Course Number: 109 Local Applications of Tetracyclines … Education Local Applications of...

Continuing Education

Local Applications ofTetracyclines in Endodontics

and Dental Trauma:A Review

Authored by Zahed Mohammadi, DMD, MSD

Course Number: 109

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ABOUT THE AUTHORS

Dr. Mohammadi is an assistantprofessor in the Department ofEndodontics at Shahid SadoughiUniversity of Medical Sciences in Yazd,Iran. He can be reached by e-mail [email protected].

Disclosure: Dr. Mohammadi did not report any disclosures.

INTRODUCTION

Antibiotics were first discovered in 1928 but were notroutinely used clinically until the Second World War. Prior tothis, most wartime deaths were due to bacterial infections ofwounds, rather than the wounds themselves. The value ofantibiotics was seen with the rapid recovery of woundedmilitary personnel, and the use of these drugs increaseddramatically after the end of the war.1

Antibiotics have been an extremely valuable addition tothe armamentarium available to clinicians for management ofbacterial infections. These drugs have saved countless livesthat would otherwise have been lost if antibiotics were notavailable. For several decades antibiotics have been

routinely prescribed in many disciplines of medicine anddentistry.1 In endodontics and cases of dental trauma,antibiotics may be applied systemically (orally andparenterally) and locally. The first reported local use of anantibiotic in endodontic treatment was in 1951 whenGrossman2 used a poly-antibiotic paste known as PBSC(penicillin, bacitracin, streptomycin, and caprylate sodium).PBSC contained penicillin to target Gram-positiveorganisms, bacitracin for penicillin-resistant strains,streptomycin for Gram-negative organisms, and caprylatesodium to target yeasts; these compounds were allsuspended in a silicone vehicle. Later, nystatin replacedcaprylate sodium as an antifungal agent in a similarmedicament (PBSN).3

While systemic antibiotics appear to be clinically effectiveas an adjunct in certain surgical and nonsurgical endodonticcases, their administration is not without the potential risk ofadverse systemic side effects, particularly allergic reactions,toxicity, and development of resistant strains of microbes.Further, systemic administration of antibiotics relies on thecirculation to bring the active drug to an infected site. Thatsite may no longer have a normal vasculature. Included hereare teeth with a necrotic pulp and associated periradiculartissues. Therefore, local application of antibiotics may be amore effective method of delivering antibiotics.4

This article reviews the literature regarding the localapplication of antibiotics in endodontic therapy and cases ofdental trauma.

ANTIBIOTICS

TetracyclinesTetracyclines, including tetracycline hydro-chloride

(HCl), minocycline, demeclocycline, and doxycycline, are agroup of broad-spectrum antibiotics that are effectiveagainst a wide range of bacteria.5 Tetracyclines arebacteriostatic in nature.5 This property may beadvantageous because in the absence of bacterial celllysis, antigenic by-products such as endotoxin are notreleased.6 Tetracyclines have unique properties other thantheir antimicrobial effect, such as the inhibition ofmammalian collagenases, which prevents tissuebreakdown7,8 and the inhibition of clastic cells,8-10 which


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Recommendations for Fluoride Varnish Use in Caries Management

LEARNING OBJECTIVES:

After reading this article, the individual will learn:

• The rationale for the local applications of antibiotics inendodontic therapy and dental trauma.

• Indications for the local applications of tetracycline-containing root canal irrigants and medicaments.

Local Applications ofTetracyclines in Endodonticsand Dental Trauma: A Review

results in anti-resorptive activity.10

Inflammatory diseases such as periodontitis includea pathological excess of tissue collagenases, which maybe blocked by tetracyclines resulting in enhancedformation of collagen and bone.6 In periodontal therapy,tetracyclines have been used to remove the smear layer(ie, dentin conditioning) and tooth/root surfacecontaminants such as endotoxin. Surface demineralizationwidens the orifices of the dentinal tubules and exposes thecementum collagen matrix, which stimulates fibroblastattachment and growth.5 In endodontics, tetracyclineshave been used to remove the smear layer from instrumentedroot canal walls6,11, for irrigation of retrograde cavities duringperiapical surgery12, and as an intracanal medicament.13

Barkhordar, et al6 evaluated the effect of doxycyclineHCL on the smear layer of instrumented root canal walls.Their findings showed that doxycycline HCl eliminated thesmear layer in a concentration-dependent manner. Resultsshowed that 100 mg/ml doxycycline HCl was moreeffective than lower concentrations in removing the smearlayer. In another investigation Haznedaroglu and Ersev11

used scanning electron microscopy to assess theeffectiveness of tetracycline HCl as an endodontic irrigantas a means of removing the smear layer. Their resultsrevealed that tetracycline HCl was as effective as citric acidin removing the smear layer. Barkhordar and Russel12

evaluated the effect of doxycycline on the apical seal ofretrograde filling materials. Their findings were that teethwith retrograde intermediate restorative material oramalgam fillings placed following doxycycline irrigation hadsignificantly less dye penetration.

Carson, et al14 compared the antimicrobial activities of6% and 3% sodium hypochlorite (NAOCl), 2% and 0.12%chlorhexidine (CHX) gluconate, and 0.01% and 0.005%doxycycline on 4 microorganisms associated with primaryendodontic infections. The agar diffusion test was used tomeasure antimicrobial activities of these agents againstPepto-streptococcus micros, Prevotella intermedia,Streptococcus sanguis, and Lactobacillus acidophilus. For3 of the 4 microorganisms, the order of antimicrobialeffectiveness was 0.01% Doxy > 0.005% Doxy > 6% > 3%NAOCl > 2% CHX > 0.12% CHX. For L acidophilus, theorder of effectiveness was 6% NAOCl > 3% NAOCl > 2%

CHX > 0.01% Doxy > 0.005% Doxy > 0.12% CHX.Pinheiro, et al15 evaluated the susceptibility to differentantibiotics of Enterococcus faecalis isolates from canals ofroot-filled teeth with periapical lesions. The followingantibiotics were used: benzylpenicillin, amoxicillin,amoxicillin-clavulanic acid, erythromycin, azithromycin,vancomycin, chloramphenicol, tetracycline, doxycycline,ciprofloxacin and moxifloxacin; 85.7% of the isolates weresusceptible to tetracycline and doxycycline. Chai, et al16

investigated the antimicrobial efficacy of 6 groups ofantibiotics (ampicillin, cotrimoxazole, erythromycin,oxytetracycline, vanco-mycin, and vancomycin followed bygentamicin) and calcium hydroxide against E faecalisbiofilm in a membrane filter model, and concluded thaterythromycin, oxytetracycline and calcium hydroxide(Ca[OH]2) were 100% effective in eliminating E faecalisbiofilm, whereas ampicillin, cotrimoxazole, vancomycin,and vancomycin followed by gentamicin were ineffective.

Based on the hypothesis that microorganisms reachthe apical area of a recently replanted tooth from the oralcavity (or from contamination when the tooth is outside thesocket), Cvek, et al17 developed a new protocol for topicaltreatment of the exposed root with doxycycline beforereplantation. The objective was to eliminatemicroorganisms from the root surface of an avulsed toothin order to reduce the inflammatory response. Theseauthors showed that topical doxycycline significantlyincreased the chances of successful pulp revascularization.Yanpiset and Trope18 recently confirmed the beneficial effect ofsoaking a tooth in doxycycline.

In an animal (dog) study, Ritter, et al19 investigated theeffect of topical antibiotic treatment on pulprevascularization in replanted teeth using laser Dopplerflowmetry (LDF), radiography, and histology. After beingextracted, teeth were kept dry for 5 minutes, and eithercovered with minocycline mixture, soaked in doxycycline, orsoaked in saline, and then replanted. Teeth in the positivecontrol group were not extracted. Post-operative radiographsand LDF readings were obtained for 2 months afterreplantation. After sacrifice, the jaws were collected andprocessed for light microscopy. Pre and postreplantationLDF readings and radiographs, and histologic findings wereanalyzed to assess revascularization. Pulp


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Local Applications of Tetracyclines in Endodontics and Dental Trauma: A Review

revascularization occurred in 91% (minocycline), 73%(doxycycline), and 33% (saline) of the specimens. Incontrast, Bryson, et al20 evaluated the effect of minocycline onhealing of replanted dog teeth after 60 minutes of drying.Results showed that the roots with and without minocyclinetreatment showed no significant differences between theremaining root mass or the percentage of favorably healedroot surfaces, and no benefit was found from the use oftopically applied minocycline in the attenuation or preventionof external root resorption.

Substantivity of TetracyclinesTetracyclines readily attach to dentin and are

subsequently released without losing antibacterial activity.5

This property creates a reservoir of active antibacterialagent, which is then released from the dentin surface in aslow and sustained manner. In periodontics, studies havebeen conducted on the antibacterial substantivity oftetracyclines. In an in vivo study, Stabholz, et al21 comparedthe antibacterial substantivity of 2 concentrations oftetracycline HCl (50 mg/ml and 10 mg/ml) and 0.12% CHX.Their findings were that both concentrations of tetracyclinedemonstrated residual antibacterial activity, and theantibacterial substantivity of the 3 solutions in descendingorder was: 50 mg/ml tetracycline > 10 mg/ml tetracycline >0.12% CHX.

Abbott, et al22 demonstrated that tetracyclines form astrong reversible bond with hard tissues and that theyexhibit slow release over an extended period of time.Khademi, et al23 compared the antibacterial substantivity of2% CHX, 100 mg/ml doxycycline HCL, and 2.6% NAOCl inbovine root dentin over 5 experimental periods of 0, 7, 14,21, and 28 days in vitro. Their findings revealed that after 7days, the NAOCl and doxycycline HCl groups showed thelowest and the highest number of colony forming units(CFU), respectively. However, at the other evaluations, theCHX group showed the lowest number of CFUs. In anotherstudy, Mohammadi, et al24 evaluated the antibacterialsubstantivity of 3 concentrations of doxycycline HCL (100mg/ml, 50 mg/ml, and 10 mg/ml) in bovine root dentin at 5time points (0, 7, 14, 21, and 28 days). Results showed thatthe numbers of CFUs in all 3 experimental groups wereminimum in first cultures (at 7 days), and the results weresignificantly different from each other at all time periods. In

first culture the 100 mg/ml group and the 10 mg/ml groupshowed the lowest and highest numbers of CFUs,respectively. In each group the numbers of CFUs increasedsignificantly over time.

BioPure MTADBioPure (DENTSPLY/Tulsa), otherwise known as

MTAD, is a relatively new root canal irrigant which wasintroduced by Torabinejad, et al in 2003.5 This solution is amixture of 3% doxycycline, 4.25% citric acid, and adetergent (0.5% Polysorbate 80).25 Several studies haveevaluated the effectiveness of MTAD for disinfection of rootcanals. Torabinejad, et al have showed that MTAD is ableto remove the smear layer5 and is effective against Efaecalis.26-28 Shabahang, et al27 cleaned and shaped rootcanals of extracted human teeth and exposed them tohuman saliva. They then compared the antibacterialefficacy of a combination of 1.3% NAOCl as a root canalirrigant and MTAD as a final rinse with that of 5.25%NAOCl. Their findings showed that the use of MTAD wasmore effective than 5.25% NAOCl in disinfecting rootcanals. However, Tay, et al29 found that when MTAD isapplied to 1.3% NAOCl-irrigated dentin, its antimicrobialsubstantivity is reduced. They attributed this phenomenonto the oxidation of MTAD by NAOCl in a manner similar tothe peroxidation of tetracycline by reactive oxygen species.

In another study, Shabahang and Torabinejad28

compared the anti-bacterial effects of MTAD with that ofNAOCl and ethylenediaminetetraacetic acid (EDTA).They used standard in vitro microbiological techniques,and reported that MTAD was significantly more effectivethan the other 2 agents against E faecalis. Kho andBaumgartner30 compared the antimicrobial efficacy againstE faecalis of 1.3% NAOCl/BioPure MTAD with that of thecombined use of 5.25% NAOCl and 15% EDTA when usedfor root canal irrigation. Bacterial samples taken early in thecanal cleaning process revealed no growth in any of the 20samples with 5.25% NAOCl/15% EDTA irrigation andgrowth in 8 of 20 samples with 1.3% NAOCl/BioPureMTAD irrigation. Further samples taken after additionalcanal enlargement revealed growth in none of 20 sampleswhen 5.25% NAOCl/15% EDTA were used, but there wasgrowth in 10 of the 20 samples when 1.3% NAOCl/BioPure MTAD was used. This investigation showed a


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consistent disinfection of infected root canals with acombination of 5.25% NAOCl/ 15% EDTA. However, thecombination of 1.3% NAOCl/BioPure MTAD left nearly 50%of the canals contaminated with E faecalis.

Krause, et al31 compared the antimicrobial effect againstE faecalis of MTAD, 2 of its components (doxycycline andcitric acid), and sodium hypochlorite in 2 in vitro models using2 different methods. In the tooth model, NAOCl anddoxycycline were more effective than the control in killing E faecalis at shallow bur depths into dentin, but at deeperbur depths the NAOCl was superior. In the agar diffusionmodel, NAOCl produced less inhibition of bacteria thanMTAD or doxycycline. Ghoddusi, et al32 evaluated the effectof MTAD as a final irrigant on bacterial leakage of the rootcanal, and its interaction with 2 conventional root canalsealers (AH-Plus or Rickert). The results revealed that it tooklonger for bacteria to penetrate when either EDTA or MTADwas used for smear layer removal. Further, the root canalsobturated with AH-Plus showed significantly longer durationof resistance to bacterial penetration than canals obturatedwith Rickert. Davis, et al33 investigated the antimicrobialaction of Dermacyn (a super-oxidized, pH-neutral solutioncontaining minimal chlorine) (Oculus Innovative Sciences),BioPure MTAD, 2% CHX, and 5.25% NAOCl against Efaecalis using the zone of inhibition test. BioPure MTADshowed significantly larger zones of microbial inhibition than5.25% NAOCl, 2% CHX, and Dermacyn. Newberry, et al34

determined the in vitro antimicrobial effect of MTAD as a finalirrigant on 8 strains o E faecalis and measured the minimuminhibitory concentration (MIC) and the minimum lethalconcentration (MLC) of MTAD. After irrigating with 1.3%NAOCl, the root canal and the external surfaces wereexposed to MTAD for 5 minutes. This treatment regimen waseffective in completely eliminating growth of 7 of 8 strains ofE faecalis. The MIC/MLC tests showed that MTAD inhibitedmost strains of E faecalis growth when diluted 1:8192, andkilled most strains of E faecalis when diluted 1:512.

Shabahang, et al35 evaluated the effect of the additionof, or substitution by, CHX for doxycycline in MTAD andcompared the 3 formulations for their ability to disinfectextracted human teeth infected with E faecalis. None of thesamples treated with MTAD or MTAD + CHX demonstratedresidual bacteria. In contrast, 7 of 10 samples treated with

MCAD (CHX substituted for doxycycline) showed positivecultures of E faecalis . The results clearly demonstrated thatalthough the addition of CHX did not negatively impact theefficacy of MTAD, the substitution of this antimicrobial agentfor doxycycline significantly reduced the antibacterialefficacy of the solution.

Substantivity of MTADAs stated previously, tetracyclines (including

doxycycline) readily attach to dentin and are subsequentlyreleased over time without losing their antibacterialactivity.11 The presence of doxycycline in MTADsuggests that MTAD may have some substantiveantimicrobial action.5 In an in vitro study, Mohammadi andYazdizadeh36 evaluated the substantivity of NAOCl, CHX,and MTAD using a bovine dentin tube model. Dentin chipswere removed from the canals with sequential sterile low-speed round burs with increasing ISO sizes of 025, 027,029, 031, and 033 at 0, 7, 14, 21, and 28 days followingirrigation with the test solution. In the first culture, theNAOCl group and the CHX group showed the lowest andhighest number of CFUs, respectively. In each group, thenumber of CFUs increased significantly over time. It wasconcluded that the substantivity of MTAD was significantlygreater than CHX and NAOCl. These findings wereconfirmed in a human model.37

In another study, Mohammadi38 assessed thesubstantivity of 3 concentrations (100%, 10%, and 1%) ofMTAD using a bovine dentin tube model. As described,dentin chips were removed from the canals with sequentialsterile low-speed round burs with increasing ISO sizes of025, 027, 029, 031, and 033 at 0, 7, 14, 21, and 28 days.Results showed that in the first culture, MTAD 100% andMTAD 1% showed the lowest and highest number ofCFUs, respectively. In each group, the number of CFUsincreased significantly over time. In conclusion, thesubstantivity of 100% MTAD was significantly greater thanthe 2 lower concentrations of MTAD.

TetracleanTetraclean (Ogna Laboratori Farmaceutici, Muggiò

(Mi), Italy), like MTAD, is a mixture of an antibiotic, an acid,and a detergent. However, the concentration of antibiotic


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(50 mg/ml doxycycline) and the type of detergent(polypropylene glycol) differ from those of MTAD. Giardino,et al39 compared the surface tension of EDTA 17%,Cetrexidin (a mixture of 0.02 Cetrimyde and CHX in anaqueous base), Smear Clear (a mixture of EDTA 17% andTween 80), and NAOCl 5.25% with the surface tension ofMTAD and Tetraclean. Sodium hypochlorite 5.25% andEDTA 17% had the highest surface tension, whereas thoseof Cetrexedin and Tetraclean had the lowest surfacetensions. In another study, they compared the antimicrobialefficacy of 5.25% NAOCl, BioPure MTAD, and Tetracleanagainst E faecalis biofilm formed on cellulose nitratemembrane filters. Results showed that only 5.25% NAOClcould consistently disgregate and remove the biofilm;however, as compared with MTAD, treatment withTetraclean led to a high degree of biofilm disgregation atevery time interval.40

LedermixLedermix is a glucocorticosteroid-antibiotic compound.

Ledermix paste was developed by Schroeder and Triadanin 1960, and became available in Europe (LederlePharmaceuticals) in 1962.41 The development of Ledermixpaste was based on the use of corticosteroid to control painand inflammation41, and the antibiotic component wasadded to compensate for what was perceived to be apossible corticoid-induced reduction in the host immuneresponse. Schroeder and Triadan initially incorporatedchloramphenicol in their first trials, but when LederlePharmaceuticals became the manufacturer, the antibioticwas changed to demeclocycline HCl. Today, Leder-mixpaste remains a combination of the same tetracyclineantibiotic (demeclocycline HCl at a concentration of 3.2%)and a corticosteroid (triamcinolone acetonide, concentration1%) in a polyethylene glycol base.41

The 2 therapeutic components of Ledermix (ie,triamcinolone and demeclocycline) are capable of diffusingthrough dentinal tubules and cementum to reach theperiodontal and periapical tissues.42 Abbott, et al22

demonstrated that dentinal tubules were the major supplyroute of the active components to the periradicular tissues,and the apical foramen was not as significant a supplyroute. Various factors can affect the supply of the active

components to the periradicular tissues, including thepresence or absence of the smear layer, the presence orabsence of cementum, and the presence of other materialswithin the canal, for example, Ca(OH)2. The concentrationof demeclocycline within Ledermix paste itself is highenough to be effective against susceptible species ofbacteria. However, within the peripheral parts of the dentinand in the periradicular tissues the concentration achievedthrough diffusion is insufficient to inactivate bacteria,especially over time.43 Immediately adjacent to the rootcanal, inhibitory levels of demeclocycline are achieved forall studied bacteria for the first day following application, butthe concentration drops to about one-tenth of the originalconcentration after one week in both the mid-root and theapical one-third of the canal. Further, away from the rootcanal towards the cementum, the concentration ofdemeclocycline after one day is not high enough to inhibitgrowth of 12 of the 13 strains of commonly reportedendodontic bacteria.43 Heling and Pecht44 evaluated theefficacy of Ledermix paste in the disinfection of dentinaltubules. Ledermix and 3% tetracycline in a hydrous base wereeffective in reducing the amount of S aureus in dentinal tubulesafter 7 days of incubation and also after recontamination.Neither were effective after 24 hours.

The use of Ledermix has been studied in other ways.Abbott45 showed that the intradental use of Ledermix pasteand Ledermix cement is unlikely to result in any systemicside effects. Pierce, et al9 demonstrated histologically thatLedermix eliminated experimentally induced externalinflammatory root resorption in vivo. They also found thatLedermix paste had no damaging effects on the periodontalmembrane, and that this paste was an effective medicationfor the treatment of progressive root resorption intraumatically injured teeth. Taylor, et al46 evaluated theeffects of Ledermix paste and Pulpdent paste (Pulpdent) onmouse fibroblasts and bacteria in vitro. Dilutions ofLedermix paste, Pulpdent paste, and a mixture of equalparts by weight of Ledermix paste and Pulpdent paste wereadded to in vitro cultures of mouse fibroblasts or bacteriafor 24 hours, and various cell functions were thenexamined: mitosis by and survival of fibroblasts, andsurvival of Lacto-bacillus casei or S mutans. Ledermix wasfound to reversibly inhibit mitosis in the concentration range


5


of 10-3 to 10-6 mg/ml. Mixing with Pulpdent did not modifythis antimitotic effect. Ledermix killed mouse fibroblasts at10-3 mg/ml and above, while Pulpdent killed these cells at 1 mg/ml and above. The toxic effect of Ledermix wasslightly inhibited by mixing it with Pulpdent. Ledermix killed S mutans at about the same concentration at which it killedthe mammalian cells, but required a one thousand-foldgreater concentration to kill L casei. Pulpdent killed both L casei and S mutans at approximately one-fifth of theconcentration at which it killed the mammalian cells.

Thong, et al47 compared the effect of Ca(OH)2

(Pulpdent) and Ledermix paste on periodontal healing and root resorption following replantation.Histomorphometrically, they found that periodontal ligamentinflammation and inflammatory root resorption weremarkedly inhibited by both Ca(OH)2 and the corticosteroid-antibiotic relative to untreated controls. Replacementresorption was lowest in the corticosteroid-antibiotic group,and significantly more normal periodontal ligament waspresent in this group than in the Ca(OH)2 and controlgroups. Wong and Sae-Lim48 evaluated the effect ofimmediate intracanal Ledermix on root resorption ofdelayed replanted monkey teeth. For the experimentalgroup, intracanal Ledermix was placed prior to extractionand replantation after 1-hour bench dry. The positive controlgroup was root filled and replanted after 1 hour while the negative control group was root filled andreplanted immediately. The negative control groupproduced more favorable healing as compared to theLedermix group. The Ledermix group showed significantlyhigher occurrence of complete healing (35.46%)compared to the positive control group (16.58%) but therewere no significant differences in the inflammatory rootresorption and replacement resorption. Nevertheless, whenthe latter 2 unfavorable healing patterns were combined,there was significantly lower unfavorable healing in theLedermix group (64.54%) when compared to the positivecontrol group (83.43%). This unfavorable healing outcomein the Leder-mix group, however, was not significantlydifferent from the favorable healing outcome with the sametreatment modality.

Bryson, et al10 evaluated the effect of immediateintracanal placement of Ledermix Paste on healing of

replanted dog teeth after an extended drying time (60 min).The Ledermix Paste-treated roots had statisticallysignificantly more healing and less resorption than the rootstreated with Ca(OH)2. Root filling with Ledermix Paste alsoresulted in significantly less loss of root mass due toresorption compared to roots filled with Ca(OH)2. Chen, etal49 evaluated the individual influence of triamcinolone anddemeclocycline on external root resorption after anextended extraoral drying time (60 minutes). The groupstreated with Ledermix, triamcinolone, and demeclocyclinehad significantly more favorable healing than the groupfilled with gutta–percha and replanted after 60 minutesdrying time (positive control). There was no statisticallysignificant difference between the Ledermix group and thetriamcinolone group, while the tetracycline group showedless favorable healing as compared to the other groups.They concluded that corticosteroid and tetracycline, asanti-inflammatory and antiresorptive agents, stopped orminimized the inflammatory response including clastic-cellmediated resorption, thus promoting more favorablehealing than the positive control group, which had nointracanal medicaments. Further-more, they proposed thatin severe traumatic injuries, where a large surface area ofperiodontal inflammation is expected, removing the pulpand placing corticosteroids into the canal at the emergencyvisit should become a standard protocol.

Trope50 evaluated the relationship of intracanalmedicaments to endodontic flare-ups. Formocresol,Ledermix, and Ca(OH)2 were placed in a specific sequenceirrespective of the presence or absence of symptoms orradiographic signs of apical periodontitis. He found nosignificant difference in the flare-up rate among the 3intracanal medicaments. Ehrmann, et al51 investigated therelationship of postoperative pain to 3 differentmedicaments placed in the root canal after completebiomechanical debridement in emergency patients. Theyfound that painful teeth with acute apical periodontitis thathad been dressed with Leder-mix paste were associatedwith less pain as compared to teeth dressed with Ca(OH)2

or no dressing at all.Kim, et al52 investigated the effects of Ledermix paste

as an intracanal medicament on discoloration of matureteeth, whether the discoloring was related to the method of


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application, as well as the effects of sunlight upondiscoloration of these teeth. After 12 weeks of sunlightexposure dark grey-brown staining of the teeth occurred inthe Leder-mix groups, but not when the teeth were kept indarkness. More severe staining was noted when Ledermixpaste filled the pulp chamber than when the paste wasrestricted to below the CEJ. It was suggested that ifplacement of the Ledermix is restricted to the canal belowthe gingival margin, staining effects could be minimized. Inanother study, they investigated the effects of Ledermixpaste as an intracanal medicament on discoloration ofimmature teeth, whether the discoloring effects wererelated to the method of application, and the effects ofsunlight upon discoloration of immature teeth. After 12weeks, sunlight exposure again caused dark grey-brownstaining in the Ledermix groups, but this did not occur whenthe teeth were kept in darkness. More severe staining wasnoted when Ledermix paste filled the pulp chamber thanwhen the paste was restricted to below the cementoenameljunction and when teeth were exposed to sunlight.53 Whencompared to the results of a similar study using matureteeth, the immature teeth were more severely stained thanthe mature teeth. The Ca(OH)2 paste caused an increase inwhiteness and yellowness in immature teeth.53

Combination of Ledermix and Calcium HydroxideThe combination of Ledermix paste with Ca(OH)2 has

been advocated by Schroeder41, initially for the treatment ofnecrotic teeth with incomplete root formation. A 50:50mixture of Ledermix paste and Ca(OH)2 has also beenadvocated as an intracanal dressing for infected rootcanals, pulp necrosis, infection with incomplete rootformation (as an initial dressing prior to using Ca(OH)2

alone for apexification), perforations, inflammatory rootresorption, inflammatory periapical bone resorption, and fortreatment of large periapical radiolucent lesions.42 It hasbeen shown that the 50:50 mixture results in slower releaseand diffusion of the active components of Ledermixpaste, which makes the medicament last longer in thecanal.41 This in turn helps to maintain the sterility of thecanal for a longer period of time and also maintains ahigher concentration of all components within the canal.54

The 50:50 mixture of Ledermix paste and Ca(OH)2

paste does not alter the pH to any noticeable degree andtherefore it is expected that the mixture will act in a similarmanner to when Ca(OH)2 is used alone. Taylor, et al46 alsoshowed that for 2 indicator microorganisms, L casei and Smutans (which are cariogenic), the 50:50 mixture wasmarginally more effective than either paste used alone.However, Seow55 showed that for S sanguis and S aureus,the addition of only 25% by volume of Calyxl (a Ca(OH)2 insaline paste; Otto and Company, Frankfurt, Germany) toLedermix converted the zone of complete inhibitionoriginally seen in Ledermix to one of only partial inhibition.This study suggested that some medicaments should notbe used in combination, and that when 2 medicaments withstrong antimicrobial activity are combined there may be noadditive or synergistic effects.55

Chu, et al56 compared the efficacy of disinfection of rootcanals with periapical radiolucencies when treated witheither antibiotics/steroid medicaments (Ledermix or Septo-mixine [10 million IU neomycin + 20 million IU polymixine Bsulfate]) or a Ca(OH)2 paste (Calasept). In the Ledermixgroup, 38 strains of bacteria were recovered, theSeptomixine group had 25 strains, and the Calaseptgroup had 25 strains. In all cases, Gram-positive facultativeanaerobic cocci (including staphylococci and streptococci)were more prevalent than the Gram-negative obligateanaerobic rods after treatment.

SUMMARY

Local application of antibiotics within the root canalsystem may be a more effective mode for delivering thedrug. Tetracyclines have been used to remove the smearlayer from instrumented root canal walls, for irrigation ofretrograde cavities during periapical surgical procedures,and as an intracanal medicament. Substantivity oftetracyclines has been shown for up to at least 12 weeks.BioPure MTAD is effective in removing the smear layer.However, the antimicrobial efficacy against E faecalis of1.3% NAOCl/MTAD compared with that of the combinedalternate use of 5.25% NAOCl and 15% EDTA is stillcontroversial. Substantivity of MTAD has been shown for upto 4 weeks. Further-more, application of MTAD to 1.3%NAOCl-irrigated dentin may reduce its substantivity.


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Tetraclean is a mixture of an antibiotic (doxycycline), anacid, and a detergent (like MTAD), with a very low surfacetension and high degree efficacy against bacterial biofilms.Ledermix, a glucocorticosteroid-antibiotic compound, dueto anti-inflammatory and antiresorptive properties, reducesthe inflammatory reaction including clastic-cell mediatedresorption, significantly lowers the incidence ofreplacement resorption, and thus prompts more favorablehealing in replanted teeth. A 50:50 mixture of Ledermixpaste and Ca(OH)2 has been advocated as an intracanaldressing in cases of infected root canals, pulp necrosis andinfection with incomplete root formation (apexification),perforations, inflammatory root resorption, inflammatoryperiapical bone resorption, and for the treatment of largeperiapical radiolucent lesions.

REFERENCES

1. Abbott PV. Selective and intelligent use of antibiotics inendodontics. Aust Endod J. 2000;26:30-39.

2. Grossman LI. Polyantibiotic treatment of pulpless teeth. J Am Dent Assoc. 1951;43:265-278.

3. Weine FS. Endodontic Therapy. 3rd ed. St Louis, MO:Mosby; 1982:325.

4. Gilad JZ, Teles R, Goodson M, et al. Development of aclindamycin-impregnated fiber as an intracanal medicationin endodontic therapy. J Endod. 1999;25:722-727.

5. Torabinejad M, Khademi AA, Babagoli J, et al. A newsolution for the removal of the smear layer. J Endod.2003;29:170-175.

6. Barkhordar RA, Watanabe LG, Marshall GW, et al. Removalof intracanal smear by doxycycline in vitro. Oral Surg OralMed Oral Pathol Oral Radiol Endod. 1997;84:420-423.

7. Vernillo AT, Ramamurthy NS, Golub LM, et al. Thenonantimicrobial properties of tetracycline for the treatment ofperiodontal disease. Curr Opin Periodontol. 1994;2:111-118.

8. Pierce A, Lindskog S. The effect of anantibiotic/corticosteroid paste on inflammatory rootresorption in vivo. Oral Surg Oral Med Oral Pathol.1987;64:216-220.

9. Pierce A, Heithersay G, Lindskog S. Evidence for directinhibition of dentinoclasts by a corticosteroid/antibioticendodontic paste. Endod Dent Traumatol. 1988;4:44-45.

10. Bryson EC, Levin L, Banchs F, et al. Effect of immediateintracanal placement of Ledermix Paste on healing ofreplanted dog teeth after extended dry times. DentTraumatol. 2002; 18:316-321.

11. Haznedaroglu F, Ersev H. Tetracycline HCl solution as a rootcanal irrigant. J Endod. 2001; 27:738-740.

12. Barkhordar RA, Russel T. Effect of doxycycline on the apicalseal of retrograde filling materials. J Calif Dent Assoc.1998;26:842-845.

13. Molander A, Dahlen G. Evaluation of the antibacterial potentialof tetracycline or erythromycin mixed with calcium hydroxideas intracanal dressing against Enterococcus faecalis in vivo.Oral Surg Oral Med Oral Pathol Oral Radiol Endod.2003;96:744-750.

14. Carson KR, Goodell GG, McClanahan SB. Comparison ofthe antimicrobial activity of six irrigants on primaryendodontic pathogens. J Endod. 2005;31:471-473.

15. Pinheiro ET, Gomes BP, Drucker DB, et al. Antimicrobialsusceptibility of Enterococcus faecalis isolated from canalsof root filled teeth with periapical lesions. Int Endod J.2004;37:756-763.

16. Chai WL, Hamimah H, Cheng SC, et al. Susceptibility ofEnterococcus faecalis biofilm to antibiotics and calciumhydroxide. J Oral Sci. 2007;49:161-166.

17. Cvek M, Cleaton-Jones P, Austin J, et al. Effect of topicalapplication of doxycycline on pulp revascularization andperiodontal healing in reimplanted monkey incisors. EndodDent Traumatol. 1990;6:170-176.

18. Yanpiset K, Trope M. Pulp revascularization of replantedimmature dog teeth after different treatment methods. EndodDent Traumatol. 2000; 16:211-217.

19. Ritter AL, Ritter AV, Murrah V, et al. Pulp revascularization ofreplanted immature dog teeth after treatment with minocyclineand doxycycline assessed by laser Doppler flowmetry,radiography, and histology. Dent Traumatol. 2004;20:75-84.

20. Bryson EC, Levin L, Banchs F, et al. Effect of minocyclineon healing of replanted dog teeth after extended dry times.Dent Traumatol. 2003;19:90-95.

21. Stabholz A, Kettering J, Aprecio R, et al. Retention ofantimicrobial activity by human root surfaces after in situsubgingival irrigation with tetracycline HCl or chlorhexidine.J Periodontol. 1993;64:137-141.

22. Abbott PV, Heithersay GS, Hume WR. Release and diffusionthrough human tooth roots in vitro of corticosteroid andtetracycline trace molecules from Ledermix paste. EndodDent Traumatol. 1988;4:55-62.

23. Khademi AA, Mohammadi Z, Havaee A. Evaluation of theantibacterial substantivity of several intra-canal agents. AustEndod J. 2006; 32:112-115.

24. Mohammadi Z, Farhad AR, Ardakani FE. Anti-bacterialsubstantivity of three concentrations of doxycycline on bovineroot dentin infections: an in vitro study. Dent Res J. 2007;4:48-52.

25. Torabinejad M, Johnson WB, inventors. Irrigation solutionand methods for use. US patent application 20,030,235,804.December 25, 2003.


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26. Torabinejad M, Shabahang S, Aprecio RM, et al. Theantimicrobial effect of MTAD: an in vitro investigation. J Endod. 2003;29:400-403.

27. Shabahang S, Pouresmail M, Torabinejad M. In vitroantibacterial efficacy of MTAD and sodium hypochlorite. J Endod. 2003;29:450-452.

28. Shabahang S, Torabinejad M. Effect of MTAD onEnterococcus faecalis-contaminated root canals of extractedhuman teeth. J Endod. 2003;29:576-579.

29. Tay FR, Hiraishi N, Schuster GS, et al. Reduction inantimicrobial substantivity of MTAD after initial sodiumhypochlorite irrigation. J Endod. 2006;32:970-975.

30. Kho P, Baumgartner JC. A comparison of the anti-microbialefficacy of NAOCl/BioPure MTAD versus NAOCl/EDTAagainst Enterococcus faecalis. J Endod. 2006;32:652-655.

31. Krause TA, Liewehr FR, Hahn CL. The antimicrobial effectof MTAD, sodium hypochlorite, doxycycline, and citric acidon Enterococcus faecalis. J Endod. 2007;33:28-30.

32. Ghoddusi J, Rohani A, Rashed T, et al. An evaluation ofmicrobial leakage after using MTAD as a final irrigation. J Endod. 2007; 33:173-176.

33. Davis JM, Maki J, Bahcall JK. An in vitro comparison of theantimicrobial effects of various endodontic medicaments onEnterococcus faecalis. J Endod. 2007;33:567-569.

34. Newberry BM, Shabahang S, Johnson N, et al. Theantimicrobial effect of biopure MTAD on eight strains ofEnterococcus faecalis: an in vitro investigation. J Endod.2007;33:1352-1354.

35. Shabahang S, Aslanyan J, Torabinejad M. The substitutionof chlorhexidine for doxycycline in MTAD: the antibacterialefficacy against a strain of Enterococcus faecalis. J Endod.2008; 34:288-290.

36. Mohammadi Z, Yazdizadeh M. Evaluation of theantibacterial substantivity of a new root canal irrigationsolution. J Dent Clin Res. 2006;2:271-275.

37. Mohammadi Z, Shahriari S. Residual antibacterial activity of chlorhexidine and MTAD in human root dentin in vitro. J Oral Sci. 2008;50:63-67.

38. Mohammadi Z. Evaluation of the residual antibacterialactivity of three concentrations of a new root canal irrigationsolution. N Y State Dent J. In press.

39. Giardino L, Ambu E, Becce C, et al. Surface tensioncomparison of four common root canal irrigants and two newirrigants containing antibiotic. J Endod. 2006;32:1091-1093.

40. Giardino L, Ambu E, Savoldi E, et al. Comparativeevaluation of antimicrobial efficacy of sodium hypochlorite,MTAD, and Tetraclean against Enterococcus faecalis biofilm.J Endod. 2007;33:852-855.

41. Athanassiadis B, Abbott PV, Walsh LJ. The use of calciumhydroxide, antibiotics and biocides as antimicrobialmedicaments in endodontics. Aust Dent J.2007;52(suppl):S64-S82.

42. Abbott PV. Medicaments: aids to success in endodontics. Part1. A review of the literature. Aust Dent J. 1990;35:438-448.

43. Abbott PV, Hume WR, Pearman JM. Antibiotics andendodontics. Aust Dent J. 1990;35:50-60.

44. Heling I, Pecht M. Efficacy of Ledermix paste in eliminatingStaphylococcus aureus from infected dentinal tubules invitro. Endod Dent Traumatol. 1991;7:251-254.

45. Abbott PV. Systemic release of corticosteroids followingintra-dental use. Int Endod J. 1992;25:189-191.

46. Taylor MA, Humen WR, Heithersay GS. Some effects ofLedermix paste and Pulpdent paste on mouse fibroblasts andon bacteria in vitro. Endod Dent Traumatol. 1989;5:266-273.

47. Thong YL, Messer HH, Siar CH, et al. Periodontal responseto two intracanal medicaments in replanted monkey incisors.Dent Traumatol. 2001;17:254-259.

48. Wong KS, Sae-Lim V. The effect of intracanal Ledermix onroot resorption of delayed-replanted monkey teeth. DentTraumatol. 2002;18:309-315.

49. Chen H, Teixeira FB, Ritter AL, et al. The effect of intracanalanti-inflammatory medicaments on external root resorptionof replanted dog teeth after extended extra-oral dry time.Dent Traumatol. 2008;24:74-78.

50. Trope M. Relationship of intracanal medicaments to endodonticflare-ups. Endod Dent Traumatol. 1990;6:226-229.

51. Ehrmann EH, Messer HH, Adams GG. The relationship ofintracanal medicaments to postoperative pain inendodontics. Int Endod J. 2003;36:868-875.

52. Kim ST, Abbott PV, McGinley P. The effects of Ledermixpaste on discolouration of mature teeth. Int Endod J.2000;33:227-232.

53. Kim ST, Abbott PV, McGinley P. The effects of Ledermixpaste on discolouration of immature teeth. Int Endod J.2000;33:233-237.

54. Abbott PV, Hume WR, Heithersay GS. Effect of combiningLedermix and calcium hydroxide pastes on the diffusion ofcorticosteroid and tetracycline through human tooth roots invitro. Endod Dent Traumatol. 1989;5:188-192.

55. Seow WK. The effects of dyadic combinations of endodonticmedicaments on microbial growth inhibition. Pediatr Dent.1990;12:292-297.

56. Chu FC, Leung WK, Tsang PC, et al. Identification ofcultivable microorganisms from root canals with apicalperiodontitis following two-visit endodontic treatment withantibiotics/steroid or calcium hydroxide dressings. J Endod.2006;32:17-23.


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POST EXAMINATION INFORMATION

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POST EXAMINATION QUESTIONS

1. The first reported local use of an antibiotic inendodontics was by________.a. Seltzerb. Grossmanc. Weined. Ingle

2. Tetracyclines are a group of _______ and ________antibiotics. a. narrow spectrum-bactericidalb. broad spectrum-bactericidalc. broad spectrum-bacteriostaticd. narrow spectrum-bacteriostatic

3. Substantivity of BioPure MTAD lasts for up to____weeks. a. 2b. 4c. 12d. 24

4. BioPure MTAD is a mixture of __________. a. tetracycline, nitric acid, and Tween 80b. doxycycline, citric acid, and Cetrimydec. minocycline, citric acid, and Tween 80d. doxycycline, citric acid, and Tween 80

5. The components of ________ are similar to MTAD. a. Tetracleanb. EDTAc. Cetrexidind. Smear Clear

6. Dentin pre-treatment with________ reduces thesubstantivity of MTAD. a. sodium hypochloriteb. EDTAc. Smear Cleard. Dermacyn

7. Ledermix is a ________ - _________ compound. a. antibiotic-antibioticb. antibiotic-corticosteroidc. corticosteroid-corticosteroidd. antibiotic-mineral corticoid


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8. The type of detergent in Tetraclean is__________.a. Tween 80b. Polypropylene glycolc. Polysorbate 80d. Cetrexidin

9. The bacteriostaticity of tetracyclines may beconsidered as an advantage because:a. by-products such as endotoxin are not released.b. it has anti-resorptive activity.c. bacterial cell is not lysed.d. a and c.

10. Presence of the antibiotic component in Ledermix is to:a. control pain.b. prevent root resorption.c. compensate possible reduction in the immune

response. d. control inflammation.

11. Ledermix reversibly inhibits mitosis in theconcentration range of _______ mg/mL. a. 10-1 to 10-3b. 10-6 to 10-9c. 10-3 to 10-6d. 1

12. Currently, Ledermix paste is a combination of ______and _______. a. triamcinolone acetonide-doxycyclineb. dexamethasone-tetracyclinec. hydrocortisone-demeclocyclined. triamcinolone acetonide-demeclocycline

13. The concentrations of antibiotic in Tetraclean andBioPure MTAD are______ and_____ mg/ mL,respectively. a. 100 and 50b. 50 and 100c. 100 and 200d. 25 and 50

14. The accurate formula of BioPure MTAD is as follows: a. 3% doxycycline, 4.25% citric acid, and 0.5%

Tween 80. b. 3% tetracycline, 4.25% citric acid, and 0.5%

Polysorbate 80.c. 4.25% doxycycline, 3% citric acid, and 0.5%

Tween 80. d. 3% minocycline, 4.25% citric acid, 0.5%

polypropylene glycol

15. Ledermix paste, after______ weeks of sunlightexposure, causes staining of teeth. a. 12b. 4c. 24d. 2

16. ________ slightly reduces the toxicity of Ledermix. a. Chlorhexidineb. Calcium hydroxidec. Septomixined. Streptomycin


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Course Number: 109 Local Applications of Tetracyclines … Education Local Applications of...

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