Effect of triple antibiotic paste and calcium hydroxide on the rate of healing of periapical lesions: A systematic review.

Aim: The rate of healing of periapical lesion after the antibacterial dressing with triple antibiotic paste and calcium hydroxide was assessed. Materials and
Methods: Case reports which used triple antibiotic paste and calcium hydroxide as the intracanal dressing was searched in PubMed, Google Scholar and Cochrane Oral Health's Trials Register up to August 2020, without language and period restriction. Two authors independently reviewed all identified titles and abstracts for eligibility. Tables were generated to summarize the included studies.
Results: Sixteen (n = 16) articles met the eligibility criteria. Nonsurgical endodontic treatment was carried out in eleven cases with triple antibiotic paste and in nineteen cases calcium hydroxide was used. Results of the study after analyzing the case reports indicate that both triple antibiotic paste and calcium hydroxide are equally effective as intracanal medicament. In cases where calcium hydroxide failed to eliminate symptoms, triple antibiotic paste was found to be effective.
Conclusion: As far as the effect on the healing of the periapical lesions is concerned, all the studies showed a high success rate. Available scientific data indicates nonsurgical treatment can be adopted as a routine measure to conservatively treat large periapical lesions of endodontic origin. Copyright:

INTRODUCTION

Periapical lesions develop as an inflammatory response to the invasion of the root canal system by microorganisms and their by-products.[1] The rationale of endodontic therapy is to eliminate the microbes and disinfect the root canal system.[2] The reduction in microbial load is essential before obturation not only to get rid of symptoms but also to lessen the occurrence of refractory periapical pathosis.[3] Microbial eradication during an endodontic procedure is achieved using chemomechanical debridement. However, this method alone cannot render the root canal microbial free, particularly when there is a large periapical lesion. Complexities in the root canal system and the lodging of microbes into deep layers of root canal dentin pose a challenge in disinfection and persistence of these microbes can lead to the recurrence of periapical complications.[4] In addition, the polymicrobial nature of endodontic infections makes total disinfection of the canal space difficult.[1]

Currently, periapical lesions are managed either with a surgical or nonsurgical approach.[5] When the lesion size was huge, resorting to a surgical approach was the dictum in the management of periapical lesions. However, advancements in scientific knowledge of the genesis, pathologic nature, and clinical behavior of endodontic periapical lesions, the potential of the pulpo-periapical lesion to heal without intervention has favored nonsurgical approach.[6] Moreover, surgical methods have many drawbacks such as long healing time, lack of resolution of pain, fistula, and swelling. Hence, it should be considered as an option only when nonsurgical endodontic treatment fails to induce resolution of the lesion. In the case of large periapical lesions, nonsurgical endodontic therapy with the use of an antimicrobial intracanal medicament should be the primary line of management.

Different techniques can be used in the nonsurgical management of periapical pathologies, most commonly employed being lesion sterilization and repair therapy. This includes the employment of various intracanal medicaments such as calcium hydroxide and triple antibiotic paste.[7]

Calcium hydroxide has gained popularity as an intracanal medicament since its introduction to dentistry by Hermann in 1920. Healing is observed in clinical situations with this medicament which is due to its antimicrobial property, induction of hard-tissue formation, and ability to promote periodontal repair.[8] The major limitation of calcium hydroxide is its ineffectiveness against some microorganisms like Enterococcus faecalis and Candida albicans which are commonly associated with persistent endodontic infections.[9]

To overcome the limitations of calcium hydroxide many other medicaments were advocated. Antibiotic therapy has become an inseparable part of antimicrobial treatments and various antibiotics are used to cure active and acute infections. The use of antibiotics as intracanal medicament has proven beneficial in treating endodontic infections. The triple antibiotic paste is a blend of Ciprofloxacin, Metronidazole, and Minocycline.[10] When used in a concentration of 1:1:1 (33% each) as intracanal medicament, it has given promising results in eliminating E. faecalis in the root apex to a depth of about 400 μ.[11]

Hence, we aimed to review the influence of calcium hydroxide and triple antibiotic paste on the rate of healing of periapical lesions, by studying the currently available literature on the intracanal use of these medicaments.

Objectives

To assess the effects of triple antibiotic paste and calcium hydroxide on the healing of periapical lesions associated with infected mature permanent teeth.

MATERIALS AND METHODS

This systematic review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Registration

Registered at the international prospective register of systematic reviews (PROSPERO-CRD42020192568).

Research hypothesis

Our focused question was based on the Participants, Interventions, Comparison, and Outcomes principle “Does the rate of healing of periapical lesions remain the same with calcium hydroxide and triple antibiotic paste?”

Population: Mature permanent teeth with periapical lesion

Intervention: Triple antibiotic paste

Comparator: Calcium hydroxide

Outcome: Healing of periapical lesion.

Criteria for considering studies for this review:

Inclusion criteria

Type of study

Randomized controlled trials, in-vivo studies.

Type of participants

Mature permanent teeth with periapical lesion.

Type of intervention

Nonsurgical management, triple antibiotic paste, double antibiotic paste, calcium hydroxide.

Type of outcome

Rate of healing of periapical lesion with minimum 1-year follow-up.

Exclusion criteria

All the reviews, animal studies, in–vitro studies, periapical lesion with associated external/internal resorption and teeth with the associated periodontal lesion, teeth treated with MTA and Biodentine.

Search methods for the identification of studies:

The search strategy aimed at identifying all published randomized controlled trials and in-vivo studies/case reports dealing with the subject of this review. Detailed search strategies were utilized for each database to identify the relevant studies. The subject search used a combination of mesh words using the Boolean method.

Database searched

PubMed, Google Scholar, Cochrane Oral Health's Trials Register.

Search terms

The following search string summarizes the initial search done in PubMed: ([”Periapical pathology” OR “Periapical diseases” OR “Periapical lesion” OR “Chronic periapical lesion” OR “Apical lesions”] AND [”calcium hydroxide” OR “triple antibiotic paste” OR “Antibiotic paste” OR “Lesion sterilization and tissue repair” OR “Intracanal dressing”] AND [Periapical healing” OR “Periapical radiolucency” OR “Periapical radiopacity” OR “Periapical repair” OR “Periapical bony healing” OR “Tissue repair”]).

Data collection and analysis

Review authors, independently and not blinded, assessed the titles, keywords, abstracts and/or methods sections of studies identified by the search strategy. The search included controlled clinical trials and case reports. We obtained relevant articles identified by reference searching as well as full-text articles selected by the review authors. We read in full, the articles on which review authors disagreed and made the decision to include or exclude on discussion based on eligibility criteria.

Data extraction

Review authors extracted relevant data from the included studies independently and in duplicate. We recorded the following types of data: study design, risk of bias, studied outcome measures, year of publication, duration of follow-up, sample size, number and characteristics of participants in each group, and reported results. We assessed the comparability of participant characteristics at baseline, how researchers dealt with confounding, eligibility criteria, and the methodology used in measuring outcomes. We discussed the results until we reached agreement. In cases of uncertainty, we contacted study authors for clarification. In case of uncertainty persist, we did not use the data.

RESULTS

Literature search

In database search 5908 reports were identified. After title and abstract screening, the study culminated in 40 case reports that fulfilled both the inclusion and exclusion criteria and which were conducted in the last 10 years. After full-text reading, case reports including apexification, retreatments, cases with <1 year follow-up, cases treated with MTA, Biodentine, or medicaments other than triple antibiotic paste and calcium hydroxide were excluded to avoid possible bias in the study. Sixteen articles which met eligibility were included for final reviewing [Figure 1].

Figure 1

Flow chart

These identified studies investigated the healing of periapical lesion after nonsurgical root canal treatment using triple antibiotic paste and calcium hydroxide including success rates, follow-up duration, and updated studies in nonsurgical root canal treatment. In all of the studies, the procedures were performed on systemically healthy persons.

Study characteristics

Characteristics of studies finalized after abstract and full-text screening are summarized in Table 1. In the sixteen studies selected, nineteen patients were treated with calcium hydroxide (63.33%) and eleven patients with triple antibiotic paste (36.66%). Studies also varied in their follow-up duration. In two studies, Caliskan et al.[12] and Matos et al.,[13] follow up was from 2 to 20 years and 2–5 years, respectively. Al-Kandari et al.,[13] Vijayshankar et al.[15] recalled cases up to 2 years, cases were also recalled at 14 months,[15]15 months,[16]18 months,[17] and in the remaining studies, there was only 1-year recall. As far as the effect on the healing of the periapical lesions is concerned, all the studies showed a highly significant success rate. Complete healing of periapical lesion after nonsurgical treatment was achieved.

Table 1

Summary of studies

Authors	Study design	Intervention	Lesion size	Duration of follow-up	Main results	Conclusion
Çalışkan[12]	Clinical review	Calcium hydroxide	7-18 mm	2-10 years	Complete healing in 73.8%Incomplete healing 9.5%	Study demonstrated that nonsurgical root canal treatment using calcium hydroxide in teeth with cyst-like large periapical lesions can be an alternative treatment to surgical therapy
Matos et al. (2014)[13]	Case report	Calcium hydroxide	-	Case 1: 2 years+5 years follow-upCase 2: 1 year follow-up	Case 1: At 2 years showed complete healingCase 2: At 1 year showed decreased radiolucency	Apical endodontic surgery is not always recommended for cases of large periapical lesions compromising several teethProper means of disinfection by calcium hydroxide paste contributes to clinical success
Al-Kandari et al. (1994)[14]	Case report	Calcium hydroxide	-	2 years follow-up	Complete healing at 2 years	The largeness of the lesion does not command its surgical removal and that even cyst-like lesions resolve following conservative therapy
Vijayshankar et al.[15]	Case report	Case 1: Calcium hydroxideCase 2: TAP	Case 1: 2 cm×2 cmCase 2: 2 cm×2 cm	Case 1: 3 years follow-upCase 2: 2 years follow-up	Case 1 : Marked reduction in size at 3 yearsCase 2: Resolution of lesion at 2 years	Calcium hydroxide and TAP used for a prolonged period afford an environment favorable to periapical bone regeneration
Soares et al.[16]	Case report	Calcium hydroxide	32 mm×25 mm	14 months follow-up	Significant reduction in lesion size at 14 months follow up	Extensive periapical lesion can be healed by nonsurgical treatment involving biomechanical preparation, lesion decompression by intracanal aspiration and long term renewal of aqueous calcium hydroxide paste
Taneja et al. (2012)[17]	Case report	Calcium hydroxide followed by TAP	13 mm×17 mm	15 months follow-up	15 months: Complete bony healing	Root canal treatment with TAP as an antibacterial dressing was successful in healing the large periradicular lesion when conventional calcium hydroxide fails to eliminate the symptoms
Mutluay et al. (2017)[18]	Case report	Calcium hydroxide for 2 days followed by TAP	-	6 and 18 months follow-up	At 18 months: Healing of periapical lesion	The success at 18 months of clinical and radiographic follow up confirms that periapical inflammatory lesions should be treated first by conservative means and application of TAP is an effective treatment method
Majumdar et al. (2017)[19]	Case report	Calcium hydroxide	>4 mm	10 months follow-up	At 10 months: Progressive healing	Nonsurgical endodontic treatment was found to be successful in healing large periapical lesions
Taneja et al. (2010)[20]	Case report	Calcium hydroxide for 3 weeks followed by TAP	Case 1: 10 mmCase 2: 14 mmCase 3: 13 mm×17 mm	Case 1: 16 months follow-upCase 2: 10 months follow-upCase 3: 1 year	Case 1: At 16 months, complete bony healingCase 2: At 10 months, progressive healingCase 3: Progressive healing	When conventional medicament calcium hydroxide failed to eradicate symptoms, TAP showed progressive resolution of large periradicular lesions
Mandhotra et al.[21]	Case report	Case 1 and 2: Calcium hydroxide with iodoform pasteCase 3: RC call	Case 1: 16 mm×10 mmCase 2: 6 mm×9 mm	Case 1: 1 yearCase 2: 6 months and 1 year follow-upCase 3: 1 year follow-up	Complete healing at 1 year	Periapical lesions can be successfully treated with the nonsurgical endodontic approach with long term calcium hydroxide therapy
Karunakaran et al. (2017)[22]	Case report	Calcium hydroxide	-	Case 1, 2, and 3: 3 months, 6 months and 1 year follow up	Case 1, 2, 3 at 1 year follow-up showed significant healing	A nonsurgical approach should be accepted as a routine method in periapical lesions as conservative orthograde endodontic therapy demonstrates a favorable outcome
Saatchi et al. (2007)[23]	Case report	Calcium hydroxide	-	Recalled at 1, 3, 6, 12 months	At 1-year progressive healing	Nonsurgical root canal treatment with calcium hydroxide is successful in promoting the healing of a large periapical lesion
Bonny et al.[24]	Case report	Calcium hydroxide for 1 month followed by TAP	-	1-year follow-up	Considerable resolution of radiolucency at 1 year	Conventional endodontic treatment with calcium hydroxide was not enough for treating large cyst-like lesions. TAP was successful at healing large periapical lesion
Tomaret al. (2015)[25]	Case report	TAP	Case 1: 15 mm×15 mmCase 2: 25 mm×25 mm	1-year follow-up	Case 1: At 6 months, complete healing of the lesionCase 2: At 1 year showed complete healing	Simple aspiration technique and LSTR technique together was successful in healing large cyst-like periradicular lesion
Pandey et al. (2018)[26]	Case report	TAP	Case 1: 10 mmCase 2: 13 mm×17 mm	Case 1: 12 months and 16 months follow-upCase 2: 1 year follow-up	Case 1: At 16 months, complete healingCase 2: At 1 year showed progressing healing	Case report demonstrates the resolution of the periradicular lesion using nonsurgical endodontic treatment that uses TAP
Kusgoz et al.[27]	Case report	Calcium hydroxide followed by TAP	-	30 months follow-up	1 year complete healing	A TAP can be an effective substitute material to calcium hydroxide in teeth with large periradicular lesion where calcium hydroxide fails

TAP: Triple antibiotic paste, LSTR: Lesion sterilization and tissue repair

DISCUSSION

Case reports and case series are unconstrained study designs known for increased risk of bias but have profoundly influenced the medical literature and continue to advance our knowledge. Even though the evidence derived from these case reports has less certainty, inferences from these reports can be beneficial in clinical decision-making.

The study was intended to systematically review the available information on the rate of healing of periradicular lesions treated nonsurgically with calcium hydroxide and triple antibiotic paste as antibacterial dressing in mature permanent teeth. The information given will aid the clinician in treatment planning when managing similar case scenarios.

To the authors' knowledge, this is the first systematic review focusing on the effect of triple antibiotic paste and calcium hydroxide on the rate of healing of the periapical lesion. This presents a comprehensive compilation of evidence taken from 16 articles. The selected articles comprised of case reports/case series of patients seeking treatment for teeth with large periapical lesions. Only those cases involving mature permanent teeth which were managed with nonsurgical endodontic treatment using either calcium hydroxide or triple antibiotic paste were considered. The healing time for periapical lesion when treated nonsurgically ranged from 18 to 24 months. Periapical lesions take at least 6–12 months to show any dimensional changes on periapical radiograph following the completion of endodontic therapy.[5] Hence, a follow-up period of minimum of 12 months was added in the inclusion criteria for selecting the articles.

Case reports selected for final review consisted of 19 teeth treated with calcium hydroxide as antibacterial dressing and 11 teeth treated with triple antibiotic paste. Among those treated with calcium hydroxide, fourteen cases showed signs of healing. Complete healing was observed in twelve cases and two cases showed progressive healing. Four cases[16182326] treated with calcium hydroxide failed to eliminate symptoms and one case[20] showed incomplete healing at 1 year follow up.

Failure to eliminate symptoms in four cases can be attributed to the polymicrobial nature of root canal infections. Calcium hydroxide antibacterial activity is mainly due to the release of hydroxyl ions. Hosoya et al. analyzing the pH and the concentration of calcium ions within the periapical area concluded that a minimum of 2 weeks are necessary for calcium hydroxide bactericidal activity. However, some bacteria like E. faecalis are resistant to pH variations and are capable of forming biofilm. This makes calcium hydroxide an ineffective medicament in such situations.[28] Another possible reason is the buffering capacity of dentin which brings down the alkalinity of calcium hydroxide rendering it less effective.[29] These cases were further treated with triple antibiotic paste.

One case which showed incomplete healing at 1 year follow-up, had received 5 months of antibacterial dressing with calcium hydroxide. Despite it there was delay in healing. The authors suggest that the intentional pushing of calcium hydroxide beyond the apex might have been the cause for delayed healing.[30] De Moor and De Witte advocated that extrusion of calcium hydroxide beyond the apical limit prolongs healing.[31] Yoshishige et al. reported that such extrusion can lead to apical tissue damage, affecting the healing rate.

The duration of antibacterial dressing with calcium hydroxide in the majority of the studied case reports was 2–3 weeks. This period of treatment was sufficient to promote healing in most of cases.

Rapid healing within 14 months was observed with antibacterial dressing with calcium hydroxide for 3 weeks in a case reported by Hariprakash et al. However, on the contrary, in the cases reported by Vijayshankar et al. healing did not occur at 3-year follow-up with 3 weeks of calcium hydroxide treatment. The huge size of the lesion (2 cm × 2 cm) might have been the cause.

Caliskan et al. and Karunakaran et al. observed healing in periapical lesion sized (7–18 mm) at 12–14 months with a calcium hydroxide dressing given for a duration of 3 months which was changed every 3 weeks. Prabhat et al. showed faster healing within 1 year in 2 cases in which the dressing was extended for 6 months to 1 year. Healing was observed in the shorter period in these cases despite the periapical lesions being large (16 mm × 10 mm, 6 mm × 9 mm). The extended duration of intracanal dressing might have contributed to faster healing. Hence, it can be suggested that as the lesion size increases, extended duration of treatment might be required for faster resolution of periapical lesions.

Among the eleven cases treated with triple antibiotic paste, all cases showed signs of healing. Complete healing was observed in seven cases and progressive healing in four cases. Four of these cases received triple antibiotic paste after calcium hydroxide failed to eliminate the symptoms.

Complete resolution of the lesion could be achieved in cases with triple antibiotic paste dressing for 3 months. Triple antibiotic paste being a mixture of 3 antibiotics can address polymicrobial infections better than calcium hydroxide. In lesions resistant to calcium hydroxide therapy triple antibiotic paste is a viable alternative.

The average duration of treatment with triple antibiotic paste was 3 months with the antibacterial dressing changed every 3 weeks. Healing occurred within a period of 1–2 years. Increase in bone density was observed in 18 months with triple antibiotic paste medicament given for 3 months in cases reported by Abidin et al.

Soares at al. reported quick healing in a large lesion of size 32 mm × 25 mm treated with calcium hydroxide for up to 1 year with medicament changed quarterly. The repair occurred in 12 months. They had done aspiration of the lesion before antibacterial dressing. This additional step would have hastened up the repair process.

Such surprisingly faster rates of healing in 6 months and 1-year follow-up despite large lesion sizes (15 mm × 15 mm and 25 mm × 25 mm) was reported by Deepak et al. with the aspiration of lesion before antibacterial dressing with triple antibiotic paste for 4 weeks and 8 weeks respectively.

From the case reports studied it can be stated that the cardinal factors affecting the healing of periradicular lesions are the size and type of lesions and the type and duration of antibacterial dressing.

True cysts are self-sustaining and are independent of the presence or absence of irritants in the root canal system. Such lesions may not respond to antibacterial dressing necessitating a surgical intervention for successful management. Pocket or bay cyst tend to heal faster with the cleaning of the canal system and antibacterial dressing.[32]

As the size of the lesion increases, the extension of the duration of antibacterial dressing might become necessary for the proper repair process. Bacterial flora in root canal infections are complex with the number ranging from 102 to 108 colony-forming units and a symbiotic relationship is established between bacterial species which adds up the virulence of the existing organisms.[33] Complete disinfection of the lesion is mandatory to enable repair of damaged tissues as stated by the Cariology Department of the University of Niigata. To achieve this longer duration of treatment may be necessary depending on the size of the lesion.

Calcium hydroxide could successfully disinfect and enable repair in most of the cases. However, some cases with resistant root canal infections might respond better to a combination drug therapy like triple antibiotic paste. Aspiration done before antibacterial dressing in very large lesions is recommended as it gives an impectus to the repair rate leading to rapid healing.

The outcomes presented suggest that it is possible to treat the mature permanent teeth with the periapical lesion in a nonsurgical method using triple antibiotic paste and calcium hydroxide. Both medicaments showed satisfactory results when used as antibacterial dressing. However, the rate of healing with triple antibiotic paste was found to be faster compared to that of calcium hydroxide.

CONCLUSION

Nonsurgical root canal treatment using calcium hydroxide and triple antibiotic paste in teeth with large periapical lesions can be a better alternative to surgical therapy. Healing rates were found to be faster with triple antibiotic paste. Furthermore, aspiration of the lesion done before this conservative orthograde therapy with antibacterial dressing demonstrated favorable outcomes and accelerated healing. Hence, this approach can be adopted as a routine measure to conservatively treat large periapical lesions of endodontic origin.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.