascularization is eliminated.[30] Investigations have proved that topical doxycycline and minocycline can improve radiographic and histological evidence of revascularization in immature avulsed permanent teeth.[3132] Several reports have recently demonstrated the potential for revascularization after infection if a sterile environment is created.[2933] After disinfection, the canal should be filled with a resorbable matrix to encourage the ingrowth of new tissue. Finally, the coronal access must be sealed to prevent re-infection.[4]

TAP was proved to be biocompatible.[28] Tetracycline inhibits collagenases and matrix metalloproteinases,[34] is not cyt otoxic,[35] and increases the level of interleukin-10, an anti-inflammatory cytokine.[36] In addition, metronidazole and ciprofloxacin can generate fibroblasts.[37]

The concern of the antibiotic paste is that it may cause bacterial resistance.[1438] Additionally, minocycline may cause tooth discoloration.[14] Thibodeau and Trope suggested cefaclor instead of minocycline in TAP.[39] Reynolds et al. used dentin bonding agent and composite resin before placement of the triple antibiotic dressing to prevent discoloration, but the discoloration was only reduced.[7] The discoloration by the tetracycline family is thought to be a photo-initiated reaction.[40] Minocycline binds to calcium ions via chelation to form an insoluble complex.[41] It should be limited to the root canal because of the potential risk of tooth discoloration.[40]

Conclusion

Success of the endodontic treatment relies upon the elimination of bacteria from the root canal. Microorganisms in the periapical region can cause re-infection and failure. From the existing literature, it is clear that TAP can be effectively used for sterilization of canals and healing of periapical pathology. The effectiveness of TAP in managing non-vital young permanent tooth is based on the availability of viable stem cells. Development of resistant bacterial strains and tooth discoloration are the possible drawbacks of this technique. TAP seems to be promising medicament in the sterilization and revascularization.