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Endodontic Topics 2002, 3, 52–66 Copyright C Blackwell Munksgaard Printed in Denmark. All rights reserved ENDODONTIC TOPICS 2002
Are antibiotics effective for
endodontic pain?
An evidence-based review
Although antibiotics are frequently prescribed to treat endodontic pain patients, there is little evidence fromthe clinical literature to support this indication. This review focuses on the clinical evidence regarding theefficacy of antibiotics for treating postendodontic pain.
Antibiotics are frequently prescribed to aid in the chemokines, kinins, serotonin, and neuropeptides are treatment of endodontic pain. Over the past 25 years, produced during the inflammatory process. These in- several surveys of general dentists and endodontists flammatory mediators activate or sensitive nocicep- have been conducted that illustrate a persistent pat- tors terminating in the pulp, the periodontal ligament tern of prescribing antibiotics in conjunction with en- or periradicular bone, induce sprouting of nocicep- dodontic treatment (1–5). However, despite concur- tors (leading to increased receptivity to stimuli), and rent advances in our understanding of the biology of evoke edema and increased tissue pressure by increas- inflammatory and infectious processes, and the in- ing vascular permeability in these tissues.
creased awareness of the side-effects of antibiotics, The ability of an antimicrobial medication to effec- most notably the emergence of resistant bacterial tively reduce pain occurring during these inflamma- strains, there seems to be little change observed in tory conditions is not clear. A spreading infection of the practice of prescribing antibiotics.
endodontic origin may be painful, particularly if there This review focuses on the effects of antibiotic is excessive increase in pressure within the tissues.
medications for reducing postendodontic symptoms, However, the pain is a result of the inflammatory re- primarily pain. This paper is not intended to be a re- action that accompanies the infectious process. Inter- view of endodontic microbiology, and the general ventions that reduce this inflammatory process (e.g.
pharmacology of antibiotics. The reader is referred to direct elimination of the microbial irritants by chemo- a number of excellent recent reviews on this topic (6– mechanical debridement of the root canal system, in- 10). Rather, the clinical studies to be reviewed focus cision and drainage of a purulent swelling, or extrac- on the efficacy of antibiotics, mostly in conjunction tion of an unrestorable tooth) are effective at reduc- with non-surgical endodontic treatment, for treating ing pain. However, there is considerable debate in the postoperative signs and symptoms of endodontic pa- literature as to whether the additional prescription of Endodontic pain is the result of an inflammatory Occasionally, the inflammation is related to a process, which is most commonly related to microbial spreading infection where the host responses do not irritation but which may also be related to mechanical appear to be capable of controlling the spread of mi- or chemical factors. A variety of chemical mediators crobial factors. In these cases antibiotics are usually such as arachidonic acid metabolites, cytokines, prescribed in addition to the local treatment to aug- ment host response mechanisms. It is important for levels in bone peaked at 6.33 mg/g, with a bone to clinicians to know, given the side-effects of anti- serum mean ratio of 0.2 (11). Using the same meth- biotics, whether the benefits of prescribing antibiotics odology, these investigators were able to study the in conjunction with standard endodontic treatment levels of bacampicillin in periapical granulomas, rad- methods outweigh the risks involved. This review will icular cyst walls and cyst fluids (14, 15). The granu- address only cases with preexisting pulpal or periradic- loma to serum, cyst wall to serum and cyst fluid to ular pain. For a review of the subject of whether anti- serum mean ratios were 0.42, 0.23 and 0.77, respec- biotics can be used prophylactically to prevent post- tively. They also showed that while the concentrations operative pain, the reader is referred to the article by in granulomas may differ between ampicillin and a R. Walton in this issue of Endodontic Topics.
macrolide antibiotic (josamycin), the levels may ex- To review this topic, we have addressed seven speci- ceed the minimum inhibitory concentration (MIC) fic issues of antibiotics that relate to their ability to of some endodontic bacteria for the former and the alter postendodontic pain or infection.
MIC80 for the latter (16, 17). Another study showedthat even within the macrolide class of antibiotics, 1) Can systemically administered
erythromycin acistrate had much higher levels in antibiotics reach pulpal and
plasma and in periradicular lesions compared with periradicular tissues in therapeutic
erythromycin stearate when both drugs were given 2– concentrations?
6 days before an apicoectomy (18). Four commonlyprescribed antibiotics were compared as to their levels Antibiotic effectiveness is related to both the type and in serum and periapical exudates from induced peri- concentration of the antibiotic. Clearly, if antibiotics apical lesions in dogs (19). In this study, the mean are to be effective in managing endodontic infections ratio of peak lesion/serum antibiotic concentration and reducing endodontic symptoms, they must reach was lowest for benzylpenicillin (0.4 at 1 h) followed the target tissues in therapeutic concentrations. This by erythromycin (0.75 at 1 h), clindamycin (0.96 at is especially a concern in pathological conditions, 4 h), and lincomycin (1.07 at 4 h). The last two anti- when the tissues may have reduced blood flow or may biotics had better permeation of periradicular lesions but had a later peak concentration. Taken together, In a study on the vital dental pulp from patients these studies show that antibiotics can permeate vital with impacted or partially erupted mandibular third pulpal and periradicular tissues within hours in levels molars, it was shown that the levels of an ampicillin that can reach MIC for some pathogens, but that per- analog (bacampicillin 250 mg oral) peaked in the pulp meation of empty pulp space may take days, and is in about 90 min and reached a concentration of 16.7 mg/g (11). The mean ratio of antibiotic in the pulpto that in serum at peak values was 0.61, with a range 2) Are systemic antibiotics effective
of 0.01–0.99. Another study was done on dogs, to for treating pulpal pain?
measure the bioavailability of ampicillin in the pulpspace of teeth in which the pulp had been extirpated Painful irreversible pulpitis is effectively managed by (12). The animals were maintained on ampicillin 500 pulpotomy or pulpectomy (20). In a survey con- mg i.m. every 12 h, and a bioassay was used to ducted in 1990, the percentage of board-certified en- measure zones of inhibition of a microorganism sensi- dodontists who would prescribe antibiotics for pa- tive to ampicillin. The antibiotic was first detected in tients with irreversible pulpitis was 4–15% (depending half the samples at 3 h following the first injection.
upon the presence of acute apical periodontitis) (3).
About 80% of the teeth had inhibitory concentrations Another survey conducted 10 years later on all mem- by the first day, and all had the same result by 3 days.
bers of the American Association of Endodontists The mean levels of the antibiotics bacampicillin, showed an almost identical pattern of prescribing clindamycin, erythromycin, and doxycycline in bone antibiotics in these conditions, where the percentages were measured in patients undergoing third molar ex- were 3.5% and 13.2%, respectively (4). The infectious tractions, and were found to be lower than in other process in these cases is localized within the pulp, and oral tissues (11, 13). For example, the bacampicillin the pain is most probably caused by the actions of inflammatory mediators on peripheral nociceptive in the last 25 years. However, there is a clear trend in neurons (21, 22). However, the specific response these studies that endodontists are more inclined to within the pulp to bacteria in deep caries has been prescribe antibiotics in cases with pulp necrosis if documented (23, 24), together with the increase in symptoms with certain bacterial species (25).
Therefore, a prospective, randomized, double- O endodontic treatment is not associated with signifi- blind, placebo-controlled study was recently con- ducted to determine the effect of penicillin on pain in untreated teeth, diagnosed with moderately to se- O if the swelling is visible extra-orally.
verely painful irreversible pulpitis (26). The outcome In treating periradicular pathosis of an acute nature, variables were the differences in spontaneous pain and the objectives are to control the spread of the infec- percussion pain between the penicillin and the pla- tion and to obtain expedient relief of symptoms. It is cebo groups after 7 days, as well as the amount of universally accepted that the main emphasis in treat- analgesic medications used by both groups during ment is on the removal of the cause, which in this this period. Importantly, this study revealed no statis- case would be the debridement of the necrotic pulp tically significant results between the two groups on tissue and disinfection of the root canal space or ex- any of the parameters evaluated, indicating, quite traction of unrestorable teeth. Incision for drainage is convincingly, that antibiotic use does not relieve pain also indicated for elimination of purulent discharge.
due to irreversible pulpitis. In other words, antibiotic It is also known from a number of studies that pa- usage produced the same responses as that seen in tients presenting with pretreatment pain (27–29), patients given an inert placebo tablet.
particularly periradicular pain (29), are more likely toexperience interappointment flare-ups. Therefore, in 3) Are antibiotics effective for
evaluating the effectiveness of antibiotics on the relief resolving localized periradicular
of periradicular symptoms in these cases, the underly- symptoms?
ing premise is that the elimination of the local irri-tants is the main focus of treatment. That leaves the Table 1 shows the main findings from three surveys following debatable question: how much can the pre- conducted among endodontists regarding the issue of scribing of antibiotics enhance and expedite the pro- prescribing antibiotics. The surveys show that most cess of symptom relief, beyond what could be ob- endodontists prescribe antibiotics for patients with tained by performing the same treatment without necrotic pulp and periradicular pain, and that this finding does not appear to have changed significantly The focus in this section will be to address cases Table 1. Trends in antibiotic prescribing for periradicular (PR) pain among endodontists
Pulp necrosis with PR pain, and localized swelling Pulp necrosis with PR pain, and diffuse swelling ‡For pulp necrosis with acute apical periodontitis, with swelling and with moderate to severe pain, 99.21% of respondents in
this study would prescribe antibiotics. *Cases with drainage obtained through the canal. †No extra-oral swelling. §With extra-
oral swelling.
Table 2. Effect of antibiotics used to augment endodontic procedures in resolving periradicular symptoms
Acetaminophen π codeineIbuprofen π penicillinIbuprofenKetoprofenPenicillinErythromycin baseMethylprednisolone π penicillin Ketoprofen (6, 12, 18, 24, 48)Penicillin (18, 24, 30, 36, 42,48, Ͼ48)Erythromycin base (6, 12, 18,24, 30, 36, 42, 48, Ͼ48)Methylprednisolone πpenicillin(6, 18, 24) *Patients in the instrumentation phase of the study with moderate to severe preoperative pain; it is not clear how many patientsin the obturation phase were in pain prior to obturation. †Numbers are time points in hours when medications were foundto be effective. ‡Patients in all three groups were given ibuprofen for 24 h.
with pulp necrosis with localized periradicular symp- mycin base 50 mg qid (ERYC, Parke-Davis, Morris toms. Table 2 summarizes the main features of four Plains, NJ, USA). In fact, ERYC was the most effec- prospective, randomized, double-blind clinical trials tive medication in patients who were in moderate to that have addressed this issue (30–33). These studies severe pain preoperatively, since it was significantly were all in agreement that there was a statistically sig- more effective than placebo at the highest number of nificant reduction in periradicular symptoms follow- time points. However, this study included patients ing conventional chemomechanical instrumentation with different pulpal and periradicular diagnoses, and in all groups, including the controls that received pla- the percentage of patients with pulp necrosis and peri- cebo or no medications. In the study by Torabinejad radicular radiolucencies was much lower in the pla- et al. (33), further benefit was shown for the use of a cebo group than in the penicillin and erythromycin number of postoperative medications (Table 2), in- groups. Pulp vitality and lack of a periradicular radio- cluding two antibiotics: penicillin 500 mg qid (Veet- lucency were, more recently, shown to be significant ids, Apothecon, Princeton, NJ, USA) and erythro factors in postoperative pain experience (34), where patients in these groups were more likely to benefit periradicular infection may or may not be associated from occlusal reduction than patients with pulp ne- with a localized swelling, depending on whether the crosis or with periradicular radiolucency. Further- cortical plate had been sufficiently resorbed for the more, the percentages of patients who were prema- infection to reach the periosteum or the mucosal turely terminated from the study because they experi- tissues. However, the conditions both with and with- enced an increase in symptoms and needed other out swelling could be considered different stages of medications, were comparable among the placebo, the same disease that could be managed primarily by penicillin and erythromycin groups (11.3%, 7% and local therapeutic measures (which may include the 10.9%) (33). When postobturation pain was studied drainage of a swelling as well as canal debridement in the same cohort of patients, there were no statisti- cally significant differences among the medications Conversely, spreading infections indicate that bac- teria have traveled to sites distant from the original In the two subsequent studies (30, 31), only pa- source of infection, and are virulent enough to invade tients with pulp necrosis, periradicular radiolucencies tissues and cause significant morbidity and even mor- and periradicular pain were included, in order to con- tality (35–38). Spreading infections are associated trol for these important variables. It is difficult to with findings such as extra-oral swelling, fascial space examine the effects of antibiotics on patients with involvement, fever, malaise, significant submandibular pain without prescribing analgesic medications, which and cervical lymphadenopathy, muscle trismus, pain are known to relieve discomfort. Therefore, both during swallowing and other respiratory or neuro- studies controlled for this variable in different ways.
logical disorders. Fever is usually above 100 æF (or In the first study, patients in all groups were given 37.7 æC) and may or may not be associated with leu- ibuprofen 600 mg every 6 h for 24 h, then as needed kocytosis and increased sedimentation rate (9, 39).
(30), whereas in the second study, the NSAID and While many infections associated with signs and the narcotic medications were given to the patients symptoms of systemic involvement are successfully with instructions on when and how to use them. The managed by general dentists and endodontists, the unused tablets were then counted and the data used more serious cases are usually referred to oral and as another dependant variable (31). The findings of maxillofacial surgeons, as they may involve extensive both studies were consistent in showing that patients surgical drainage procedures and hospitalization of with pulp necrosis and localized acute apical symp- the patient. Again, the main emphasis in treatment is toms had significant improvement of their condition on the removal of the etiologic source of the infec- following conventional cleaning and shaping of the tions at the primary site or invaded tissues, as well root canal system, and that the use of penicillin did as supportive measures that include treatment with In the study by Torabinejad et al. (33), it was The effectiveness of antibiotics in the management shown that not only the presence of preoperative of significant infections can be assessed by examining pain, but also preoperative apprehension was associ- the results of culture and sensitivity studies on bac- ated with postoperative pain. This illustrates the im- teria involved in odontogenic infections, and by portance of controlling for as many treatment vari- examining the few clinical trials that have compared ables as possible in determining post-treatment out- different antibiotics in the management of these in- fections. For sensitivity testing, a bacteriologicalsample is obtained and cultured under aerobic and 4) Are antibiotics effective in cases
anaerobic conditions. Testing may be done by the dif- with significant odontogenic
fusion method where disks impregnated with the infections?
antibiotic are placed on blood agar plates inoculatedwith the test organism, and the zone of inhibition As was mentioned before, it is essential to distinguish surrounding the disk is measured. However, this between two different forms of acute periradicular method is not reliable for strict anaerobic organisms symptoms associated with pulp necrosis, namely, lo- that need long incubation periods (40). Another calized and spreading infections. The painful localized method for microbial sensitivity testing is the dilution method, where serial dilutions of common antibiotics acterized by skin fistulae and the production of yel- are inoculated with the test organism to determine lowish granules (55). Actinomyces israelii, which is the minimum inhibitory concentration (MIC) for thought to have the ability to survive in soft tissues each antibiotic. MIC is the lowest concentration of forming the classic actinic ray colonies, is sensitive to the antibiotic that will inhibit visible growth in vitro.
penicillin, administered for extended durations of 2– MIC can be used to determine the minimum bacteri- 6 weeks (56). However, actinomycosis must be diag- cidal concentration (MBC), by incubating established nosed by its classic clinical features or through a bi- subcultures of the sensitive organism with different opsy, since the indiscriminate long-term use of peni- dilutions of the antibiotic overnight. The antibiotic is cillin not only may lead to side-effects (see below) but considered bactericidal when the MBC is equal to or is not effective in improving long-term healing of less than fourfold higher than the MIC (40).
cases with routine endodontic infections (57).
Antibiotic sensitivity testing plays a limited role in The results of a number of studies that compared most clinical cases of endodontic infections; it is gen- the effectiveness of different oral antibiotic in the erally employed when a significant infection appears treatment of odontogenic infections are shown in to be resistant to the antibiotics prescribed on an em- Table 3 (58–62). In general, the different antibiotics pirical basis, in patients who are significantly immuno- used were ones that had been shown to be effective compromised or in infections that are considered very against most odontogenic bacteria from culture and serious in nature. Because antibiotic testing is a slow sensitivity testing, namely, penicillin, amoxycillin, process, patients are frequently started on empirical clindamycin, cephalosporins and augmentin, which antibiotics while the results of sensitivity testing are combines amoxycillin with clavulanic acid, the latter being effective against penicillin-resistant organisms.
As early as 1962, Goldman & Pearson (41) recog- With the exception of the faster improvement in con- nized that a number of microorganisms cultured from stitutional symptoms by cephradine (a first generation the necrotic pulp specimens are resistant to penicillin.
cephalosporin) in one study (62), and faster reduc- Nevertheless, a large number of antibiotic sensitivity tion in pain by augmentin in another study (61), all studies performed on necrotic pulp specimens or the medications tested appear to be of similar efficacy.
aspirates from odontogenic abscesses have shown that It is difficult to assess the overall effectiveness of anti- penicillin remains the primary antibiotic of choice for biotics in these studies since they did not include endodontic infections, followed by clindamycin or groups that received surgical drainage alone or with a erythromycin as alternative choices (42–46). In a re- cent series of studies on a relatively large number of The choices of penicillin (or amoxicillin) as the pri- odontogenic infections, it was shown that most of the mary antibiotic prescribed, and clindamycin as the microorganisms identified were susceptible to b-lac- drug of second choice appear to be consistent with tam antibiotic, most notably penicillin. A small per- choices made by dentists or endodontists on recent centage of organisms produce b-lactamase, and were surveys, although some dentists seem to favor ery- members of the Prevotella and Staphylococcus genera thromycin for patients with penicillin allergy (4, 5).
(44, 47, 48). As would be expected, the incidenceof b-lactamase-producing bacterial strains was much 5) Are locally applied antibiotics
higher in patients with past history of b-lactam anti- effective for treating pain?
biotic use (44, 49). b-lactamase-positive organismswere sensitive to clindamycin (48) and some b-lactam Numerous antimicrobial agents have been used to antibiotics such as the cephalosporins cefmetazole or eliminate bacteria or bacterial products locally from cefoperazone/sublactam, imipenem, and faropenem the root canal system. These agents have been used primarily as irrigants that can be used during root ca- In the discussion of antibiotics and periradicular in- nal instrumentation, or pastes, gels or impregnated fections it is important to note that Actinomyces spp.
solid fillers that can be used as interappointment have been detected in chronic periradicular lesions in medicaments. There has always been a quest to dis- a number of studies (51–54). Cervico-facial actino- cover an agent that has potent, broad-spectrum anti- mycosis is a more aggressive form of the disease char- microbial properties, yet is relatively non-toxic. Anti- biotics have been historically attractive from this per- doxycycline hyclate in a gel delivery system (Atri- spective because of their specific antibacterial actions dox, Collagenex, Newtown, PA, USA), and mino- and their low degree of toxicity for mammalian cells.
The use of antibiotics in a locally applied manner Warminster, PA, USA). Therefore, it is prudent to could potentially provide the antimicrobial prop- review the use of locally delivered antibiotics in erties in sufficient doses for as long as is needed, endodontics, and whether they could contribute to without having the undesirable systemic side-effects.
Although the systemic use of some antibiotics has Antibiotics are generally effective during the repro- been shown to allow the diffusion of these medi- ductive cycle of the bacterial cells and thus would not cations into the root canal space in animal models be suitable for short-term use as an irrigating solution (12, 19), the local application would offer the sus- (66). The use of certain antibiotics such as tetracy- tained and concentrated presence of the medication cline-HCl as endodontic irrigants may have another to potentially allow more effective bacterial elimin- benefit, which is the removal of smear layer, thereby ation. There is also a growing interest in local deliv- allowing better cleansing of the root canal system ery of antibiotics to augment conventional treat- (67). However, for antimicrobial use, which is what ment of periodontal patients with refractory forms could potentially reduce bacterial irritation and endo- of advanced marginal periodontitis (63–65). In the dontic symptoms, antibiotics have been generally past decade, the Food and Drug Administration used as interappointment medicaments. It should also has approved three different formulations for locally be stated that in the earlier studies on the use of anti- delivered antibiotics for periodontal use. These are biotic pastes in root canals, the emphasis was on the tetracycline-HCl in an ethylene/vinyl acetate co- total elimination of cultivable bacteria from the root polymer controlled release periodontal fiber (Actis- canal prior to obturation, rather than other require- ite, ALZA Laboratories, Palo Alto, CA, USA), 10% ments such as symptoms or long-term healing.
Table 3. Double-blind studies comparing differences in effectiveness of currently available oral antibiotics, pre-
scribed for significant odontogenic infections. These studies did not have groups with placebo or no medications
Fazakerley et al. 1993 (62) Lewis et al. 1993 (61) first aid antimicrobial ointments, is not specific for Sulfonamides
endodontic bacteria and is therefore not considered Sulfonamides are synthetic bactericidal antimicrobial agents that affect the synthesis of folic acid by inter- The danger of superinfections with resistant bac- fering with the bacterial update of para-aminobenzoic teria, the risk of sensitization or allergic reactions and acid (PABA) because they are structurally similar.
the difficulty in obtaining some formulations are They are specific for gram-positive bacteria, but re- probably the main reasons for the diminished use of sistance to them develops frequently (68). Sulfanilam- polyantibiotic root canal medicaments.
ide and sulfathiozole (69) were used in the past asroot canal medicaments, presumably because strepto- Ledermix
cocci were the main organisms cultured from root ca-nals at the time. As early as 1945, Dr. Louis Ledermix is a paste that combines 1% triamcinolone Grossman published a study in which blinded oper- acitonide (a corticosteroid) and demethylchlorotetra- ators placed these sulfonamide preparations or a con- cycline (demeclocycline, a tetracycline analog). It has trol as interappointment medicaments. Comparisons been used as a pulp capping agent, and as a root canal were made on the number of appointment needed for medicament for both vital and necrotic cases because negative cultures, and sulfonamides were inferior to of its anti-inflammatory and antimicrobial properties other medicaments used at the time in all diagnostic (66). Both components of Ledermix can diffuse into categories evaluated (70). Furthermore, sulfonamides dentin and through the apical foramen (75). The con- tend to cause yellowish tooth discoloration (69) and centration of demeclocycline in the root canal was therefore are no longer used in this application.
shown to be much higher than is required to inhibitbacteria; however, this activity tends to decrease con-siderably by 7 days (66). It may be combined with Penicillin-bacitracin-streptomycin-sodium
calcium hydroxide at a 50 : 50 ratio to enhance its caprylate (PBSC)
antimicrobial efficacy, but this tends to reduce the dif- This polyantibiotic paste was introduced and evalu- fusion of its main ingredients (76).
ated by Dr. Grossman in 1951 (71). Penicillin (1 000 Ledermix was shown to be efficacious against pul- 000 U) interferes with cell wall synthesis of actively pal pain in some earlier studies (77), possibly because multiplying gram-positive bacteria and a few gram- of its corticosteroid content; however, pulp capping negative anaerobes. Bacitracin (10 000 U) is also bac- for painful cases with pulp exposures is not currently tericidal against gram-positive bacteria and was in- recommended because of its low long-term prognosis cluded to target bacteria resistant to penicillin. Strep- (78). In a randomized clinical trial to compare Leder- tomycin (1 g) is bacteriostatic against gram-negative mix with formocresol and calcium hydroxide used as facultative anaerobes and sodium caprylate (1 g) interappointment medicaments on postinstrumen- against Candida. Nystatin replaced sodium caprylate tation flare-ups, no differences were detected among in another formulation (69). Despite the finding in a later study that no detectable penicillin was absorbedsystemically (72), a few cases have been reported with Clindamycin
allergic reactions to penicillin following its adminis-tration through the root canal system (73).
There have been some trials evaluating clindamycin Other polyantibiotic combinations were marketed, as an intracanal medicament. Clindamycin is a potent primarily in Europe and Australia, in which penicillin bactericidal antibiotic that binds to the 50S ribosomal was replaced with less allergenic antibiotics (66, 74).
subunit and interferes with protein synthesis (68).
Septomixine Forte is one formulation, which was pri- However, systemic administration of clindamycin is marily composed of neomycin sulfate, an aminogly- associated with the occasional occurrence of diarrhea, coside active against many gram-negative organisms, and the uncommon, potentially serious, condition and Polymyxin B sulfate, which is bactericidal for a pseudomembranous colitis caused by overgrowth of variety of gram-negative organisms. This combi- Clostridium difficile. Therefore, local application of nation, which is now common in a lot of the OTC the drug might be advantageous to minimize these systemic side-effects. In a clinical study, clindamycin term macrolides for chronic conditions such as was shown to be comparable to calcium hydroxide in asthma have improvements of their clinical symptoms eliminating bacteria from root canals, and also in due to nonantibiotic properties of the drugs (82, 83).
being not effective against enterococci (80). Recently, Recently, controlled clinical trials have shown that clindamycin-impregnated ethylene vinyl acetate fibers chronic diseases such as panbronchiolitis and cystic were investigated in vitro and found to be effective fibrosis treated with macrolides show a decrease in against other common endodontic pathogens (81).
disease parameters and an improvement of the inflam- This fiber has the advantage over the tetracycline fiber Actisite mentioned before, in that it does not discolor A number of studies have been conducted to ex- teeth. However, further investigations of this fiber in plain the mechanisms whereby macrolides exert these clinical situations have not been reported.
anti-inflammatory actions. Using the rat carrageeninpaw edema model, roxithromycin given prophylac- 6) Do certain antibiotics have anti-
tically suppressed edema produced by injecting carra- inflammatory properties?
geenin into the paw at levels comparable to those ofthe non-steroidal anti-inflammatory drug nimesulide Clearly, the main reason for using antibiotic therapy (86). Azithromycin and clarithromycin also had po- in conjunction with endodontic therapy is to reduce tent anti-inflammatory effects in that study while ery- or eliminate bacteria, thereby reducing the infectious thromycin had the least anti-inflammatory effects.
process. If an endodontic infection is associated with These macrolides also reduced prostaglandin E2 and pain, and if the antibiotic happens to be effective TNF-a in pleural exudate when carrageenin was in- against the bacterial pathogens involved and reaches jected in the pleural cavity, with roxithromycin again the infection site in therapeutic concentrations, it is being the most effective (87). In an in vitro study, anticipated that the irritants will be eliminated and these macrolides (except for azithromycin) stimulated the inflammatory process will be reduced, resulting macrophage growth, and (except for roxithromycin) in pain resolution. Analgesic and anti-inflammatory stimulated macrophage phagocytosis, chemotaxis to medications work in a more direct and expedient lipopolysaccharide (LPS), and cytocidal activity manner to reduce inflammatory mediators or reduce against Candida albicans (88). The same four macro- hyperalgesia either centrally or peripherally, and thus lides were also shown to cause a dose-dependent inhi- are the preferred medications for immediate pain re- bition of superoxide production by activated neutro- lief. However, recently, a number of anti-inflamma- phils (89). It was recently demonstrated that rox- tory properties have been attributed to certain anti- ithromycin does not inhibit mast cell growth or its biotics that appear to be unrelated to their anti- ability to produce histamine, but suppresses this cell’s microbial functions. In the discussion of the effect of ability to produce the cytokines IL-1b, IL-6, GM- antibiotics on pain, it is important to address these CSF and TNF-a when stimulated by concanavalin A properties as they may contribute in a direct way to (90). Erythromycin was shown to reduce the cyto- the mechanisms of effectiveness of antibiotics at the kine-evoked production of chemotactic factors eo- site of endodontic pain, and may influence the choice taxin and RANTES from a human lung fibroblast cell of an antibiotic medication, if one is indicated.
line (91), and modulate the production of the chemo-kine IL-8 from alveolar macrophages (92).
These anti-inflammatory properties of macrolides Macrolides
have not been explored in the endodontic literature.
Macrolides are bacteriostatic antibiotics that exert However, erythromycin in particular has been investi- their action by interfering with bacterial protein syn- gated in a number of studies as to its antimicrobial thesis by binding to the 50S ribosomal subunit, it is efficacy, although the use of erythromycin for endo- thought by binding to the donor site during the dontic reasons has recently diminished because of its translocation step (68). Among the more commonly documented gastrointestinal side-effects (93, 94). In prescribed macrolides are erythromycin, clarithromy- the multicenter trial by Torabinejad et al. discussed cin, azithromycin and roxithromycin. It has been ob- before, it was found that erythromycin was the most served for some time that patients treated with long- effective of a group of nine drugs or drug combi- nations in reducing moderate to severe symptoms fol- treatment of patients and global public health issues.
lowing root canal instrumentation (33) (Table 2).
Among the well-documented side-effects to anti- Erythromycin was also significantly more effective biotics commonly prescribed for endodontic infec- than the other medications in reducing postobtu- tions are hypersensitivity reactions and drug fevers to ration pain in the same cohort of patients; however, penicillin and other b-lactam antibiotics, pseudo- the difference disappeared when preobturation pain membranous colitis, which occasionally occurs with was accounted for (32). As was mentioned before, clindamycin or other antibiotics, nausea, vomiting these studies had a number of variables that were not and gastrointestinal distress common with macro- clearly defined, making it difficult to draw direct con- lides, photosensitivity that may accompany tetracy- clusions. However, in light of the medical findings, cline and renal toxicity that may be associated with the role of newer macrolides in endodontic sympto- matic infections should be further explored.
Hypersensitivity side-effects are more common among b-lactam antibiotics, and while drug rash,serum sickness and anaphylactic reactions are well rec- Tetracyclines
ognized by clinicians, drug fevers are the most com- Tetracyclines are another group of bacteriostatic anti- mon antibiotic-mediated hypersensitivity side-effect biotics that bind to the 30S ribosomal subunit of bac- (102). Drug fevers account for 10–15% of unex- plained fevers in hospitalized patients in the U.S., and aminoacyl-t-RNA synthetases to the ribosomal ac- may occur with any medication, but are common ceptor site (68). A number of beneficial nonanti- with b-lactams and sulfonamides (102). Gastrointesti- microbial properties have been described for tetracy- nal side-effects are common among many medi- clines and tetracycline analogs, even when used in su- cations, but in particular macrolide antibiotics. Clar- bantimicrobial doses. The most important of these ithromycin (such as Biaxin XL) and azithromycin are properties is the inhibition of expression and produc- associated with less GI irritation than erythromycin tion of host matrix metalloproteinases (MMPs) (95– (103). Diarrhea is a frequent symptom of GI distress 97). MMPs are a group of 11 or more endopeptidases in patients on macrolides, b-lactams or clindamycin, that include collagenases, gelatinases and other en- and may be a direct irritation of the intestinal mucosa zymes that are up-regulated during inflammation, or an imbalance in intestinal flora. As was noted be- causing tissue destruction (98). It was recently shown fore, one type of complication of antibiotics due to that levels of MMP-9 (a gelatinase) were significantly the microbial imbalance is the overgrowth of Clostri- higher in inflamed than in normal dental pulps (99).
dium difficile, causing pseudomembranous colitis, a Tetracycline is also thought to inhibit osteoclasts, rare but serious condition. This condition can de- thereby reducing bone resorption, and can act syner- velop up to 6 weeks after cessation of therapy (103), gistically with other agents that reduce bone resorp- and is usually caused by clindamycin, ampicillin or ce- tion such as bisphosphonates (100). In this regard, phalosporins, especially in hospitalized patients (104, doxycycline was recently shown to reduce crestal bone resorption following endodontic flap reflection One of the most serious side-effects of the frequent, indiscriminate use of antibiotics, not only for the indi-vidual patient but also from a global public health 7) What are the potential side-
perspective, is the development of resistant bacterial effects of using antibiotics?
strains (106–109). As was noted before, the percen-tage of b-lactamase-positive bacteria tends to increase As clinicians make decisions on whether or not to pre- in endodontic infections in patients with prior use of scribe antibiotics in conjunction with endodontic b-lactam antibiotics (49). Another group of micro- treatment, it is important to be cognizant of the risks organisms that are becoming among the most serious and side-effects of antibiotics. The use of antibiotics drug-resistant bacteria are enterococci (110). Enter- is not different from any other medications in that ococci, particularly E. faecalis and E. faecium, were the benefits of using them must outweigh the risks shown to be the most prevalent among the microflora involved, from the perspectives of both the direct of root canals in failing endodontic cases in a number Fig. 1. General recommendations for
use of antibiotics in conjunction with
endodontic therapy.
of studies (111–114). Recently, it was also shown that agnosis and inclusion criteria failed to corroborate these two microorganisms, isolated from root canal specimens of 29 endodontic cases following root ca- Systemic antibiotic administration should be con- nal instrumentation and medication, had multidrug sidered if there is a spreading infection that signals resistance properties. They were resistant to ben- failure of local host responses in abating the advanc- zylpenicillin, ampicillin, clindamycin, metronidazole ing bacterial irritants, or if the patient’s medical his- and tetracycline but were only sensitive to erythro- tory includes conditions or diseases known to reduce mycin and vancomycin (115). This further under- the host defense mechanisms or expose the patient to scores the importance of limiting the use of antibiotic higher systemic risks. The effectiveness of antibiotic to cases where they are specifically indicated.
administration in these conditions is not predictable,nor is the choice of which antibiotic to use estab- Conclusions and general
lished, due to the polymicrobial nature of endodontic recommendations
infections, and the fact that systemic antibiotics maynot reach the source of bacterial proliferation, such as The current evidence indicates that local root canal the necrotic pulp, in sufficient concentrations. There- instrumentation procedures, combined with analgesic fore, the emphasis should always be on instituting lo- medications are sufficient for management of the vast cal debridement and antimicrobial measures. The pa- majority of symptomatic endodontic cases. When di- tient must be followed closely until the condition re- agnosing a case with odontogenic infection, it is im- solves. If the condition does not resolve, then changes portant that the clinician make a distinction between in antibiotic therapy, culture and sensitivity testing or localized infections, which may include cases with prompt referral should be instituted.
periradicular radiolucencies, pain and localized swell- The nonantibacterial beneficial properties of certain ings, and those with spreading systemic infections.
antibiotics such as tetracyclines and the newer macro- Antibiotic treatment is generally not recommended lides should be further studied, particularly if subanti- for healthy patients with localized endodontic infec- microbial doses can be used locally, thereby reducing tions. While one study showed advantages of the use the danger of development of resistant bacterial of certain antibiotics in enhancing endodontic pain resolution, more recent studies with well-defined di- In conclusion, the elimination of the local microbial factors remains the main treatment focus in the symp- 16. Akimoto Y et al. Ampicillin concentrations in human den- tal granuloma after a single oral administration of talampic- tomatic endodontic patient. Figure 1 proposes a rec- illin. Antimicrob Agents Chemother 1988: 32: 566–567.
ommendation for the use of antibiotics in conjunc- 17. Uda A et al. Josamycin concentrations in human dental granuloma after a single oral administration of josamycin.
Gen Pharmac 1989: 20: 823–825.
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