Antibiotics and Analgesics in Endodontic Practice: A Comprehensive Review

INTRODUCTION

^aIf Penicillin VK alone is not effective in 48–72 h, metronidazole (loading dose 1000 mg followed by 500 mg q6 h) can be used in combination with penicillin VK or penicillin VK is switched to amoxicillin/clavulanic acid or clindamycin. ^bIf the patient is allergic to penicillin.

Penicillin V is a narrow-spectrum antibiotic for infections caused by aerobic gram-negative cocci, facultative and anaerobic microorganism [32]. It has selective toxicity and exerts its antibacterial effect by the inhibition of cell wall production in bacteria. However, penicillin is not well absorbed from the intestinal tract, meaning that at least 70% of an oral dose is wasted, with diarrhoea as a frequent side effect. Penicillin is also a short-acting medication, with half of the amount circulating being removed from the body every half hour [32].

It has been documented that the majority of microorganisms have susceptibility to penicillin; therefore, it can be a good first option for the adjunctive treatment for lesions of endodontic origin. However, amoxicillin has a wide spectrum against endodontic pathogens. Testing antibiotic susceptibility on a panel of bacteria isolated from endodontic infections, the percentages of susceptibility for the 98 species analysed were 85% for penicillin V, 91% for amoxicillin, 100% for amoxicillin/clavulanic acid, 96% for clindamycin and 45% for metronidazole [33].

In a clinical study with 94 patients with abscesses, 98% were polymicrobial. Penicillin successfully treated the pathogens derived from odontogenic abscess sufficiently, when adequate surgical treatment was provided. Patients with good general health, small abscesses and without systemic symptoms were treated successfully with incision and drainage only. However, this study took place in a hospital and the standard regimen for adult patients was 5 million units penicillin G intravenously every 8 h for 5 days. Taking into account that IV penicillin G does not suffer from poor absorbance, this may have affected the outcome of the study [34].

A loading dose of 1000 mg of penicillin V should be administered orally followed by 500 mg every 4–6 h to achieve a steady serum level [35]. Following debridement of the root canal system and drainage, significant improvement should be seen within 48–72hr. However, if penicillin V therapy is ineffective, another antibiotic should be selected, ideally following culture and sensitivity testing. Clindamycin is a good alternative [36]. In case no response occurs, consultation with a specialist will be necessary.

Although penicillin is generally the antibiotic of choice in infections of endodontic origin, one disadvantage associated with its use is the possibility of allergic reactions. Approximately 8% of the population have a history of penicillin allergy, but less than one in 20 have been confirmed clinically using the gold standard test for IgE-mediated penicillin allergy [37]. Unverified penicillin allergy is being increasingly recognized as a significant public health problem [38,39]. In patients with a confirmed penicillin allergy history, the clinician can switch to other antimicrobial agents such as clindamycin, metronidazole and clarithromycin or azithromycin [40,41]. However, dentists must not overuse non-beta-lactam antibiotics in patients with a history of penicillin allergy, without an appropriate evaluation. As a minimum, the clinician should ask about the symptoms of allergy from the patient. It must be remembered that some patients may report intolerance symptoms like diarrhoea or upset stomach, as an allergy.

Clindamycin belongs to the lincosamide class of antibiotics. It kills microorganisms by blocking their ribosomes. It is effective against most gram-positive aerobes and both gram-positive and gram-negative facultative bacteria and anaerobes. The distribution of this antibiotic in most body tissues is effective and has a bone concentration approximating to that in the plasma [40]. The adult oral dosage is 600 mg loading dose followed by 300 mg every 6 h [42].

Metronidazole is a nitroimidazole that is used either as an antiprotozoal agent or an antibiotic against anaerobic bacteria, and has been suggested as a supplemental medication for amoxicillin because of its excellent activity against anaerobes [31]. Because there are many bacteria resistant to metronidazole and it is not effective against aerobic and facultative bacteria, [33,36], it is generally used in combination with penicillin or clindamycin. Metronidazole used in combination with penicillin V or amoxicillin increased the susceptibility to 93% and 99% of bacteria, respectively [33]. The adult oral dosage is 1000 mg loading dose followed by 500 mg every 6 h.

Clarithromycin and azithromycin belong to the macrolide group of antibiotics. They are effective against a variety of aerobic and anaerobic gram-positive and gram-negative bacteria with improved pharmacokinetics [43]. Whilst the usual oral dosage for clarithromycin is a 500-mg loading dose followed by 250 mg every 12 h, the dosage for azithromycin is a loading dose of 500 mg followed by 250 mg once a day.

Duration of Antibiotic Therapy

The duration of antibiotic use in endodontic infections has not been defined precisely. Even though some dental practitioners consider that bacterial infections require ‘a complete course’ of antibiotic therapy [44], there is a general tendency to administer an antibiotic for 3–7 days [45] (Table 1). As prolonged antibiotic usage destroys the commensal flora in the oral cavity and other body sites and terminates colonization resistance [46], the use and duration of systemic antibiotic therapy must be reasonable. There is a common misconception that prolonged antibiotic administration is necessary even after clinical remission of the infection in order to avoid rebound infection.

Endodontic infections do not rebound when the source of periapical infection is properly eradicated, which is complete debridement, irrigation and disinfection of an infected root canal. Because these types of infections persist for several days, patients receiving antibiotics should be observed on a daily basis. The only guide for determining the effectiveness of antibiotic therapy and local endodontic intervention is the clinical improvement in the patient’s symptoms. When there is ample clinical evidence that the symptoms are resolving or resolved, the antibiotic therapy should be ceased [31].

Fazakerley et al. and Martin et al. [45] (compared three antibiotics and duration of usage (2, 3 and 10 days). They reported that the majority of the patients were asymptomatic after 2 days. Despite the fact that antibiotics are very useful tools in cases posing risk for the patient, one should always bear in mind that they are not substitutes for endodontic treatment. The key to obtaining a successful result in an endodontic infection is the chemo-mechanical removal of the infecting agent from the root canal system as well as drainage of pus. The indications for antibiotic administration should be considered very carefully and only as an adjunct to endodontic treatment, which is the major and indispensable procedure for obtaining the optimum outcome in lesions of endodontic origin. When antibiotic usage is prescribed rationally and restricted to indicated cases only, favourable results are likely to be obtained for the complete eradication of the infection.

Antibiotic Prophylaxis for Medically Compromised Patients

The aim of antibiotic prophylaxis is to prevent local postoperative infections and prevent metastatic spread of infection in susceptible individuals. Most individuals do not need antibiotic prophylaxis in connection with dental care. The microorganisms are scavenged from the bloodstream within minutes up to 1 h without causing any complications in healthy individuals.

Over the years, the clinical recommendations for antibiotic prophylaxis have changed and there is a trend towards a definite position [47,48]. The risk of adverse reactions to antibiotics and increasing development of drug-resistant bacteria outweigh the benefits of prophylaxis for most patients [49]. Antibiotics should only be given prophylactically in cases where the benefit has been demonstrated or where consensus exists as to such use [50].

Antibiotic prophylaxis may be considered for certain patient groups with impaired immunologic function. Surgical endodontic treatment on teeth with persistent infection after orthograde treatment is considered a higher medical burden than conventional endodontic treatment and patients at risk may benefit from antibiotic prophylaxis to a greater extent.

According to the literature, there are only a few risk conditions in which it is shown that antibiotic prophylaxis may be of benefit to the patient in conjunction with dental procedures [51]. However, there may be other patient groups in which antibiotic prophylaxis may be of benefit, but case–control studies or double-blinded studies within placebo have not been performed for ethical reasons.

Individuals who are immuno-compromised are less capable of battling infections because of an immune response that is not properly functioning. Causes of immunodeficiency can be acquired (such as leukaemia or HIV/AIDS), chronic disease (such as end-stage renal disease and dialysis or uncontrolled diabetes), medication (such as chemotherapy, radiation, steroids or immunosuppressive post-transplant medications) or genetic (such as inherited genetic defects). For most of these medical conditions, the treatment must be planned in close collaboration with physicians. For some medical conditions, the treatment must be preceded by a blood sample. Severity of neutropenia relates to the relative risk of infection and is categorized as mild (1000–1500 µL^-1), moderate (500–1000 µL^-1) and severe (< 500µL^-1). When neutrophil counts fall to < 500 µL^-1, endogenous microbial flora (e.g. in the mouth or gut) can cause infections [52].

Patients with Locus Minoris Resistentiae

Locus minoris resistentiae refers to a body region more vulnerable than others, such as internal organs or external body regions with a congenital or acquired altered defence capacity [53]. Infective endocarditis, a bacterial infection of the heart valves or the endothelium of the heart, is a typical case of locus minoris resistentiae [54]. Individuals with certain pre-existing heart defects are considered at risk for developing endocarditis when a bacteraemia occurs [55]. Antibiotic prophylaxis has for a long time been considered as best practice for all patients with complex congenital heart defects, prosthetic cardiac valve or a history of infective endocarditis [56].

According to the guidelines of the American Heart Association, individuals who are at risk of developing infective endocarditis following an invasive dental procedure still benefit from antibiotic prophylaxis, even if little evidence exists to support its effectiveness [57]. In contrast, the guidelines of the National Institute for Health and Clinical Excellence in the UK have recommended that prophylactic antibiotic treatment should no longer be prescribed for any at-risk patients [58]. Even though a recent retrospective follow-up study has indicated that the incidence of infective endocarditis has increased in the UK as the more restrictive recommendations were introduced [59], a causal relationship has not been shown between IE and dental procedures. Therefore, routine prescription of antibiotic prophylaxis before endodontic treatment of patients considered at risk for endocarditis may not be justified.

However, recently, NICE has made a significant change to Clinical Guideline 64 (CG64), ‘Prophylaxis against infective endocarditis: antimicrobial prophylaxis against infective endocarditis in adults and children undergoing interventional procedures’, adding the word ‘routinely’ to Recommendation 1.1.3, that now is as follows: Antibiotic prophylaxis against infective endocarditis is not recommended routinely for people undergoing dental procedures. The addition of the word ‘routinely’ makes it clear that in individual cases, antibiotic prophylaxis may be appropriate [60]. The guidelines of the European Society of Cardiology (ESC) for the management of infective endocarditis recommended antibiotic prophylaxis only for dental procedures requiring manipulation of the gingival or periapical region of the teeth or perforation of the oral mucosa, including scaling and root canal procedures [61].

The scientific evidence is insufficient to indicate providing antibiotic prophylaxis before dental treatment for healthy patients after prosthetic joint replacement [62,63], but this is still considered a dilemma for the clinician. This is partly on anecdotal grounds, partly historical and partly for legal concerns. A prospective case–control study concluded that dental procedures were not risk factors and the use of antibiotic prophylaxis prior to dental procedures did not decrease the risk of subsequent total hip or knee infection [64,65]. The joint guideline by American Academy of Orthopaedic Surgeons and American Dental Association in 2012 (http://www.aaos.org/uploaded Files/PreProduction/ Quality/Guidelines_and_Reviews/PUDP_guideline.pdf) states: ‘The practitioner might consider discontinuing the practice of routinely prescribing prophylactic antibiotics for patients with hip and knee prosthetic joint implants undergoing dental procedures’, but they also recognize that the evidence is limited, and the practitioner should exercise judgment in decision. In general, the risk is considered to be elevated during the first 3 months after joint operations because endothelialization is not complete, and in case invasive dental treatments are necessary, antibiotic prophylaxis is recommended [66], as well as in patients with compromised host defence undergoing extensive dental procedures [67,68]. In patients with artificial joints, previous recent infection of the joint and cases with massive oral infections are considered high risk factors for prosthetic joint infections and antibiotic prophylaxis should be prescribed [64,65].

Jawbones exposed to high dose of radiation for cancer treatment in the head and neck results in lifelongchanges in microcirculation and are thus more susceptible to local infection-related complications [69]. Dental treatment with a risk to translocate infection to the bone in high-doseexposed areas should be preceded by antibiotic prophylaxis [70].

Medication with bisphosphonates changes the bone turnover and prevents loss of bone mass. Several types of bisphosphonates have different indications and varying risks of developing osteonecrosis and changes in the bone that is then more prone to develop infections. The risk is substantially greater for patients receiving bisphosphonates for cancer than for osteoporosis. Other risk factors may include concomitant use of glucocorticoids, old age (over 65 years), poorly controlled diabetes, intravenous administration and prolonged use of bisphosphonates (more than 3 years). Invasive dental procedures of the alveolar bone modified by bisphosphonates, with subsequent infection in the bone, have been linked to the development of osteonecrosis [71].

Intravenous bisphosphonate treatment as an accompanying therapy for advanced tumour diseases warrants antibiotic prophylaxis in bone invasive procedures [72].

In all treatment situations, an overall medical assessment must be based on the individual case and consideration of the risk of infection-related complications as well as the risk of adverse drug reaction. Prophylaxis may sometimes not be justified according to the medical condition in connection with dental treatment, but can be justified when considering multiple medical conditions and age, or when several risk factors predispose patients to infections (such as poorly controlled or uncontrolled diabetes mellitus, malignancy, chronic inflammatory disease, immunosuppressive disease or treatment with immunosuppressive medication). In cases of doubt over the proper management of patients prior to dental treatment, the state and control of the disease of the patient should be discussed with a physician. The choice of drug should reflect its clinical efficacy, as well as whether it is safe and has a good spectrum. The suggested prophylaxis regimen [57].